Methoxyfenozide Human Health Risk Assessment DP Barcode 420583 

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, DC 20460 

., 

0 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: May 30,2014 

SUBJECT: Methoxyfenozide. Revised 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 

Registration 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 (RABII) 

Health Effects Division (7509P) 

THROUGH: Michael Doherty, Ph.D., Senior Chemist 

Christina Swartz, Branch Chief 

Risk Assessment Branch II (RABII) 

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 pineapple, 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. 

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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 Petitioned-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, Metabolism, & 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 Used in Dietary Assessment ..................................... 23

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

5.4.3 Acute Dietary Risk Assessment .............................................................................. 23
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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 Profile and Executive Summaries .................................................. 33

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

Appendix C. Review of Human Research................................................................................ 39
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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-dimethylbenzoyl)-2-(1,1-dimethylethyl)hydrazide, 

and CAS number 161050-58-4) is a diacylhydrazine insecticide 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, meat and fat of livestock (40CFR §180.544[a][1]), 

and for the combined residues of the parent and its glucuronide conjugate (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; methoxyfenozide only) to 8.0 ppm (straw 

of non-grass animal feeds, Group 18; methoxyfenozide, 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 previously reassessed in accordance with current 

policies, based on the potential for residential handlers to use products in and around home 

gardens. The toxicology database 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 across species and studies were decreased red blood cell parameters 

and increased liver, thyroid, adrenal and spleen weights. Many of the available short-term or 

subchronic toxicity studies showed little or no toxicity. Increases in thyroid and adrenal weights 

were observed in the rat chronic oral study. Thyroid weights were also increased in the dog 

following chronic exposure, but no accompanying histopathology was observed. 

 

Toxicological testing indicates that methoxyfenozide is not neurotoxic or immunotoxic; it has 

been categorized as “not likely” to be carcinogenic to humans. There is no evidence of 

qualitative or quantitative susceptibility of the developing fetus or offspring, based on the 

developmental and reproductive toxicity study results. Therefore, based on the completeness of 

the database, the lack of susceptibility, 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 current 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 dietary risk was not evaluated because there were 

no toxic effects associated with a single dose, and therefore an appropriate 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 no 
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quantitative dermal exposure and risk assessments were conducted (i.e., there is no hazard via 

the dermal route). Furthermore, HED did not select an endpoint for incidental oral risk 

assessment, since the potential for 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) approach, the HASPOC concluded, that a 28-day 

inhalation toxicity study is not required 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/carcinogenicity study in the rat; the blood effects seen in the dog study 

were considered co-critical. For inhalation risk assessment, the endpoint selected was based on 

blood effects seen in a range-finding study in the dog. 

HED used modeling to assess chronic dietary exposure to methoxyfenozide. In combination 

with an extensive database of food consumption 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 residues 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 rate in vulnerable areas. The highest potential 

drinking water exposure is from ground water sources. The chronic dietary exposure and risk 

estimates are below HED’s level of concern (LOC) of 100% of the chronic population adjusted 

dose (cPAD) for the general U.S. population and all population subgroups, including those of 

infants and children. The highest exposed population subgroup was children 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 activities 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 registration of the existing use of methoxyfenozide on 

ornamentals. Since then an inhalation endpoint was selected and the OPP HED Residential 

SOPs were finalized and approved for risk assessment purposes. Therefore, in a previous newuse risk assessment, HED assessed potential inhalation exposure for residential handlers treating 

ornamentals in and around home gardens (D388978, M. Collantes et al, 05/23/2012). The 

resulting risk estimates are margins of exposure (MOEs) ranging from 76,000 to more than 3 

million, which are not of concern. 

In accordance with the FQPA, in evaluating human 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 highly exposed adult population subgroup (general US 

adult population) to determine aggregate exposure and risk. The calculated exposure resulted in 
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an aggregate MOE of 540; this risk estimate is not of concern, since 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. There were no chemical-specific data available to 

assess handlers’ inhalation exposure, so HED relied 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 quantitative post-application exposure assessment was not 

completed due to the lack of dermal toxicity, and because the handlers’ MOEs are expected to be 

protective of post-application exposure via the inhalation route. 

The risk assessment is based, in part, on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies are compliant with 

applicable ethical requirements (refer to Appendix C). 

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment (see Section 3.5). 

2.0 HED Recommendations 

HED recommends in favor of the proposed registration of the new use of methoxyfenozide on 

pineapple and establishment of the associated permanent tolerances as summarized in Table 

2.2.3. 

Note to RD: Analytical standards for methoxyfenozide and its 4 metabolites are currently 

available at EPA’s National Pesticide Standards Repository (NPSR). However, the RH1521,055 metabolite standard expires 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 methoxyfenozide in primary crop 

commodities are 0.010-0.050 ppm. The tolerance enforcement methods include use of high 

performance liquid chromatography (HPLC), with either tandem mass spectrometric detection 
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(LC-MS/MS), or ultraviolet 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 tolerance enforcement in plant and animal commodities 

(EFSA, 2014). 

2.2.2 International Harmonization

Neither Codex nor Canada’s PMRA has established MRLs in pineapple. As such, there are no 

harmonization issues with Codex or PMRA associated with this proposed new use on pineapple. 

Methoxyfenozide has been the subject of a significant amount of discussion with PMRA 

regarding harmonization of existing tolerances on other agricultural commodities. There are 

currently no pending or proposed uses of methoxyfenozide in pineapple under review by PMRA. 

However, in the interest of avoiding future harmonization issues, PMRA was consulted to 

determine how they would handle this dataset should 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 recommended by HED (ChemSAC minutes, 02/19/2014; 

03/26/2014). HED’s recommended tolerance for the 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 pineapple (0.7 ppm), HED recommends establishing the 

tolerances at 0.70 ppm, in order to avoid the situation where a field sample containing residues 

significantly above the tolerance (0.74 ppm, for example) would be considered non-violative. 

2.3 Label Recommendations From Residue Review 

None. 

3.0 Introduction

3.1 Chemical Identity 

Methoxyfenozide is a diacylhydrazine insecticide used on a variety of crops for control of 

armyworms and other lepidopterous pest species. It mimics the action of the molting hormone of 
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lepidopterous larvae, causing the 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 C22H28N2O3

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 methoxyfenozide does not 

indicate that there are any special concerns in terms of bioaccumulation, exposure or other risk 

assessment considerations. A table of physical and chemical properties 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 both 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 traverses 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) formulation of methoxyfenozide was conducted in the rat. Cumulative 

absorption of approximately 2% of the applied dermal dose was observed after a 10 or 24 hour 

dermal exposure duration. Consistent with the low level of absorption, a 28-day dermal study in 

the rat showed no toxicity up to the limit dose (1000 mg/kg/day). Furthermore, 

methoxyfenozide has a large octanol-water partition coefficient (Kow) of 103.72 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 (t1/2 = 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 methoxyfenozide is not expected. 

3.3 Pesticide Use Pattern

CH3

O

N

H

N

O

CH3

CH3

H3C CH3

H3C O

CH3
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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. Intrepid 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 and hand-held equipment. Methoxyfenozide may 

not be applied to pineapples by chemigation. 

The PPE statement on the proposed label requires applicators and other handlers to wear longsleeved shirt and long pants, socks, shoes, 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 included 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 methoxyfenozide, humans may 

be exposed through food and drinking water, since 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 exposed while handling the pesticide prior to 

application (i.e., mixing/loading), as well as during application. There is also potential for postapplication exposure for workers re-entering treated fields. 

Since methoxyfenozide is also registered for use on ornamentals there is likely to be exposure in 

Table 3.3. Summary of Directions for Proposed Uses of Methoxyfenozide 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. 
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residential and non-occupational settings as well. While the product does not appear to be 

intended for homeowner use, there 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 post-application oral exposure to children is not expected since the 

extent to which young children engage in oral-exposure activities associated 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 relevant exposure pathways, combining them as 

appropriate, to estimate overall exposure and risk. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the 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 Nutrition Examination Survey, What We Eat in 

America, (NHANES/WWEIA). These food consumption patterns are used in pesticide risk 

assessments for all registered food uses of a pesticide. 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 exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for children, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers 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 complete for methoxyfenozide. The following studies, 

which use exposure routes (oral and dermal) consistent with potential human 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 oral carcinogenicity; rat and rabbit 

oral toxicity; rat oral two-generation reproductive toxicity; genotoxicity battery; rat acute and 

subchronic neurotoxicity; rat general metabolism; rat dermal penetration (on formulation); and 

rat immunotoxicity. Although a 28-day inhalation toxicity study has not been submitted, HED 
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has determined that this study is not needed (i.e., the study has been waived) for 

methoxyfenozide, based on a weight of evidence (WOE) approach that considered all of the 

available 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 the 

inhalation route due to residential and occupational exposures (TXR #0053782, 4/17/12). 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) 

In the rat, 14C-radiolabeled methoxyfenozide was rapidly absorbed following gavage 

administration, with maximum peak plasma concentrations observed within 15 minutes of 

dosing. Peak plasma concentrations following 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 T1/2 of 0.2 to 0.6 hr and a β-phase 

T1/2 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 more prominent in female rats. Radioactivity 

was extensively distributed among tissues, with the highest concentrations at Cmax (0.25 hr) 

observed in the intestinal tract, stomach, liver and residual carcass. Enterohepatic circulation 

was observed. Methoxyfenozide did not show evidence 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 time. Excretion of radiolabel was essentially complete by 48 hrs 

post dosing. Based on the minimal level of radioactivity in tissues at 72 hours, absorption was 

estimated to be at least 62 to 70% of the administered 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 differences in metabolic 

disposition were not observed. 

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

demethylation and oxidative hydroxylation of the 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 excreta. 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 majority represented <1-2% of the radioactive dose. Up to 16 

metabolites were identified in the feces, including 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. Levels of excreted parent 

compound in the feces were greater in animals receiving 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 were detected, with the primary metabolite (13-18% 

of dose) being derived by glucuronide conjugation at the 0-demethylated alpha ring. 

4.2.1 Dermal Absorption 

An in vivo dermal absorption study on an 80% wettable powder (WP) formulation of 

methoxyfenozide was conducted in the rat. Cumulative absorption of approximately 2% of the 
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applied dermal dose was observed after 10 or 24 hours of dermal exposure. Consistent with this 

low level of absorption, a 28-day dermal study in the rat showed no toxicity up to the limit dose 

(1000 mg/kg/day). 

4.3 Toxicological Effects 

Many of the available short-term or subchronic toxicity studies on methoxyfenozide showed 

little or no toxicity. The main target organs were the liver, thyroid and red blood cells. In the rat 

metabolism study, liver contained 2-9% of the administered radioactivity at Cmax, but levels 

decreased and bioaccumulation was not observed. Levels in the blood were negligible. The 

effects of methoxyfenozide on the blood in mammals (methemoglobinemia, decreased red blood 

cell parameters, Heinz body formation) are consistent 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 and hemoglobin) was observed in both species 

following chronic dietary exposure, along with methemoglobinemia and RBC structural 

abnormalities. Increased platelets were also observed. 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 range-finding studies; however, 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 studies that were not observed in the subchronic 

study, and on more pronounced changes in hematological parameters at Week 14 in the rat and 

dog chronic studies than were observed at evaluations conducted at later times in those studies. 

No hematological effects were reported in the mouse. 

 

Increased liver weight and periportal hypertrophy were observed in the rat and dog. These 

findings were observed in the rat following two-week, subchronic or chronic dietary exposure, 

and in the dietary reproductive toxicity study, and in the dog following chronic exposure. In the 

rat two-week study, increased adrenal gland weight and minimal hypertrophy of the zona 

fasciculata, and increased thyroid 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 decreased body weights and weight gain in the subchronic 

study; however, no effects were seen in the carcinogenicity study at dietary concentrations 

exceeding the limit dose. No body weight effects were observed in the rat or dog. 

Acute and subchronic oral neurotoxicity studies in the rat did not show evidence of potential 

neurotoxicity. In the acute study, decreased hindlimb 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 the 
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subchronic neurotoxicity study and was therefore not considered evidence of neurotoxicity. No 

clinical signs of neurotoxicity or neurohistopathology were observed 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 reproductive toxicity study, parental 

effects were limited to increased liver weight and microscopic 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 increased liver weight. 

Dermal effects were not observed in the rat following a 28-day exposure period (5 exposure days 

per week for a total of 20 exposures). This finding is consistent with the 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-month carcinogenicity study. No 

mutagenic or clastogenic potential was observed in the battery of genotoxicity studies on 

methoxyfenozide. Based on these findings, methoxyfenozide 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 methoxyfenozide was reduced to 1X, based on the 

following considerations: 1) the toxicity database for methoxyfenozide is complete, including 

studies addressing potential pre- and post-natal susceptibility; 2) there is no evidence that 

methoxyfenozide is neurotoxic, and a developmental neurotoxicity study is not required; 3) there 

is no residual uncertainty, and no evidence of increased quantitative or qualitative susceptibility 

in the developing or young animal; and 4) the dietary exposure assessments do not underestimate 

potential exposure from food and drinking 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) and a rat two-generation reproduction study have been submitted, as 

well as rat acute and subchronic neurotoxicity and immunotoxicity studies. A developmental 

neurotoxicity study is not required, based on the lack of evidence of neurotoxicity in the adult 

animal and lack of increased sensitivity/susceptibility in the developing or young animal. 

4.4.2 Evidence of Neurotoxicity 

The available toxicity data, which include acute and subchronic neurotoxicity studies in the rat, 

do not demonstrate neurotoxic potential. A decrease in hindlimb grip strength, observed in male 

rats on Day 0 of the acute neurotoxicity study, was not considered to be evidence of 

neurotoxicity because it was an isolated finding in males, not observed in females and seen only 
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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 susceptibility in the developing or 

young animal. No developmental toxicity was observed in either the rat or rabbit developmental 

toxicity studies, and there was no evidence of offspring or reproductive toxicity in the rat twogeneration reproductive toxicity study. Dosing in all studies achieved the limit dose (≥1000 

mg/kg/day). 

 

4.4.4 Residual Uncertainty in the Exposure Database 

There is no residual uncertainty with respect to the exposure assessments conducted for 

methoxyfenozide. The dietary exposure estimates incorporate conservative estimates of all 

residues of concern from the food exposure pathways. 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. Thus, the Environmental Fate and Effects Division (EFED) 

continues to have concerns about the persistence 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 assessment for adult handlers only includes exposure 

from the existing use on ornamentals based on high-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 provided in Appendix A of this document. 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 toxicity endpoint selections 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 was 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 and 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. 
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For selection of a chronic dietary exposure assessment dose and endpoint, the dietary rat chronic 

toxicity/carcinogenicity, dog chronic (1 year) and rat reproductive toxicity studies were 

considered. The mouse carcinogenicity study showed no effects at dietary concentrations 

administering methoxyfenozide slightly above the limit 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 reproductive effects. The rat 

chronic toxicity/carcinogenicity 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 available 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, periportal liver hypertrophy, thyroid hypertrophy and altered 

colloid and increased adrenal weight were also observed at the LOAEL. The selected dose and 

endpoint is protective for potential 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 range-finding studies (see 

below). The NOAELs/LOAELs from all other available studies were observed at higher dose 

levels. 

Endpoints were not selected for incidental oral exposure because, based on current and proposed 

use patterns which specify use on ornamentals and not turf, there are no residential uses for 

methoxyfenozide where significant post-application oral exposure to young children is 

anticipated. 

For dermal exposure (all durations, residential and occupational exposure), an endpoint was not 

selected. The rat 28-day dermal 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 the rat reproductive toxicity study. However, the effects observed 

in the oral studies, which included liver hypertrophy 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 showed no maternal or developmental toxicity and the rat subchronic 

dietary neurotoxicity showed no toxicity at doses up to the limit dose (1000 mg/kg/day). The rat 

28-day dermal toxicity study was therefore considered protective of sensitive populations, 

including potential developmental effects. 

Although a 28-day inhalation toxicity study has not been submitted, HED has determined that 

this study is not needed (i.e., the study has been waived) for methoxyfenozide, based on a weight 

of evidence (WOE) approach that considered all of the available 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 the inhalation route due to residential and 

occupational exposures (TXR #0053782, 4/17/12). 

Therefore, a two week dietary study in the dog was selected for both short- and intermediateterm inhalation exposure because it provided the most sensitive dose and endpoint available 
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(NOAEL = 16.8 mg/kg/day, based on hematological effects at the LOAEL of 90.8 mg/kg/day) 

and was of an appropriate duration. The NOAEL and LOAEL were selected from the highest 

individual animal NOAEL and lowest LOAEL because 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 individual 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 chronic 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 mechanism for the toxicity of 

methoxyfenozide with prolonged exposure. This dose and endpoint are therefore considered to 

be very conservative, but protective of all populations that may be exposed. In light of the 

conservative endpoint, low acute inhalation toxicity of methoxyfenozide, 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 background levels in food and water to determine 

aggregate exposure. For children’s residential exposure, oral post-application exposure was not 

assessed; only exposure from background levels of food and drinking water were assessed. For 

occupational workers, only inhalation exposure and risk were assessed. 

4.5.3 Cancer Classification and Risk Assessment Recommendation 

Methoxyfenozide is classified as “not likely to be carcinogenic to humans,” according to the 

revised 2005 Agency Guidelines for Carcinogen Risk 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 Toxicity Endpoints Used in Human Risk 

Assessment 

Tables 4.5.4.1 and 4.5.4.2, below, summarize the dose and endpoint selection for dietary/nonoccupational and occupational exposure: 
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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 for a single oral exposure. 

Chronic 

Dietary (All 

Populations) 

NOAEL= 

10.2 

mg/kg/day 

UFA= 10X 

UFH= 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. 

Incidental 

Oral 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) or 

Intermediateterm (1-6 

months) 

No toxicity, i.e., no hazard, was identified for dermal exposure. 

Inhalation 

Short- Term 

(1-30 days) 

and 

IntermediateTerm (1-6 

months) 

NOAEL = 

16.8 

mg/kg/day 

UFA=10X 

UFH=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. 
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Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). 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) or 

IntermediateTerm (1-6 

months) 

No toxicity, i.e., no hazard, was identified for dermal exposure 

Inhalation 

Short-Term (1-

30 days) and 

IntermediateTerm (1-6 

months) 

NOAEL = 

16.8 

mg/kg/day 

UFA=10X 

UFH=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 point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). 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 depicting the metabolic fate of methoxyfenozide in target crops, 

rotational crops and livestock. The main distinction between 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 primary crops is adequately understood, based on 

acceptable metabolism studies in cotton, apples, grapes and rice. Methoxyfenozide does not 

undergo extensive metabolism in primary crops. HED has determined that the residue of 
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concern for both the tolerance expression and risk assessment in primary crops is the parent 

compound only, methoxyfenozide. 

However, in rotational crops and livestock, additional 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 primary crop metabolism study. In rotational crops, 

methoxyfenozide was highly metabolized by oxidation, demethylation and hydroxylation to nonconjugated metabolites, which were then conjugated with biomolecules, yielding bound residues 

and precursors in the sugar synthesis pathway. The residues of concern in rotational crops 

include methoxyfenozide, its free phenol metabolite (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 tolerance definition for rotated crops includes 

parent only in high-moisture crops, and the combined 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 tissues (other than liver and kidney) is parent 

compound; in ruminant liver and kidney methoxyfenozide 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 meat 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 (t1/2 = 1 to 3 years in soil and water) and moderately mobile 

(Koc = 219 – 922 L/kgoc 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-methylbenzoic 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 application 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 excretion was feces (86-97%) with lesser amounts in 

the urine (5-13%). An enterohepatic circulation was observed. The 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 conjugation 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. 
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Metabolism of methoxyfenozide in other animals (poultry and ruminants) appears to be similar 

to its metabolism in rats. Although methoxyfenozide does not undergo extensive metabolism in 

primary crops, it is highly metabolized in rotational crops. Methoxyfenozide is metabolized by 

oxidation, demethylation and hydroxylation to non-conjugated metabolites, which were then 

conjugated with biomolecules, yielding bound residues 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 hydroxylation and oxidation of methyl groups. These 

degradates were also found in the 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 since 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 similarities of chemical structure, the non-conjugated 

metabolites would be expected to be no more toxic than the parent compound. The metabolites 

were included in risk assessment and the tolerance expression, based on the potential for toxicity 

similar to that of the parent, as well as the potential 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 tolerance expression and the risk assessment in primary 

crops is methoxyfenozide. 

Livestock: The qualitative nature of methoxyfenozide residues in livestock is also adequately 

understood, based on available ruminant and poultry 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 residues of concern in meat byproducts and eggs 

are methoxyfenozide and its RH-141,518 metabolite. 

Rotational Crops: The nature of methoxyfenozide residues in rotational crops is adequately 

understood, based on the adequate confined accumulation study. For enforcement purposes, the 

tolerance definition for rotated crops includes parent only in high-moisture crops, and the 

combined 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. 
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The toxicological and residue chemistry 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 metabolites 

RH-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 and 

degradates RH-117,236 and RH131,154 

Not Applicable 

1 Chemical structures for the residues of concern for tolerance 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 available to support the proposed use on pineapple. 

Quantifiable residues were observed in/on all crop commodities. The residue decline data 

indicate that residues of methoxyfenozide on pineapple were variable but generally decreased 

with increasing PHIs. The available data are 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 adequate. Based on the lack of concentration 

in processed pineapple commodities, no separate tolerances on these commodities are required. 

The available storage stability data are adequate, and support the storage conditions and 

durations for samples from the submitted pineapple field trial and processing studies. 

 

Adequate livestock feeding studies are available for methoxyfenozide. No livestock feeding 

studies were submitted with this petition. The only feedstuff associated with the proposed new 

uses is pineapple process residue, 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 effect on the estimated residue levels in livestock 

commodities. The currently established tolerances for residues of methoxyfenozide and its 
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metabolites in livestock commodities are thus adequate to support the proposed new use on 

pineapple. 

TABLE 5.2. Summary of Residue Data from Pineapple Field Trials with Methoxyfenozide.

Commodity Total Rate 

lb ai/A 

(g ai/ha) 

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min. 

Sample 

Max. 

LAFT2 HAFT2 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 (EDWCs) 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 Modeling System (PRZM-EXAMS), using EFED's 

standard index reservoir which incorporates flow into and out of the reservoir. Groundwater 

residues were estimated using the Pesticide Root Zone Model – Ground Water (PRZM-GW) 

model, which accounts for pesticide fate in the crop root zone and multiple years of application. 

The surface water values are based on the existing globe artichoke use represented by the CA 

lettuce scenario with an application rate of 0.25 lbs. a.i./acre/application and a total of 1.0 lb 

a.i./acre/season. The estimated drinking water concentrations (EDWCs) are listed in Table 2. 

The EDWC used in this assessment is bolded in the table below, with the value of 214 ppb 

coming from the groundwater residues estimated 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 persistence of methoxyfenozide. This persistence makes it 

plausible that methoxyfenozide may pose a greater long-term drinking water exposure concern 

than what is suggested by the screening-level assessment. In particular, once introduced into the 

environment, this compound could travel to key aquatic environmental compartments, such as 

aquatic sediment, and persist for extended periods of time. Thus, there are significant 

uncertainties regarding the potential long-term drinking water exposure associated with the use 

of methoxyfenozide. Therefore EFED has used a conservative approach 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 methoxyfenozide (PRZM-EXAMS) 

Drinking 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 37.4 
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Table 5.3. Tier II estimated drinking water concentrations (EDWCs) resulting from 

 applications of methoxyfenozide (PRZM-EXAMS) 

Drinking 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 Breakthrough 

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 tolerance 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 juice (D358341, D. Rate, 6/10/2009) from a reviewed 

processing study. The existing tolerances for livestock commodities were considered adequate 

(D413705, E. Holman, 04/4/2014). 

Drinking water was incorporated directly into the dietary assessment 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, based on food and drinking water, includes the 

assumption of 100% CT for all existing 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 methoxyfenozide was conducted using tolerance-level 

residues and 100% CT for all existing and proposed primary crop uses, 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 the population subgroups. Chronic dietary exposure 

was 30% of the cPAD for the U.S. population. The chronic dietary exposure for the highest 
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reported exposed population subgroup, children 1-2 years old, was 83% of the cPAD. The 

results of the analysis indicate that chronic risk from the dietary (food + drinking water) 

exposure to methoxyfenozide will not exceed HED’s LOC for the general U.S. population, nor 

any other population subgroups. Based on the very conservative assumptions used, actual 

dietary exposure to methoxyfenozide from food and drinking water is expected to be 

significantly lower than the exposures 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 Subgroup1

DEEM Acute Dietary Analysis, 

95th 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 risk 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 carcinogenetic to humans” and, therefore, 

cancer risk is not of concern 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 this time; however, there are existing residential 

ornamental uses that were previously reassessed to reflect updates to HED’s 2012 Residential 

SOPs1

 along with policy changes for body weight assumptions (M. Collantes, D389739, 

02/27/12). In order to incorporate 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 ornamentals is provided below. 

 

1

 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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6.1 Residential Handler Exposure 

The Intrepid 2F label indicates that it is to be used on trees, shrubs, foliage plants and flowers 

grown in commercial nurseries and greenhouses, Christmas 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 Using Manually Pressurized Handwand 

 Mixing/Loading/Applying for Sprays with Back-Pack Sprayer 

 Mixing/Loading/Applying for Sprays with Hose-end Sprayer 

HED’s LOC is a MOE greater than or equal to 100 for residential exposure. A quantitative 

dermal assessment for residential handlers was not conducted since there is no systemic toxicity 

associated with dermal exposure to methoxyfenozide. Handler inhalation 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 risks, 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 Handler Exposure and Risk Estimates 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 (Reg. 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) 
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6.2 Dermal Post-Application Exposure 

Although there is potential for post-application dermal exposure as a result of the use on 

ornamentals, there’s no dermal toxicity associated with this exposure, and a dermal postapplication exposure assessment was not conducted. Furthermore, post-application oral 

exposure to children is not expected since the extent to which young children engage in activities 

associated with areas where residential ornamentals are grown or utilize these areas for 

prolonged periods of play is low. Therefore an incidental oral endpoint was not selected and an 

incidental oral post-application exposure assessment was not conducted. 

 

6.3 Inhalation Post-Application Exposure 

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for methoxyfenozide at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category 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 pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for methoxyfenozide. 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 Offices 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 drift as a potential source of exposure in risk 

assessments for pesticides through existing programs 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 which 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 quantitative 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). However, volatilization of pesticides may be a source 

of post-application inhalation exposure to individuals nearby pesticide applications. The Agency 

sought expert advice and input on issues related to volatilization of pesticides 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, 20102

. 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.html
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the need for and, subsequently, the way to incorporate post-application inhalation exposure into 

the Agency's risk assessments. If new policies or procedures are developed, the Agency may 

revisit the need for a quantitative post-application inhalation exposure assessment for 

methoxyfenozide. 

Although a quantitative residential post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for residential handlers. These 

exposure scenarios are representative of worse case inhalation exposures and should be 

considered protective of most post-application 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 the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers 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, based on ornamental use only. Therefore, 

aggregate exposure and risk for children are equivalent to those from food and water (see Section 

5.4). 

 

7.1 Acute Aggregate Risk 

There are no single dose effects associated with methoxyfenozide, and therefore no acute 

aggregate risk. 

7.2 Short-Term Aggregate Risk 

The residential handler exposure from applying 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 aggregate risk estimate is 

not of concern. 
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Table 7.2. Short-Term Aggregate Risk Calculations for Methoxyfenozide. 

Population NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day 

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

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 uncertainty factors totaling 100. The FQPA Safety Factor has been 

reduced to 1X. 

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

3 Residential Exposure (Adult Handler) = Inhalation Exposure (Table 6.1). 4 Total Exposure = (Avg. Food & Water 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 chronic 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 followed 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 and methoxyfenozide does not appear to produce a 

toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA 

has not assumed that methoxyfenozide has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/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), hand-held equipment (backpack sprayer, 

manually-pressurized handwand and hand gun), and hose-end sprayer. Therefore, there is 

potential for short- and intermediate-term occupational handler and post-application exposure; 

long-term exposures are not expected. 

The proposed new use of methoxyfenozide in pineapples is applied using the same application 

methods and agricultural practices as the currently 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 the previously assessed uses (0.25 lb ai/acre 

or 0.025 lb ai/gal). Short-term handler inhalation risk estimates for methoxyfenozide use on 
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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 exposure 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 expected 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 Exposure and Risk Estimates for Methoxyfenozide.

Exposure Scenario Crop or Target 

Baseline 

Inhalation Unit 

Exposure 

 (μg/lb ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Inhalation 

No Respirator Dose 

(mg/kg/day)4 MOE5

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 Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline for 

mixer/loader/flaggers, Eng. Controls 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 (μg/lb ai) × Conversion Factor (0.001 mg/μg) × 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) ÷ Inhalation Dose (mg/kg/day). 

9.2 Post-Application Risk 

9.2.1 Post-Application Dermal Exposure 

Since there’s no dermal toxicity associated with methoxyfenozide, a dermal post-application 

exposure and risk assessment was not conducted. 
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9.2.2. Post-Application Inhalation Exposure 

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for methoxyfenozide at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category III and IV), vapor pressure (1 x 10-7 mm Hg), and 

the low proposed use rate (0.31 lb ai/A). However, there are multiple potential sources of postapplication inhalation exposure to individuals performing post-application activities in 

previously treated fields. These potential sources include volatilization of pesticides and 

resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides 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, 20103

. The Agency is in the process of evaluating 

the SAP report as well as available post-application inhalation exposure data generated by the 

ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, 

subsequently, the way to incorporate occupational post-application inhalation 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-application inhalation exposure assessment 

for methoxfenozide. 

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios. 

Restricted Entry Interval 

The REI specified on the proposed label is based on the acute toxicity of methoxyfenozide. 

Methoxyfenozide is classified as Toxicity Category III via the dermal route and Toxicity 

Category IV for skin-irritation potential. It is not a skin sensitizer. Under 40 CFR 

156.208(c)(2)(iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary 

skin irritation are assigned a 12-hour REI. Therefore, 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 criteria are met for both the 

technical material and the different end-use 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 Category III or IV based upon data for acute dermal 

toxicity, acute inhalation toxicity, primary skin irritation, 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.html
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(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 information that are “definitely” or “probably” related to 

the post-application exposures to the active ingredient. 

With respect to the active ingredient, methoxyfenozide is not classified as a carcinogen or a 

neurotoxicant, nor is it associated with known reproductive or developmental effects, which 

classifies it as a reduced-risk candidate. Therefore, the proposed 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 Establishment 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 chives), Dates, Sorghum, Fruiting Vegetable 

Group 8-10, Pome Fruit Group 11-10, Berry Subgroups 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 Registration 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 Residential Exposure Assessment for a 

Proposed Use on Dates, Sorghum, Herbs (subgroup 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. 
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EFSA (European Food Safety Authority), 2014. Reasoned opinion on the review of the existing 

maximum residue levels (MRLs) for methoxyfenozide 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 Science 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 #0053782 
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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 Inhalation Toxicity .............................................. 

870.2400 Primary Eye Irritation .................................................... 

870.2500 Primary Dermal Irritation .............................................. 

870.2600 Dermal Sensitization ..................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent) ............................................... 

870.3150 Oral Subchronic (nonrodent) ......................................... 

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 Reproduction ................................................................. 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) .............................................. 

870.4100b Chronic Toxicity (nonrodent) ........................................ 

870.4200a Oncogenicity (rat) .......................................................... 

870.4200b Oncogenicity (mouse) ................................................... 

870.4300 Chronic/Oncogenicity ................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial ..................... 

870.5300 Mutagenicity—Gene Mutation - mammalian ................ 

870.5xxx Mutagenicity—Structural Chromosomal Aberrations ... 

870.5xxx Mutagenicity—Other 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 General Metabolism ...................................................... 

870.7600 Dermal Penetration ........................................................ 

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. 
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile – Methoxyfenozide technical

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

870.1100 Acute oral [rat] 44144415 LD50 >5000 

mg/kg, both sexes 

IV 

870.1100 Acute oral [mouse] 44144416 LD50 >5000 

mg/kg, both sexes 

IV 

870.1200 Acute dermal [rat] 44144418 LD50 >2000 

mg/kg, both sexes 

III 

870.1300 Acute inhalation [rat] 44144420 LC50 >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) 

Maternal NOAEL = 1000 mg/kg/day 

LOAEL > 1000 mg/kg/day (HDT) 

Developmental 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 carcinogenicity
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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 increased 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 increased 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. 
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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. The 

primary 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 Properties 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/cm3) 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, pKa None 

Octanol/water partition coefficient 

(Log [KOW]) 

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. These data, which include studies from 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler 

Exposure Task Force (AHETF) database; and the Outdoor Residential Exposure Task Force 

(ORETF) database; are subject to ethics review pursuant to 40 CFR 26, have received that 

review, and are compliant with applicable ethics requirements. For certain studies that review 

may have included review by the Human Studies Review 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/pesticides/science/post-app-exposure-data.html.