Methoxyfenozide Human Hea lth Risk Assessment DP Barcode 422208 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, DC 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: September 8, 2015 

SUBJECT: Methoxyfenozide. Human Health Draft Risk Assessment for Registration 

Review and New Use Risk Assessment to Support the Registration of Proposed 

Use on Chives, and Crop Group Expansions for Stone Fruit and Tree Nuts. 

PC Code: 121027 DP Barcode: 0 422208, 0427542 

Decision No.: 493332?"0S"f3' Registration No.: 627 19-442: 62719-438: 62719-666; 

62719-667 

Petition No.: 4E8298 Regulatory Action: Registration Review; Section 3 

Risk Assessment Type: Single Chemical Aggregate Case No.: 7431 

TXR No.: NA CAS No.: 161050-58-4 

MRID No.: NA 40 CFR: 180.544 

FROM: 

THROUGH: 

Elizabeth Holman, Physical Scientis 

William T. Drew, Chemist 

Zaida Figueroa. J ndustrial Hygienist 

Linnea J. Hansen, Ph.D., Biologist 

Risk Assessment Branch TI (RABII) 

Health Effects Division (7509P) 

Chr

Risk 

ist

Assessme

ina Swartz

nt 

, 

Branch 

Branch 

II 

Chi

(RA

ef 

Bii

~~ ) 

Health Effects Division (7509P) 

TO: Barbara Madden and Andrew Ertman, RM Team 5 

Minor Use and Emergency Response Branch (MUERB) 

Registration Division (RD), 7505P 

AND 

Jill Bloom, Team Leader 

Risk Management and Implementation Branch V 

Pesticide Re-evaluation Division 

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

assessment for the active ingredient (ai) methoxyfenozide to estimate the risk to human health 

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Methoxyfenozide Human Health Risk Assessment DP Barcode 422208 

that will result from the proposed new use on chive, and crop group conversions for stone fruit 

and tree nuts. 

In addition, the Pesticide Re-evaluation Division (PRD) requested that HED conduct a human 

health risk assessment based on the current actively registered uses of the insecticide 

methoxyfenozide. Therefore, this new use assessment and registration review assessment have 

been conducted together as a single assessment. A hwnan health assessment scoping document 

in support of registration review was completed in 2013 ; no new data were considered necessary 

to support registration review. The attached human health risk assessment addresses exposure 

and risk associated with the proposed new uses, 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. In addition, HED conducted a 

spray drift assessment which addressed the potential for incidental oral exposure for children 

coming into contact with areas adjacent to treated fields. There were no risks of concern 

identified for any route or duration of exposure. Further, no label changes are recommended in 

conjunction with the evaluation of existing uses under registration review. 

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Table of Contents

1.0 Executive Summary ........................................................................................................... 5

2.0 HED Recommendations .................................................................................................... 7

2.1 Data Deficiencies/Conditions of Registration .............................................................. 8

2.2 Tolerance Considerations.............................................................................................. 8

2.2.1 Enforcement Analytical Method............................................................................... 8

2.2.2 International Harmonization ..................................................................................... 8

2.2.3 Recommended Tolerances........................................................................................ 9

2.2.4 Revisions to Petitioned-For Tolerances.................................................................. 10

2.3 Label Recommendations From Residue Review....................................................... 10

3.0 Introduction...................................................................................................................... 10

3.1 Chemical Identity ......................................................................................................... 10

3.2 Physical/Chemical Characteristics ............................................................................. 11

3.3 Pesticide Use Pattern.................................................................................................... 12

3.4 Anticipated Exposure Pathways................................................................................. 13

3.5 Consideration of Environmental Justice.................................................................... 14

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 14

4.1 Toxicology Studies Available for Analysis................................................................. 14

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................. 15

4.2.1 Dermal Absorption.................................................................................................. 16

4.3 Toxicological Effects .................................................................................................... 16

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 17

4.4.2 Evidence of Neurotoxicity ...................................................................................... 17

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 18

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 18

4.5.1 Dose-Response Assessment.................................................................................... 18

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment........ 20

4.5.3 Cancer Classification and Risk Assessment Recommendation.............................. 20

4.6 Endocrine Disruptor Screening Program...................................................................... 23

5.0 Dietary Exposure and Risk Assessment......................................................................... 24

5.1 Metabolite/Degradate Residue Profile ....................................................................... 24

5.1.1 Summary of Plant and Animal Metabolism Studies............................................... 24

5.1.2 Summary of Environmental Degradation ............................................................... 24

5.1.3 Comparison of Metabolic Pathways....................................................................... 25

5.1.4 Residues of Concern Summary and Rationale........................................................ 25

5.2 Food Residue Profile .................................................................................................... 26

5.4 Dietary Risk Assessment.............................................................................................. 28

5.4.1 Description of Residue Data Used in Dietary Assessment..................................... 28

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 29

5.4.3 Acute Dietary Risk Assessment.............................................................................. 29
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5.4.4 Chronic Dietary Risk Assessment .......................................................................... 29

5.4.5 Cancer Dietary Risk Assessment............................................................................ 30

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 30

6.1 Residential Handler Exposure .................................................................................... 30

6.2 Residential Post-Application Dermal & Incidental Oral Exposure ........................ 31

6.4 Residential Risk Estimates for Use in Aggregate Assessment.................................. 32

6.5 Spray Drift.................................................................................................................... 32

6.5.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications.............. 33

6.6 Residential Bystander Post-Application Inhalation Exposure ................................ 34

7.0 Aggregate Exposure/Risk Characterization.................................................................. 34

7.1 Acute Aggregate Risk................................................................................................... 35

7.2 Short-Term Aggregate Risk ........................................................................................ 35

7.3 Chronic Aggregate Risk .............................................................................................. 35

8.0 Cumulative Exposure/Risk Characterization ............................................................... 35

9.0 Occupational Exposure/Risk Characterization ............................................................ 36

9.1 Post-Application Risk .................................................................................................. 38

9.1.1 Post-Application Dermal Exposure ........................................................................ 38

9.1.2. Post-Application Inhalation Exposure .................................................................... 38

11.0 References......................................................................................................................... 40

Appendix A. Toxicology Profile and Executive Summaries .................................................. 42

Appendix B. Physical/Chemical Properties. ........................................................................... 51

Appendix C. Review of Human Research................................................................................ 51

Appendix D. Summary of Special Local Need (SLN) Registrations for Methoxyfenozide. 52
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1.0 Executive Summary

Interregional Research Project #4 (IR-4) has submitted a petition requesting the establishment of 

permanent tolerances for residues of methoxyfenozide in or on chive, and crop group 

conversions for stone fruit and tree nuts. In addition, methoxyfenozide is currently undergoing 

registration review and this human health risk assessment has been conducted as part of this 

review. 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 RBC 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 
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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 

quantitative dermal exposure and risk assessments were conducted (i.e., there is no hazard via 

the dermal route). As part of conducting the registration review assessment, HED selected an 

endpoint for incidental oral risk assessment that was based on the potential for exposure due to 

spray drift. However, the potential for direct post-application oral exposure to children resulting 

from the existing use of methoxyfenozide on ornamentals is extremely low and was not included 

in the assessment of incidental oral exposure. 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; 0055054).

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 incidental oral and 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 84% 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 

chives and the requested crop group conversions currently under review. However, as part of the 

registration review assessment, HED has conducted a spray drift assessment. Since 

methoxyfenozide can be applied via ground and aerial equipment to agricultural crops, there is 

potential for indirect exposure to methoxyfenozide related to spray drift. As a result, incidental 

oral risk estimates for children 1 to <2 years old were calculated. The highest exposure resulted 

from drift following methoxyfenozide applications using aerial equipment for children 1 to <2 

years old (margins of exposures (MOEs) ≥ 11,000 with an LOC ≤ 100). There were no risks of 

concern at the field’s edge. 

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 
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endpoint was selected and the OPP HED Residential Standard Operating Procedures (SOPs)

were finalized and approved for risk assessment purposes. Therefore, in a previous new-use 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 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 

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 450 to 570,000 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 4-hour REI listed on the registered 

labels is consistent with the 4-hour REI requirements and is adequate to protect agricultural 

workers from post-application exposures to methoxyfenozide.

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 has examined the residue chemistry database for methoxyfenozide. Pending submission of 

a revised Section F (to propose tolerances and commodity definitions recommended by HED), 

there are no residue chemistry issues that would preclude establishing the recommended 

tolerances. The recommended tolerances are listed in Table 2.2.3, below. 

Notes to RD: Upon establishment of the recommended tolerance in herb subgroup 19A, except 

chive, fresh leaves, the existing tolerance in herb subgroup 19A except chive should be removed 

(40CFR §180.544[a][1]). 
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Upon establishment of the recommended tolerance in chive, fresh leaves, at 30 ppm (40CFR 

§180.544[a][1]), the existing tolerance for indirect or inadvertent methoxyfenozide residues in

rotational crop chives at 4.5 ppm should be removed (40CFR §180.544[d][2]). 

Upon establishment of the recommended tolerance in green onion subgroup 3-07B except chive, 

fresh leaves, the existing tolerance in green onion subgroup 3-07B should be removed (40CFR 

§180.544[a][1]). 

Upon establishment of the proposed tolerance in tree nut group 14-12, the existing tolerances in 

tree nut group 14 and pistachio should be removed (40CFR §180.544[a][1]). 

Upon establishment of the proposed tolerance in stone fruit group 12-12 except fresh prune 

plum, the existing tolerance in stone fruit group 12 except fresh prune plum should be removed 

(40CFR §180.544[a][1]). 

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 

(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

Codex has not established maximum residue limits (MRLs) for methoxyfenozide in either green 

onions or herbs. Canada’s Pest Management Regulatory Agency (PMRA) has an existing MRL 

in various green onions/leeks at 5 mg/kg, which is harmonized with the existing tolerance of 5.0 

ppm in green onion subgroup 3-07B. PMRA has an existing MRL in various fresh herbs at 80 

mg/kg, which is not harmonized with the recommended tolerance of 400 ppm in herb subgroup 

19A, nor the recommended tolerance of 30 ppm in chive. HED cannot recommend for 

harmonization of the subgroup 19A tolerance with PMRA’s MRL, because 400 ppm was the 

result of the Organization for Economic Cooperation and Development (OECD) tolerance 

calculation procedure for methoxyfenozide residues in basil, and reduction of the tolerance

would result in the risk of violative residues resulting from proper use according to label 
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directions. HED also cannot recommend for harmonization of the chive tolerance with PMRA’s 

MRL, because increasing the recommended tolerance to 80 ppm in chive would result in the risk 

of undetected misuse (via seasonal application rates exceeding the label directions). 

Codex has an existing MRL in stone fruit at 2 mg/kg, which is not harmonized with the 

recommended tolerance of 3.0 ppm in stone fruit group 12-12 except fresh prune plum. HED 

cannot recommend for harmonization of the group 12-12 tolerance with Codex’s MRL, because 

3.0 ppm was the result of the OECD tolerance calculation procedure for methoxyfenozide 

residues in stone fruit, and reduction of the tolerance would result in the risk of violative residues 

resulting from proper use according to label directions. PMRA has existing MRLs in various 

plums/apricots/jujubes/sloes at 0.7 mg/kg, and in various cherries/peaches/nectarines at 6 mg/kg, 

neither of which is harmonized with the recommended tolerance of 3.0 ppm in stone fruit group 

12-12 except fresh prune plum. HED cannot recommend for harmonization of the group 12-12

tolerance with PMRA’s MRLs, because EPA’s tolerance is established in the entire crop group, 

not in separate subgroups. 

Codex has an existing MRL in tree nuts at 0.1 mg/kg, which is harmonized with the 

recommended tolerance of 0.10 ppm in tree nut group 14-12. PMRA has an existing MRL in a 

large variety of tree nuts at 0.1 mg/kg, which is harmonized with the recommended tolerance of 

0.10 ppm in tree nut group 14-12. 

In addition, as part of the registration review process, in spring 2013 HED had discussions with 

Health Canada (PMRA) about harmonizing tolerances for methoxyfenozide. As a result of these 

discussions, several commodities were targeted for possible harmonization. These commodities 

are currently out of harmonization between USEPA and Codex and/or PMRA. Therefore, HED 

is recommending increasing several tolerances solely for the purposes of harmonization, 

specifically those on Bushberry subgroup 13-07B; Pea and bean, succulent shelled, subgroup 6B; 

and Vegetable, legume, edible podded, subgroup 6A. 

2.2.3 Recommended Tolerances

TABLE 2.2.3. Tolerance Summary for Methoxyfenozide (40CFR §180.544). 

Proposed or Existing*

Commodity

Proposed or Existing*

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Correct Commodity Definition; 

Comments

40CFR §180.544[a][1]

Fruit, stone, group 12-12, 

except plum, prune, fresh

3.0 3.0 Conversion from stone fruit group 12 

except fresh prune plum.

Nut, tree, group 14-12 0.10 0.10 Conversion from tree nut group 14.

Herb subgroup 19A, 

except chive, fresh, leaves

400 400 Herb subgroup 19A, except chive, fresh 

leaves; based on field trial data on dried 

chives submitted by IR-4. 

Onion, green, subgroup 3-

07B, except chive

5.0 5.0 Onion, green, subgroup 3-07B, except 

chive, fresh leaves. Based on field trial 

data on fresh chives submitted by IR-4.

Chive, fresh, leaves 30.0 30 Chive, fresh leaves, based on field trial 

data on fresh chives submitted by IR-4.

Herb subgroup 19A, 

except chive*

400* Remove Replace with the tolerance in herb 

subgroup 19A, except chive, fresh 

leaves. 
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TABLE 2.2.3. Tolerance Summary for Methoxyfenozide (40CFR §180.544). 

Proposed or Existing*

Commodity

Proposed or Existing*

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Correct Commodity Definition; 

Comments

40CFR §180.544[a][1]

Onion, green, subgroup 3-

07B*

5.0* Remove Replace with the tolerance in green 

onion subgroup 3-07B, except chive, 

fresh leaves. 

Fruit, stone, group 12, 

except plum, prune, 

fresh*

3.0* Remove Conversion to stone fruit group 12-12

except fresh prune plum.

Nut, tree, group 14* 0.10* Remove Conversion to tree nut group 14-12.

Pistachio 0.10* Remove Conversion to tree nut group 14-12.

Bushberry subgroup 13-

07B*

3.0* 4.0 Increase tolerance to harmonize with 

Codex and PMRA. 

Pea and bean, succulent 

shelled, subgroup 6B*

0.2* 0.30 Increase tolerance to harmonize with 

Codex and PMRA. 

Vegetable, legume, edible 

podded, subgroup 6A*

1.5* 2.0 Increase tolerance to harmonize with 

Codex and PMRA. 

40CFR §180.544[d][2]

Chive* 4.5* Remove Covered by new chive tolerance in 

§180.544[a][1]. 

* A tolerance is currently established at the listed level in the corresponding commodity. 

2.2.4 Revisions to Petitioned-For Tolerances

HED recommends in favor of IR-4’s proposal to remove the chive exception to the existing herb 

subgroup 19A except chive tolerance, concurring with IR-4’s proposal to replace it with an 

exception for fresh chive leaves. The chive field trial data support a tolerance of 30 ppm in/on

fresh chives, and 300 ppm in/on dried chives, based on input of the residue data into the 

Organization for Economic Development and Cooperation (OECD) tolerance calculation 

procedure. However, dried chives will be covered under herb subgroup 19A, which has an 

existing tolerance established at 400 ppm. The Agency also determined that the petitioned-foramended tolerance in or on onion, green, subgroup 3-07B, except chive should be established in 

or on onion, green, subgroup 3-07B, except chive, fresh leaves. This is due to the fact that only 

chive, fresh leaves are included in subgroup 3-07B, and the Agency is establishing a separate 

tolerance for chive, fresh leaves at 30 ppm. 

Instead of the proposed tolerance in chive (30.0 ppm), HED recommends establishing the 

tolerance at 30 ppm. The Agency establishes tolerances using whole numbers for tolerances of 

10 ppm or more, per the OECD’s User Guide ENV/JM/MONO(2011)2 for the OECD tolerance 

calculation procedure. 

2.3 Label Recommendations From Residue Review

None. 

3.0 Introduction

3.1 Chemical Identity
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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 

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.

CH3 O

N

H

N

O

CH3

CH3

H3C CH3

H3C O

CH3
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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

Methoxyfenozide is currently registered for use on ornamentals and a wide variety of 

agricultural crops.

Methoxyfenozide is a diacylhydrazine insecticide and is active against lepidopterous insects 

(moths and butterflies). It is currently registered for use on ornamentals and numerous 

agricultural crops. 

This assessment contains a summary of the registered uses and the proposed use of 

methoxyfenozide to control pests on chives. In addition, a petition to update the crop groups for

stone fruit (Group 12 except fresh prune plums to Group 12-12 except fresh prune plums) and 

tree nuts (Group 14 to Group 14-12) has been requested.

There are total of four registered Sec. 3 end-use products (EPs), with three EPs formulated as a 

liquid concentrate and one other formulated as water soluble packets (WSP). There are a number 

of Special Local Need (SLN) registrations, also known as FIFRA Section 24(c) registrations (see 

Appendix D for a complete description). The registered application methods for 

methoxyfenozide include the use of aerial, ground (groundboom and airblast), chemigation, and 

handheld equipment. 

Baseline attire is required for handlers, consisting of a single layer of clothing (i.e., long sleeve 

shirt, long pants, shoes plus socks), along with personal protective equipment such as chemicalresistant gloves (for 62719-442 only) and no respirator. The restricted entry interval (REI) for 

methoxyfenozide is 4 hours. Table 3.3 provides a summary of all the uses for methoxyfenozide.

Table 3.3. Summary of Directions for Use of Methoxyfenozide.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. 

No.]

Max. Single 

Applic. Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate 

(lb ai/A)

Use Directions and Limitations

Registered Uses

Bushberries (Subgroup 13 07B), Cilantro Leaves, Brassica (Cole) Leafy Vegetables (Crop Group 5), Leafy Vegetables (Crop Group 

4), Leaves of Root and Tuber Vegetables (Crop Group 2), Turnip Greens, Citrus Fruits (Crop Group 10-10), Corn (Field, Sweet, 

Seed), Cotton, Cranberry, Cucurbit Vegetables (Crop Group 9), Fruiting Vegetables (Crop Group 8), Globe artichoke, Grape, Green 

Onion (Subgroup 3-07B), Legume Vegetables (Succulent or Dried) (Crop Group 6), Legume Vegetables (Except Soybean) 

(Subgroup 7A), Okra, Peppermint, Pome Fruits (Crop Group 11), Pomegranate, Popcorn, Root Vegetables (Subgroups 1A, 1B),

Soybean, Spearmint, Stone Fruits (Crop Group 12), Strawberry, Tree Nuts (Crop Group 14) and Pistachios, Tropical Tree Fruits, 

Tuberous and Corm Vegetables (Except Potato) (Subgroup 1D) (on 62719-442, 62719-666, 62719-667)

Leek, and Shallot (only on 62719-666)

Grass Forage, Fodder, and Hay (Crop Group 17), Nongrass Forage, Fodder, Straw and Hay (Crop Group 18) (only on 62719-442 

and 62719-667)

Broadcast 

Foliar; Aerial, 

Ground, 

Chemigation 

Intrepid 2F

Flowable 

Concentrate

[62719-442]

0.25-0.4 lb 

ai/A

1-4 

(depending on 

rate)

1.0 lb ai/A

Various pre-harvest intervals (PHIs) are 

allowed, ranging from 1 to 30 days. There are 

rotational restrictions on the label depending 
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Table 3.3. Summary of Directions for Use of Methoxyfenozide.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. 

No.]

Max. Single 

Applic. Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate 

(lb ai/A)

Use Directions and Limitations

22.6% ai

2.0 lb ai/gal

on the crop. The minimum retreatment interval 

depends on the crop (see label for specifics). 

Broadcast 

Foliar; Aerial, 

Ground, 

Chemigation

Intrepid Edge

Soluble 

Concentrate

[62719-666]

28.3% ai

2.5 lb ai/gal

0.08-0.35 lb 

ai/A

1-4 

(depending on 

rate)

1.0 lb ai/A

Broadcast 

Foliar; Aerial, 

Ground, 

Chemigation

GF-2986

Soluble 

Concentrate

[62719-667]

20.6% ai

1.84 lb ai/gal

0.043-0.26 lb 

ai/A

1-6 

(depending on 

rate)

0.98 lb ai/A

Ornamentals

Broadcast 

Foliar; Aerial, 

Ground, 

Chemigation, 

Handheld 

Equipment

Intrepid 2F

Flowable 

Concentrate

[62719-442]

22.6% ai

2.0 lb ai/gal

0.06-0.25 lb 

ai/A

(4-16 fl oz/A)

or 0.025 lb 

ai/gal

1-4 

(depending on 

rate)

0.5 lb ai/A/yr

or

32 fl oz/A/yr

Repeat application on a 10-14 day interval or 

as necessary based upon pest reinfestation.

Hand sprayers – apply until runoff. Allow at 

least 6 hrs between applications and onset of 

precipitation to assure thorough spray drying.

The spray volume per acre depends on 

equipment (see specifics on label).

Cotton; Pome Fruit (Crop Group 11 - Apples, Crabapples, Loquat. Mayhaw, Pears including Oriental, Quince)

Broadcast 

Foliar; Aerial 

and Ground 

Equipment.

Intrepid

80WSP

Water Soluble 

Packets

[62719-438]

80% ai

Manufacturing 

Use Product

0.05-0.4 lb 

ai/A

1-4

(depending on 

rate)

1.0 lb ai/A

Allow 14 days between applications. Aerial 

application is allowed only for the last two 

applications prior to harvest.

The label has no plant-back interval restrictions 

for cotton. For leafy vegetables and root/tuber 

crops, the plant-back interval is 1 year and 

“prohibited” for all other crops. The spray 

volume per acre depends on the equipment; for 

cotton (2-5 gal/A) and for pome fruits (20-50 

gal/A) (see specifics on label).

Proposed Use

Chives

Broadcast 

Foliar; Aerial 

and Ground

Equipment.

Intrepid 2F

Flowable 

Concentrate

[62719-442]

22.6% ai

2.0 lb ai/gal

0.06-0.25 lb 

ai/A

1-4 

(depending on 

rate)

1.0 lb ai/A Minimum retreatment interval of 10 days. May 

not be applied via chemigation.

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 
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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 

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. 

Finally, there is also the potential for indirect exposure to adults and children from spray drift 

following agricultural applications. 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 
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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 

has determined that this study is not needed for methoxyfenozide, based on a weight of evidence 

(WOE) approach that considered all of the available hazard and exposure information, including 

physicochemical properties and the use of a highly conservative oral point of departure (POD). 

With the exception of a single occupational exposure MOE of 450, all residential and 

occupational exposure MOEs for risk via the inhalation route were above 1000 and ranged from 

9,600 to 3,500,000 (TXR #0053782, 4/17/12; TXR#005487). 

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 
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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 

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. 

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.
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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 

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 
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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 

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.2 of this document. For 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 have been updated since the 2013 assessment and 

the more recent 2014 assessment on pineapple (D420583, E Holman et al., 05/30/2014) to 

include a short-term incidental oral endpoint for potential exposure resulting from potential spray 

drift (see Appendix A.3). No new toxicity data have been evaluated as part of this current 

assessment. 

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 
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mg/kg/day). There were also no clinical effects on the initial day of dosing in any other oral 

toxicity study.

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. 

For short-term incidental oral exposure the two week dietary study in the dog was selected 

because it provided the most sensitive dose and endpoint available (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, including young 

children. 

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 
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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 for methoxyfenozide, based on a weight of evidence (WOE) approach 

that considered all of the available hazard and exposure information (TXR #0053782, 4/17/12; 

TXR# 0053782). With the exception of a single occupational exposure MOE of 450 (for liquid 

formulations with mechanically-pressurized handgun, baseline with no respirator), all residential 

and occupational exposure MOEs for risk via the inhalation route were above 1000 and ranged 

from 9,600 to 3,500,000. The oral endpoint selected for this risk assessment is considered highly 

conservative because the observed hematological changes appeared to be adaptive, and were not 

consistently observed in the subchronic or chronic dog studies. Furthermore, the vapor pressure 

and Henry’s law constant are very low, indicating low potential for volatilization. Based on 

these considerations, an inhalation toxicity study was not required.

Therefore, the 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 

(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. 

The rationale for selection of this study is described above for incidental oral exposure. 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 Health 

Risk Assessment
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Tables 4.5.4.1 and 4.5.4.2, below, summarize the dose and endpoint selection for dietary/nonoccupational and occupational exposure:

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)

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.

Dermal ShortTerm (1-30 

days) or 

Intermediateterm (1-6 

months)

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

Inhalation 

Short- Term 

(1-30 days)

and 

IntermediateTerm (1-6 

months)

NOAEL =

16.8

mg/kg/day

(Inhalation 

toxicity 

considered 

equivalent to 

oral 

toxicity.)

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.

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

(Inhalation 

toxicity 

considered 

equivalent 

to oral 

toxicity.)

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 
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sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable

4.6 Endocrine Disruptor Screening Program

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute,

subchronic, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include endpoints 

which may be susceptible to endocrine influence, including effects on endocrine target organ 

histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, 

reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates 

acute tests and chronic studies that assess growth, developmental and reproductive effects in 

different taxonomic groups. As part of its reregistration decision for methoxyfenozide, EPA 

reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p), 

methoxyfenozide is subject to the endocrine screening part of the Endocrine Disruptor Screening 

Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients (a.i.’s) and 9 inert ingredients. A 

second list of chemicals identified for EDSP screening was published on June 14, 20131and 

includes some pesticides scheduled for Registration Review and chemicals found in water. 

Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.2

 

1

See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of

chemicals

2 http://www.epa.gov/endo/
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5.0 Dietary Exposure and Risk Assessment 

For the purposes of the new use and the registration review assessment, adequate residue data are 

available, including metabolism, field and rotational crops, storage stability, and analytical 

method studies. 

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 

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)-
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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.

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; the potential for significant levels in crops and livestock; as well as 

the metabolites determined by the enforcement methods (as described below).

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 
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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-117,236 and RH-131,154, but these are only present at low 

concentrations.

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

D425285, W. Drew, 31 March 2015; D429009, W. Drew, 09/08/2015

D408668, L. Hansen, 05/10/2013

The residue chemistry database supporting the registered uses is complete. 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. Acceptable analytical methods are available to enforce the established 
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tolerances. The tolerance expressions for methoxyfenozide listed in 40CFR §180.544 are

appropriate, and include both coverage and compliance statements for enforcement purposes. 

The data submitted in support of the current action (PP#4E8298) along with previously reviewed 

data, are adequate for purposes of risk assessment and tolerance assessment for the proposed use 

under review. The available storage stability data are adequate, and support the storage 

conditions and durations for samples from the submitted chive field trials. Maximum residues of 

methoxyfenozide are expected to occur at moderate to high levels (up to 30 ppm in fresh chive

leaves, and up to 300 ppm in dried chive leaves) from the new use on chives proposed in the 

current petition. The results from these field trials are summarized in Table 5.2.

Methoxyfenozide residues generally tend to decline or remain stable with increasing PHI, and do 

not increase to any significant degree. Following foliar applications, methoxyfenozide is present 

primarily as surface residues; translocation does not appear to be extensive. In general, 

methoxyfenozide residues do not tend to concentrate in processed fractions, other than via 

dehydration or from surface residues. 

Residues of methoxyfenozide are not expected to accumulate above the LOQ in rotational crops

planted at PBIs of 7 days following application of methoxyfenozide to primary crops.

 

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

studies were submitted with this petition. The currently established tolerances for residues of 

methoxyfenozide and its metabolites in livestock commodities are adequate to support the 

proposed new use on chive, the proposed crop group conversions, and all existing registered 

uses.

Table 5.2. Summary of Residue Data from Chive Field Trials with Methoxyfenozide. 

Commodity Total Use 

Rate (lb ai/A)

PHI 

(Days)

Residue Levels (ppm)1

n Min. Max. HAFT2 Median Mean Std. Dev.

Chives (Fresh Leaves) 0.994-1.00 1 6 5.7 13 12.5 7.1 8.6 3.1

Chives (Dried Leaves) 1 6 12 118 115 64 64 46

1. HAFT = Highest Average Field Trial. 

2. Except for sample minimum and maximum, values reflect per trial averages; n = number of field trials. 

5.3 Water Residue Profile

D422209, K. Milians, 12/09/2014

D416709, I. Negrón-Encarnación, 12/19/2013

Estimated drinking water concentrations (EDWCs) were generated using the FIRST model 

(FQPA Index Reservoir Screening Tool) for surface water, the SCI-GROW (Screening 

Concentration In GROund Water (SCI-GROW v2.3, Jul. 29, 2003) and PRZM-GW (Pesticide 

Root Zone Model for Groundwater, version 1.0, August 31, 2012) models for groundwater. 

These were the highest EDWCs obtained (of all registered methoxyfenozide uses) and were 

based on the fruiting vegetable use represented by the WI corn scenario in PRZM-GW. Because 

the new use on chive, as well as the proposed crop group conversions for stone fruit and tree 

nuts, are proposed at the same maximum application rates as those for previously-assessed uses, 

EFED refers to the previous assessment for a new use on pineapple (D416709, I. NegrónEncarnación, 12/19/2013). The EDWCs for the pineapple use are lower than the EDWCs from 
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the fruiting vegetable use mainly due to lower application rate of the pineapple use (0.44 lb 

a.i./A/year) compared to the fruiting vegetable use (1.0 lb a.i./A/year). 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 I estimated drinking water concentrations (EDWCs) resulting from

applications of methoxyfenozide.

FIRST

Drinking water source Use

(modeled rate)

Peak Day

Concentration (ppb)

Annual Average

Concentration (ppb)

Surface water

(aerial application)

Pineapple

(0.11 lb a.i./A x 4 applic.; total

of 0.44 lb ai/A/yr) 23.5 7.57

SCI-GROW

Drinking water source Use

(modeled rate) Screening Concentration (ppb)

Groundwater

Pineapple

(0.11 lb a.i./A x 4 applic.;

total of 0.44 lb ai/A/yr)

1.76

PRZM-GW

Crop/Scenario Highest Daily value 

(μg/L)

Post Breakthrough 

Average (μg/L)

Average Simulation 

Breakthrough Time (days)

Pineapple/WI corn 108 93.1 8685

Fruiting Vegetable/WI corn 251 214 8684.63

5.4 Dietary Risk Assessment

Memo, E. Holman, 09/08/2015, D426657

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 
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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

(D425285, W. Drew, 31 March 2015). 

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 LOC

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 reported 

exposed population subgroup, children 1-2 years old, was 84% 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 (Food + Drinking Water) Exposure and Risk for

Methoxyfenozide.

Population Subgroup

Acute Dietary

95th Percentile Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population

N/A2

0.030975 30 N/A2 N/A

All Infants (<1 year old) 0.046676 46

N/A N/A

Children 1-2 years old1 0.085216 84

Children 3-5 years old 0.064809 64

Children 6-12 years old 0.035914 35

Youth 13-19 years old 0.023505 23
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Table 5.4.4. Summary of Dietary (Food + Drinking Water) Exposure and Risk for

Methoxyfenozide.

Population Subgroup

Acute Dietary

95th Percentile Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

Adults 20-49 years old 0.027082 27

Adults 50-99 years old 0.026924 26

Females 13-49 years old 0.027696 27

1 The subpopulation with the highest risk estimate. 

2 N/A = Not Applicable; no acute dietary endpoint or cancer 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

M. Collantes, D389739, 02/27/12

Memo, Z. Figueroa, D426658, 09/09/2015

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 

SOPs3along 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. In addition, as part of the registration 

review assessment, a spray drift assessment has been conducted due to the potential for indirect 

exposure to adults and children from spray drift following agricultural applications. 

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, and

 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 

 

3 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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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 the registered label Intrepid® 2F (Reg. No.: 62719-442): 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 the revised Residential (Garden and Trees) SOP.

c. Inhalation Dose (mg/kg/day) = Inhalation Unit Exposure (mg/lb ai) * Application Rate * Amount treated / Body 

Weight (80 kg).

d.Inhalation MOE = NOAEL (16.8 mg/kg/day)/ Inhalation Dose (mg/kg/day). LOC=100.

6.2 Residential Post-Application Dermal & Incidental Oral Exposure

Although there is potential for post-application dermal exposure to adults and children (6 to < 11 

years old) as a result of the use on ornamentals or from treated ornamentals purchased at a retail 

location, a dermal endpoint was not selected. Therefore, a dermal post-application exposure 

assessment was not conducted. 

Furthermore, the potential for post-application oral exposure to children is not expected as a 

result of the use on ornamentals. Therefore, an incidental oral post-application exposure 

assessment was not conducted. 

6.3 Inhalation Post-Application Exposure

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, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 
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During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

methoxyfenozide.

6.4 Residential Risk Estimates for Use in Aggregate Assessment

The recommended residential exposure estimate for use in the adult aggregate assessment has 

not changed since the 2012 assessment (M. Collantes, D389739, 02/27/12). HED selected the 

most conservative residential adult scenario to be included in the aggregate assessment; the 

recommended residential exposure scenario for use in the adult aggregate assessment reflects 

residential handler inhalation exposure from applications to ornamentals via backpack sprayer. 

The estimated risk estimate for this scenario resulted in a MOE of 76,000, which is greater than 

the LOC of 100 and is not of concern. Table 6.4 reflects the residential exposure estimate that is

recommended for use in the aggregate assessment for methoxyfenozide.

Table 6.4. Summary of Residential Risk Estimates for Use in the Methoxyfenozide Aggregate Assessment.

Lifestage

Residential Handler

Dose (mg/kg/day)2 MOE3

Dermal Inhalation Total Dermal Inhalation Total

Adult N/A 0.00022 N/A N/A 76,000 N/A

Child N/A

1. Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

2. Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed in Table 4.1.2 located in D389739. 

3. Residential Handler MOE = the MOEs associated with the highest doses identified in Table 4.1.2 located in D389739.

6.5 Spray Drift

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those the chemical may directly contact. Sprays can also 

deposit on surfaces where individuals come into contact with residues on these surfaces, leading

to indirect exposures (e.g., children playing on lawns where residues have deposited next to 

treated fields).

The approach to be used for quantitatively incorporating spray drift into risk assessment is based 

on a premise of compliant applications which, by definition, should not result in direct exposures 

to individuals because of existing label language and other regulatory requirements intended to 

prevent them4. [Direct exposures would include inhalation of the spray plume or being sprayed 

directly.] Rather, the exposures addressed here are thought to occur indirectly through contact 

with impacted areas, such as residential lawns, when compliant applications are conducted. 

Given this premise, exposures for children (1 to <2years old) and adults who have contact with 

turf where residues are assumed to have deposited via spray drift thus resulting in an indirect 

exposure are the focus of this analysis analogous to how exposures to turf products are 

considered in risk assessment. 

 

4 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.
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In order to evaluate the drift potential and associated risks, an approach based on drift modeling 

coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, 

a residential turf assessment based on exposure to deposited residues has been completed to 

address drift from the agricultural applications of methoxyfenozide. In the spray drift scenario, 

the deposited residue value was determined based on the amount of spray drift that may occur at 

varying distances from the edge of the treated field using the AgDrift (v2.1.1) model and the 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift Policy. Once the deposited residue values were determined, the remainder of the 

spray drift assessment was based on the algorithms and input values specified in the 2012 

Standard Operating Procedures for Residential Risk Assessment (SOPs). 

A screening approach was developed based on the use of the AgDrift model in situations where 

specific label guidance that defines application parameters is not available56. AgDrift is 

appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and 

groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier

1 option) were incorporated into the model and represent each equipment type and use under 

varied conditions. The screening options specifically recommended in this methodology were 

selected because they are plausible and represent a reasonable upper bound level of drift for 

common application methods in agriculture. These screening options are consistent with how 

spray drift is considered in a number of ecological risk assessments and in the process used to 

develop drinking water concentrations used for risk assessment. In all cases, each scenario is to 

be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are 

not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are 

not allowed). Section 6.5.1 provides the screening level drift related risk estimates. 

In many cases, risks are of concern when the screening level estimates for spray drift are used as 

the basis for the analysis. In order to account for this issue and to provide additional risk 

management options additional spray drift deposition fractions were also considered. These drift 

estimates represent plausible options for pesticide labels.

6.5.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications

Methoxyfenozide is used on a variety of agricultural crops (e.g., cotton, tree nuts, etc) and can be 

applied via groundboom, airblast and aerial equipment. The spray drift risk estimates are based 

on an estimated deposited residue concentration as a result of the screening level agricultural 

application scenarios. The potential risk estimates from these residues can be calculated using 

drift modeling onto 50 feet wide lawns coupled with methods employed for residential risk 

assessments for turf products. The recommended drift scenario screening level options are listed 

below: 

• Groundboom applications are based on the AgDrift option for high boom height 

and using very fine to fine spray type using the 90th percentile results. 

 

5 http://www.agdrift.com/

6 Note that for many cases the scenarios outlined in the screening approach represent actual use practice so risk 

assessors should be aware and characterize these appropriately.
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• Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fine to 

medium spray type and a series of other parameters which will be described in more 

detail below (e.g., wind vector assumed to be 10 mph in a downwind direction for 

entire application/drift event). 

• Airblast applications are based on the AgDrift option for Sparse (Young/Dormant) 

tree canopies.

The spray drift assessment is based on incidental oral exposures only. The highest exposure 

resulted from drift following methoxyfenozide applications using aerial equipment for children 1 

to <2 years old (margins of exposure (MOEs) ≥ 11,000, with a LOC =100). There are no risks of 

concern at the field’s edge (i.e., assuming a residential lawn is directly adjacent to a field where 

agricultural crops are grown and treated with aerial, groundboom or airblast equipment). See 

Table 6.5.1 for detailed results.

1 HED’s default assumption that 10% of the application is available for transfer on day 0 following the application and the residues dissipate at a 

rate of 10% each following day.

6.6 Residential Bystander Post-Application Inhalation Exposure

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, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

methoxyfenozide.

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 

Table 6.5.1. Screening Risk Estimates for Children (1<2 years old) (MOEs) Related to Indirect Exposure (Incidental 

Oral) to Spray Drift from Methoxyfenozide.

Crop/Rate 

Group Spray Type/ Nozzle Configuration Appl. Rate (lb ai/A) TTR1

(ug/cm2) At Edge of the Field

Tree Nuts

Aerial Fine to Medium

0.4 0.042237

11,000

Groundboom High Boom Very fine to Fine 15,000

Airblast Sparse 19,000
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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.

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 0.030975 0.00022 0.031195 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 
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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, Z. Figueroa, D426658, 09/09/2015. 

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. 

No chemical-specific handler exposure data were submitted in support of this assessment; 

therefore, HED relied on surrogate data and default assumptions in accordance with standard 

policies. In the absence of a dermal toxicity, dermal handler and post-application exposure 

assessments were not conducted. All occupational handler scenarios for the registered uses 

resulted in inhalation MOEs greater than 100 at baseline (i.e., no respirator) and with engineering 

controls for aerial applications (i.e., enclosed cockpits) and, therefore, are not of concern. The 

lowest MOE of 450 is associated with mixing/loading/applying sprays using a mechanicallypressurized handgun in ornamental plants. All other MOEs were significantly higher, ranging 

from 9,600 to 570,000. No additional PPE recommendations are needed on the registered labels. 

Based on the current labeling, types of equipment and techniques that can potentially be used, 

occupational handler exposure is expected from the proposed use on chives and all the registered 

uses. This assessment covers all existing uses and the proposed use on chives. Since there is no 

difference between the occupational scenarios, the agronomics/practices, application rates, 

formulations and methods of application, the exposure resulting from methoxyfenozide use on 

the additional crops in the expanded crop groups are covered by this risk assessment. A 

summary of the occupational handler risk estimates is provided in Table 9.1.

Table 9.1. Occupational Short- and Intermediate-term Handler Exposure and Risk Estimates for Methoxyfenozide.

Exposure Scenario

Mitigation 

Levela

Inhalation Unit 

Exposureb

(ug/lb ai)

Applicati

on Ratec

Area Treated

or Amount 

Handledd

Inhalation 

Dosee

(mg/kg/day)

Inhalation

MOEf

Mixer/Loader

Liquids for Airblast 

Application Baseline 0.219

0.4 lb 

ai/A

40 A/day 0.0000438 380,000

Liquids for Aerial 

Application Baseline 0.219 1,200 A/day 0.00131 13,000

Liquids for Groundboom 

Application Baseline 0.219 200 A/day 0.000219 77,000

Liquids for Chemigation 

Application Baseline 0.219 350 A/day 0.000384 44,000
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Table 9.1. Occupational Short- and Intermediate-term Handler Exposure and Risk Estimates for Methoxyfenozide.

Exposure Scenario

Mitigation 

Levela

Inhalation Unit 

Exposureb

(ug/lb ai)

Applicati

on Ratec

Area Treated

or Amount 

Handledd

Inhalation 

Dosee

(mg/kg/day)

Inhalation

MOEf

Water Soluble Packets

(WSP) for Airblast 

Application

Engineering 

Controls* 0.24 40 A/day 0.000048 350,000

Water Soluble Packets

(WSP) Aerial Application

Engineering 

Controls* 0.24 1,200 A/day 0.00144 12,000

Water Soluble Packets 

(WSP) for Groundboom 

Application

Engineering 

Controls* 0.24 200 A/day 0.00024 70,000

Applicator

Sprays for Aerial 

Application

Engineering 

Controls 

(Enclosed 

Cockpit)

0.0049

0.4 lb 

ai/A

1,200 A/day 0.0000294 570,000

Sprays for Groundboom 

Application Baseline 0.34 200 A/day 0.00034 49,000

Sprays for Airblast 

Application Baseline 4.71 40 A/day 0.000943 18,000

Flagger

Flagging Sprays for Aerial 

Application Baseline 0.35 0.4 350 A/day 0.000613 27,000

Mixer/Loader/Applicator

Liquids for Mechanicallypressurized Handgun 

Applications

Baseline 120

0.025 lb 

ai/gal

1,000 gal/day

0.0375 450

PF5 

Respirator 24 0.0075 2,200

Liquids for Backpack 

Sprayer Baseline 140 40 gal/day 0.00175 9,600

Liquids for Manuallypressurized Handwand

Applications

Baseline 30 40 gal/day 0.000375 45,000

*Water Soluble Packets are considered engineering controls.

a. Mitigation Level: “baseline” (i.e., single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks); “engineering controls”

for aerial applications (i.e., enclosed cockpit). 

b. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (February, 2015).

c. Based on maximum single application rates on registered labels (Table 4.1).

d. Based on the Science Advisory Council for Exposure Policy 9.1: Standard Values for Daily Acres Treated in Agriculture.

e. Inhalation Dose (mg/kg/day) = [Rate (lb ai/A) x UE (ug /lb ai) x CF (0.001) x Acres Treated or Amount Handled (A or gal/day)]/BW (80 kg).

f. MOE = Inhalation NOAEL (16.8 mg/kg/day)/ Short-term Inhalation Dose (mg/kg/day). LOC=100.
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9.1 Post-Application Risk

9.1.1 Post-Application Dermal Exposure

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

exposure and risk assessment was not conducted. 

9.1.2. Post-Application Inhalation Exposure

There are multiple potential sources of post-application 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, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for methoxyfenozide.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

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.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and 

mechanical harvesting is another potential source of post-application inhalation exposure. 

However, the airblast applicator scenario is believed to represent a reasonable worst case 

surrogate estimate of post-application inhalation exposure during these dusty mechanical 

harvesting activities. The non-cancer inhalation risk estimate for commercial airblast application 

is not of concern (i.e., MOE > 100).

Restricted Entry Interval

Methoxyfenozide has been previously classified as a reduced risk chemical. It is classified as 

Toxicity Category III via the dermal route. Methoxyfenozide is not irritating to the skin and it is 

not a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute 

III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12-hour REI. 
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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].7 

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.

(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.

The 4-hour REI listed on the registered labels is consistent with these criteria and is appropriate.

10.0 Public Health and Pesticide Epidemiology Data 

Both the OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event 

Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for 

pesticide incident data on the active ingredient methoxyfenozide (PC Code: 121027) (D408715, 

E. Evans and S. Recore, January 31, 2013). The purpose of the database search is to identify 

potential patterns in the frequency and severity of the health effects attributed to 

methoxyfenozide exposure. 

OPP’s IDS includes reports of alleged human health incidents from various sources, including 

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports 

from registrants, other federal and state health and environmental agencies, and individual 

consumers. Since 1992, OPP has compiled these reports in IDS. The IDS contains reports from 

across the U.S. and most incidents have all relevant product information recorded. Reports 

submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in 

the report. 

IDS records incidents in one of two modules: Main IDS and Aggregate IDS. Main IDS contains 

incidents resulting in higher severity outcomes and provides more case-specific detail. This 

system stores incident data for death, major and moderate incidents, and it includes information 

about the location, date and nature of the incident. Main IDS incidents involving only one 

pesticide are considered to provide more certain information about the potential effects of 

exposure from the pesticide. Aggregate IDS contains incidents resulting in less severe human 

incidents (minor, unknown, or no effects outcomes). These are reported by registrants only as 

counts in what are aggregate summaries. 

 

7 Available: http://www.epa.gov/PR_Notices/pr95-3.html
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For the Main IDS, from January 1, 2007 to December 11, 2012, there were no incidents reported 

for methoxyfenozide only in the database. There were three incidents reported involving more 

than one chemical. Overall, there are few incidents involving methoxyfenozide reported to IDS. 

In Aggregate IDS, from January 1, 2007 to December 11, 2012, there were two reported 

incidents involving methoxyfenozide.

The NIOSH SENSOR database covers 11 states from 1998-2009, although reporting varies from 

state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

including: reports from local Poison Control Centers, state Department of Labor workers’ 

compensation claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. Although both occupational 

and non-occupational incidents are included in the database, SENSOR focuses on occupational 

pesticide incidents. The SENSOR data system is accessible to participating states and EPA, and 

includes more detailed follow-up regarding the specifics of identified incidents, including 

physician’s reports when available.

A query of SENSOR-Pesticides 1998-2009 identifies 12 cases involving methoxyfenozide 

stemming from 10 events. One case was moderate in severity and the remaining 11 cases were 

low in severity. Only two of these 12 cases involved a single active ingredient (methoxyfenozide 

only) and ten involved multiple active ingredients. The two cases with the single active 

ingredient resulted from one non-occupational drift event that occurred in Texas in 2008. Two 

cases were exposed to drift in their backyard after the pecan trees next door were sprayed with 

Intrepid 2F using a mist blower. Both cases experienced (low severity) dermal and ocular 

symptoms. Ten of the 12 cases include product-specific information and all 10 of these cases 

involved Intrepid 2F. 

Based on the low frequency and severity of incident cases reported for methoxyfenozide in both 

IDS and SENSOR-Pesticides, there does not appear to be a concern at this time that would

warrant further investigation. The Agency will continue to monitor the incident information and 

if a concern is triggered, additional analysis will be included in the risk assessment.

11.0 References

D425285. Methoxyfenozide. Petition to Establish Permanent Tolerances, and Associated 

Section 3 Registration, for Residues Resulting from Use of the Insecticide on Chives; and to 

Convert Stone Fruit Group 12 (Except Fresh Prune Plums) to Stone Fruit Group 12-12 (Except 

Fresh Prune Plums), and Tree Nut Group 14 to Tree Nut Group 14-12. Summary of Analytical 

Chemistry and Residue Data. W. Drew, 31 March 2015.

D429009. Methoxyfenozide. Addendum to D425285 - Petition to Establish Permanent 

Tolerances, and Associated Section 3 Registration, for Residues Resulting from Use of the 

Insecticide on Chives; and to Convert Stone Fruit Group 12 (Except Fresh Prune Plums) to Stone 

Fruit Group 12-12 (Except Fresh Prune Plums), and Tree Nut Group 14 to Tree Nut Group 14-

12. Summary of Analytical Chemistry and Residue Data. W. Drew, 09/08/2015.
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D422209. Drinking Water Assessment for the IR-4 New Use Petition for the Use of 

Methoxyfenozide on Chives, Herb Subgroup 19A, Green Onion Subgroup 3-07B and Crop 

Group Conversions for Stone Fruit Group 12-12 (except plum) and Tree Nut Group 14-12.” K. 

Milians, 12/09/2014.

D416709. Drinking Water Assessment for the IR-4 New Use Petition for the Use of 

Methoxyfenozide on Pineapple. I. Negrón-Encarnación, 12/19/2013. 

D406608. Methoxyfenozide. Human Health Assessment Scoping Document in Support of 

Registration Review. L.Hansen, 05/10/2013. 

D426657. Methoxyfenozide. Chronic Aggregate Dietary (Food and Drinking Water) Exposure 

and Risk Assessment as Part of the Methoxyfenozide Registration Review and for the Section 3 

Registration on Chives; Crop Group Conversions for Stone Fruit and Tree Nuts. E. Holman, 

09/08/2015.

D426658. Methoxyfenozide. Occupational and Residential Exposure/Risk Assessment for 

Registration Review and to Support the Registration of Proposed Use on Chives and Crop Group 

Expansions. Z. Figueroa, 09/09/2015.

D389739. Methoxyfenozide. Human Health Risk Assessment to Support Proposed Uses on 

Root Vegetables and Citrus.M. Collantes, 02/27/12.

D258034. PP#8F5004 & PP#8F5006: Methoxyfenozide. Conclusions of the 7/13/99 Meeting 

of the Metabolism Assessment Review Committee. W. Wassell, 7/13/99.

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.

Methoxyfenozide: Summary of Hazard and Science Policy Council (HASPOC) Meeting of 

April 30, 2015: Reevaluation of the need for a rat 28-day inhalation study. J. Leshin, June 26, 

2015. TXR # 0055054.
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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 A.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.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 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)
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700b 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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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.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) – All Populations including Infants and Children and 

Females age 13-49

An acute reference dose for methoxyfenozide was not selected. An appropriate toxicity dose and 

endpoint were not identified that could be attributed to a single exposure. Decreased hindlimb 

grip strength in male rats in the acute neurotoxicity study was only observed at the limit dose of 

2000 mg/kg on the day of dosing.
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A.3.2 Chronic Reference Dose (cRfD)

Study Selected: Chronic Feeding-Rat and Dog (co-critical studies)

MRID Nos.: 44617731 (rat) and 44617728 (dog)

Executive Summaries: See Appendix A.4 of D407285, Guideline [§ 870.3150 (dog study) and 

870.3500 (rat study)] 

Dose and Endpoint for Risk Assessment: NOAEL = 10.2 mg/kg/day (rat study) based on 

hematological changes (decreased RBC counts, hemoglobin concentrations, and/or hematocrit in 

males and females), liver effects (increased liver weights in males; periportal hepatocellular 

hypertrophy in males and females), histopathological changes in the thyroid (increased follicular 

cell hypertrophy, altered colloid in males) and possible adrenal toxicity (increased adrenal weights 

in males and females) seen at the LOAEL = 411 mg/kg/day. Supported by the co-critical chronic 

dog NOAEL = 9.8 mg/kg/day, based on mild hematological changes (decreased RBC counts, 

hemoglobin concentrations and/or hematocrit in males and females; slight methemoglobinemia in 

males and females; increased platelets in males) and clinical chemistry changes (increased total 

serum bilirubin in males and females; slightly increased severity of bilirubinemia in males) seen 

at the LOAEL = 106 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: These studies were selected because 

they were of the appropriate duration (chronic) and route of exposure (dietary) and provided the 

most sensitive doses and endpoints. They were selected as co-critical because of their similar 

NOAELs, both of which provide a cRfD of 0.10 mg/kg/day. The selected dose is protective of 

potential hematological, hepatic and thyroid effects identified in two-week dietary studies in the 

rat and dog, which identified slightly higher NOAELs (see A.3.5, below), as well as potential 

developmental effects. A combined UF of 100x was utilized (10x each to account for inter- and 

intra-species variability). 

A.3.3 Incidental Oral Exposure (Short-Term)

An incidental oral exposure dose and endpoint was selected for potential exposure resulting from 

spray drift. Methoxyfenozide may be used on ornamental plants in a residential setting. 

However, postapplication incidental oral exposure from direct contact with treated ornamental 

plants is not expected since the extent to which young children engage in prolonged play or other 

activities involving such areas is low. Therefore only postapplication incidental oral exposure 

due to spray drift was assessed. 

Study Selected: Two-week range-finding study for the subchronic dietary study in the dog

MRID No.: 44617722

Executive Summary: See Appendix A.4 of D407285, Guideline [§ 870.3150] 

Dose and Endpoint for Risk Assessment: NOAEL = 16.8 mg/kg/day based on hematological 

changes seen at LOAEL = 90.8 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: The dog 2-week dietary range-finding 

study was selected because it is of an appropriate duration and it identified the most sensitive dose 

and endpoint for this exposure scenario. Findings included hematological effects (including 

decreased RBC counts, decreased hemoglobin concentrations, Heinz bodies and changes in RBC 

morphology, increased reticulocyte counts and methemoglobinemia). The range-finding study 

was selected in lieu of the 90-day subchronic dog study because no effects were reported at doses 
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up to about 200 mg/kg/day. However, in the chronic dog study, mild hematological changes were 

reported at 14 weeks at the LOAEL of 106 mg/kg/day, with a NOAEL of 9.8 mg/kg/day. The 

reason for the early effects is unclear, but it may reflect adaptation of the animals to the test 

material. A similar circumstance was observed with the rat two-week and 90-day dietary studies: 

thyroid and adrenal effects were observed at lower dose levels in the two-week study (1000 ppm, 

or estimated 69 mg/kg/day with a NOAEL of 250 ppm or 17 mg/kg/day) whereas the subchronic 

NOAEL was 1000 ppm with a LOAEL of 5000 ppm or 353 mg/kg/day) based on liver weight 

increases and hypertrophy. Decreased body weight was observed in the subchronic mouse dietary 

study, but no effects were seen in the 18-month carcinogenicity study.

Because only two animals/sex/dose were in each dose group, the NOAEL and LOAEL for this risk 

assessment were selected from the highest NOAEL and lowest LOAEL from individual animals’ 

average daily compound intake. The selected dose and endpoint are considered to be conservative 

endpoints that provide protection from potential hematological effects, which may be transient at 

the selected study LOAEL, based on the lack of effects in the subchronic dog study. The study is 

protective of potential developmental effects, because no offspring toxicity was observed in the 

reproductive toxicity study. A combined UF of 100x was utilized (10x each to account for interand intra-species variability).

A.3.4 Dermal Exposure (Short- and Intermediate-Term)

A dose and endpoint for dermal exposure were not selected, based on the lack of toxicity in the 

rat dermal exposure study and a dermal absorption study demonstrating low (about 2%) 

absorption of methoxyfenozide in the 80WP formulation. An oral study was not selected

because the appropriate studies either showed no toxicity at any dose tested, or the parameters 

affected in oral studies (e.g., hematologic changes) were examined but showed no treatmentrelated changes in the dermal study.

A.3.5 Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected: Two-week range-finding study for the subchronic dietary study in the dog

MRID No.: 44617722

Executive Summary: See Appendix A.4 of D407285, Guideline [§ 870.3150] 

Dose and Endpoint for Risk Assessment: NOAEL = 16.8 mg/kg/day based on hematological 

changes seen at LOAEL = 90.8 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: No short-term or subchronic 

inhalation toxicity studies were available; an oral study was therefore selected for route-to-route 

extrapolation. The dog 2-week dietary range-finding study was selected because it is of an 

appropriate duration and it identified the most sensitive dose and endpoint for this exposure 

scenario (see detailed description and rationale under Incidental Oral Exposure, above). The study 

is protective of potential developmental effects, because no developmental or offspring toxicity 

was observed in any of the available developmental and reproductive toxicity studies. Although a 

repeated-dose inhalation toxicity study is not available, the oral study is considered adequately 

protective, based on the conservative endpoint selected, low vapor pressure of methoxyfenozide, 

low application rate for current use patterns, and low acute inhalation toxicity; a 10x UFDB is 

therefore not required. Absorption following inhalation exposure is considered to be equivalent 
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to oral absorption (100%). A combined UF of 100x was utilized (10x each to account for interand intra-species variability).
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Appendix B. Physical/Chemical Properties.

TABLE B.1. 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.
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Appendix D. Summary of Special Local Need (SLN) Registrations for Methoxyfenozide

Based on the scoping document, there are a number of Special Local Need (SLN), also known as 

FIFRA Sec. (24c) registrations, for methoxyfenozide insecticide (see Table D.1). The SLN uses, 

application rates and equipment are covered by the assessment presented above. Occupational 

exposures and risks were not of concern (see Table 9.1). 

Table D.1. Special Local Need (SLN) Registrations for Methoxyfenozide Insecticide.

SLN No. and

Parent Reg. No.

% AI of 

Parent Use Site Single Appl. Rateand Method Comments

MS060014, 62719-442

22.6 F Sweet potatoes 0.16 lb ai/A; ground/aerial NC060003, 62719-442

CA060026, 62719-442

LA060011, 62719-442

CA060013, 62719-442 22.6 F Alfalfa for seed 

productions 0.25 lb ai/A; ground; aerial

Maximum of 

1lb 

ai/A/season; 

maximum of 

60,000 Acres

CA070015, 62719-442 22.6F Citrus (non-bearing) 0.18 lb ai/A; ground/aerial

Maximum of 

4 applications 

per year to 

avoid 

resistance 

development

FL100001, 62719-442 22.6F Citrus crop group 10 0.25 lb ai/A; ground

Maximum of 

1 lb 

ai/A/season

WY120005, 62719-442 22.6F Beans, dried type; 

sugar beet 0.25 lb ai/A; aerial

Low volume 

spray 

concentrate