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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: August 6, 2013

SUBJECT: Methoxyfenozide. Human Health Risk Assessment to Support Proposed New 

Uses on Herbs, Caneberries, Dates and Sorghum; to Establish Rotational Crop 

Tolerances in the Rapeseed and Sunflower Oilseed Subgroups; as well as to 

extend and update Crop Group Tolerances on Multiple Commodities. 

PC Code: 121027 DP Barcode: D407285

Decision No.: 472142 Registration No.: 62719-442; 13-CA-09

Petition No.: 2E8118 Regulatory Action: Section 3 Registration; Section 18 

Registration (Dates only)

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: Elizabeth Holman, Physical Scientist/Risk Assessor

Margarita Collantes, Biologist

William Drew, Chemist

Linnea J. Hansen, Ph.D., Biologist

Risk Assessment Branch II (RABII)

Health Effects Division (7509P)

THROUGH: Christina Swartz, Branch Chief

Risk Assessment Branch II (RABII)

Health Effects Division (7509P)

TO: Laura Nollen/Barbara Madden, RM Team 05

Risk Integration Minor Use, and Emergency Response Branch (RIMUERB)

Registration Division (7505P)

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

assessment for the active ingredient methoxyfenozide to estimate the risk to human health that 

will result from proposed new uses on herbs (subgroup 19A) except chives, caneberry (subgroup 

13-07A), date, and sorghum. In addition, this assessment also updates existing tolerances for 

multiple commodities; specifically, tolerances in the updated crop groups 8-10 and 11-10, and in 

the updated subgroups 13-07F and 13-07G were requested. Tolerances in sugar apples, 

cherimoyas, atemoyas, custard apples, ilamas, soursops, and biribas were also requested, based 
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on translation of avocado residues. Additionally, indirect or inadvertent tolerances in the 

rapeseed subgroup (20A) and the sunflower subgroup (20B) were requested. While the proposed 

Section 3 use on dates was undergoing review in the Agency, the state of California submitted a 

Section 18 Specific Emergency Exemption request for use of methoxyfenozide on dates to 

control carob moth. The proposed use pattern in CA is the same as the use pattern proposed for 

Section 3 registration, and therefore this risk assessment addressed the proposed S18 use.

The attached human health risk assessment addresses exposure and risk associated with the 

proposed uses, revisions to existing tolerances, as well as the existing use on ornamentals. The 

exposures assessed include dietary (food and water), inhalation for occupational workers and 

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

on ornamentals. There were no risks of concern identified for any route or duration of exposure.
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Table of Contents

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

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

2.1 Data Deficiencies/Conditions of Registration .............................................................. 7

2.2 Tolerance Considerations.............................................................................................. 7

2.2.1 Enforcement Analytical Method............................................................................... 7

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

2.2.3 Recommended Tolerances........................................................................................ 8

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

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

3.0 Introduction...................................................................................................................... 11

3.1 Chemical Identity ......................................................................................................... 12

3.2 Physical/Chemical Characteristics ............................................................................. 12

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

3.4 Anticipated Exposure Pathways................................................................................. 14

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

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 15

4.1 Toxicology Studies Available for Analysis................................................................. 15

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) ............................... 18

4.4.2 Evidence of Neurotoxicity ...................................................................................... 18

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

4.5 Toxicity Endpoint and Point of Departure Selections.............................................. 19

4.5.1 Dose-Response Assessment.................................................................................... 19

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

4.5.3 Cancer Classification and Risk Assessment Recommendation.............................. 21

5.0 Dietary Exposure and Risk Assessment......................................................................... 23

5.1 Metabolite/Degradate Residue Profile ....................................................................... 23

5.1.1 Summary of Plant and Animal Metabolism Studies............................................... 23

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

5.1.3 Comparison of Metabolic Pathways....................................................................... 24

5.1.4 Residues of Concern Summary and Rationale........................................................ 24

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

5.3 Water Residue Profile.................................................................................................. 27

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 Dermal Post-application Exposure............................................................................. 31

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

7.0 Aggregate Exposure/Risk Characterization.................................................................. 32

7.1 Acute Aggregate Risk................................................................................................... 32

7.2 Short-Term Aggregate Risk........................................................................................ 32

7.3 Chronic Aggregate Risk .............................................................................................. 33

8.0 Cumulative Exposure/Risk Characterization ............................................................... 33

9.0 Occupational Exposure/Risk Characterization ............................................................ 33

9.1 Occupational Handlers................................................................................................ 34

9.2 Post-application Risk ................................................................................................... 36

9.2.1 Post-application Dermal Exposure ......................................................................... 36

9.2.2. Post-application Inhalation Exposure ..................................................................... 36

10.0 References......................................................................................................................... 37

Appendix A. Toxicology Profile and Executive Summaries .................................................. 38

Appendix B. Physical/Chemical Properties........................................................................... 60

Appendix C. Review of Human Research................................................................................ 60
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1.0 Executive Summary

The Interregional Research Project Number 4 (IR-4) has submitted a petition requesting the 

establishment of permanent tolerances for residues of methoxyfenozide in or on dates;

caneberries (subgroup 13-07A); grain sorghum forage; grain sorghum stover; grain sorghum 

grain; sweet sorghum forage; sweet sorghum stover; sweet sorghum grain; sweet sorghum stalk; 

aspirated grain fractions (AGF), based on sorghum data; dried shelled peas and beans, except 

soybean (subgroup 6C), except blackeyed pea and southern pea; fresh herbs (subgroup 19A), 

except chives; and dried herbs (subgroup 19A), except chives. Tolerances in the updated crop 

groups 8-10 and 11-10, and in the updated subgroups 13-07F and 13-07G were requested. 

Tolerances in sugar apples, cherimoyas, atemoyas, custard apples, ilamas, soursops, and biribas 

were also requested, based on translation of avocado residues. 

Additionally, indirect or inadvertent tolerances in the rapeseed subgroup (20A) and the 

sunflower subgroup (20B) were requested. The proposed new uses in dates, caneberries, 

sorghum and herbs are supported by magnitude of residue data generated by IR-4. Other 

changes are supported by data previously reviewed by the Agency in 2009. The requested 

changes for rapeseed and sunflower group are based on 2012 recommendations by EPA. The 

petition proposes the deletion of the (expired) temporary tolerances in sorghum commodities, 

and their replacement with permanent tolerances in those commodities. The tolerance in AGF 

would be increased from 2.0 to 120 ppm. The tolerance of 0.5 ppm in dried shelled peas and 

beans, except soybean (subgroup 6C) was proposed at the Agency's request to better harmonize 

with existing Codex MRLs, with no changes in the existing use pattern for these commodities. 

The existing tolerances in dried beans and dried peas would be deleted concurrently with the 

establishment of tolerances in subgroup 6C. The tolerance in coriander leaves would be deleted 

concurrently with the establishment of the tolerance in subgroup 19A. Finally, California is 

requesting a Section 18 for use of Intrepid 2F on dates/palm only. The proposed use pattern for 

this Section 18 use is identical to that for the Section 3 IR-4 petition, with the same submitted 

residue data being used in support of both petitions. 

In developing this human health risk assessment, HED has examined the available hazard and 

exposure information regarding methoxyfenozide as it relates to its registered and requested 

uses. The existing use on ornamentals was previously reassessed in accordance with current 

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

gardens. The toxicology database is considered complete for the purpose of characterizing the 

hazard associated with methoxyfenozide and for conducting a human health risk assessment. 

The main target organs in the rat and dog were the liver, thyroid and red blood cells (RBCs). 

The most consistent findings across species and studies were decreased red blood cell parameters 

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

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

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

following chronic exposure, but no accompanying histopathology was observed.

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

been categorized as “not likely” to be carcinogenic to humans. There is no evidence of 
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qualitative or quantitative susceptibility of the developing fetus or offspring, based on the 

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

the database, the lack of susceptibility, the lack of neurotoxicity and the conservative nature of 

the exposure assessment, HED has reduced the 10X Food Quality Protection Act (FQPA) Safety 

Factor to 1X.

Based on the submitted toxicology data and the current and proposed use patterns, HED selected 

endpoints for chronic dietary risk assessment, as well as for inhalation risk assessment for 

residential and occupational handlers. Acute dietary risk was not evaluated because there were 

no toxic effects associated with a single dose, and therefore an appropriate endpoint was not 

identified. There was no toxicity observed in the dermal toxicity study, and no concern for 

potential developmental effects; therefore, a dermal endpoint was not selected, and no dermal 

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

Furthermore, HED did not select an endpoint for incidental oral risk assessment, since the 

potential for post-application oral exposure to children resulting from the existing use of 

methoxyfenozide on ornamentals is extremely low. Inhalation risks were assessed using the 

endpoint and dose from an oral study, with the assumption that inhalation toxicity would be 

equivalent to oral toxicity for the purpose of route-to-route extrapolation. The endpoint selected 

for chronic dietary risk assessment was based on liver and thyroid effects observed in the 

chronic/carcinogenicity study in the rat; the blood effects seen in the dog study were considered 

co-critical. For inhalation risk assessment, the endpoint selected was based on blood effects seen 

in a range-finding study in the dog.

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

with an extensive database of food consumption patterns for the U.S. population and population 

subgroups, this modeling used conservative upper-bound assumptions regarding residues of 

methoxyfenozide and its breakdown products in food and drinking water. Specifically, the 

dietary assessment included tolerance-level residues from the existing and proposed uses, the 

assumption of 100% crop treated (CT) for all crops, and drinking water residues 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 31% cPAD.

Residential exposures are those that may occur as a result of activities in and around the home, 

schools and recreational areas. Prior to 2012, a residential exposure assessment was not 

performed in conjunction with registration of the use of methoxyfenozide on ornamentals. Since 

then an inhalation endpoint was selected and the OPP HED Residential SOPs were finalized and 

approved for risk assessment purposes. Therefore, in the most recent 2012 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 margins of exposure (MOEs) ranging from 76,000 to more than 3 

million, which are not of concern.
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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 530; this risk estimate is not of concern, since it is significantly higher than 

the LOC of 100.

An occupational exposure assessment was also performed for handler and post-application 

activities, based on standard assumptions with respect to body weight and area treated, in 

accordance with HED’s standard procedures. There were no chemical specific data available to 

assess handlers’ inhalation exposure, so HED relied on surrogate data generated by various task 

forces. The resulting inhalation risk estimates were MOEs ranging from 20,000 to more than 3

million and were not of concern. A quantitative post-application exposure assessment was not 

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

protective of post-application exposure via the inhalation route.

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

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

applicable ethical requirements (refer to Appendix C).

2.0 HED Recommendations

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

dates, sorghum, caneberries (subgroup 13-07A), and herbs (subgroup 19A) except chives, as well 

as updates to multiple existing tolerances supported by the existing database (with no changes in 

the use pattern), and establishment of the associated permanent tolerances as summarized in 

Table 2.2.3.

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). 
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2.2.2 International Harmonization

Codex has not established MRLs in any of the proposed new uses. As such, there are no 

harmonization issues associated with Codex for the proposed new uses in the current action. 

Canada’s PMRA has established MRLs in fresh Chinese chive leaves and fresh chive leaves at 5 

mg/kg. There are no Canadian MRLs in dates, caneberries or sorghum commodities. However, 

for basil and caneberries, this action is being performed as a joint review with Canada’s PMRA,

and the recommended tolerances have been harmonized with the recommended PMRA 

tolerances as appropriate. HED’s recommended tolerances for the new uses were determined 

using the Organization for Economic Cooperation and Development (OECD) tolerance 

calculation procedures.

Codex has established MRLs in grapes at 1 mg/kg, in strawberries and pome fruits at 2 mg/kg, in 

avocadoes at 0.7 mg/kg, and in papayas at 1 mg/kg. 

The recommended tolerance of 2.0 ppm in the updated pome fruits group (11-10), increased 

from the current tolerance of 1.5 ppm in group 11, would be harmonized with the Codex MRL. 

It is noted that this recommended revised tolerance in pome fruit will not be harmonized with the 

existing PMRA tolerance of 1.5 ppm. HED has made PMRA aware of this issue, but has 

determined that Codex harmonization is beneficial at this time. 

The recommended tolerance of 1.0 ppm in small vine-climbing fruit, except fuzzy kiwifruit 

(subgroup 13-07F), translated from grape data, would be harmonized with the Codex MRL in 

grapes. The recommended tolerance of 2.0 ppm in low-growing berries (subgroup 13-07G), 

translated from strawberry data, and increased from the current tolerance of 1.5 ppm in 

strawberries, would be harmonized with the Codex MRL in strawberries. 

The recommended tolerance of 0.50 ppm in dried shelled peas and beans, except soybeans 

(subgroup 6C) was proposed at the Agency's request to better harmonize with the existing Codex 

MRL of 0.5 mg/kg in dried beans. This tolerance would replace the current tolerances of 0.24 

ppm in dried beans, and 2.5 ppm in dried peas, which would both be removed. 

The recommended tolerance of 0.60 ppm in various tropical tree fruits is translated from avocado 

data, where there is an existing USEPA tolerance of 0.6 ppm. There is also an existing USEPA 

tolerance of 0.6 ppm on papaya. With the existing avocado and papaya tolerances not being 

harmonized, these new tropical tree fruit tolerances would also not be harmonized with the 

Codex MRLs as well. During registration review, to the extent possible USEPA will consider 

opportunities for harmonizing tropical tree fruit tolerances with Codex. 

2.2.3 Recommended Tolerances
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TABLE 2.2.3. Tolerance Summary for Methoxyfenozide. 

Commodity Tolerance (ppm) Correct Commodity 

Existing Proposed Recommended Definition. Rationale

180.544[a][1]

Herb subgroup 19A, fresh, except 

chives

None 70 400 Herb subgroup 19A, 

except chive. Based 

on submitted dried 

basil field trial data. 

Herb subgroup 19A, dried, except 

chives

None 400

Date None 7.0 8.0 Based on submitted 

Caneberry subgroup 13-07A None 6.0 6.0 crop field trial data. 

Sorghum, grain, forage None 9.0 15

Sorghum, grain, stover None 15 20

Sorghum, grain, grain None 4.0 6.0

Sorghum, sweet, forage None 9.0 15

Sorghum, sweet, stover None 15 20

Sorghum, sweet, grain None 4.0 6.0

Sorghum, sweet, stalk None 9.0 15

Grain, aspirated grain fractions 2.0 80 120 Based on sorghum 

field trial and 

processing study data. 

Pea and bean, dried shelled, 

except soybean, subgroup 6C, 

except pea, blackeyed, seed and 

pea, southern, seed

None 0.5 0.50 To harmonize with 

Codex MRLs. 

Fruit, small, vine climbing, 

except fuzzy kiwifruit, subgroup 

13-07F

None 1.0 1.0 Translated from grape 

data. 

Berry, low growing, subgroup 13-

07G, except cranberry

None 1.5 2.0 Translated from 

strawberry data, and 

raised to harmonize 

with Codex MRL in 

strawberries. 

Fruit, pome, group 11-10 None 1.5 2.0 Update of group 11, 

and raised to 

harmonize with Codex 

MRL in apples. 

Vegetable, fruiting, group 8-10 None 2.0 2.0 Update of group 8. 

Sugar apple None 0.6 0.60 Translated from 

Cherimoya None 0.6 0.60 avocado data. 

Atemoya None 0.6 0.60

Custard apple None 0.6 0.60

llama None 0.6 0.60

Soursop None 0.6 0.60

Biriba None 0.6 0.60

Pea, blackeyed, seed 4.0 4.0 4.0 Keep as exceptions to

Pea, southern, seed 4.0 4.0 4.0 subgroup 6C. 

Coriander, leaves 30 Remove Remove Covered under 

subgroup 19A

tolerance. 

Grape 1.0 Remove Remove Covered under 

subgroup 13-07F

tolerance. 
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TABLE 2.2.3. Tolerance Summary for Methoxyfenozide. 

Commodity Tolerance (ppm) Correct Commodity 

Existing Proposed Recommended Definition. Rationale

Strawberry 1.5 Remove Remove Covered under 

subgroup 13-07G

tolerance. 

Okra 2.0 None Remove Covered under group 

8-10 tolerance. 

Pea, dry seed 2.5 Remove Remove Covered under

subgroup 6C 

tolerance. 

Bean, dry, seed 0.24 Remove Remove

180.544[b]

Sorghum, grain, forage 30 None Remove Expired time-limited 

Sorghum, grain, stover 60 None Remove tolerances. 

Sorghum, grain, grain 0.05 None Remove

180.544[d][2]

Herb and spice, group 19, except 

coriander, leaves

4.5 None Remove Replaced by primary 

tolerance in subgroup 

19A, except chive, 

and rotational 

tolerances in chive 

and subgroup 19B. 

Spice subgroup 19B None None 4.5 These replace the 

rotational crop 

tolerance in group 19, 

except coriander

leaves. 

Chive None None 4.5

Rapeseed subgroup 20A None 1.0 1.0 Based on existing 

rotational crop data,

and HED’s previous

recommendation. 

Sunflower subgroup 20B None 1.0 1.0

2.2.4 Revisions to Petitioned-For Tolerances

In fresh herbs, subgroup 19A (except chives), the petitioner proposed a tolerance of 70 ppm, 

based on the Organization of Economic Development and Cooperation’s (OECD’s) tolerance 

calculation procedure. However, the petitioner entered all 10 sample residues into the MRL

calculator. When the average residues from each of the 5 basil field trials were entered, as the 

OECD guidance stipulates, the resulting recommended tolerance would be 80 ppm. However, 

USEPA has determined that setting separate subgroup 19A tolerances for fresh and dried 

commodities is not feasible from a regulatory perspective. Therefore, HED recommends setting 

the entire subgroup 19A tolerance, except chives, for both fresh and dried commodities at the 

higher 400 ppm level. This 400 ppm level is derived using the submitted dried basil field trial 

data in the OECD calculation procedure. 

The primary crop tolerance in coriander leaves, along with the rotational crop tolerance in herbs 

and spices (group 19), except coriander leaves, would be removed concurrently with the 

establishment of the primary crop tolerance in subgroup 19A, except chives. Although not 

proposed in the petition, rotational crop tolerances would necessarily be established in chives and 
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in spices (subgroup 19B) upon establishment of the primary crop tolerance in subgroup 19A, 

except chives. 

 

In dates, the petitioner proposed a tolerance of 7.0 ppm, based on 4 date field trials and OECD’s

tolerance calculation procedure. However, HED determined that only 3 of the trials were truly 

independent. The 4 sample residues from the 2 trials deemed to be non-independent were 

averaged together as one input into the MRL calculator. In addition, the total application rate at 

one of the other trials was only half the proposed maximum seasonal use rate, a difference of 

>25%. Therefore, the residue values from this trial were doubled, per OECD’s preliminary

guidance on proportionality of sample residues to application rate [EPA Chemistry Science 

Advisory Council (ChemSAC), minutes, 3/28/2012]. When the average of these residues, along 

with the average residues from each of the other 2 field trials were entered into the MRL

calculator, the resulting recommended tolerance was 8.0 ppm. 

In sorghum commodities, the petitioner proposed tolerances of 9.0, 15 and 4.0 ppm in the forage, 

stover and grain, respectively, of both grain and sweet sorghum, and 9.0 ppm in sweet sorghum

stalks, based on OECD’s tolerance calculation procedure. A tolerance of 80 ppm in sorghum 

AGF was proposed, based on the sorghum processing study. However, with the use of the 

correction for proportionality, the resulting recommended tolerances were 15, 20 and 6.0 ppm in 

the forage, stover and grain, respectively, of both grain and sweet sorghum, and 15 ppm in sweet 

sorghum stalks. The increase in the proposed tolerance of 80 to 120 ppm for residues in AGF 

was also based on the adjustment for proportionality. Although not proposed by the registrant, 

HED recommends that existing time-limited sorghum tolerances (established under 180.544[b]), 

be removed for forage, stover, and grain, as these tolerances have now expired.

Instead of the proposed tolerances in the various tropical tree fruits (0.6 ppm), HED recommends 

establishing the tolerances at 0.60 ppm, in order to avoid the situation where a field sample 

containing residues significantly above the tolerance (0.64 ppm, for example) would be 

considered non-violative. For the same reason, HED recommends that the proposed tolerance of 

0.5 ppm in subgroup 6C (except blackeyed and southern peas) be revised to 0.50 ppm. 

As previously discussed, HED recommends the tolerance of 2.0 ppm in the updated pome fruits 

group (11-10), increased from the proposed tolerance of 1.5 ppm, in order to be harmonized with 

the Codex MRL. The recommended tolerance of 2.0 ppm in low-growing berries (subgroup 13-

07G), translated from strawberry data, was increased from the proposed tolerance of 1.5 ppm, in 

order to be harmonized with the Codex MRL in strawberries.

2.3 Label Recommendations From Residue Review

Methoxyfenozide is a candidate for a 4-hour restricted entry interval (REI) which appears on the 

proposed supplemental and master labels. However, the Registration Division should confirm 

that methoxyfenozide is a reduced risk chemical and that the correct REI is on the final 

registered label.

3.0 Introduction
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3.1 Chemical Identity

TABLE 3.1 Methoxyfenozide Nomenclature. 

Chemical structure

Common name Methoxyfenozide

Company experimental name RH-2485

Molecular formula C22H28N2O3

Molecular weight 368.47

IUPAC name N-tert-butyl-N′-(3-methoxy-o-toluoyl)-3,5-xylohydrazide

CAS name 3-methoxy-2-methylbenzoic acid 2-(3,5-dimethylbenzoyl)-2-(1,1-

dimethylethyl)hydrazide

CAS registry number 161050-58-4

End-use product (EP) 2 lb ai/gal F (Intrepid 2F, EPA Registration #62719-442)

3.2 Physical/Chemical Characteristics

The information regarding physical chemical characteristics of methoxyfenozide does not 

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

assessment considerations. A table of physical and chemical properties for methoxyfenozide is 

included in Appendix B.

Methoxyfenozide has a low dermal absorption factor. Dermal absorption is the process by which 

chemicals are transported from the outer surface of the skin into both the inner layers of the skin 

and into the body. The dermal absorption factor is a numerical estimate of the percentage of the 

topical external dose that traverses the skin layers to the systemic circulation (e.g. the percentage 

of the topical external dose that is bioavailable). An in vivo dermal absorption study on an 80% 

wettable powder (WP) formulation of methoxyfenozide was conducted in the rat. Cumulative 

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

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

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

methoxyfenozide has a large octanol-water partition coefficient (Kow) of 103.72 which further 

supports that methoxyfenozide is not easily absorbed by the skin and thus would result in lower 

dermal exposure.

Although methoxyfenozide is very persistent (t1/2 = 1 to 3 years in soil and water), it is not 

significantly volatile, and has a vapor pressure of 1.0 x 10-7 mm Hg at 25 ̊ C. Therefore, 

significant inhalation exposure to methoxyfenozide is not expected. 

3.3 Pesticide Use Pattern

CH3

O

N

H

N

O

CH3

CH3

H3C CH3

H3C O

CH3
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Methoxyfenozide is currently registered for use on ornamentals and a wide variety of 

agricultural crops.

Dow AgroSciences LLC is requesting new proposed uses of the insecticide methoxyfenozide be 

added to the Intrepid 2F (Reg. No. 62719-442) label. The proposed Section 3 registration 

includes use on herbs (subgroup 19A) except chives, dates, sorghum and caneberries (subgroup 

13-07A). In addition, California is requesting a Section 18 for use of Intrepid 2F on dates/palm 

only. Intrepid 2F is formulated as a flowable concentrate containing 22.6% active ingredient (ai) 

or 2 lb ai per gallon. Intrepid 2F may be applied by air, groundboom, airblast and hand held 

equipment. The master label specifies that the product is not to be applied by chemigation 

unless specified in crop-specific directions on the label or supplemental labeling. Therefore, 

since the supplemental labels did not specify use of chemigation for the proposed crops, it was 

not assessed as a potential method of application.

The Personal Protective Equipment (PPE) statement on the proposed label requires applicators 

and other handlers to wear long-sleeved shirt and long pants, socks, shoes, and chemical-resistant 

gloves. 

Table 3.3 provides a summary of the proposed uses. 

TABLE 3.3 Summary of Directions for Use of Methoxyfenozide. 

Application Type; 

Equipment

Use Rate

(lb ai/A)

Max. Uses 

Per Season

Max. Seasonal 

Use Rate

(lb ai/A)1

PHI1

(Days)

Use Directions, Application Timing, 

and Limitations

Herbs (Subgroup 19A), Except Chives

Foliar; Ground and 

Aerial

0.12 NS21.0 1 Minimum RTI3of 10 days. Ground 

application: Apply in a minimum of 10 

GPA4to young crop or small plants. 

Apply in a minimum of 20 GPA to 

densely foliated or difficult-to-cover 

crops to ensure thorough coverage. 

Aerial application: Apply in a 

minimum of 10 GPA. 

Dates

Ground (Airblast) 0.31 NS 1.0 7 Begin applications before eggs hatch. 

Minimum RTI of 10 days. Alternate or 

intersperse with other insecticides. 

Apply in a minimum of 100 GPA. 

Sorghum

Foliar; Ground and 

Aerial

0.16 NS 0.75 3, 215 Apply at first sign of egg hatch or 

when infestations reach threshold 

levels. Ground application: Apply in a 

minimum of 15 GPA. Aerial 

application: Apply in a minimum of 

10GPA. 
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TABLE 3.3 Summary of Directions for Use of Methoxyfenozide. 

Application Type; 

Equipment

Use Rate

(lb ai/A)

Max. Uses 

Per Season

Max. Seasonal 

Use Rate

(lb ai/A)1

PHI1

(Days)

Use Directions, Application Timing, 

and Limitations

Caneberries (Subgroup 13-07A)

Foliar; Ground and 

Aerial

0.25 3 0.75 3 Apply at initiation of egg-laying. 

Make second application at 100% petal 

fall. A third application may be 

required under high pest pressure. 

Minimum RTI of 7 days. Ground 

application: Apply in a minimum of 30 

GPA. Aerial: Apply in a minimum of 

10 GPA. 

1. PHI = Pre-Harvest Interval. 

2. NS = Not Specified. 

3. RTI = Re-Treatment Interval. 

4. GPA = Gallons Per Acre. 

5. Minimum PHI of 3 days for forage and sweet sorghum stalks, and 21 days for grain and stover. 

3.4 Anticipated Exposure Pathways

As a result of the registered and proposed uses of the insecticide methoxyfenozide, humans may

be exposed through food and drinking water, since the chemical may be applied directly to 

growing crops and may reach surface and ground water sources of drinking water. In an 

occupational setting, applicators may be exposed while handling the pesticide prior to 

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

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

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 activities associated with areas where residential 

ornamentals are grown or use these areas for prolonged periods of play is low. 

This risk assessment considers all of the relevant exposure pathways, combining them as 

appropriate, to estimate overall exposure and risk. 

3.5 Consideration of Environmental Justice

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

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

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

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

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

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

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

and activities in and around the home that involve pesticide use in a residential setting. 
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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 utilize exposure routes (oral and dermal) consistent with potential human exposure 

scenarios, have been submitted: primary acute toxicity, irritation and dermal sensitization; 

subchronic oral toxicity in the rat, mouse and dog; rat 28-day dermal toxicity; rat chronic oral 

toxicity/carcinogenicity; dog chronic oral toxicity; mouse oral carcinogenicity; rat and rabbit 

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

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

rat immunotoxicity. Although a 28-day inhalation toxicity study has not been submitted, HED 

has determined that this study is not needed (i.e., the study has been waived) for 

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

available hazard and exposure information, including the use of a conservative oral point of 

departure (POD) that results in MOEs ranging from 20,000 to 3,100,000 for risk via the 

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

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

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

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

dosing. Peak plasma concentrations 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 1000 mg/kg, 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 a potential for bioaccumulation: by 5 days’ post-treatment, the highest levels were 
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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 postdosing. 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, metabolites also identified in residues 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 on the A-ring and, to a lesser extent, the Bring. Levels of excreted parent compound in the feces were greater in animals receiving 1000 

mg/kg test material (30 to 39% of dose) when compared to the 10 mg/kg groups (14-26% of 

dose), consistent with saturation of absorption. In the bile, up to 24 metabolites were detected, 

with the primary metabolite (13-18% of dose) being derived by glucuronide conjugation at the 0-

demethylated alpha ring. 

4.2.1 Dermal Absorption

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

methoxyfenozide was conducted in the rat. Cumulative absorption of approximately 2% of the 

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

Methoxyfenozide is a diacylhydrazine insecticide active against lepidopterous insects (moths and 

butterflies) by competitively binding to receptors of the molting hormone in larvae. Many of the 

available short-term or subchronic toxicity studies on methoxyfenozide showed little or no 

toxicity. The main target organs were the liver, thyroid and red blood cells. In the rat 

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

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

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

cell parameters, Heinz body formation) are consistent with those of other hydrazine compounds.

Hematologic parameters in the rat and dog were affected by exposure to methoxyfenozide. Mild 

anemia (decreases in RBC count, hematocrit and hemoglobin) was observed in both species 

following chronic dietary exposure, along with methemoglobinemia and RBC structural 

abnormalities. Increased platelets were also observed. An increase in the cellularity of rib and 

sternum bone marrow, along with macrophage pigmentation in the liver and spleen, were 
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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 zone 

fasciculata, and increased thyroid follicular cell hypertrophy/hyperplasia were also observed; 

however, these findings were not seen with subchronic exposure. Thyroid hypertrophy and 

altered colloid and increased adrenal weights were observed in the rat chronic oral study, and the 

incidence and severity of chronic progressive glomerulonephropathy was increased. Thyroid 

weights were increased in the dog following chronic exposure, but there was no accompanying 

histopathology.

In the mouse, effects were limited to decreased body weights and weight gain in the subchronic 

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

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

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

neurotoxicity. In the acute study, decreased hindlimb grip strength on Day 0 was reported in 

males. This finding was only observed at the limit dose in males and was not observed in the 

subchronic neurotoxicity study and was therefore not considered evidence of neurotoxicity. No 

clinical signs of toxicity 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).
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4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The required 10X FQPA safety factor for methoxyfenozide was reduced to 1X, based on the 

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

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

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

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

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

potential exposure from food and drinking water, and the use pattern indicates a low potential for 

residential exposure.

4.4.1 Completeness of the Toxicology Database

The database is considered complete with respect to evaluation of potential 

susceptibility/sensitivity of infants and children. Acceptable developmental toxicity studies in 

two species (rat and rabbit) and a rat two-generation reproduction study have been submitted, as 

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

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

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

4.4.2 Evidence of Neurotoxicity

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

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

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

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

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 
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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 including exposure from the proposed use

on ornamentals also used high-end default assumptions; there is a very low potential for 

children’s exposure to residues resulting from treatment of ornamentals.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

A toxicity profile table, endpoint selection rationales and detailed summaries of the toxicity

studies considered in the selection of toxicity endpoints for exposure assessment are provided in 

Appendix A of this document.

For acute dietary exposure assessment, the rat acute oral neurotoxicity study was considered for 

selection of a dose and endpoint. This study was not selected because the only finding was 

decreased grip strength in males on Day 0 (day of dosing) at the limit dose of 2000 mg/kg; no 

toxicity was observed at 1000 mg/kg in males or in females up to 2000 mg/kg. The 

developmental oral toxicity studies in the rat and rabbit were also considered but not selected 

because no maternal or developmental toxicity was observed at doses up to the limit dose (1000 

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

toxicity study.

For selection of a chronic dietary exposure assessment dose and endpoint, the dietary rat chronic 

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

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

administering methoxyfenozide slightly above the limit dose of 1000 mg/kg/day. Increased liver 

weight at doses exceeding the limit dose was the only effect observed in parental animals in the 

rat reproductive toxicity study, and there were no offspring or reproductive effects. The rat 

chronic toxicity/carcinogenicity study with a NOAEL of 10.2 mg/kg/day was selected for 

determination of the cRfD. The chronic dog study was selected as the co-critical study because 

these were the most sensitive studies available and the similar NOAELs (10.2 and 9.8 mg/kg/day

for the rat and dog, respectively) yielded the same cRfD of 0.10 mg/kg/day. Hematological 

effects were observed in both studies at the LOAELs of 106 mg/kg/day in the dog and 411 

mg/kg/day in the rat. In the rat, periportal liver hypertrophy, thyroid hypertrophy and altered 

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

endpoint is protective for potential developmental effects and toxicity to the young, based on 

lack of developmental effects (rat and rabbit developmental studies) or toxicity to offspring (rat 

reproductive toxicity study) and lack of evidence of neurotoxicity. It is also protective of 

hematological and other effects observed in the dog and rat two-week range-finding studies (see 

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

levels. 

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

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

methoxyfenozide where significant post-application exposure to young children is anticipated.
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For dermal exposure (all durations, residential and occupational exposure), an endpoint was not 

selected. The rat 28-day dermal toxicity study demonstrated no toxicity up to the limit dose 

(1000 mg/kg/day). Several oral toxicity studies with observed LOAELs were also considered, 

including the subchronic dietary studies in the rat, mouse and dog, two-week range-finding 

studies in the rat and dog, and the rat reproductive toxicity study. However, the effects observed 

in the oral studies, which included liver hypertrophy and hematologic parameters, were evaluated 

in the 28-day dermal study but showed no effect of treatment. The developmental oral toxicity

studies in the rat and rabbit showed no maternal or developmental toxicity and the rat subchronic 

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

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

including potential developmental effects. 

In past risk assessments, HED did not quantitatively assess inhalation exposure and risk, and 

there is no route-specific repeated-dose inhalation toxicity study available for this purpose; 

however, in accordance with the current policy for conducting inhalation assessments, the risk 

assessment team selected a dose and endpoint from the available oral studies. The studies 

considered included two-week oral range-finding studies in the rat and dog, subchronic oral 

toxicity studies in the rat and mouse, and the reproductive toxicity study in the rat. The 

subchronic oral dog study, rat and rabbit oral developmental toxicity and the rat 90-day

neurotoxicity and immunotoxicity studies were not considered because no toxicity was observed. 

The two week dietary study in the dog was selected for both short- and intermediate-term 

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. Effects 

observed at the LOAEL included mild anemia, methemoglobinemia and abnormal RBC 

structure, and were consistently observed in individual animals. Although these effects were not 

identified in the dog 90-day dietary study at dose levels up to about 200 mg/kg/day, mild anemia 

and methemoglobinemia were observed at Week 14 and later in the chronic dog study at doses of 

106 mg/kg/day. Additionally, in the rat two week range-finding study there were effects 

observed on the thyroid and adrenal gland at a comparable dose (69.3 mg/kg/day), with a 

NOAEL of 17 mg/kg/day (effects not observed in the subchronic rat study). These findings were 

not seen in the subchronic studies, suggesting a compensatory mechanism for the toxicity of 

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

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

conservative endpoint, low acute inhalation toxicity of methoxyfenozide, low vapor pressure and 

low application rates for current use patterns, this oral study is considered to be protective for 

potential inhalation toxicity.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Dermal exposure was not assessed due to a lack of toxicity via the dermal route. Since adults 

were assessed for potential inhalation exposure while applying methoxyfenozide to ornamentals, 

this exposure should be combined with background levels in food and water to determine 

aggregate exposure. For children’s residential exposure, oral post-application exposure was not 
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assessed; only exposure from background levels of food and drinking water were assessed. For 

occupational workers, only inhalation exposure and risk were assessed.

4.5.3 Cancer Classification and Risk Assessment Recommendation

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

revised 2005 Agency Guidelines for Carcinogen Risk Assessment. The classification is based on 

lack of evidence of carcinogenicity in long-term dietary studies in the rat and the mouse, and 

lack of evidence of genotoxicity in the battery of mutagenicity studies.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

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

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/FQPA 

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 

Short-Term

(1-30 days)

There are no residential uses for methoxyfenozide that would result in significant post-application 

incidental oral exposure to children.
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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/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1-30 

days) or 

Intermediateterm (1-6 

months)

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

Inhalation 

Short- Term

(1-30 days)

and 

IntermediateTerm (1-6 

months)

NOAEL =

16.8

mg/kg/day

UFA=10X

UFH=10X

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

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.
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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

Cancer (oral, 

dermal, 

inhalation)

Classification: not likely to be carcinogenic to humans.

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

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

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

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

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

concern. N/A = not applicable

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Acceptable studies are available depicting the metabolic fate of methoxyfenozide in target crops, 

rotational crops and livestock. The main distinction between study results was that although 

methoxyfenozide does not undergo extensive metabolism in primary crops, it is highly 

metabolized in livestock and rotational crops.

The nature of methoxyfenozide residues in primary crops is adequately understood, based on 

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

undergo extensive metabolism in primary crops. HED has determined that the residue of 

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 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, RH141,518.

In rotational crops, methoxyfenozide was highly 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. The metabolites 

identified in the rotational crops were not similar to those found in the primary crop metabolism 

study. 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 RH152,072), 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, 
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and the combined residues of parent and metabolites RH-151,055, RH-152,072 and RH-117,236 

in low-moisture crops.

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-117236 (3,5-dimethylbenzoic acid N-tert-butyl-N’-(3-hydroxy-2-

methylbenzoyl)hydrazide) and RH-131154 (3-[N-tert-butyl-N’-(3-methoxy-2-methylbenzoyl)-

hydrazinocarbonyl]-5-methylbenzoic acid), but these are only present at low concentrations. 

Because of its resistance to degradation and its mobility, methoxyfenozide has the potential to 

accumulate and to move off the site of application by leaching and erosion/runoff resulting in 

ground- and surface-water contamination.

5.1.3 Comparison of Metabolic Pathways

Methoxyfenozide is rapidly absorbed, distributed, metabolized and almost completely excreted 

within 48 hours in rats. The major route of excretion was feces (86-97%) with lesser amounts in 

the urine (5-13%). An enterohepatic circulation was observed. The test material was 

metabolized principally by O-demethylation of the A-ring methoxy group and oxidative 

hydroxylation of the B-ring methyl groups followed by conjugation with glucuronic acid. No 

significant sex-related or dose-dependent differences in metabolic disposition were noted. Seven 

metabolites and the parent accounted for 74-90% of the administered dose in all groups. These 

metabolites included RH-131,157, RH-141,518 and RH-117,236, metabolites also identified in 

residues 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
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similar to that of the parent, as well as the potential for significant levels in crops and livestock, 

as well as the metabolites determined by the enforcement methods.

Primary Crops: Based on acceptable metabolism studies in cotton, apples, grapes and rice, the 

nature of methoxyfenozide residues in primary crops is adequately understood. HED concluded 

that the residue of concern for both the tolerance expression and the risk assessment in primary

crops is methoxyfenozide. 

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

understood, based on available ruminant and poultry metabolism studies. HED determined that 

the residue of concern is the parent compound in milk and ruminant tissues (except meat 

byproducts), and in poultry meat and fat. The residues of concern in meat byproducts and eggs 

are methoxyfenozide and its metabolite, RH-141,518. 

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-117236 (3,5-dimethylbenzoic acid N-tert-butyl-N’-(3-hydroxy-2-

methylbenzoyl)hydrazide) and RH-131154 (3-[N-tert-butyl-N’-(3-methoxy-2-methylbenzoyl)-

hydrazinocarbonyl]-5-methylbenzoic acid), 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 

141,518
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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

Drinking Water

Parent methoxyfenozide and 

degradates RH-117236 and RH131154

Not Applicable

1

Chemical structures for the residues of concern for tolerance enforcement purposes are provided in HED’s 

Metabolism Committee memorandum of 7/23/99 (D258034, W. Wassell).

5.2 Food Residue Profile

Memo, W. Drew, Chemist, 7/16/2013, D407758

Acceptable crop field trial data are available to support uses on herbs (subgroup 19A) except 

chives, dates, sorghum, and caneberry (subgroup 13-07A), and to establish tolerances for 

residues in the associated commodities. Quantifiable residues were observed in/on all crop 

commodities. Residue decline data indicate that residues generally declined for caneberries and 

sorghum. The available data are adequate for risk assessment and tolerance assessment. The 

results from these field trials are summarized in Table 5.2.

Because there are no processed commodities for caneberries or dates, processing studies were 

not required for these raw agricultural commodities (RACs). The processed commodity for basil 

is dried basil, samples of which were produced at the field trial sites, and subsequently analyzed 

along with the fresh basil samples. The submitted sorghum processing study data are adequate, 

and support a tolerance of 120 ppm in sorghum AGF. This will be reflected in an increase of the 

currently established tolerance in AGF, from 2.0 to 120 ppm. A tolerance in sweet sorghum 

syrup is not required. 

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

durations for samples from the submitted caneberry, date, sorghum, and basil field trials, and the 

sorghum processing study.

 

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

studies were submitted with this petition. Although the proposed tolerances for this action 

include an increase of the tolerance in sorghum grain, the revised estimated dietary burdens 

resulted in anticipated residues that do not exceed the tolerances currently established in 

livestock commodities. Therefore, revisions to the currently established livestock tolerances are

not needed as a result of the new uses.
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TABLE 5.2 Summary of Residue Data from Crop Field Trials with Methoxyfenozide.

Crop Matrix Total Use 

Rate (lb ai/A)

[g ai/ha]

PHI 

(Days)

Residue Levels (ppm)

n Min. Max. LAFT HAFT Median Mean Std. Dev.

Basil

Fresh leaves 

and stems

0.988-1.032

[1107-1157]

1 10 9.26 47.2 -- -- 19.2 21.7 12.3

5 -- -- 9.88 43.4 19.2 21.7 12.8

Dried leaves 

and stems

10 56.3 194 -- -- 100 110 44.8

5 -- -- 60.5 188 102 110 47.0

Caneberries

Caneberries 0.744-0.778

[834-872]

3 12 0.62 2.5 -- -- 1.90 1.70 0.65

6 -- -- 0.68 2.5 1.90 1.73 0.67

Dates

Dried fruit 0.501-0.933 7 8 1.5 3.3 1.6 2.3 2.0 2.0 0.70

Grain Sorghum

Forage 0.478-0.494 2-4 12 0.70 5.6 0.77 5.0 2.15 2.76 1.45

Grain 11; 21-

23

12 0.15 2.6 0.15 2.3 0.40 0.72 0.72

Stover 21-23 12 0.29 9.7 0.45 7.6 2.95 3.18 2.39

Sweet Sorghum

Stalks 0.481 3 1 0.045 0.18 0.11 0.11 0.11 0.11 NA

Adequate residue data are available to support proposed updates to crop group tolerances, and to 

establish indirect or inadvertent tolerances. Specifically, tolerances in the updated crop groups 

8-10 and 11-10, and in the updated subgroups 13-07F and 13-07G were requested. Tolerances in 

sugar apples, cherimoyas, atemoyas, custard apples, ilamas, soursops, and biribas were also 

requested, based on translation of avocado residues. Additionally, indirect or inadvertent 

tolerances in the rapeseed subgroup (20A) and the sunflower subgroup (20B) were requested.

The requested changes for the rapeseed and sunflower subgroups are based on 2012 

recommendations by EPA. Other changes are supported by data previously reviewed by the 

Agency in 2009. 

5.3 Water Residue Profile

Memo, K. Milians, Ph.D., Chemist, 4/23/2013, D407566

The estimated drinking water concentrations (EDWCs) are based on all current methoxyfenozide 

uses as well as the new proposed uses. Surface water residues were modeled with the Pesticide 

Root Zone Model and Exposure Analysis Modeling System (PRZM-EXAMS), using EFED's 

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

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

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

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

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

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

The EDWC used in this assessment is bolded in the table below, with the value of 251 ppb 

coming from the groundwater residues estimated by the PRZM-GW model. 
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There remains an outstanding data requirement for monitoring of surface water and sediment in a 

representative sample of high use areas in proximity to surface water. Additionally, EFED 

continues to have concerns about the persistence of methoxyfenozide. This persistence makes it 

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

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

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

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

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

of methoxyfenozide. Therefore EFED has used a conservative approach to modeling potential 

residues in ground water sources of drinking water. 

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

applications of methoxyfenozide (PRZM-EXAMS)

Drinking water source Use

(modeled rate)

1-in-10 year acute 

(ppb)

1-in-10 year 

chronic (ppb)

30- year average 

(ppb)

Surface water

(aerial application)

Globe Artichoke

(0.25 lb a.i./A x 4 

applic.; total of 1.0 

lb/A/yr)

77.7 51.6 37.4

Surface water

(ground application)

Globe Artichoke

(0.25 lb a.i./A x 4 

applic.; total of 1.0 

lb/A/yr)

77.4 50.4 35.8

Tier I EDWCs for Groundwater (PRZM-GW)

Crop/Scenario Highest Daily value 

(μg/L)

Post Breakthrough 

Average (μg/L)

Average Simulation 

Breakthrough Time (days)

Fruiting Vegetable/WI corn 251 214 8684.63

5.4 Dietary Risk Assessment

Memo, E. Holman, 7/16/2013, D412460

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 an 

Alternative Risk Integration Assessment Team (ARIA) determined 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 (D407758, W. Drew, 7/16/13). 

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 251 ppb.
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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. Methoxyfenozide chronic dietary (food + drinking water) 

exposure estimates using the DEEM-FCIDTM software are below HED’s level of concern for the 

U.S. population and each of the population subgroups. Chronic dietary exposure was 31% 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 

form food and drinking water is expected to be significantly lower than the exposures presented 

in Table 5.4.4.

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

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

Population Subgroup1

DEEM Acute Dietary Analysis,

95th Percentile

DEEM Chronic Dietary Analysis

Exposure 

(mg/kg/day)

% aPAD Exposure 

(mg/kg/day)

% cPAD

General U.S. Population

NA 2

0.031520 31

All Infants (< 1 year old) 0.047975 47

Children 1-2 years old 0.085207 84

Children 3-5 years old 0.065025 64

Children 6-12 years old 0.036288 36

Youth 13-19 years old 0.023942 24

Adults 20-49 years old 0.027714 27

Adults 50+ years old 0.027499 27

Females 13-49 years old 0.028308 28

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

2 NA = Not Applicable; no acute dietary endpoint was identified for these population subgroups.
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5.4.5 Cancer Dietary Risk Assessment

HED classified methoxyfenozide as “not likely to be carcinogenetic to humans” and, therefore, 

cancer risk is not of concern for methoxyfenozide.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Memo, M. Collantes 2/27/2012; D389739

Memo, M. Collantes 6/07/2013; D411612

There are no new proposed residential uses at this time; however, there are existing residential 

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

SOPs1along 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.

6.1 Residential Handler Exposure

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

grown in commercial nurseries and greenhouses, Christmas tree farms, outdoor landscapes areas, 

parks, recreational areas, institutional grounds and “residential property”. Since the label does 

not identify this product as a restricted use, a residential handler exposure assessment was 

performed to be protective of potential home owner exposure. The following use scenarios and 

sources of unit exposures were used to assess residential handler exposures:

 Mixing/Loading/Applying for Sprays Using Manually Pressurized Handwand

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

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

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

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

associated with dermal exposure to methoxyfenozide. Handler inhalation exposure scenarios 

resulted in MOEs greater than 100, ranging from 76,000 to greater than 3 million, and these risk 

estimates are not of concern. Although a point of departure from an oral study was used to 

assess the handler inhalation risks, the calculated MOEs are all >76,000, thus providing an ample 

margin of safety to account for any uncertainties in the route-to-route extrapolation. Handler 

exposure and risk estimates are summarized in Table 6.1. 

Table 6.1.: Residential Handler Exposure and Risk Estimates for Methoxyfenozide

Exposure 

Scenario

Application 

Rate a

(lb ai/gal)

Amount 

Treated b

(gallons)

Inhalation 

Unit Exposure b

(mg/lb ai)

Inhalation 

Dose c

(mg/kg/day)

Inhalation 

MOE d

Liquid with 

Manually 

Pressurized

0.025 5 0.018 0.0000283 590,000

 

1 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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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

Handwand

Liquid with

Back Pack

5 0.14 0.00022 76,000

Liquid with 

Hose-end 

Sprayer

11 0.0014 0.00000484 3,500,000

a. In accordance with Intrepid® 2F (Reg. No.: 62719-442) label: 0.025 lb ai per gallon for treatment of 

ornamentals (0.25 lb ai/A ÷ 10 gallons/A for mist blowers and air blast sprayers)

b. In accordance with revised Residential (Garden and Trees) SOP

c. Inhalation dose (mg/kg/day) = inhalation unit exposure (mg/lb ai) * application rate * acres treated / 

body weight (80 kg)

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

6.2 Dermal Post-application Exposure

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

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

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

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

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

incidental oral post-application exposure assessment was not conducted. 

6.3 Inhalation Post-application Exposure

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

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

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

25oC), and the low proposed use rate (0.31 lb ai/A). However, volatilization of pesticides may

be a source of post-application inhalation exposure to individuals nearby pesticide applications. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from 

its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 20102. The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

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

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

for methoxyfenozide.

 

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for 

methoxyfenozide. The Agency has been working with the Spray Drift Task Force, EPA 

Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop 

the best spray drift management practices (see the Agency’s Spray Drift website for more 

information3. The Agency has completed its evaluation of the new database submitted by the 

Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on 

how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risk estimates associated with drift.

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

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worst case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. In the case of methoxyfenozide, chronic aggregate risks result from 

exposure through food and water only. For short-term risk, adult residential handlers’ inhalation 

exposure was combined with background exposure from food and water. As previously

discussed (see Section 6.2), there are no residential uses for methoxyfenozide that would result in 

significant post-application exposure to children, based on ornamental use only. Therefore, 

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

5.4). 

7.1 Acute Aggregate Risk

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

aggregate risk.

7.2 Short-Term Aggregate Risk

 

3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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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 MOEs are 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 0.031520 0.00022 0.03174 530

1

The LOC is based on the standard inter- and intra- species uncertainty factors totaling 100. The FQPA Safety Factor has been 

reduced to 1X.

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

3 Residential Exposure (Adult Handler) = Inhalation Exposure (Table 6.1). 

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

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

7.3 Chronic Aggregate Risk

Chronic aggregate risk is equivalent to chronic dietary exposure and risk, which is not of 

concern. Refer to Section 5.4.4.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to methoxyfenozide and any other substances and methoxyfenozide does not appear to produce a 

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

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

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

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

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

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

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Memo, M. Collantes 6/07/2013; D411612

Methoxyfenozide is intended for use by commercial and professional applicators for the control 

of lepidopterous pests on herbs (subgroup 19A) except chives, dates, sorghum, and caneberries 

(subgroup 13-07A). In addition, California is requesting a Section 18 for use of Intrepid 2F 

on dates/palm only. Methoxyfenozide is an insecticide currently registered for use on 

ornamentals and on numerous agricultural crops, such as dried peas and beans (subgroup 6C; 
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except soybean), pomegranate, popcorn, citrus fruits (group 10-10), and root vegetables, except 

sugar beet (subgroup 1B).

It 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. 

9.1 Occupational Handlers

Based upon the proposed use pattern, HED expects the most highly exposed occupational 

pesticide handler scenarios to be:

 Mixing/loading liquid for aerial application to orchards (i.e., caneberries) and high 

acreage field crops (i.e.,herbs and sorghum)

 Mixing/loading liquid for airblast to orchards (i.e., caneberries and dates)

 Mixing/loading liquid for groundboom to high acreage field crops (i.e., herbs and 

sorghum)

 Mixing/loading liquid for groundboom to low acreage field crops (i.e, caneberries)

 Applying sprays via aerial application to orchards (i.e., caneberries) and high acreage 

field crops (i.e., herbs and sorghum)

 Applying sprays via airblast to orchards (i.e., caneberries and dates)

 Applying sprays via groundboom to high acreage field crops (i.e.,herbs and sorghum)

 Flagger for aerial application to orchards (i.e., caneberries) and high acreage field crops 

(i.e.,herbs and sorghum)

 Mixing/loading/applying liquid via backpack (ground/soil directed) to orchards (i.e., 

caneberries and dates)

 Mixing/loading/applying liquid via mechanically pressurized handwand (broadcast 

foliar and drench) to orchards (i.e., caneberries and dates)

Handler exposure is expected to be short- or intermediate-term in duration, based on information 

provided on proposed labels. However, since the short- and intermediate-term toxicological 

endpoints are the same; only short-term dermal exposures have been assessed. HED estimates 

exposure based on day-0 residues. Using day-0 residues to assess intermediate-term exposure 

does not take into account dissipation of residues over time and thus results in a conservative 

estimate. Therefore, the short-term exposure assessment represents the worst case scenario and 

is protective of intermediate-term exposure. Long-term exposures are not expected, based on the 

existing and proposed use pattern.

No chemical-specific handler exposure data were submitted in support of the proposed uses, and 

therefore HED relied on the best available surrogate data to complete the occupational handler 

assessment. 

The proposed product label involved in this assessment directs applicators and other handlers to 

wear long sleeved shirt and long pants, shoes plus socks, and chemical-resistant gloves. HED 
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typically assesses handler exposure using “baseline” clothing assumptions, and if risks of 

concern are identified, the use of personal protective equipment (PPE) may be incorporated into 

the exposure assessment. In the case of methoxyfenozide, there is no toxicity via the dermal 

route, and only inhalation exposures were assessed. Table 9.1 presents the estimated risks for 

workers, based on short-term inhalation exposures at baseline (i.e. single layer clothing and no 

respirator), and in some situations the use of gloves or engineering controls for aerial 

applications. Short- term risks for handlers are not of concern (i.e., MOEs were equal to or 

greater than 100) with inhalation MOEs ranging from 20,000 to 3,100,000. No additional PPE 

(i.e., respirators) were needed to achieve MOEs above the LOC of 100.

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

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure

(μg/lb ai)1

Maximum

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Inhalation

Mitigation Level Dose 

(mg/kg/day)4 MOE5

Mixer/Loader

Aerial 

Orchard 

(caneberries) 0.219

(no respirator) 0.25 lb ai/A

350 A 0.00024 70,000

High acreage field 

crop (herbs and 

sorghum)

1200 A 0.00082 20,000

Groundboom High acreage field 

crop (herbs and 

sorghum)

0.25 lb ai/A 200 A 0.000138 120,000

Airblast Orchard (caneberries 

and dates) 0.31 lb ai/A 40 A 0.0027 490,000

Applicator

Aerial

Orchard 

(caneberries)

0.0049 0.25 lb ai/A

350 A 0.0000053 3,100,000

High acreage field 

crop (herbs and 

sorghum)

1200 A 0.000018 910,000

Groundboom

High acreage field 

crop (herbs and 

sorghum)

0.34 

(no respirator) 0.25 lb ai/A 200 A 0.000213 79,000

Airblast Orchard (caneberries

and dates)

4.71

(no respirator) 0.31 lb ai/A 40 A 0.00073 23,000

Flagger

Aerial

Orchard and High 

acreage field crop 

(caneberries, herbs 

and sorghum)

0.35

(no respirator) 0.25 lb ai/A 350 A 0.00038 44,000

Mixer/Loader/Applicator

Back Pack Orchard (caneberries 

and dates)

2.58

(no respirator)

0.0083 lb ai/gal

40 gals 0.000010 1,600,000

Mechanically 

Pressurized Handgun 3.9

(no respirator)

1000 gals 0.00040 41,000
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1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ([DATE]); Level of mitigation: Baseline, PPE, Eng. 

Controls.

2 Based on registered or proposed label (Reg. No. 62719-442).

3 Exposure Science Advisory Council Policy #9.1.

6 Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or 

Amount Handled Daily (A or gal/day) ÷ BW (80 kg).

7 Inhalation MOE = Inhalation NOAEL (16.8 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

9.2 Post-application Risk

9.2.1 Post-application Dermal Exposure

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

exposure and risk assessment was not conducted. 

9.2.2. Post-application Inhalation Exposure

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

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

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

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

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

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

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and 

received the SAP’s final report on March 2, 20104. The Agency is in the process of evaluating 

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

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

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

Agency's risk assessments. If new policies or procedures are put into place, the Agency may

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

for methoxfenozide.

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

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

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

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

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

inhalation exposure scenarios.

Restricted Entry Interval

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

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

Category IV for skin irritation potential. It is not a skin sensitizer. Since a dermal endpoint was

not selected a post-application risk estimates were not required for post-application activities. 

Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye

 

4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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irritation and primary skin irrigation are assigned a 12-hour REI. Therefore, the [156 subpart K]

Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers

from post-application exposures to methoxyfenozide. 

However, methoxyfenozide is not classified as a carcinogen or a neurotoxicant, nor is it 

associated with known reproductive or developmental effects. Therefore, methoxyfenozide is a 

candidate for a 4-hour REI which appears on the proposed supplemental and master label.

10.0 References

D407758. Methoxyfenozide. Petition to Establish Permanent Tolerances (and Section 3 

Registration) for Residues Resulting from Food/Feed Uses of the Insecticide on Herbs (Subgroup 

19A) Except Chives, Caneberries (Subgroup 13-07A), Dates and Sorghum; to Update Pome 

Fruits from Group 11 to 11-10, and Fruiting Vegetables from Group 8 to 8-10; to Extend the 

Tolerance in Grapes to Small Vine Climbing Fruits Except Fuzzy Kiwifruit (Subgroup 13-07F), 

the Tolerance in Strawberries to Low Growing Berries (Subgroup 13-07G) Except Cranberry, 

and the Tolerance in Avocadoes to Various Tropical Tree Fruits; to Delete the Tolerances in 

Dried Shelled Peas and Beans and Add a Tolerance in Subgroup 6C; and to Establish Rotational 

Crop Tolerances in the Rapeseed (Subgroup 20A) and Sunflower (Subgroup 20B) Oilseed 

Subgroups. Summary of Analytical Chemistry and Residue Data. W. Drew, 7/16/13

D407566. Drinking Water Assessment for the IR-4 New Use Petitions for the Use of 

Methoxyfenozide on Herb Subgroup 19A (except chives), Dates, Sorghum, Fruiting Vegetable 

Group 8-10, Pome Fruit Group 11-10, Berry Subgroups 13-07 A, F & G and Tropical Tree 

Fruits. K. Milians, 4/23/13.

D412460. Methoxyfenozide. Chronic Aggregate Dietary (Food and Drinking Water) Exposure

and Risk Assessment for the Section 3 Registration on Herbs (Subgroup 19A) Except Chives, 

Caneberries (Subgroup 13-07A), Dates and Sorghum; to Establish Rotational Crop Tolerances in 

the Rapeseed (Subgroup 20A) and Sunflower (Subgroup 20B) Oilseed Subgroups; as well as to 

extend and update Crop Group Tolerances on Multiple Commodities. E. Holman, 7/16/2013.

D394924. Methoxyfenozide. Occupational and Residential Exposure Assessment for New Uses

on Root Vegetables and Citrus. M. Collantes, 2/27/12.

D394924. Methoxyfenozide. Occupational and Residential Exposure Assessment for a 

Proposed Use on Dates, Sorghum, Herbs (subgroup 19A except chives) and Caneberries 

(subgroup 13-07A). M. Collantes, 6/7/13.

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

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

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.
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Appendix A.	 Toxicology	Profile	and	Executive	Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for methoxyfenozide are in Table 1. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 28-or 90-Day Inhalation ................................................

yes

yes

yes

no

no*

yes

yes

yes

-

no

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

no

-

-

yes

yes

-

870.7485 General Metabolism ......................................................

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

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

-

-

 -

* The required repeated dose inhalation toxicity study has been waived.
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile – Methoxyfenozide technical

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

870.1100 Acute oral [rat] 44144415 LD50 >5000 

mg/kg, both sexes

IV

870.1100 Acute oral [mouse] 44144416 LD50 >5000 

mg/kg, both sexes

IV

870.1200 Acute dermal [rat] 44144418 LD50 >2000 

mg/kg, both sexes

III

870.1300 Acute inhalation [rat] 44144420 LC50 >4.3 mg/L, 

both sexes

IV

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

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

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

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Nonguideline 2-week oral 

range-finding 

(rat)

44617722 (1995)

Acceptable/nonguideline

0, 50, 250, 1000, 5000, 

20,000 ppm in the diet

[note: mg/kg/day 

equivalents not calculated; 

see 90-day oral rat for 

mg/kg/day]

NOAEL = 250 ppm (approximately 17.0/19.1 

mg/kg/day M/F based on main study doses)

LOAEL = 1000 ppm (approximately 69.3/72.4 

mg/kg/day M/F based on main study doses), 

based on thyroid gland hypertrophy/hyperplasia 

in males and females, and increased adrenal 

hypertrophy of zona fasciculata in females.

At ≥5000 ppm, increased abs/rel liver and 

adrenal weights, hepatocellular hypertrophy

870.3100 90-Day oral 

toxicity (rat)

44617722 (1995)

Acceptable/guideline

0, 50, 250, 1000, 5000, 

20,000 ppm in the diet

M: 0, 3.4, 17.0, 69.3, 

353.4, 1368.8 mg/kg/day

F: 0, 3.7, 19.1,72.4, 379.3, 

1531.2 mg/kg/day

NOAEL = 69.3/72.4 mg/kg/day [M/F]

LOAEL = 353.4 mg/kg/day [M/F] based on 

periportal hepatocellular hypertrophy and 

increased liver weight.

At 1368.8/1531.2 mg/kg/day: decreased RBC 

and Hg in females.
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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.
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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.

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, 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 cocritical 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- and Intermediate-Term)

An incidental oral exposure dose and endpoint were not selected. Methoxyfenozide may be used 

on ornamental plants in a residential setting. However, post-application incidental oral exposure 

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

activities involving such areas is low, and this assessment was not performed. 
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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, 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. 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 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 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. A combined UF of 100x was utilized 

(10X each to account for inter- and intra-species variability).
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A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity - Rat

In a subchronic oral toxicity study (MRID No. 44617722), methoxyfenozide technical (99.2% 

purity, Lot No. WS-10395, TD No. 92-014) was administered by dietary admix to Charles River 

Crl:CD BR rats (10/sex/group) at doses of 0, 50, 250, 1000, 5000 or 20,000 (limit dose) ppm 

(equivalent to average daily intakes of 0, 3.4, 17.0, 69.3, 353.4 or 1368.8 mg/kg/day in males and 

0,3.7, 19.1, 72.4, 379.3 and 1,531.2 mg/kg/day in females) for 13 weeks. The following 

parameters were examined: mortality, clinical signs, body weights, food consumption, 

ophthalmology, hematology, clinical chemistry, urinalysis, organ weights, macroscopic 

pathology and microscopic pathology.

The following effects were observed: a statistically significant reduction in red blood cells and 

hemoglobin in 20,000 ppm females (7-8% less than controls) and slight or moderate periportal 

hepatocellular hypertrophy in all 5000 and 20,000 ppm males and females compared with none 

observed in controls or lower dose rats. There were statistically significant increases in relativeto-body weight liver weights in 5000 and 20,000 ppm males as well as in 20,000 ppm females

(11-16% above controls). There were increases in absolute liver weights in both sexes at 5000 

and 20,000 ppm when compared to controls (+7 to 13% in males and +9 to 10% in females), 

however these increases were not statistically significant.

[It is noted that in the 2-week range-finding study, which tested at 0, 50, 250, 1000, 5000 and 

20,000 ppm, some effects were observed which were not observed in the 13-week study, and 

these findings were seen at a lower dose than the LOAEL for the subchronic study. At 1000 

ppm, follicular cell thyroid follicular cell hypertrophy/hyperplasia in 3/5 males and 2/5 females, 

and minimal hypertrophy of the adrenal gland zona fasciculata in 1/5 female (all vs. 0/5 controls) 

were observed; these effects were also seen at higher doses. At ≥5000 ppm, liver absolute and 

relative weights in males, adrenal absolute and relative weights in females, and hepatocellular 

hypertrophy in females were also increased. Necrosis of hepatocytes was observed in males at 

20,000 ppm.] 

The LOAEL (subchronic study only) is 5000 ppm (353.4/379.3 mg/kg/day, males/females),

based on effects on the liver (increased absolute and relative weights, and periportal 

hepatocellular hypertrophy in both sexes). The NOAEL is 1000 ppm (69.3/72.4 mg/kg/day 

in males/females).

This study is classified Acceptable/guideline and satisfies the data requirement for OPPTS 

§870.3100 for a three-month oral toxicity study in rats.

870.3100 90-Day Oral Toxicity - Mouse

In a. subchronic toxicity study (MRID No. 44617723), methoxyfenozide technical (99.2% purity, 

Lot No. WS-10395, TD No. 92-014) was administered by dietary admix to Charles River 
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Crl:CD-1 (ICR) BR VAF/+ mice (10/sex/group) at doses of 0, 70, 700, 2500 or 7000 ppm 

(equivalent to average daily intakes of 0, 11.9, 112.5, 428.2 or 1149.3 mg/kg/day in males and 0, 

17.4, 165.1, 589.4 and 1742.1 mg/kg/day in females) for 13 weeks. The following parameters 

were examined: mortality, clinical signs, body weights, feed consumption, hematology, clinical 

chemistry, organ weights, macroscopic pathology and microscopic pathology.

There were no clinical signs and all mice survived until scheduled sacrifice. Body weight gains 

in the 7,000 ppm group were less than respective controls for males (18%) and females (15%) 

for the 13-week period. Food consumption did not appear to be altered. There were no apparent 

effects on the following parameters: hematology, clinical chemistry, organ weights, macroscopic 

pathology or microscopic pathology.

The LOAEL is 7000 ppm (1149.3/1742.1 mg/kg/day in males/females; limit dose), based on 

a decrease in body weight gain in males and females. The NOAEL is 2500 ppm 

(428.2/589.4 mg/kg/day in males/females). 

This study is classified acceptable/guideline and satisfies the data requirement for a subchronic 

oral toxicity study in the mouse (OPPTS §870.3100).

870.3150 90-Day Oral Toxicity - Dog

In a subchronic toxicity study (MRID No.44617724), methoxyfenozide technical (99.8% purity, 

Lot No. WS-10395, TD No. 92-014) was administered by dietary admix to Hazleton Research 

Products beagle dogs (4/sex/group) at doses of 0, 15, 50, 500 or 5000 ppm (equivalent to average 

daily intakes of 0, 0.6, 2.0, 21.4 or 197.5 mg/kg/day in males and 0, 0.6, 1.9, 20.4 or 208.8

mg/kg/day in females) for 13 weeks. The 15 ppm group was then dosed for an additional 2 

weeks at 15 ppm, followed by an increase in dose to 15,000 ppm for another 6 weeks. The doses 

in mg/kg/day for the additional 6 weeks were 422.0 mg/kg/day for males and 460.4 mg/kg/day

for females. No control animals were kept beyond the original 13 weeks for comparison with 

these higher dose levels. The following parameters were examined: mortality, clinical signs, 

ophthalmology, body weights, feed consumption, hematology, clinical chemistry, urinalysis, 

organ weights, macroscopic pathology and microscopic pathology.

There was the suggestion (no statistical significance) that 5000 ppm caused a decrease in body

weight gain in both sexes over the 13-week period (males: controls = 3.7 kg, 5000 ppm 3.3 kg; 

females: controls = 3.0 kg, 5000 ppm = 2.4 kg). However, these differences were not considered 

sufficient to establish an adverse effect. All dogs treated with 15,000 ppm for the 6 additional 

weeks gained weight. However, there was no additional control group with which to compare the 

results. No other parameters were affected by test article administration.

[Results of a two week range-finding study were also provided in this report, which dosed 2 

dogs/sex/group at 0, 300, 3500, 7000, 15,000 or 30,000 ppm (equivalent to individual animal 

intakes of 0, 11.7-14.7, 141.6-167.6, 264.7-370.4, 571.4-631.7 or 1113.7-1337.0 mg/kg/day for 

males and 0, 13.3-16.8, 90.8-184.8, 285.9-336.8, 582.3-630.9 or 1092.6-1169.1 mg/kg/day for 

females). Although there were no clear-cut definitive effects on any hematology parameters in 

the 13-week study, in the 2-week range-finding study, there were decreases for all animals of 
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both sexes in RBC count (13-20%), hemoglobin (9-18%) and hematocrit (8-16%) for all animals 

of both sexes at ≥3500 ppm after two weeks when compared with the pre-dose values. 

Methemoglobinemia and abnormal RBC morphology (Heinz bodies, Howell-Jolly bodies, 

polychromasia) were reported as well. Increased spleen weights were also observed at ≥3500 

ppm. Bilirubinemia was observed at ≥7000 ppm in males. No effects were identified in the 

range-finding study at 300 ppm. 

The NOAEL (subchronic study only) is 5000 ppm (197.5/208.8 mg/kg/day, males/females; 

HDT). A LOAEL was not determined (>5000 ppm). 

This study is classified acceptable/guideline and satisfies the data requirement for a three-month 

toxicity study in dogs (OPPTS §870.3150). Although a LOAEL was not achieved, toxicity was 

observed in a two-week range-finding study and an acceptable chronic dog toxicity study is 

available (MRID 44617728).

870.3200 28-Day Dermal Toxicity – Rat

In a 28-day repeated dose dermal toxicity study (MRID 44617725), groups of 10 male and 10 

female Crl:CD®BR rats were treated with RH-2485 Technical (98%, Lot No. 1), by dermal 

application to shaved skin moistened with tap water and held in place by dermal occlusion, at 

doses of 0, 75, 300, or 1000 mg/kg/day for 6 hours/day, 5 days/week. 

No mortality was recorded, and there were no clinical signs indicative of systemic toxicity at any 

treatment level. No treatment-related dermal irritation was produced. Additionally, there were no 

treatment-related effects on body weight, food consumption, absolute or relative organ weight, 

hematology, or clinical chemistry in either sex of rats. No gross or microscopic changes in either 

sex were found to be caused by the treatments.

The systemic NOAEL is 1000 mg/kg/day (HDT). The systemic LOAEL was not determined

for either male or female rats (>1000 mg/kg/day). The dermal NOAEL was 1000 

mg/kg/day. The dermal LOAEL was not established (>1000 mg/kg/day).

This study is classified as Acceptable/guideline and satisfies the guideline requirement for a 28-

day dermal study in rats (OPPTS §870.3200). Although a LOAEL was not established, the 

highest dose tested (1000 mg/kg) is the limit dose.

870.3465 90-Day Inhalation – Rat

Not required and not submitted

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study - Rat

In a developmental toxicity study (MRID No. 44638201), methoxyfenozide technical (99.2% 

purity) was administered by gavage to Charles River Crl:CD BR VAF/Plus (Sprague-Dawley) 
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rats (25/group) at doses of 0 (0.5% aqueous methylcellulose vehicle), 100, 300 or 1,000 

mg/kg/day on gestation days 6 through 15. The following parameters were examined: maternal 

(clinical signs, morbidity, mortality, body weights, food consumption, corpora lutea, 

implantation sites, resorption sites, abdominal/thoracic cavities and the position of live/dead 

fetuses) and fetuses (weights, external changes, Bouin’s soft tissue examination and skeletal 

changes).

Maternal toxicity: There were no deaths or clinical signs, nor where there any effects on body 

weights or food consumption. No changes were noted in any of the reproductive parameters. 

The maternal NOAEL is 1,000 mg/kg/day (HDT, limit dose). A maternal LOAEL was not 

determined (>1,000 mg/kg/day).

Developmental toxicity: Fetal examinations did not reveal any affects on body weight or 

gross/visceral/skeletal aspects. The developmental NOAEL is 1,000 mg/kg/day. A 

developmental LOAEL was not determined (>1,000 mg/kg/day).

This study is classified Acceptable/guideline and satisfies the guideline criteria for a 

developmental toxicity study in the rat (OPPTS §870.3700a).

870.3700b Prenatal Developmental Toxicity Study - Rabbit

In a developmental toxicity study (MRID No. 44617726), methoxyfenozide technical (98.0% 

purity) was administered by gavage to Hazleton Research Products New Zealand White rabbits 

(16/group) at doses of 0 (0.5% aqueous methylcellulose vehicle), 100, 300 or 1,000 mg/kg/day

on gestation days 7 through 19. The following parameters were examined: maternal (clinical 

signs, morbidity, mortality, body weights, food consumption, corpora lutea, implantation sites, 

resorption sites, abdominal/thoracic cavities and the position of live/dead fetuses) and fetuses 

(weights, external changes, soft tissue examination, brain, eyes and skeletal changes).

Maternal toxicity: There were no deaths or clinical signs, nor where there any effects on body

weights or food consumption. No changes were noted in any of the reproductive parameters. 

The maternal NOAEL is 1,000 mg/kg/day (HDT, limit dose). A maternal LOAEL was not 

determined (>1,000 mg/kg/day).

Developmental toxicity: Fetal examinations did not reveal any affects on body weight or 

gross/visceral/skeletal aspects. The developmental NOAEL is 1,000 mg/kg/day. A 

developmental LOAEL was not determined (>1,000 mg/kg/day).

This study is classified Acceptable/guideline and satisfies the guideline criteria for a 

developmental toxicity study in the rabbit (OPPTS §870.3700b).

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat
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In a two-generation reproduction study (MRID 44617727), RH-2485 Technical (98.0% a.i.) was 

administered to 30 Crl:CD®BR rats/sex/dose in the diet at concentrations of 0, 200, 2000, or 

20,000 ppm (equivalent to average daily intake for P1 males of 0, 15.4, 153.4, or 1551.9 

mg/kg/day, respectively; for P1 females of 0, 17.9, 180.7, or 1820.7 mg/kg/day, respectively; for 

P2 males of 0, 19.1, 193.1, or 1956.0 mg/kg/day, respectively; and for P2 females of 0, 20.4, 

202.7, or 2036.5 mg/kg/day, respectively). Treatment was continuous throughout the study. The 

two parental generations, P1 and P2, produced one litter of pups each (F1 and F2, respectively). 

The parental animals received the test diet for 10 weeks before mating and throughout mating, 

pregnancy, and lactation of their litters. Pups were selected from the F1 litters to parent the F2

generation. The P1 generation produced 22 to 27 litters/group consisting of liveborn pups, the P2

generation produced 24 to 28 liveborn litters/group.

Parental toxicity: In this study, the target organ for the systemic toxicity of RH-2485 Technical 

to adult rats was the liver. For the P1 and P2 males and females exposed to 20,000 ppm, the 

absolute and relative terminal liver weights were significantly increased by 13 to 27% (p<0.05), 

in comparison to control values. Microscopic changes in the liver included midzonal to 

periportal hepatocellular hypertrophy in all of the animals of both generations at 20,000 ppm, 

and in females, only, at 2000 ppm. The incidence rates for hepatocellular hypertrophy at 0, 200, 

2,000 and 20,000 ppm were as follows: 0/30, 0/30, 0/30, and 30/30 (100%), respectively, for the 

P1 and P2 males: 0/30, 0/30, 4/30 (13.3%) and 30/30 (100%), respectively, for the P1 females; 

and 0/30, 0/30, 1/30 (3.3%), and 30/30 (100%), respectively, for the P2 females.

Statistically significant reductions (p<0.05) in body weights and cumulative body weight gains 

were observed among the high-dose P1 males during the last 12 weeks of the study; however, the 

reductions were never more than 7% ( p<0.05), in comparison to control values; the overall body

weight gain (weeks 0-20) for this group was depressed by 10% (p<0.05). Body weights, food 

consumption, and body-weight gains were comparable to, or significantly higher than, control 

values for the P2 males throughout the study and for the P1 and P2 females during premating, 

gestation, and lactation. Therefore, the biological significance of the reduced body weights of 

the P1 males is questionable.

The following parameters of systemic toxicity were comparable for RH-2485 Technical-treated 

and control P1 and P2 males and females: mortality, clinical signs, gross pathology, relative and 

absolute terminal weights of the reproductive organs, and microscopic pathology of the 

reproductive organs. The LOAEL for parental toxicity is 20,000 ppm (1551.9 mg/kg/day), 

based on increased absolute and relative liver weights in males and females and on 

hepatocellular hypertrophy in males and females. The NOAEL for parental toxicity is 

2000 ppm (153.4 mg/kg/day).

Offspring toxicity: Treated F1 and F2 litters were comparable to control litters with regard to 

macroscopic abnormalities, malformations, or variations; number of liveborn pups (total and per 

litter); number of live pups/litter on days 4, 7, 14, or 21 of lactation; the number of stillborn pups 

(total and per litter); body weights on days 0, 4, 7, 14, and 21 of lactation; sexual maturity; sex 

ratios; anogenital distance; and indices of survival. The NOAEL for offspring toxicity is 

20,000 ppm (1551.9 mg/kg/day; HDT). A LOAEL for offspring toxicity was not established 

(>20,000 ppm).
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Reproductive toxicity: There were no treatment-related reproductive effects on the P1 and P2

males and females or their F1 and F2 offspring. The endpoints of reproductive function and 

performance for P1 and P2 parental generations were comparable for RH-2485 Technical-treated 

and control animals with regard to the following: length and periodicity of the estrous cycle; 

copulatory interval; number of females inseminated and/or pregnant; length of gestation; sperm 

motility, morphology, and concentration; and indices of mating, fertility, and gestation. The 

NOAEL for reproductive toxicity is >20,000 ppm (1551.9 mg/kg/day). The LOAEL for 

reproductive toxicity was not identified (>20,000 ppm).

This study is classified Acceptable/guideline and satisfies the guideline criteria for a reproductive 

toxicity study in the rat (OPPTS §870.3800).

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

See 870.4300, below

870.4100b Chronic Toxicity - Dog

In a chronic oral toxicity study (MRID 44617728), RH-2486 technical (methoxyfenozide, 98.9% 

a.i., Lot No. 1, TD94-134) was administered in the diet to 4 beagle dogs/sex/dose at dietary

concentrations of 0, 60, 300, 3000 or 30,000 ppm for 52 weeks (equivalent to average daily 

intakes of 0, 2.2, 9.8, 106.1 or 1152.4 mg/kg/day in males and 0, 2.2, 12.6, 110.6 or 1199.2 

mg/kg/day in females).

The most notable compound-related hematologic effects consisted of methemoglobinemia, 

nucleated red blood cells (RBCs) and mild hemolysis, particularly in females. At 3000 ppm, 

mild hematological effects were observed by 14 weeks of treatment. Methemoglobinemia was 

observed in males (increased to 157-167% of controls) and females (153-183% of controls) at 

most or all time points. In males, platelets were significantly increased (156-163%) at all time 

points and RBCs were significantly decreased at week 14. Hct, Hg and RBCs were generally 

decreased in females throughout the study (13-18%), but only occasionally achieved statistical 

significance. No overt clinical signs of treatment-related toxicity were observed, and survival, 

body weights, body weight gains and food consumption were also unaffected by compound 

administration.

At 30,000 ppm, hematological effects were more pronounced and increased cellularity of the rib 

and sternum marrow were observed in 1-2 males and females. Absolute and relative liver weight 

were slightly increased (10-24%), but only absolute weight in males was statistically significant 

(24% above controls). An increase in pigmented macrophages was observed in the liver and 

spleen in 1-3 animals in both sexes. Absolute and relative thyroid weights were increased 

(144%/163%), but there was no corresponding histopathology. Bilirubinemia in males was also 

observed.

The LOAEL is 3000 ppm (106.1/110.6 mg/kg/day in males/females), based on hematological 
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effects including mild anemia and methemoglobinemia. The NOAEL is 300 ppm (9.8/12.6 

mg/kg/day in males/females).

This study is classified Acceptable/guideline and satisfies the guideline criteria for a chronic oral 

toxicity study in the dog (OPPTS §870.4100b).

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - rat

See 870.4300, below

870.4200b Carcinogenicity (feeding) – Mouse

In a carcinogenicity feeding study (MRID 44617729), RH-2485 (98.0% a.i.; Sample No. 94-134, 

Lot No. 1) was administered to 60 Crl:CD-1 (ICR) BR (VAF/+) mice/sex/dose in the diet at 

concentrations of 0, 70, 2800 or 7000 ppm for 18 months (intake for males: 0, 10.0, 405, or 1020 

mg/kg/day; for females: 0, 12.8, 529, or 1354 mg/kg/day).

No toxicologically significant differences were found between the treated and control animals of 

either sex. Clinical signs, survival, body weight, and food consumption were comparable in 

treated and control animals. The lower lymphocyte count and alterations in kidney and testes 

weights in males were small in magnitude ( 16%, p < 0.05), not dose-related, and/or lacked 

histopathological correlates. There were no treatment-related gross or microscopic lesions.

The NOAEL is 7000 ppm (1020/1354 mg/kg/day for males/females)(HDT). A LOAEL was 

not established in this study (> 7000 ppm).

There was no evidence of carcinogenicity in male or female mice. The incidence of 

neoplasms found in numerous organs and tissues was comparable in treated and control 

groups. The animals were dosed adequately since their intake exceeded the limit dose of 

1000 mg/kg/day.

Discussion of Tumor Data: There was no evidence of carcinogenicity in this study. 

Adequacy of the Dose Levels Tested: In this study, methoxyfenozide was administered at 

adequate dose levels for carcinogenicity testing since it was tested at the limit dose of 7000 ppm 

(1020 mg/kg/day in males and 1354 mg/kg/day in females). 

This study is classified Acceptable/guideline and satisfies the guideline requirement for a dietary

carcinogenicity study in the mouse (OPPTS §870.4200b)

870.4300 Chronic toxicity/carcinogenicity (feeding) – Rat

In a combined chronic toxicity /carcinogenicity study (MRID 44617731), RH-2485 technical 

(methoxyfenozide 98% a.i.; Lot Number 1, TD94-134) was administered in the diet to 70 male 
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and 70 female Crl:CD®BR rats per group at concentrations of 0, 200, 8000, or 20,000 ppm (0, 

10.2, 411, or 1045 mg/kg/day for males and 0, 11.9, 491, or 1248 mg/kg/day for females) for up 

to 99 weeks in males (only 89 weeks in the 20,000-ppm group) and 95 weeks in females except 

for 10 animals per sex per dose that were sacrificed at 52 weeks for interim evaluation. 

Survival was adversely affected in males at the 20,000-ppm dose level. Survival rates to week 

89 in the 0 and 20,000-ppm groups in the main experiment on males were 28/60 (53% dead) and 

17/60 (72% dead), respectively, with this difference being significant, p<0.05 as calculated by

reviewer. The only significant (p<0.05) effects on absolute body weight, body-weight gain, and 

food efficiency were in the 20,000-ppm females. In approximately the last year of the experiment, reductions in absolute body weight were often to a level of slightly less than 90% that of 

the control. At the end of the experiment, absolute body weight was reduced 17% in females. 

Reductions in body-weight gain were often to a level of about 80% of the control. Reductions in 

food efficiency were about 11% and 49% in the first and second years, respectively.

Treatment-related and significant (p<0.05) hematology changes at the two higher doses consisted 

of small reductions (less than 10% compared to control) in RBC counts, hemoglobin 

concentrations, and/or hematocrit, and these effects were seen in both sexes. At the highest dose, 

there were significant (p<0.05) increases in methemoglobin over the control in both sexes, and 

there was a significant (p<0.05) increase in platelet counts over control in females. Clinical 

chemistry evaluations in both sexes at the two higher doses showed significant (p<0.05) and 

probably treatment-related increases in serum levels of gamma glutamyl transpeptidase (GGT) 

and reductions in total bilirubin in the serum. These two effects on clinical chemistry are of 

uncertain, and probably unlikely, biological significance.

The liver, kidneys and thyroid were identified as targets for RH-2485 Technical toxicity. 

Significant increases (p<0.05) were found in absolute and relative liver weights compared to 

control in both sexes at the 20,000 ppm dose. These ranged up to 23% increase in males and 

24% increase in females at the terminal sacrifice. At the 8000 ppm dose in males at 52 weeks, a 

significant increase (p<0.05) was found in relative liver weight (19%) and a non-significant 

increase was found in absolute liver weight (21%). These changes are consistent with the 

finding of much increased and significant (p<0.01) incidences of periportal hepatocellular 

hypertrophy in both sexes at both the 8000- and 20,000-ppm doses. At the terminal sacrifice, the 

incidences of this lesion in control males and females were 2% and 3%, respectively. [Here and 

below in this paragraph, percents refer to all animals in the main study.] In contrast, in males of 

the 8000- and 20,000-ppm groups, the incidences were 35% and 53%, respectively. In females 

of these same groups at the terminal sacrifice, the incidences were 40% and 70%, respectively. 

An increase in the incidence of the more serious manifestations of chronic progressive 

glomerulonephropathy is thought to have increased the mortality rate of males fed 20,000-ppm 

of the test substance. Microscopic analysis demonstrated two treatment-related lesions in the 

thyroid at the terminal sacrifice: 1) follicular cell hypertrophy in 8000-ppm males (25%, not 

significant) and 20,000-ppm males (31%, p<0.05) compared with 13% in controls; 2) altered 

colloid in 8000 ppm males (22%, not significant) and 20,000 ppm males (24%, not significant) 

compared with 12% in controls as well as in 20,000-ppm females (38%, p<0.01) compared with 

17% in controls. Increases were found at the terminal sacrifice for absolute and relative weights 

of adrenal glands compared to controls in 20,000-ppm males (up to 25%, not significant) and in 
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20,000 ppm females (up to 100%, p<0.05 for relative weight). Similar increases were found at 

the terminal sacrifice for absolute and relative weights of adrenal glands compared to controls in 

8000-ppm males (up to 55%, not significant) and in 8000 ppm females (up to 31%, not 

significant). Numerous other treatment-related microscopic lesions were identified only in 

20,000-ppm females (mainly mineralizations of tissues found in from 7-13% of the animals); 

these were considered secondary changes attributable to uremia that resulted from the chronic 

progressive glomerulonephropathy. No effects attributable to the test material were observed at 

200 ppm. The LOAEL is 8000 ppm (411 mg/kg/day for males and 491 mg/kg/day for 

females), based on hematological changes (decreased RBC counts, hemoglobin 

concentrations, and/or hematocrit in males and females), liver toxicity (increased liver 

weights in males and periportal hepatocellular hypertrophy in males and females), 

histopathological changes in the thyroid (increased follicular hypertrophy and altered 

colloid in males) and possible adrenal toxicity (increased adrenal weights in males and 

females). The absence of treatment-related effects identifies a NOAEL of 200 ppm (10.2 

mg/kg/day for males and 11.9 mg/kg/day for females).

No evidence of carcinogenicity was observed in rats fed RH-2485 Technical at dietary 

concentrations of 200, 8000, or 20,000 ppm for up to 99 weeks. Dosing was considered 

adequate because of the decreases in body weights, body-weight gain, and food efficiency in 

female rats fed the 20,000-ppm diet and because of the decrease in survival in male rats fed 

the 20,000-ppm diet. The highest dose tested for both males and females is also higher than 

the limit dose of 1000 mg/kg/day.

This study is classified Acceptable/guideline and satisfies the guideline requirement for a dietary

carcinogenicity study in the rat (OPPTS §870.4200a)

A.4.6 Mutagenicity

Gene Mutation

870.5100 Bacterial reverse gene 

mutation assay (S. typhimurium strains 

TA 98, TA100, TA1535, TA1537

MRID 44617728

Acceptable/guideline

Dose range 

Negative for gene mutation up to insoluble concentrations (precipitation 

observed at ≥2000 μg/plate) in the presence or absence of S9 metabolic 

activation

870.5100 Bacterial reverse gene 

mutation assay (S. typhimurium strains 

TA 98, TA100, TA1535, TA1537

MRID 44617733

Acceptable/guideline

Dose range 50 to 5000 μg/plate, test material RH-117,236 (metabolite of 

methoxyfenozide)

Negative for gene mutation up to insoluble concentrations (precipitation 

observed at 5000 μg/plate) in the presence or absence of S9 metabolic 

activation.

870.5300 Mammalian in vitro cell 

forward gene mutation assay (CHO 

cells)

MRID 44617734

Acceptable/guideline

Dose range 0.1 to 1250 μg/mL.

Negative for gene mutation up to insoluble concentrations (precipitation 

observed at ≥100 μg/mL) in the presence or absence of S9 metabolic 

activation.
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Cytogenetics

870.5375, Mammalian in vitro 

chromosomal aberration assay (CHO 

cells)

MRID 44617735

Acceptable/guideline

Dose range 0.21 to 1250 μg/mL.

Negative for increased frequency of chromosomal aberration, up to 

concentrations (≥50 μg/mL) at which the mitotic indices were decreased, in

the presence or absence of S9 metabolic activation.

Other Genotoxicity

870.5395, Mouse micronucleus assay

MRID 44617801

Acceptable/guideline

Dose range 500 to 5000 mg/kg (single IP dose).

Negative for increased frequency of micronucleus formation in CD-1 mice at 

24 or 48 hrs postdosing up to the limit dose for this assay.

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study - Hen

Not required and not submitted

870.6200 Acute Neurotoxicity Screening Battery

In an acute oral neurotoxicity study (MRID 44617802), groups of 10 Crl:CD®BR rats/sex/group 

were administered single gavage doses of RH-2485 technical (Toxicology Department Sample 

Number 94-134; Lot No. 1; 98 % active ingredient) at 0 (control), 500, 1000, or 2000 mg a.i./kg. 

The active ingredient was suspended in 0.5% aqueous methylcellulose and administered at a 

constant volume of 20 ml/kg. Functional observational battery (FOB) and motor activity (MA) 

testing were performed prior to administration and within 3 hours (time of peak effect) of dosing 

(day 0), and on days 7 and 14 post-dose. Body weights were recorded pre-test, weekly during 

the study period and on FOB assessment days. Clinical signs were recorded daily. At necropsy 

all rats were perfused in situ and given a limited gross necropsy; six rats/sex/dose (high-dose and 

control) were further processed for neuropathological evaluation at study termination.

All animals survived to scheduled termination. Daily cage-side observations revealed no overt 

signs of treatment-related effects in males or females at any exposure concentration. No 

treatment-related effects on body weight were observed during the study.

There were no observable signs of a neurotoxic effect even at the highest concentration in 

females. FOB assessment on Day 0 (3 hours after dosing) revealed a decrease in hindlimb grip 

strength (% below controls) for males in the 2000 mg/kg group. MA assessment remained 

comparable to controls throughout the study for males and females in all exposure groups.

No neuropathological endpoints were observed during the histological examinations of the 

peripheral or central nervous systems of these animals at any exposure concentration.

Based on the absence of any substance-related effects on body weight or body weight gain 

and any clinical signs of toxicity, the NOAEL for systemic toxicity is a concentration of 
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2000 mg/kg for males and females. The NOAEL for neurotoxic effects is 2000 mg/kg for 

females. Based on a decrease in hindlimb grip strength on day 0 in the 2000 mg/kg male 

group, the NOAEL for males is 1000 mg/kg and the LOAEL for males is 2000 mg/kg. No 

LOAEL was established for systemic effects in males or females or for neurotoxic effects in 

females. 

This study is classified as Acceptable/guideline and satisfies the guideline requirement for an 

acute oral neurotoxicity screening study in the rat (OPPTS §870.6200a).

870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic oral neurotoxicity study (MRID 44617803), groups of Crl:CD®BR rats (10 

rats/sex/group) were administered concentrations of 0, 200, 2000 or 20,000 ppm of RH-2485 

technical (Toxicology Department Sample Number 94-0134; Lot No. 1; 98 % active ingredient) 

in the diet for 3 months. These doses resulted in average daily intake values of 0, 13, 130, and 

1318 mg/kg/day for males and 0, 16, 159, and 1577 mg/kg/day in females for 0, 200, 2000, and 

20,000 ppm, respectively. Functional observational battery (FOB) and motor activity (MA) 

testing were performed prior to administration and in the 4th, 8th, and 13th week of the 

administration period. Body weights were recorded pre-test, weekly during the study period and 

on FOB assessment days. Food consumption was determined weekly for each animal. All rats 

surviving to necropsy were perfused in situ and given a limited gross necropsy. Six/rats/sex/dose 

(high-dose and control) were further processed for neuropathological evaluation at study

termination.

One male in the 20,000 ppm group was found dead during week 5 of the study; this death was 

attributed to a urethral obstruction and was not considered to be treatment-related. All animals in 

all other exposure groups survived to scheduled termination.

Daily cage-side observations and weekly physical examinations revealed no overt signs of 

treatment-related effects in males or females at any exposure concentration. No treatment-related 

effects on body weight, body weight gain, or food consumption were observed during the study.

There were no observable signs of a neurotoxic effect even at the highest concentration in males 

or females. FOB and MA remained comparable to controls throughout the study and no 

neuropathological endpoints were observed during the histological examinations of these animals 

at any exposure concentration.

Based on the absence of any substance-related effects on body weight or body weight gain 

and any clinical signs of toxicity, the NOAEL for systemic toxicity is 20,000 ppm for males 

(1318 mg/kg/day) and females (1577 mg/kg/day). The NOAEL for neurotoxic effects is 

20,000 ppm (1318/1577 mg/kg/day in males/females). A LOAEL was not established for 

either systemic or neurotoxic effects (>20,000 ppm). 

This study is classified as Acceptable/guideline and satisfies the guideline requirement for a 

subchronic oral neurobehavioral screening study in the rat (§870.6200b).
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870.6300 Developmental Neurotoxicity Study

Not required and not submitted

A.4.8 Metabolism

870.7485 Metabolism – Rat

In an oral metabolism study (MRID 44617804), groups of five Crl:CD®BR rats/sex/dose group 

received methoxyfenozide (technical grade, several lots labeled at different positions with 

radiochemical purity ranging from 96.4 to 99.0%) according to the following schedules: a single 

low dose (10 mg/kg labeled with 14 C at the t-butyl, A-ring or B-ring); high dose (1000 mg/kg 

labeled at the t-butyl or A-ring); or diets containing 10 mg/kg unlabeled test material for two 

weeks, followed by a single 10 mg/kg gavage dose of test material labeled on the A-ring. Other 

groups of 3-6 male and 3-6 female rats received five daily doses of 10 mg/kg test material 

labeled on the A-ring or a single low- or high-dose of test material labeled at the t-butyl or Aring to determine pharmacokinetics and tissue distribution. One additional group of 4 male and 4 

female cannulated rats received a single low-dose of test material labeled on the A-ring to 

determine biliary excretion. In a preliminary study, expired air was collected from male and 

female rats that received 1000 mg/kg test material labeled at the t-butyl, A-ring, or B-ring 

positions. It was found that < 0.1% of the administered dose was removed in this manner and no 

further expired air studies were done.

No test material-related deaths occurred and mass balance, ranging from 93-104%, was 

acceptable. The total plasma elimination rate for male and female rats was longer for high dose 

relative to low dose animals; suggestive of metabolic pathway saturation. This particular effect 

was more prominent with female rats, regardless of label position. Following absorption, the test

material was rapidly metabolized and excreted. The highest radiolabel tissue concentrations at 

Cmax (0.25 hours post-treatment) were found in the intestinal tract, stomach, and liver, 

respectively, although at Cmax the liver contained <9% of the administered dose. By 1/2 Cmax, (1-

2 hours post-treatment), radiolabel concentrations in the stomach and liver had decreased to <3% 

of the dose but remained relatively constant in the intestinal tract. Male and female cannulated 

rats excreted 62-70% of the administered dose into the bile and urine, indicating that absorption 

would at least be equivalent. By five days after treatment, the highest concentrations of 

radioactivity were found in the liver (<0.2% of dose) and carcass (<0.1% of dose) with <0.01% 

of the dose in other tissues and organs. No apparent effects attributable to label position or sex 

were noted.

The test material was excreted primarily into the feces with approximately 86-97% of a 10

mg/kg or 1000 mg/kg dose eliminated by this route. Urinary excretion was relatively minor and 

accounted for 5-13% of the administered dose. No substantial quantitative differences in the 

urine and fecal excretion profiles for the different radiolabel positions were observed. 

Elimination of the radiolabel by all treatment groups and both sexes was essentially complete 

within 48 hours of treatment.
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Before excretion, the test material was metabolized principally by O-demethylation and 

oxidative hydroxylation on the A-ring phenyl and/or B-ring methyl groups followed by

glucuronic acid or sulfate conjugation. Cleavage of the amide linkage from either the A-ring or 

B-ring side and conjugation with glycine to form the corresponding substituted hippuric acid 

metabolite was a minor route. No significant sex-related differences in the metabolic disposition 

of the test material were noted, although there were some minor sex-related differences. No 

significant dose-dependent differences in metabolic disposition were found.

This metabolism study in the rat is classified as Acceptable/guideline and satisfies the guideline 

requirement for a general metabolism study (OPPTS §870.7485) in the rat.

870.7600 Dermal Absorption - Rat

In an in vivo dermal penetration study (MRID 44638202), four male rats per experimental group 

were dosed by dermal application to shaved skin of methoxyfenozide as either the a-ring labeled 

14C-RH-1 12,485 80WP (80% a.i.) or the 2F formulation (2% a.i.) at 0.25, 0.025 or 0.0025 

mg/cm2a.i. for 1, 10 or 24 hours. 

Percent absorption of the 80WP formulation at 24 hours was 0.64, 1.02 and 1.83 for the 

respective high to low doses. After washing, 8.90, 9.53 and 7.35 percent of the dose remained in 

the washed skin. Percent absorption of the 2F formulation at 24 hours was 0.44, 0.83 and 3.20 

for the respective high to low doses. After washing, 6.40, 8.85 and 10.64 percent of the dose 

remained in the washed skin. Because of the combination effects of the low doses used and the 

low rates of absorption, the sample assay values tended to be scattered. The absorption patterns

of the two formulations overlapped with no apparent differences. Because of the absorption 

pattern, the quantity remaining in the skin is not expected to add significantly to the total 

absorbed and should not be used for risk assessment.

This study is classified as Acceptable/guideline and satisfies the guideline requirement for a 

dermal absorption study in the rat (OPPTS §870.7600).

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 48592601), Methoxyfenozide (98.0% a.i., Lot #6329B01)

was administered to female Crl:CD(SD) rats (10/dose) in the diet targeted to deliver nominal 

doses of 0, 75, 300, or 1000 mg/kg bw/day (actual doses of 0, 76.9, 324, or 1076 mg/kg bw/day, 

respectively) for 28 days. On Day 25, animals in all groups were immunized with a suspension 

of sheep red blood cells (SRBC) by intravenous injection (2x108SRBC/animal, 0.5 mL/animal 

dose volume). Animals in the positive control group received an intraperitoneal injection of 

cyclophosphamide at a dose of 20 mg/kg bw (1 mL/kg bw dose volume) on Days 24-28. All 

animals were evaluated for mortality, clinical signs, body weight changes, and gross pathology. 

The vehicle control and test substance treatment groups also were evaluated for food 

consumption and hematologic parameters. Immunotoxicity was assessed for all animals by an 

Enzyme-linked Immunosorbent Assay (ELISA). Spleen and thymus weights were measured at 
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necropsy (Day 29) for all animals; liver weights were measured for the vehicle control and test 

substance treatment groups.

There were no test substance treatment-related effects on mortality, clinical signs, body weight 

changes, food consumption, or hematologic parameters. A statistically significant increase in 

relative but not absolute liver weight was found in the 300 and 1000 mg/kg bw/day groups; one 

animal in the 1000 mg/kg bw/day group also had a grossly observable enlarged liver. These 

increases in liver weights were treatment-related and are consistent with previously reported 

results.

The systemic toxicity LOAEL for Methoxyfenozide in female rats is 300 mg/kg bw/day 

(actual dose of 324 mg/kg bw/day), based on increased relative liver weight which was

consistent with previously reported results. The NOAEL for systemic toxicity is 75 mg/kg 

bw/day (actual dose of 76.9 mg/kg bw/day).

For immunotoxicity, there were no test substance treatment-related effects on thymus and spleen 

weights or serum anti-SRBC IgM antibody levels as measured by an ELISA. A high interindividual variability of anti-SRBC antibody level was noted in all the treatment groups as well 

as in the control group. Evaluation of individual animal data of this study did not show any trend 

or distribution that would demonstrate significant suppression of anti-SRBC antibody response. 

Animals in the positive control group showed marked decreases of anti-SRBC abtibody

response. The positive control group confirmed the ability of the test system to detect immunosuppressive effects and confirmed the validity of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database 

for Methoxyfenozide does not reveal any evidence of treatment-related effects on the immune 

system. The only potential evidence of immunotoxicity in the submitted studies was anemia and 

other related blood effects observed in rats and dogs; however, additional parameters indicated 

these effects were compensatory response to the anemia, which was observed primarily after 

chronic dosing. The overall weight of evidence suggests that this chemical does not directly 

target the immune system. Under HED guidance, a NK cells activity assay is not required at this 

time.

Under conditions of this study, the immunotoxicity NOAEL is 1000 mg/kg/day (actual dose 

of 1076 mg/kg/day); the LOAEL was not established. 

This immunotoxicity study is classified acceptable/guideline and satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800) in rats. 
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Appendix B. Physical/Chemical Properties.

TABLE 2 Physicochemical Properties of Methoxyfenozide. 

Parameter Value Reference

Molecular Weight 368.47 D231303; H. Podall; 19 May 1997

Melting point/range (oC) 206.1-208

pH 7.0

Density (g/cm3) 0.740 ± 0.0081

Water solubility (mg/L at 20oC) 3.3

Solvent solubility (g/L at 20oC) N-heptane 1.87

Xylene 3.38

1,2-dichloroethane 36.72

Methanol 192.92

2-Propanol 50.22

Vapor pressure (25oC) 1.33 x 10-5Pa (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.