Methoxyfenozide Hum a n H ea lth Ri sk Assessment DP Barc ode 422208

UNITE D STATES ENV IRONM ENTAL PROTECTION AGENCY WASHINGTON, DC 20460

OFFICE OF C H E MICAL S AFETY A N D
POLLUTION PREVENTION

MEMORANDUM

Date: September 8

, 2015

SUBJECT: Methoxyfenozide. Human H ea l th Draft Risk Assessme nt for Regi stra ti on
R eview and New Use Ri sk Assessment to Su pp o rt the Regi st ration of Pr oposed

Use o n Ch i ves, a nd Crop Group Expans i o n s for S t o n e F ruit a nd Tr ee N ut s

.

P C Co d e : 121027 DP Barcode: 0 422208

, 0427542

Deci s ion No.: 493332?"0S"f3' Re g istrati o n No.: 627 1 9-442: 62719-438 : 62719

- 666;
62719-667

Petition No.: 4E 8 298 Re g ulat ory Action: R eg i stra ti on R ev i ew; Section 3

Case No.: 7431 Ri sk A ss essment T y p e: Single Chemical Aggregate

TXR No.: NA CAS No.: 1610 50- 58-4
40 CFR: 180.544 MRID No.: NA

FROM :

THRO U GH: E l izabeth Ho lm an , Ph ys ic a l Scientis

Wi lli a m T. Dr ew, Chemist
Zaida Fi g ueroa. J ndu stria l Hygienist

Linnea J

. Hansen, Ph .D., Biolo g ist

Ri sk Assessment Branch TI (RABII)

H ealth Effec t s Di v i s ion (7509P)

Chr i st in a Swartz

, Branch C hi ef

# ~~ Ri sk Assessme n t Branch II (RA Bii )

H ealt h E ffects Divis i o n (7509P)

TO: B arbara Madde n an d Andrew Ertman, RM Team 5
Minor Use and Eme rg ency Re s pon se Bran c h ( M UE RB )

R eg i s tra t i o n Di v i sio n ( RD )

, 7505P

AND

Jill B l oom , Team Leade r Ri sk Management and I mplementation Branch V

Pest i c id e R e -evaluation Divi s ion

The R eg istr at i o n Di vis ion ( RD ) requ es ted th at the H ea l t h Effects Di v i s ion ( HED) co ndu c t a ri sk

assessmen t fo r t h e ac tiv e ingredient (ai) methoxyfenozide to estimate the risk to human health

Page I of52Methoxyfenozide Human Health Ri s k Asses s ment DP Barcode 422208

that will result from the proposed new use o n chive

, and crop group conversions for sto n e fruit

an d tr ee nut s.

In addition, th e P es ticid e Re- eva luation Di v i sio n ( PRD ) r eq ue sted that HED conduct a human

health risk assessment based on the curre nt actively registered uses of the insecticide methoxyfenozide. Therefore, this n ew use assessment and registration review assess m ent have

been conducted together as a single assessment. A hwnan health assessment scop in g document

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

to support registration review. The attac h ed human health risk assessme nt addresses exposure and risk associated with the proposed new uses, as well as the existing uses on various agric ultural commodities and orname ntals

. The exposures assessed includ e dietary (food and

wate r )

, inhalation for occupational wo r kers and res id entia l handlers

, and aggregate exposure and

risk for residentia l handlers resulting from use on o rnam en tals. In addition, HED conducted a

s pray drift assessment whic h addressed the potential for incidental oral exposure for ch ildr en

co min g into contact with areas adjacent to treated fields. There were no risks of concern identified for any route or duration of exposure. Further, no label changes are recommended in

co njunction w ith the evaluation of existing uses under registration review.

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Page 3 of 52 

### Table of Contents

1.0 Executive Summary

................................ ................................ ................................ ........... 5
2.0 HED Recommendations

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

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

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

................................ ................................ ............... 8

2.2.2 International Harmonization

................................ ................................ ..................... 8

2.2.3 Recommended Tolerances

................................ ................................ ........................ 9

2.2.4 Revisions to Petitioned

- For Tolerances

................................ ................................ .. 10

2.3 Label Recommendations From Residue Review

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

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

................................ ................................ ................................ ......... 10
3.2 Physical/Chemical Characteristics

................................ ................................ ............. 11
3.3 Pesticide Use Pattern

................................ ................................ ................................ .... 12
3. 4 Anticipated Exposure Pathways

................................ ................................ ................. 13
3.5 Consideration of Environmental Justice

................................ ................................ .... 14
4.0 Hazard Characterization and Dose

- Response Assessment

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

................................ ................................ . 14
4.2 Absorption, Distribution, Metabolism, & Eliminat ion (ADME)

............................. 15
4.2.1 Dermal Absorption

................................ ................................ ................................ .. 16

4.3 Toxicological Effects

................................ ................................ ................................ .... 16
4. 4 Safety Factor for Infants and Children (FQPA Safety Factor)

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

................................ ................................ ...................... 17

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

......... 18

4.5 Toxicity Endpoint and Point of Departure Selections

................................ .............. 18
4.5.1 Dose

- Response Assessment

................................ ................................ .................... 18

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

........ 20

4.5.3 Cancer Classification and Risk Assessment Recommendation

.............................. 20

4.6 Endocrine Disruptor Screening Program

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

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

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

................................ ............... 24

5.1.2 Summary of Environmental Degradation

................................ ............................... 24

5.1.3 Comparison of Metabolic Pathways

................................ ................................ ....... 25

5.1.4 Residues of Concern Summary and Rationale

................................ ........................ 25

5.2 Food Residue Profile

................................ ................................ ................................ .... 26
5.4 Dietary Risk Assessment

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

................................ ..... 28

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................ 29

5.4.3 Acute Dietary Risk Assessment

................................ ................................ .............. 29Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 4 of 52 

### 5.4.4 Chronic Dietary Risk Assessment

................................ ................................ .......... 29

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............ 30

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

................................ ................................ .................... 30
6.2 Residential Post

- Application Dermal & Incidental Oral Exposure

........................ 31
6.4 Residential Risk Estimates for Use in Aggregate Assessment

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

................................ ................................ ................................ .................... 32 6.5.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications

.............. 33

6.6 Residential Bystander Post

- Application Inhalation Exposure

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

................................ ................................ .. 34
7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 35
7.2 Short

- Term Aggregate Risk

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

................................ ................................ .............................. 35
8. 0 Cumulative Exposure/Risk Characterization

................................ ............................... 35
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 36
9.1 Post

- Application Risk

................................ ................................ ................................ .. 38
9.1.1 Post

- Application Dermal Exposure

................................ ................................ ........ 38

9.1.2. Post

- Application Inhalation Exposure

................................ ................................ .... 38

11.0 References

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

................................ .................. 42 Appendix B. Physical/Chemical Properties

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

................................ ................................ ................ 51 Appendix D. Summary of Special Local Need (SLN) Registrations for Methoxyfenozide

. 52Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

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### 1.0 Executive Summary

Interregional Research Project #4 (IR

- 4) has submitted a petition re questing the establishment of permanent tolerance s for residues of methoxyfenozide in or on chive, and crop group conversions for stone fruit and tree nuts

. In addition, methoxyfenozide is currently undergoing registration review and this human health risk assessment has been conducted as part of this
review. Methoxyfenozide (with CAS name 3

- methoxy

- 2

- met hylbenzoic acid 2

- (3,5

- dimethylbenzoyl)

- 2

- (1,1

- dimethylethyl)hydrazide, and CAS number 161050

- 58

- 4) is a diacylhydrazine insecticide used on a wide variety of food and feed crops for the control of lepidopterous pest species. Permanent tolerances are esta blished for residues of methoxyfenozide in or on a wide variety of plant commodities, at levels ranging from 0.02 ppm in peanuts and tuberous/corm vegetables (subgroup 1D), to 400 ppm in Herb Subgroup 19A (40CFR §180.544[a][1]). Permanent tolerances are a lso established for residues of methoxyfenozide in the milk, meat and fat of livestock (40CFR §180.544[a][1]), and for the combined residues of the parent and its glucuronide conjugate (RH

- 141,518) in eggs and meat byproducts at 0.02

- 0.40 ppm (40CFR §180.5 44[a][2]). In addition, tolerances have been
established for indirect or inadvertent residues in a number of commodities (40CFR §180.544[d][1 and 2]) ranging from 0.02 ppm (potato; methoxyfenozide only) to 8.0 ppm (straw
of non

- grass animal feeds, Group 18; methoxyfenozide, its free

- phenol metabolite, and glucose and malonylglycosyl conjugates of the free

- phenol metabolite).

In developing this human health risk assessment, HED has examined the available hazard and exposure information regarding methoxyfe nozide as it re l ates 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 bloo d cells (RBC s ). The most consistent findings across species and studies were decreased RBC parameters and increased liver, thyroid, adrenal and spleen weights. Many of the available short

- term or subchronic toxicity studies showed little or no toxicity. Increases in thyroid and adrenal weights were observed in the rat chronic oral study. Thyroid weights were also increased in the dog following chronic exposure, but no accompanying histopathology was observed.

Toxicological testing indicates that metho xyfenozide is not neurotoxi c or immunotoxi c; it has been categorized as “not likely” to be carcinogenic to humans. There is no evidence of qualitative or quantitative susceptibility of the developing fetus or offspring, based on the developmental and repr oductive toxicity study results. Therefore, b ased 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 e valuated because there wereMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 6 of 52 

### 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 ; therefor e , a dermal endpoint was not selected, and no quantitative dermal exposure and risk assessments were conducted (i.e., there is no hazard via the dermal route)

. As part of conducting the registration review assessment

, HED select ed an endpoint for incidental oral risk assessment that was based on the potential for exposure due to spray drift. However , the potential for direct post

- application oral exposure to children resulting from the existing use of methoxyfenozide on ornamental s is extremely low and was not included in the assessment of incidental oral exposure

. Inhalation risks were assessed using the endpoint
and dose from an oral study, with the assumption that inhalation toxicity would be equivalent to oral toxicity for the purpose of route

- to

- route extrapolation. B ased on a weight of evidence ( WOE) approach, the HASPOC concluded that a 28

- day inhalation toxicity study is not required for methoxyfenozide at this time ( TXR # 0053782 ; 0055054 )

.

The endpoint selected for chronic dietary risk assessment was based on liver and thyroid effects
observed in the chronic / carcinogenicity study in the rat; the blood effects seen in the dog study
were considered co

- critical. For incidental oral and inhalat ion 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 pattern s for the U.S. population and population subgroups, t h is modeling used conservative upper

- bound assumptions regarding residues of methoxyfenozide and its breakdown products in food and drinking water

. Specifically, t he dietary assessment included toleranc e

- level residues from the existing and proposed use s , the assumption of 100% crop treated (CT) for all crops, and high

- end residues in drinking water

, derived from modeling the maximum application rate in vulnerable areas . The highest potential drinking water exposure is from ground water sources. The chronic dietary exposure and risk
estimates are below HED’s level of concern (LOC) of 100% of the chronic population adjusted dose (cPAD) for the general U

. S

. populat i on an d 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 8 4 % cPAD; all other population subgroups had lower risk estimates, including the gener al U

. S

. population at 3 0 % cPAD.

Residential exposures are those that may occur as a result of activities in and around the home,
schools and recreational areas. No new residential uses are associated with the new use on chives and the requested crop grou p conversions currently under review. However, as part of the registration review assessment, HED has conducted a spray drift assessment. Since methoxyfenozide can be applied via ground and aerial equipment to agricultural crops , there is potential for indirect exposure to methoxyfenozide related to spray drift. As a result, incidental oral risk estimates for children 1 to <2 years old were calculated. The highest exposure resulted
from drift following methoxyfenozide applicati ons using aerial equipment for children 1 to <2 years old (margins of exposures (MOEs) ≥ 11,000 with a n LOC ≤ 100). There were no risks of

concern at the field’s edge

.

Prior to 2012, a residential exposure assessment was not performed in conjunction wi th registration of the existing use of methoxyfenozide on ornamentals. Since then an inhalationMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 7 of 52 

### endpoint was selected and the OPP HED Residential Standard Operating Procedures ( SOPs ) were finalized and approved for risk assessment purposes. Therefore, in a previous new

- use risk assessment, HED assessed potential inhalation exposure for residential handlers treating ornamentals in and around home gardens (D388978, M. Collantes et al, 05/23/2012) . The resulting risk estimates are MOEs ranging from 76,000 t o more than 3 million, which are not of

concern.

In accordance with the FQPA, i n evaluating human health risks from exposure to pesticides, HED aggregate s 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 5 4 0 ; this risk estimate is not of concern, since it is significantly higher than
the LOC of 100.

An occupational exposure assessment wa s 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’ inha lation exposure, so HED relied on surrogate data generated by various task
forces. The resulting inhalation risk estimates were MOEs ranging from 450 to 570,000 and were not of concern. A quantitative post

- application e xposure assessment was not complete d due to the lack of dermal toxicity, and because the handlers’ MOEs are expected to be protective
of post

- application exposure via the inhalation route. The 4

- hour REI listed on the registered
labels is consistent with the 4

- hour REI requirements and is adequate to protect agricultural workers from post

- application exposures to methoxyfenozide.

The risk assessment is based, in part, on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies are compliant with applicable ethic al requirements (refer to Appendix C )

.

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment (see Section 3.5).

2.0 HED Recommendations

HED has examined the residue chemistry database for methoxyfenozide. Pending submission of a revised Section F (to propose tolerances an d commodity definitions recommended by HED), there are no residue chemistry issues that would preclude establishing the recommended
tolerances . The recommended tolerances are listed in Table 2.2. 3 , below.

Note s to RD: Upon establishment of the recomme nd ed tolerance in herb subgroup 19A, except chive, fresh leaves, the existing tolerance in h erb subgroup 19A except chive should be remov ed (40CFR §180.544[a][1])

.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

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### Upon establishment of the recommended tolerance in chive , fresh leaves, at 30 ppm (40CFR §180.544[a][1]) , t he existing tolerance for i ndirect or inadvertent methoxyfenozide residues in rotational crop chive s at 4.5 ppm should be removed (40CFR §180.544[ d ][ 2 ]).

Upon establishment of the recommended tolerance in green onion subgroup 3

- 07B except chive

, fresh leaves, the existing tolerance in green onion subgroup 3

- 07B should be removed (40CFR §180.544[a][1]).

Upon establishment of the proposed tolerance in t ree nut group 14

- 12 , the existing tolerance s in tree nut group 14 and pistachio should be removed (40CFR §180.544[a][1]).

Upon establishment of the proposed tolerance in stone fruit group 12

- 12 except fresh prune plum , the existing tolerance in stone fruit group 12 except fresh prune plum should be removed (40CFR §180.544[a][1]).

2.1 Data Deficiencies/Conditions of Registration

None

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The FDA multiresidue methods are not suitable for analysis of methoxyfenozide or its regulated metabolites. However, a dequate sing le 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. T he tolerance enforcement methods include u se of high performance liquid chromatography (HPLC), with either tandem mass spectrometric detection (LC

- MS/MS), or ultraviolet detection (HPLC

- UV)

. It is also noted that the European Food Safety Authority (EFSA) has concluded that the multiresidue QuEChERS method, combined
with an HPLC

- MS/MS, is adequate for tolerance enforcement in plant and animal commodities (EFSA, 2014).

2.2.2 International Harmonization

Codex has not established maximum residue limit s (MRLs) for methoxyfenozide in either green
onions or herbs. Canada’s Pest Management Regulatory Agency (PMRA) has an existing MRL in various green onions/leeks at 5 mg/kg, which is harmonized with the existing tolerance of 5.0

ppm in green onion subgrou p 3

- 07B . PMRA has an existing MRL in various fresh herbs at 80 mg/kg, which is not harmonized with the recommended tolerance of 400 ppm in herb subgroup
19A , nor the recommended tolerance of 30 ppm in chive

. HED cannot recommend for
harmonization of the subgroup 19A tolerance with PMRA’s MRL, because 400 ppm was the result of the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedure for methoxyfenozide residues in basil, and reduction of the tolerance would result in the risk of violative residues resulting from proper use according to labelMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 9 of 52 

### directions. HED also cannot recommend for harmonization of the chive tolerance with PMRA’s MRL, because increasing the recommended tolerance t o 8 0 ppm in chive wo uld result in the risk
of undetected mis use (via seasonal application rates exceeding the label directions )

.

Codex has an existing MRL in stone fruit at 2 mg/kg, which is not harmonized with the
recommended tolerance of 3.0 ppm in stone fruit group 12

- 1 2 except fresh prune plum. HED

can not recommend for harmonization of the group 12

- 12 tolerance with Codex’s MRL, because 3.0 ppm was the result of the OECD tolerance calculation procedure for methoxyfenozide
residues in stone fruit , and reduction of the t olerance would result in the risk of violative residues resulting from proper use according to label directions. PMRA has existing MRLs in various plums/apricots/jujubes/sloes at 0.7 mg/kg, and in various cherries/peaches/nectarines at 6 mg/kg,
neither of which is harmonized with the recommended tolerance of 3.0 ppm in stone fruit group
12

- 12 except fresh prune plum

. HED cannot recommend for harmonization of the group 1 2

- 12
tolerance with PMRA’s MRL s , because EPA’s tolerance is established in the entire c rop group, not in separate subgroups

.

Codex has an existing MRL in tree nuts at 0.1 mg/kg, which is harmonized with the
recommended tolerance of 0.10 ppm in tree nut group 14

- 12. PMRA has an existing MRL in a large variety of tree nuts at 0.1 mg/kg, wh ich is harmonized with the recommended tolerance of 0.10 ppm in tree nut group 14

- 12.

In addition, as part of the registration review process, in spring 2013 HED had discussions with Health Canada (PMRA) about harmonizing tolerances for methoxyfenozide. As a result of these discussions, several commodities were targeted for possible harmonization. These commodities are currently out of harmonization betwe en USEPA and Codex and/or PMRA. Therefore, HED is recommending increasing several tolerances solel y for the purposes of harmonization, specifically those on Bushberry subgroup 13

- 07B; Pea and bean, succulent shelled, subgroup 6B ; and Vegetable, legume, edible podded, subgroup 6A

.

2.2.3 Recommended Tolerances

TABLE 2.2.3. Tolerance Summary for Methoxyfenozide (40CFR §180.544 ). Propose d or Existing * Commodity Proposed or Existing *

Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition ; Comments
40CFR § 180.544[a][1] Fruit, stone, group 12

- 12

, except plum, prune, fresh 3.0 3.0 Conversion from stone fruit group 12 except fresh prune plum

. Nut, tree, group 14

- 12 0.10 0. 1 0 Conversion from tree nut group 14. Herb subgroup 19A, except chive, fresh, leaves 400 400 Herb subgroup 19A , except chive, fresh
leaves ; based on field trial data on dried chives submitted by IR

- 4. Onion, green, subgroup 3

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

- 07B, except chive, fresh leaves

. Based on field trial data on fresh chives submitted by IR

- 4. Chive, fresh, leaves 30.0 30 Chive

, fresh leaves

, b ased on field trial data on fresh chives submitted by IR

- 4. Herb subgroup 19A, except chive * 400* Remove Replace with the tolerance in h erb subgroup 19A , except chive, fresh
leaves

.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 10 of 52 TABLE 2.2.3. Tolerance Summary for Methoxyfenozide (40CFR §180.544 ). Propose d or Existing * Commodity Proposed or Existing *

Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition ; Comments
40CFR § 180.544[a][1] Onion, green, subgroup 3

- 07B * 5.0* Remove Replace with the tolerance in green

o nion subgroup 3

- 07B

, except chive

, fresh leaves

. Fruit, stone, group 12, except plum, prune,
fresh * 3 .0 * Remove Conversion to stone fruit group 12

- 12 except fresh prune plum

.

Nut, tree, group 14 * 0. 1 0 * Remove Conversion to tree nut group 14

- 12.

Pistachio 0.10* Remove Conversion to tree nut group 14

- 12. Bushberry subgroup 13

- 07B * 3.0 * 4.0 Increase tolerance to harmonize with
Codex and PMRA. Pea and bean, succulent shelled, subgroup 6B * 0.2 * 0.3 0 Increase tolerance to harmonize with
Codex and PMRA. Vegetable, legume, edible podded, subgroup 6A * 1.5 * 2.0 Increase tolerance to harmonize with
Codex and PMRA.
40CFR § 180.544[ d][2 ]

Chive* 4.5* Remove Covered by new chive tolerance in §180.544[a][1].

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



### 2.2.4 Revisions to Petitioned

- For Tolerances

HED recommends in favor of IR

- 4’s proposal to remove the chive exception to the existing h erb subgroup 19A except chive tolerance

, concurring with IR

- 4’s proposal to replace it with an exception for fresh chive leave s . The chive field trial data support a tolerance of 30 ppm in/on
fresh chive s, and 300 ppm in/on dried chive s, based on input of the residue data into the Organization for Econom ic Development and Cooperation (OECD) tolerance calculation procedure

. However, dried chives will be covered under herb subgroup 19A , which has an existing tolerance established at 400 ppm. The Agency als o determined that the petitioned

- for

amended tolerance in or on onion, green, subgroup 3

- 07B, except chive should be established in or on onion, green, subgroup 3

- 07B, except chive, fresh leaves. This is due to the fact that only chive, fresh leaves are i ncluded in subgroup 3

- 07B, and the Agency is establishing a separate tolerance for chive, fresh leaves at 30 ppm.

Instead of the proposed tolerance in chive (30.0 ppm), HED recommends establishing the tolerance at 30 ppm. The Agency establishes toleran ces using whole numbers for tolerances of 10 ppm or more, per the OECD’s User Guide ENV/JM/MONO(2011)2 for the OECD tolerance calculation procedure.

2.3 Label Recommendations From Residue Review

None.

3.0 In troduction

3.1 Chemical IdentityMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 11 of 52 

### Methoxyfenozide is a diacylhydrazine insecticide used on a variety of crops for control of armyworms and other lepidopterous pest species. It mimics the action of the molting hormone of lepidopterous larvae, causing the larvae to undergo an incomplete and premature molt, which ultimately results in their death.

TABLE 3. 1

. Methoxyfenozide Nomenclature.

Chemical structure

Common name Methoxyfenozide Company experimental name RH

- 2485

Molecular formula C 22 H 28 N 2 O 3 Molecular weight 368.47

IUPAC name N

- tert

- butyl

- N′

- (3

- methoxy

- o

- toluoyl)

- 3,5

- xylohydrazide

CAS name 3

- methoxy

- 2

- methylbenzoic acid 2

- (3,5

- dimethylbenzoyl)

- 2

- (1,1

- dimethylethyl)hydrazide CAS registry number 161050

- 58

- 4

End

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

- 442)



### 3.2 Physical/Chemical Characteristics

The information regarding physical chemical characteristics of methoxyfenozide does not indicate that there are any special concerns in terms of bioaccumulation, exposure or other risk
assessment consi derations. 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 s kin 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 topica l 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 (K ow 

### ) of 10 3.72 

### which further supports that methoxyfenozide is not easily absorbed by the skin and thus would result in lower dermal exposure.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

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### Although methoxyfenozide is very persistent (t 1/2 

### = 1 to 3 years in soil and water), it is not significantly volat ile, and has a vapor pressure of 1.0 x 10

- 7 

### mm Hg at 25 ̊C. Therefore, significant inhalation exposure to methoxyfenozide is not expected.

3.3 Pesticide Use Pattern

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

.

Methoxyfenozide is a diacylhydrazine insecticide and is active against lepidopterous insects ( moths and butterflies). It is currently registered for use on ornamentals and numerous agricultural crops.

This assessment contains a s ummary of the registered uses and the proposed use of methoxyfenozide to control pests on chives . In addition, a petition to update the crop groups for

s tone f ruit (G roup 12 except fresh prune plums to Gro up 12

- 12 e xcept f resh p rune p lums) and

t ree n ut s ( Group 14 to Group 14

- 12 ) has been requested

.

There are total of four registered Sec. 3 end

- use products (EPs), with three EPs formulated as a liqu id concentrate and one other formulated as water soluble packets (WSP). There are a number of Special Local Need (SLN) registrations, also known as FIFRA Sec tion 24 ( c) registrations (see Appendix D for a complete description). The registered application methods for methoxyfenozide include the use of aerial, ground (groundboom and airblast), chemigation, and
hand held equipment.

Baseline attire is required for handlers

, consist ing of a single layer of clothing ( i.e., long sleeve shirt, long pants, shoes plus s ocks ), along with personal protective equipment such as chemical

resistan t gloves (for 62719

- 442 only ) and no respirator. The restricted entry interval (REI) for methoxyfenozide is 4 hours. Table 3.3 provides a summary of all the uses for methoxyfenozide

.

Table 3.3 . Summary of Directions for Use of Methoxyfenozide

. Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Max. Single

Applic. Rate (lb ai/A) Max. No.

Applic. per
Season Max. Seasonal

Applic. Rate (lb ai/A) Use Directions and Limitations

Registered Uses Bushberries (Subgroup 13 07B), Cilantro Leaves, Brassica (Cole) Leafy Vegetables (Crop Group 5), Leafy Vegetables (Crop Group 4), Leaves of Root and Tuber Vegetables (Crop Group 2), Turnip Greens, Citrus Fruits (Crop Group 10

- 10), Corn (Field, Sweet, Seed), Cotton, Cranberry, Cucurbit Vegetables (Crop Group 9)

, Fruiting Vegetables (Crop Group 8 ), Globe artichoke, Grape, Green Onion (Subgroup 3

- 07B), Legume Vegetables (Succulent or Dried) (Crop Group 6), Legume Vegetables (Except Soybean) (Subgroup 7A), Okra, Peppermint, Pome Fruits (Crop Group 11), Pome granate, Popcorn, Root Vegetables (Subgroups 1A, 1B), Soybean, Spearmint, Stone Fruits (Crop Group 12), Strawberry, Tree Nuts (Crop Group 14) and Pistachios, Tropical Tree Fruits

,

Tuberous and Corm Vegetables (Except Potato) (Subgroup 1D) (on 62719

- 442, 62 719

- 666, 62719

- 667)
Leek, and Shallot (only on 62719

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

- 442
and 62719

- 667)

Broadcast Foliar; Aerial, Ground, Chemigation Intrepid 2F

Flowable
C oncentrate [62719

- 442] 0.25

- 0.4 lb

ai/A 1

- 4

(depending on rate) 1.0 lb ai/A Various p re

- harvest intervals (PHIs) are allowed, ranging from 1 to 30 days. There are
rotational restrictions on the label dependingMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 13 of 52 Table 3.3 . Summary of Directions for Use of Methoxyfenozide

. Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Max. Single

Applic. Rate (lb ai/A) Max. No.

Applic. per
Season Max. Seasonal

Applic. Rate (lb ai/A) Use Directions and Limitations

22.6% ai 2.0 lb ai/gal on the crop. The minimum retreatment interval depends on the crop (see label for specifics).

Broadcast Foliar; Aerial, Ground, Chemigation Intrepid Edge

Soluble
Concentrate [62719

- 666]
28.3% ai 2.5 lb ai/gal 0.08

- 0.35 lb

ai/A 1

- 4

(depending on rate) 1.0 lb ai/A

Broadcast Foliar; Aerial, Ground, Chemigation GF

- 2986

Soluble
Concentrate [62719

- 667]
20.6% ai 1.84 lb ai/gal 0.043

- 0.26 lb

ai/A 1

- 6

(depending on rate) 0.98 lb ai/A

Ornamentals

Broadcast Foliar; Aerial, Ground, Chemigation,
Handheld Equipment Intrepid 2F

Flowable
C oncentrate [62719

- 442]
22.6% ai 2.0 lb ai/gal 0.06

- 0.25 lb

ai/A (4

- 16 fl oz/A)

or 0.025 lb ai/gal 1

- 4

(depending on rate) 0.5 lb ai/A/yr

or 32 fl oz/A/yr Repeat application on a 10

- 14 day interval or

as necessary based upon pest rein festation

. Hand sprayers

– apply until runoff. Allow at least 6 hrs between applications and onset of precipitation to assure thorough spray drying. The spray volume per acre depends on equipment (see specifics on label). Cotton; Pome Fruit (Crop Group 11

- Apples, Crabapples, Loquat. Mayhaw, Pears including Oriental, Quince )

Broadcast Foliar; Aerial
and Ground Equipment. Intrepid

80 WSP
Water Soluble
Packets [ 62719

- 438 ]
80% ai Manufacturing
Use Product 0.05

- 0.4 lb

ai/A 1

- 4

(depending on rate) 1.0 lb ai/A Allow 14 days between applications. Aerial application is allowed only for the last two applications prior to harvest.
The label has no plant

- back interval restrictions
for cotton . For leafy veg etables and root/tuber

crops, the plant

- back interval is 1 year and

“ prohibited” for all other crops. The spray volume per acre depends on the equipment; for cotton (2

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

- 50 gal/A) (see specifics on label).
Proposed Use

Chives

Broadcast Foliar; Aerial
and G round

E quipment. Intrepid 2F

F lowable
C oncentrate [62719

- 442]
22.6% ai 2.0 lb ai/gal 0.06

- 0. 2 5 lb

ai/A 1

- 4

(depending on rate) 1.0 lb ai/A Minimum retreatment interval of 10 days. May

not be applied via chemigation.



### 3.4 Anticipated Exposure Pathways

As a result of the registered and proposed uses of the insecticide methoxyfenozide , humans may be exposed through food and drinking water, since the chemical may be applied directly to growing crops and may reach surface and ground water sources of drinking water. In an occupational setting, applicators may be exposed while handling the pesticide prior toMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 14 of 52 

### application (i.e., mixing/loading), as well as during application. There is also potential for post

application exposure for work ers 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 t here is also potential for dermal exposure , there is no expectation of derma l risk

, based on the lack of dermal toxicity for methoxyfenozide.
Furthermore

, t he potential for post

- application oral exposure to children is not expected since the extent to which you ng children engage in oral

- exposure activities associated with areas where residential ornamentals are grown or u se these areas for prolonged periods of play is low. Finally, there is also the potential for indirect exposure to adults and children from spray drift following agricultural applications. This risk assessmen t 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 considere d 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 po pulation subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns ar e compiled by the U.S. Department of Agriculture under the National Health and Nutrition Examination Survey, What We E at 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 dieta ry 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 a nd 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 toxicologic al database is considered complete for methoxyfenozide. The following studies, which use exposure routes (oral and dermal) consistent with potential human exposure scenarios, have been submitted: primary acute toxicity, irritation and dermal sensitizati on; subchronic oralMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 15 of 52 

### 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 toxic ity; 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 st udy is not needed for methoxyfenozide, based on a weight of evidence (WOE) approach that considered all of the available hazard and exposure information, including physicochemical properties and the use of a highly conservative oral point of departure (POD )

. With the exception of a single occupational exposure MOE of 450, all residential and occupational exposure MOEs for risk via the inhalation route were above 1000 and ranged from 9,600 to 3,500,000 (TXR #0053782, 4/17/12 ; TXR# 005487 ).

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

In the rat, 14 

### C

- radiolabeled methoxyfenozide was rapidly absorbed following gavage administration, with maximum peak plasma concentrations observed within 15 minutes of dosing. Peak plasma concentrations following dosing at 10 mg/kg ranged from 0.70 to 1.09 ppm in males and 0.5 to 0.59 ppm in females, depending on the ring location of the radiolabel; at the
1000

- mg/kg dose, peak levels were 26.11

- 35.52 ppm in males and 21.92 to 29.74 ppm in females. Plasma elimination was biphasic, with an α

- phase T 1/2 

### of 0.2 to 0.6 hr and a β

- phase

T 1/2 

### of 15.2

- 35.6 hr and showed some variation with radiolabel location. The total plasma elimination rate was longer for the high dose compared to the low dose animals, suggesting metabolic pathway saturation, and the effect was more prominent in female rats. Radioactivity was extensively distributed among tissues, with the highest concentrations at C max 

### (0.25 hr) observed in the intestinal tract, stoma ch, liver and residual carcass. Enterohepatic circulation was observed. Methoxyfenozide did not show evidence of bioaccumulation: by 5 days’ post

treatment, the highest levels were observed in the liver and carcass, but tissue radioactivity in all
tissu es was insignificant by that time. Excretion of radiolabel was essentially complete by 48 hrs post dosing. Based on the minimal level of radioactivity in tissues at 72 hours, absorption was estimated to be at least 62 to 70% of the administered dose (bil iary 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.

Metho xyfenozide 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 co mpound, seven major metabolites were identified in excreta. These included RH

- 131,157; RH

- 141,581 and RH

117,236; these metabolites were also identified in crops or livestock. Up to 25 metabolites were isolated from urine, but the majority represented <1

- 2% of the radioactive dose. Up to 16 metabolites were identified in the feces, including the parent compound, with only six containing ≥5% of the administered radiolabel. The major fecal metabolites in all groups were products of
Phase I O

- demethylation and oxidative hydroxylation noted above. Levels of excreted parent compound in the feces were greater in animals receiving 1000 mg/kg test material (30 to 39% of dose) when compared to the 10 mg/kg groups (14

- 26% of dose), consistent with saturation ofMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 16 of 52 

### a bsorption. 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 th is low level of absorption, a 28

- day dermal study in the rat showed no toxicity up to the limit dose (1000 mg/kg/day).

4.3 Toxicological Effects

Many of the available short

- term or subchronic toxicity studies on methoxyfenozide showed
little or no toxici ty. 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 C max 

### , but levels decreased and bioaccumulation was not observed. Levels in the blood were negl igible.

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 methemoglobinemi a and RBC structural abnormalities. Increased platelets were also observed. An increase in the cellularity of rib and sternum bone marrow, along with macrophage pigmentation in the liver and spleen, were reported in the dog. No significant hematological changes were seen in the dog or rat subchronic studies, or the rat two week range

- finding studies; however, hematological effects were observed in the dog two week range

- finding study, along with increased spleen weight. The data suggest that a compensat ory 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
fin dings 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 hyp ertrophy of the zona fasciculata, and increased thyroid follicular cell hypertrophy/hyperplasia were also observed; however, these findings were not seen with subchronic exposure. Thyroid hypertrophy and altered colloid and increased adrenal weights were observed in the rat chronic oral study, and the incidence and severity of chronic progressive glomerulonephropathy was increased. Thyroid weights were increased in the dog following chronic exposure, but there was no accompanying histopathology.

In the m ouse, 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.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 17 of 52 

### 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 m ales and was not observed in the subchronic neurotoxicity study and was therefore not considered evidence of neurotoxicity. No clinical signs of neurotoxicity or neurohistopathology were observed in other guideline studies.

No maternal or developmental e ffects 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 r eproductive 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.

Ther e 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
metho xyfenozide. Based on these findings, methoxyfenozide is classified as “not likely to be carcinogenic to humans” (2005 Agency revised carcinogenicity assessment guidelines).

4.4 Safety F actor 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 t hat 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 o f the Toxicology Database

The database is considered complete with res pect 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 subchro nic 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 maleMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 18 of 52 

### rats on Day 0 of the acute neurot oxicity 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 subchr onic 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 susceptibili ty 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 two

generation 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 outsta nding 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 me thoxyfenozide and potential uncertainties regarding the long

- term drinking water exposure associated with the use of methoxyfenozide

, and has used a highly conservative approach in deriving modeled drinking water values for the purpose of risk assessment

. The aggregate assessment for adult handlers only includes exposure from the existing use on ornamentals based on high

- end default assumptions, combined with the conservative dietary exposure assessment summarized above.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

A toxicity profile table is provided in Appendix A.2 of this document. For detailed summaries of the toxicity studies considered in the selection of toxicity endpoints for exposure assessment, please s ee the recent 2013 detailed risk assessment document (D407285, E. Holman et al., 08/06/2013). The toxicity endpoint selections have been updated since the 2013 assessment and the more recent 2014 assessment on pineapple (D420583, E Holman et al., 05/30/20 14) to
include a short

- term incidental oral endpoint for potential exposure resulting from potential spray drift (see Appendix A.3). No new toxicity data have been evaluated as part of this current

assessment.

For acute dietary exposure assessment, the rat acute oral neurotoxicity study was considered for selection of a dose and endpoint. This study was not selected because the only finding was decreased grip strength in males on Day 0 (day of dosing) at the limit dose of 2000 mg/kg; no toxicity was ob served 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 (100 0Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 19 of 52 

### 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 ye ar) 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 exceedin g 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
d etermination 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 m g/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 to xicity 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 hig her dose
levels.

For short

- term incidental oral exposure the two week dietary study in the dog was selected because it provided the most sensitive dose and endpoint available (NOAEL = 16.8 mg/kg/day, based on hematological effects at the LOAEL of 90.8 m g/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 (effec ts 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 v ery conservative, but protective of all populations that may be exposed, including young
children.

For dermal exposure (all durations, residential and occupational exposure), an endpoint was not
selected. The rat 28

- day dermal toxicity study demonstrat ed 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 r at reproductive toxicity study. However, the effects observed in the oral studies, which included liver hypertrophy and hematologic parameters, were evaluatedMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 20 of 52 

### in the 28

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

s tudies 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 protect ive of sensitive populations, including potential developmental effects.

Although a 28

- day inhalation toxicity study has not been submitted, HED has determined that this study is not needed for methoxyfenozide, based on a weight of evidence (WOE) approa ch that considered all of the available hazard and exposure information (TXR #0053782, 4/17/12; TXR# 0053782). With the exception of a single occupational exposure MOE of 450 (for liquid formulations with mechanically

- pressurized handgun, baseline with no respirator)

, all residential and occupational exposure MOEs for risk via the inhalation route were above 1000 and ranged from 9,600 to 3,500,000

. The oral endpoint selected for this risk assessment is considered highly
conservative because the observed h ematological changes appeared to be adaptive, and were not consistently observed in the subchronic or chronic dog studies. Furthermore, the vapor pressure and Henry’s law constant are very low, indicating low potential for volatilization. Based on
these considerations, an inhalation toxicity study was not required.

Therefore, the two week dietary study in the dog was selected for both short

- and intermediate

term inhalation exposure because it provided the most sensitive dose and endpoint available (NOAE L = 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 teste d. The rationale for selection of this study is described above for incidental oral exposure. In light of the conservative endpoint, low acute inhalation toxicity of methoxyfenozide, low vapor pressure and low application rates for current use patterns, this oral study is considered to be protective for potential inhalation toxicity.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Dermal exposure was not assessed due to a lack of toxicity via the dermal route. Since adults were assessed for potential inhalation exposure while applying methoxyfenozide to ornamentals, this exposure should be combined with background levels in food an d water to determine
aggregate exposure. For children’s residential exposure, oral post

- application exposure was not assessed; only exposure from background levels of food and drinking water were assessed. For occupational workers, only inhalation exposure and risk were assessed.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Methoxyfenozide is classified as “not likely to be carcinogenic to humans,” according to the revised 2005 Agency Guidelines for Carcinogen Risk Assessment. Th e 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 Endpoin ts Used in Human Health
Risk AssessmentMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 21 of 52 

### Tables 4.5.4.1 and 4.5.4.2 , below, summarize the dose and endpoint selection for dietary/non

occupational and occupational exposure:

Table 4 .5. 4. 1

. Summary of Toxicological Doses and Endpoints for Methoxyfenozide for Use in Dietary
and Non

- Occupational Human Health Risk Assessments

.

Exposure/
Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary ( All Population s , 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 UF A = 10X

UF H = 10X FQPA SF= 1 Chronic RfD =

0.10 mg/kg/day

cPAD = 0.10 mg/kg/day Co

- critical studies:

Combined oral chronic toxicity/carcinogenicity

- rat LOAEL = 411/491 mg/kg/day [M/F],
based on hematological changes (decreased RBC parameters), periportal liver hypertrophy, thyroid hypertrophy and altered colloid; possibly increased adrenal weight.

Chronic oral toxicity

- dog NOAEL = 9.8/12.6 mg/kg/day[M/F] LOAEL = 106.1/110.6 mg/kg/day,
based on hematological changes (decreased RBC parameters, slight methemoglobinemia) and increased
serum bilirubin.

Incidental
Oral Short

Term (1

- 30
d ays) NOAEL =

16.8 mg/kg/day UF A = 10X

UF H = 10X Residential

LOC for MOE

≤ 100 Two

- week oral range

- finding study

- dog

LOAEL = 90.8 mg/kg/day

, based on hematological changes (decreased RBC parameters, increased Heinz body count, reticulocyte counts, erythrocyte morphology and methemoglobinemia) and increased spleen weights.

Dermal Short

Term (1

- 30 days) or Intermediate

term (1

- 6 months) No toxicity, i.e., no hazard, was identified for dermal exposure.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 22 of 52 Table 4 .5. 4. 1

. Summary of Toxicological Doses and Endpoints for Methoxyfenozide for Use in Dietary
and Non

- Occupational Human Health Risk Assessments

.

Exposure/
Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Inhalation
Short

- Term (1

- 30 days)
and
Intermediate

Term (1

- 6 months) NOAEL =

16.8 mg/kg/day (Inhalation toxicity
considered equivalent to
oral toxicity

. ) UF A = 10X

UF H = 10X Residential

LOC for MOE

≤ 100 Two

- week oral range

- finding study

- dog

LOAEL = 90.8 mg/kg/day

, based on hematological changes (decreased RBC parameters, increased Heinz body count, reticulocyte counts, erythrocyte morphology and methemoglobinemia) and increased spleen weights.

Cancer (oral, dermal, inhalation) Classification: not likely to be carcinogenic to humans

.

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 lev el. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Fa ctor. 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 Short

Term (1

- 30 days) or Intermediate

Term (1

- 6 months) No toxicity, i.e., no hazard, was identified for dermal exposure

Inhalation
Short

- Term (1

- 30 days) and
Intermediate

T erm (1

- 6 months) NOAEL =

16.8 mg/kg/day (Inhalation toxicity
considered equivalent
to oral toxicity.) UF A = 10X

UF H = 10X Occupational

LOC for MOE ≤
100 Two

- week oral range

- finding study

- dog

LOAEL = 90.8 mg/kg/day

, based on hematological changes (decreased RBC parameters, increased Heinz body count, reticulocyte counts, erythrocyte morphology and methemoglobinemia)
and increased spleen weights.

Cancer (oral, dermal, inhalation) Classification : not likely to be carcinogenic to humans

.

Point of Departure (POD) = A data point or an estimated 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. UF A = extrapolation from anima l to human (interspecies). UF H = potential variation inMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 23 of 52 sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable



### 4.6 Endocrine Disrupt or Screening Program

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects o n endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates
acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision for methoxyfenozide , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment
scenarios from the existing hazard database. However, as required by FFDCA section 408(p), methoxyfenozide is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tier ed approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemic als that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the availabl e data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and
establish a dose

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

Under FFDCA section 408(p), the Agency must screen all pe sticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients (a.i.’s) and 9 inert ingredients. A
second list of chemicals identified fo r EDSP screening was published on June 14, 2013 1 

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

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

For further inform ation on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our
website. 2

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals

2 http://www.epa.gov/endo/Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 24 of 52 

### 5.0 Dietary Exposure and Risk Assessment

For the purposes of the new use and the registration review assessment, adequate residue data are available, including metabolism, field and rotational crops, storage stability, and analytical
method studies.

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

A cceptable 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 methoxyfen ozide 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, a pples, 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, methoxyfeno zide.

However, in rotational crops and livestock, additional metabolites are included in both the tolerance expression and the risk assessment. The metabolites identified in the rotational crops were not similar to those found in the primary crop metab olism study. 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 synthes is pathway. T he residues of concern in rotational crops include methoxyfenozide, its free phenol metabolite (RH

- 117,236), conjugated forms of the phenol metabolite (RH

- 151,055 and RH

- 152,072), and the metabolites RH

- 152,067 ; RH

- 131,157
and RH

- 152,071. Fo r 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 low

- moisture crops.

T he residue of concern in milk and ruminant tissues (other than liver and kidney) is parent compound; in ruminant liver and kidney methoxyfenozide and its RH

- 141,518 metabolite are of

concern

. The residue of concern in poultry meat (muscle) and fat is parent methoxyfenozide; however, in eggs, poultry liver, and poultry meat byproducts, residues of concern include methoxyfenozide and its metabolite, RH

- 141,518.

5.1.2 Summary of Environmental Degradation
Memo, K. Milians, Ph.D

. , Chemist, 8/17/2011, D388876



### Methoxyfenozide is very persistent (t 1/2 

### = 1 to 3 years in soil and water) and moderately mobile (K oc 

### = 219

– 922 L/kg oc 

### in various soils). It is stable to photolysis and hydrolysis, is not significantly volatile, and degrades only very slowly by microbial activity. Degradates are predominantly RH

- 117

, 236 ( 3,5

- d imethylbenzoic acid N

- tert

- butyl

- N’

- (3

- hydroxy

- 2

-

m ethylbenzoyl)hydrazide) and RH

- 131

, 154 ( 3

- [ N

- tert

- butyl

- N’

- (3

- methoxy

- 2

- methylbenzoyl)

-Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 25 of 52 

### hydrazinocarbonyl]

- 5

- methylbenz o ic a cid), but these are only present at low concentr ations. 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 dos e

- 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

- 141,5 1 8 and RH

- 117,236, which were also identified in crops or livestock.

Metabolism of methoxyfenozide in other animals (poultry and ruminants) appears to be similar
to its metabolism in rats. Although m ethoxyfenozide 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 pathwa y. 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 residu es 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 t o 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, bas ed 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
simi lar to that of the parent ; the potential for significant levels in crops and livest ock ; as well as
the metabolites determined by the enforcement methods (as described below)

.

Primary Crops : B ased on acceptable metabolism studies in cotton, apples, grapes and rice , t he 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 prim a ry 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 m eatMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 26 of 52 

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

are methoxyfenozide and its RH

- 141,518 m etabolite

.

Rotational Crops: The nature of methoxyfenozide residues in rotational crops is a dequately 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 low

moisture 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 d egradates : RH

- 117

, 236 and RH

- 131

, 154

, but these are only present at low
concentrations.

The toxicological and residue chemistry databases for methoxyfenozide have been examined to
determine residue definitions for the purposes of setting tolerance s and risk assessment s . 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 m ethoxyfenozide and

metabolites

, RH 117,236; RH 151,055; RH 152,072; RH

- 152,067 ; RH

- 131,157 ; and RH

- 152,071 Parent m ethoxyfenozide, and metabolites

RH

- 151,055 ; RH

- 152,072 ; and RH

117,236

Livestock Ruminant Parent m ethoxyfenozide and
metabolite RH

- 141,518 Parent methoxyfenozide and metabolite

RH

- 141,518

Poultry Parent methoxyfenozide and

metabolite 141,518 Parent methoxyfenozide and metabolite

RH

- 141,518

Drinking Water Parent m ethoxyfenozide and degradates RH

- 117

, 236 and RH

131

, 154 Not Applicable

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

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

.



### 5 .2 Food Residue Profile

D425285, W. Drew, 31 March 2015 ; D429009, W. Drew, 09/08/2015 D408668, L. Hansen , 05/10/2013



### The residue chemistry database supporting the registered uses is complete. Acceptable studies are available depicting the metabolic fate of methoxyfenozide in target crops, rotational crops, and livestock. The main distinction between study results was t hat although methoxyfenozide does not undergo extensive metabolism in primary crops, it is highly metabolized in livestock and rotational crops. Acceptable analytical methods are available to enforce the establishedMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 27 of 52 

### tolerances

. T he tolerance expression s for methoxyfenozide listed in 40CFR §180.544 are appropriate , and include both coverage and compliance statements for enforcement purposes

.

The data submitted in support of the current action (PP#4 E 829 8 ) along with previously reviewed data, are adequate for purposes of risk assessment and tolerance assessment for the proposed use
under review. The available storage stability data are adequate, and support the storage conditions and durations for samples from the submitted chive field trials. Maximum residues of methoxyfenozide are expected to occur at moderate to high levels (up to 3 0 ppm in fresh chive
leaves , and up to 30 0 ppm in dried chive leaves) from the new use on chives proposed in the
current p etition. The results from these field trials are summarized in Table 5.2.

M ethoxyfenozide residues generally tend to decline or remain stable with increasing PHI, and do not increase to any significant degree. Following foliar applications, methoxyfenoz ide is present primarily as surface residues; translocation does not appear to be extensive. In general, methoxyfenozide residues do not tend to concentrate in processed fractions, other than via dehydration or from surface residues.

Residues of methox yfenozide are not expected to accumulate above the LOQ in rotational crops planted at PBIs of 7 days following application of methoxyfenozide to primary crops.

Adequate livestock feeding studies are available for methoxyfenozide. No livestock feeding
studies were submitted with this petition. The currently established tolerances for residues of methoxyfenozide and its metabolites in livestock commodities are adequate to support the proposed new use on chive, the proposed crop group conversions, and all existing registered

uses

.

T able 5. 2. Summary of Residue Data from Chive Field Trials with Methoxyfenozide. Commodity Total Use

Rate (lb ai/A) PHI

(Days) Residue Levels (ppm) 1

n Min. Max. HAFT 2 Median Mean Std

. Dev

. Chives (Fresh Leaves) 0 .994

- 1.00 1 6 5.7 13 12.5 7.1 8.6 3.1
Chives (Dried Leaves) 1 6 12 118 115 64 64 46

1. HAF T = Highest Average Field Trial.
2. Except for sample min imum and max imum , values reflect per trial averages; n = number of field trials.



### 5.3 Water Residue Profile
D422209, K. Milians, 12/09/2014 D416709, I. Negrón

- Encarnación, 12/19/2013



### Estimated d rinking water concentrations (EDWCs) were generated using the FIRST model (FQPA Index Reservoir Screening Tool) for surface water, the SCI

- GROW (Screening Concentration In GROund Water (SCI

- GROW v2.3, Jul. 29, 2003) and PRZM

- GW (Pesticide Root Zone Model for Groundwater, version 1.0, August 31, 2012) models for groundwater. These were the highest EDWCs obtained (of all registered methoxyfenozide uses) and were
based on the fruiting vegetable use represented by the WI corn scenario in PRZM

- GW

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

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

- assessed uses,

EFED refers to the previous assessment for a new use on pineapple ( D416709, I. Negrón

Encarnación, 12/19/2013 ). T he EDWCs for the pineapple use are lower than the EDWCs fromMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 28 of 52 

### the fruiting vegetable use mainly due to lower application rate of the pineapple use (0.44 lb a.i./A/year) compared to the fruiting vegetable use (1.0 lb a.i./ A/year). The EDWC used in this assessment is bolded in the table below, with the value of 214 ppb coming from the groundwater residues estimated by the PRZM

- GW model, as recommended by EFED for chronic dietary risk

assessments.

There remains an outstan ding 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 i t 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 environm ental 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 us ed a conservative approach to modeling potential residues in ground water sources of drinking water.

Table 5.3. Tier I estimated drinking water concentrations (EDWCs) resulting from applications of methoxyfenozide

. FIRST
Drinking water source Use (modeled rate) Peak Day Concentration (ppb) Annual Average Concentration (ppb)

Surface water ( aerial application ) Pineapple

(0.11 lb a.i./A x 4 applic.; total of 0.44 lb ai/A/yr) 23.5 7.57

SCI

- GROW
Drinking water source Use (modeled rate) Screening Concentration (ppb)

Groundwater Pineapple

(0.11 lb a.i./A x 4 applic.; total of 0.44 lb ai/A/yr) 1.76

PRZM

- GW

Crop/Scenario Highest Daily value (μg/L) Post Breakthrough

Average (μg/L) Average Simulation

Breakthrough Time (days)

Pineapple/WI corn 108 93.1 8685
Fruiting Vegetable/WI corn 251 214 8684.63



### 5.4 Dietary Risk Assessment
Memo, E. Holman, 09/08/2015

, D 4 26657



### 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 aMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 29 of 52 

### processing factor of 0.2 X for orange juice (D 358341, D. Rate, 6/10/2009) from a reviewed processing study . The existing tolerances for livestock commodities were considered adequate ( D 4 25285

, W

. Drew

, 31 March 2015 ).

Drinking water was incorporated directly into the dietary assessment using the maximum chronic
concentration for ground water generated by the Pesticide Root Zone Model

– Ground Water (PRZM

- GW) at 214 ppb.

5.4.2 Percent Crop Treated Used in Dietary Assessme nt

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 di etary exposure; therefore, no acute dietary risk assessment was performed.

5.4.4 Chronic Dietary Risk Assessment

An unrefined chronic dietary analysis for methoxyfenozide was conducted using tolerance

- level residues and 100% CT for all existing and proposed primary crop uses, and additional residues of
concern in livestock commodities and rotational crops . Methoxyfenozide chronic dietary (food + drinking water) exposure estimates using the DEEM

- FCIDTM software are below HED’s LOC for the U.S. populat ion and each of the population subgroups. Chronic dietary exposure was 3 0 % 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 8 4 % of the cPAD. The results o f 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 f

r om food and drinking water is expected to be significantly lower than the exposures presented in Table 5.4.4.

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

.

Table 5.4

. 4

. Summary of Dietary (Food + Drinking Water) Exposure and Risk for Methoxyfenozide.

Population Subgroup Acute Dietary
95 th Percentile Chronic Dietary Cancer

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

General U.S. Population

N/A 2 0.030975 30 

### N/A 2 

### N/A
All Infants (<1 year old) 0.046676 4 6



### N/A N/A Children 1

- 2 years old 1 0.085216 84

Children 3

- 5 years old 0.064809 64

Children 6

- 12 years old 0.035914 35

Youth 13

- 19 years old 0.023505 23Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 30 of 52 Table 5.4

. 4

. Summary of Dietary (Food + Drinking Water) Exposure and Risk for Methoxyfenozide.

Population Subgroup Acute Dietary
95 th Percentile Chronic Dietary Cancer

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

Adults 20

- 49 years old 0.027082 2 7

Adults 50

- 99 years old 0.026924 2 6

Females 13

- 49 years old 0.027696 2 7

1 The subpopulation with the highest risk estimate.

2 N / A = Not Applicable; no acute dietary endpoint or cancer endpoint was identified for these population subgroups

.



### 5.4.5 Cancer Dietary Risk Assessment

HED classified methoxyfenozide as “not likely to be carcinogenetic to humans” and, therefore,
cancer risk is not of concern for methoxyfenozide

.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization
M. Collantes, D389739, 02/27/12 Memo, Z. Figueroa

, D426658, 09/09/2015



### There are no new proposed residential uses at this time; however, there are existing residential
ornamental uses that were previously reassessed to reflect updates to HED’s 2012 Residential
SOPs 3 

### along with policy changes for body weight assumptions (M. Collantes, D389739, 02/27/12)

. In order to incorporate residential exposure into the short

- term aggregate risk

assessment, a summary of the residential exposure and risk estimates resulting from the use of methoxyfenozide on o rnamentals is provided below

. In addition, as part of the registration review assessment, a spray drift assessment has been conducted due to the potential for indirect exposure to adults and children from spray drift following agricultural applications.

6.1 Residential Handler Exposure

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

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

,

 Mixing/Loading/Applying for Sprays with Back

- Pack Sprayer , and

 Mixing/Loading/Applying for Sprays wit h H ose

- end Sprayer

.

HED’s LOC is a MOE greater than or equal to 100 for residential exposure. A quantitative
dermal ass essment for residential handlers was not conducted since there is no systemic toxicity

3 Available: http://www.epa.gov/p esticides/science/residential

- exposure

- sop.htmlMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 31 of 52 

### 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. R esidential 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

Pressur ized
Handwand 0.025 5 0.018 0.0000283 590,000

Liquid with
Back Pack 5 0.14 0.00022 76,000

Liquid with

Hose

- end Sprayer 11 0.0014 0.00000484 3,500,000

a. In accordance with the registered label Intrepid® 2F (Reg. No.: 62719

- 442) : 0.025 lb ai per gallon for treatment of ornamentals (0.25 lb ai/A ÷ 10 gallons/A for mist blowers and air blast sprayers)

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

.

c. Inhalation D ose (mg/kg/day) = I nhalation U nit E xposure (mg/lb ai) * A pplication R a te * Amount treated / B ody

W eight ( 80 kg)

. d. Inhalation MOE = NOA E L (16.8 mg/kg/day)/ Inhalation Dose (mg/kg/day) . LOC=100.



### 6.2 Residential Post

- Application Dermal & Incidental Oral Exposure

Although there is potential for post

- application dermal exposure to adults and children (6 to < 11

years old ) as a result of the use on ornamentals or from treated ornamentals purchased at a retail location, a dermal endpoint was not selected. Therefore, a dermal post

- application exposure
assessment was not conducted.

Furthermore, t he potential for post

- application oral exposure to children is not expected as a result of the use on ornamentals . Therefore

, an incidental oral post

- application exposure
assessment was not conducted

.

6.3 Inhalation Post

- A pplication Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issu es related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120 109meeting.html). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219).Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 32 of 52 

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

- specific inhalation toxicological studies) or further analysis is required for methoxyfenozide.

6.4 Residential Risk Estimates for Use in Aggregate Assessment

The recommended residential exposure estimate for use in the adult aggregate assessment has not changed since the 2012 assessment (M. Collantes, D389739, 02/27/12)

. HED selected the most conservative residential adult scenario to be included in the aggreg ate assessment; t he recommended residential exposure scenario for use in the adult aggregate assessment reflects
residential handler inhalation exposure from applications to ornamentals via backpack sprayer.
The estimated risk estimate for this scenario r esulted in a MOE of 76,000, which is greater than
the LOC of 100 and is not of concern. Table 6

. 4 reflects the residential exposure estimate that is recommended for use in the aggregate assessment for methoxyfenozide.

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

Lifestage Residential Handler

Dose (mg/kg/day) 2 MOE 3

Dermal Inhalation Total Dermal Inhalation Total

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

Child N/A

1. Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.
2. Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed in Table 4.1.2 located in D389739

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

.



### 6.5 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those the chemical may di rectly contact. Sprays can also deposit on surfaces where individuals come into contact with residues on these surfaces, lead ing to indirect exposures (e.g., children playing on lawns where residues have deposited next to treated fields).

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory re quirements intended to prevent them 4



### . [ Direct exposures would include inhalation of the spray plume or being sprayed directly. ] Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, such as residential lawns, when compliant applications are conducted. Given this premise, exposures for children (1 to <2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indirect
exposure are t he focus of this analysis analogous to how exposures to turf products are
considered in risk assessment.

4 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 33 of 52 

### In order to evaluate the drift potential and associated risks, an approach based on drift modeling coupled with techniques used to evaluate resident ial uses of pesticides was utilized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to address drift from the agricultural applications of methoxyfenozide . In the spray drift scenario, the deposited residue value was determined based on the amount of spray drift that may occur at varying distances from the edge of the treated field using the AgDrift (v2.1.1) model and the Residential Exposure Assessment Standard Operating Procedures Addenda 1: Conside ration of Spray Drift Policy . Once the deposited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the 2012 Standard Operating Procedures for Residential Risk Assessment (S OPs)

.

A screening approach was developed based on the use of the AgDrift model in situations where specific label guidance that defines application parameters is not available 5 6 

### . AgDrift is appropriate for use only when applications are made by aircraft , airblast orchard sprayers, and groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 1 option) were incorporated into the model and represent each equipment type and use under varied conditions. The screening opt ions specifically recommended in this methodology were selected because they are plausible and represent a reasonable upper bound level of drift for common application methods in agriculture. These screening options are consistent with how spray drift is considered in a number of ecological risk assessments and in the process used to develop drinking water concentrations used for risk assessment. In all cases, each scenario is to be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are not allowed). Section 6.5 .1 provides the screening level drift related risk estimates.

In many cases, risks are of concern when the screening level estimates for spray drift are used as the basis for the analysis. In order to account for this issue and to provide additional risk management options additional spray drift deposition fractions were also considered. These drift
estim ates represent plausible options for pesticide labels

.

6.5 .1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications

Methoxyfenozide is used on a variety of agricultural crops (e.g., cotton, tree nuts, etc) and can be applied via groundboom , airblast and aerial equipment . The spray drift risk estimates are based on an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. The potential risk estimates from these residues ca n be calculated using drift modeling onto 50 feet wide lawns coupled with methods employed for residential risk assessments for turf products. The recommended drift scenario screening level options are listed
below:

• Groundboom applications are based on the AgDrift option for high boom height and using very fine to fine spray type using the 90th percentile results.

5 http://www.agdrift.com/

6 Note that for many cases the scenarios outlined in the screening approach represent act ual use practice so risk assessors should be aware and characterize these appropriately.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 34 of 52 

### • Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fine to
medium spray type and a series of other parameters wh ich will be described in more detail below (e.g., wind vector assumed to be 10 mph in a downwind direction for entire application/drift event).

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

The spray drift assessment is based on incidental oral exposures only . The highest exposure resulted from drift following methoxyfenozide applications using aerial equipment for children 1 to <2 years old (margins of exposure (MOEs) ≥ 11,000 , with a LOC =100). The re are no risks of concern at the field’s edge (i.e., assuming a residential lawn is directly adjacent to a field where agricultural crops are grown and treated with aerial, groundboom or air blast equipment). See
Table 6.5 .1 for detailed results.

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



### 6.6 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fu ngicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has evaluated the SAP report and has develope d a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219).

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

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

.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and com pared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and Table 6 .5 .1

. Screening Risk Estimates for Children (1<2 years old) (MOEs) Related to Indirect Exposure (Incidental Oral) to Spray Drift from Methoxyfenozide

. Crop/Rate Group Spray Type/ Nozzle Configuration Appl

. Rate (lb ai/A) TTR 1 (ug/cm 2 ) At Edge of the Field

Tree Nuts

Aerial Fine to Medium

0.4 0.042237 11,000

Groundboom High Boom Very fine to Fine 15,000

Airblast Sparse 19,000Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 35 of 52 

### 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 w as combined with background exposure from food and water. As previously discussed (see Section 6.2), there ar e no residential uses for methoxyfenozide that would result in significant post

- application exposure to children, based on ornamental use only

. 

### T herefore,
aggregate exposure and risk for children are equivalent to those from food and water (see Section
5.4 ).

7.1 Acute Aggregate Risk

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

7.2 Short

- Term Aggregate Risk

The residential handler exposure from applying methoxyfenozide using a backpack ( Table 6.1 )

w as combined with the chronic dietary exposure from the mostly highly exposed adult ( General U.S. Population ) sub

- population , to determine aggregate exposure and ris k as shown in Table
7.2

. T he aggregate MOE is above the LOC of 100, and therefore the ag gregate risk estimate is

not o f concern.

Table 7.2

. Short

- Term Aggregate Risk Calculations for Methoxyfenozide

.

Population NOAEL

mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and
Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult (Handler) 1 6.8 100 0. 1 68 0.030975 0.00 022 0. 0 3 1195 5 4 0

1 T he 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) = I nhalation Exposure (Table 6.1)

. 4 Total Exposure = ( Avg

. Food & Water Exposure + Residential Exposure)

5 Aggregate MOE = [NOAEL 16.8 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 methoxyfenoz ide 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 e fforts to determine which chemicals have aMethoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 36 of 52 

### 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 proced ures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Memo, Z. Figueroa

, D426658, 09/09/2015.



### Methoxyfenozide may be applied through a variety of application methods including: aerial, ground equipment (airblast and groundboom), hand

- held equipment (backpack sprayer, manually

- pressurized h andwand and hand gun), and hose

- end sprayer. Therefore, there is potential for sho rt

- and intermediate

- term occupational handler and post

- application exposure; long

- term exposures are not expected.

No chemical

- specific handler exposure data were submitted in support of this assessment ; therefore, HED relied on surrogate data and defa ult assumptions in accordance with standard poli cies. In the absence of a dermal toxicity , dermal handler and post

- application exposure

assessment s were not conducted

. All occupational handler scenarios for the registered uses
resulted in inhalation MOEs greater than 100 at baseline ( i.e., no respirator) and with engineering
control s for aerial applications (i.e., enclosed cockpits) and, therefore, are not of concern. The lowest MOE of 450 is associated with mixing/loading/applying sprays using a mechani cally

pressurized handgun in ornamental plants. All other MOEs were significantly higher, ranging from 9,600 to 570, 000. No additional PPE recommendations are needed on the registered labels.

Based on the current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed use on chives and all the registered

uses

. This assessment covers all existing uses and the proposed use on chives. S ince there is no
difference between the occupational scenarios

, the agrono mics/practices, application rates, formulations and methods of application, the exposure resulting from methoxyfenozide use on the additional crops in the expanded crop groups are covered by this risk assessment. A

su mmary of the occupational handler risk estimates is provided in Table 9 .1

.

Table 9.1. Occupational Short

- and Intermediate

- term Handler Exposure and Risk Estimates for Methoxyfenozide.

Exposure Scenario Mitigation
Level a Inhalation Unit

Exposure b (u g/lb ai) Applicati

on Rate c Area Treated

or Amount
Handled d Inhalation

Dose e (mg/kg/day) Inhalation
MOE f

Mixer/Loader
Liquids for Airblast Appl ication Baseline 0.219

0.4 lb
ai/A 40 A/day 0.0000438 380,000

Liquids for Aerial Appl ication Baseline 0.219 1

, 200 A/day 0.00131 13,000

Liquids for Groundboom Application Baseline 0.219 200 A/day 0.000219 77,000

Liquids for Chemigation Application Baseline 0.219 350 A/day 0.000384 44,000Methoxyfenozide Human Health Risk Assessment DP Barcode 422208

Page 37 of 52 Table 9.1. Occupational Short

- and Intermediate

- term Handler Exposure and Risk Estimates for Methoxyfenozide.

Exposure Scenario Mitigation
Level a Inhalation Unit

Exposure b (u g/lb ai) Applicati

on Rate c Area Treated

or Amount
Handled d Inhalation

Dose e (mg/kg/day) Inhalation
MOE f

Water Soluble Packets (WSP) for Airblast Appl ication Engineering
Controls* 0.24 40 A/day 0.000048 350,000

Water Soluble Packets (WSP) Aerial Appl ication Engineering
Controls* 0.24 1

, 200 A/day 0.00144 12,000

Water Soluble Packets (WSP) for Groundboom Application Engineering
Controls* 0.24 200 A/day 0.00024 70,000

Applicator

Sprays for Aerial Application Engineering
Controls (Enclosed Cockpit) 0 .0049

0.4 lb
ai/A 1

, 200 A/day 0.0000294 570,000

Spray s for Groundboom Application Baseline 0.34 200 A/day 0.00034 49,000

Sprays for Airblast Application Baseline 4.71 40 A/day 0.000943 18,000

Flagger Flagging Sprays for Aerial Application Baseline 0.35 0.4 350 A/day 0.000613 27,000

Mixer/Loader/Applicator

Liquids for Mechanically

pressurized Handgun Applications Baseline 120

0.025 lb ai/gal 1,000 gal/day 0.0375 450

PF5 Respirator 24 0.0075 2,200

Liquids for Backpack Sprayer Baseline 140 40 gal/day 0.00175 9,600

Liquids for Manually

pressurized Hand wand Applications Baseline 30 40 gal/day 0.000375 45,000

* Water Soluble Packets are considered engineering controls. a. Mitigation Level: “ baseline ” (i.e., single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks); “ engineering controls ” for aerial applications (i.e., enclosed cockpit).
b. Based on the “ Occupational Pesticide H andler Unit Exposure Surrogate Reference Table ” (February, 2015). c. Based on maximum single application rates on registered labels (Table 4.1). d. Based on the Science Advisory Council for Exposure Policy 9.1: Standard Values for Daily Acres Treated in Ag riculture. e. Inhalation Dose (mg/kg/day) = [Rate (lb ai/A) x UE (ug /lb ai) x CF (0.001) x Acres Treated or Amount Handled (A or gal/da y)]/BW (80 kg). f. MOE = Inhalation NOAEL (16.8 mg/kg/day)/ Short

- term Inhalation Dose (mg/kg/day). LOC=100.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 38 of 52 9. 1 Post

- A pplication Risk

9. 1 .1 Post

- A pplication Dermal Exposure

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

- application exposure and risk assessment was not conducted.

9. 1 .2. Post

- A pplication Inhalation Exposure

There are multiple potential sources of p ost

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( ht tp://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological stu dies) or further analysis is required for methoxyfenozide.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency wil l continue to identify the need for and, subsequently, the way to incorporate occupational post

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

Although a quantitative occupational post

- application inhalation exposure assessment was no t performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and
mechanical harvestin g is another potential source of post

- application inhalation exposure. However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post

- application inhalation exposure during these dusty mechanical
harv esting activities. The non

- cancer inhalation risk estimate for commercial airblast application is not of concern (i.e., MOE > 100).

Restricted Entry Interval Methoxyfenozide has been previously classified as a reduced risk chemical. It is classified as Toxicity Category III via the dermal route . Methoxyfenozide is not irritating to the skin and it is

not a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation and primary s kin irrigation are assigned a 12

- hour REI.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 39 of 52 However , REIs may be further reduced from 12 hours if certain criteria are met for both the
technical material and the different end

- use products in accordance with the Pesticide Registration (PR) Notice 95

- 3 [Re d uction of Worker P rotection Standard (WPS) Interim Restricted Entry Intervals (REIs) for Certain Low Risk Pesticides]. 7



### The criteria for reducing REIs include the following: (1) The active ingredient is in Toxicity Category III or IV based upon data for ac ute dermal toxicity, acute inhalation toxicity, primary skin irritation, and primary eye irritation. (2) The active ingredient is not a dermal sensitizer. (3) The active ingredient is not a cholinesterase inhibitor. (4) The active ingredient is not associated with kno wn reproductive, developmental, carcinogenic, or neurotoxic effects. (5) EPA does not possess incident information that are “definitely” or “probably” related to the post

- application exposures to the active ingredient.

The 4

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

. 10.0 Public Health and Pesticide Epidemiology Data

Both the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupati onal Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases were consulted for pesticide incident data on the active ingredient methoxyfenozide (PC Code: 121027) (D408715,
E. Evans and S. Recore , January 31, 2013). The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to methoxyfenozide exposure.

OPP’s IDS includes reports of alleged human health incidents from vari ous sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports from registrants, other federal and state health and environmental agencies, and individual consumers. Since 1992, OPP has compiled these re ports in IDS. The IDS contains reports from across the U.S. and most incidents have all relevant product information recorded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report.

IDS reco rds incidents in one of two modules: Main IDS and Aggregate IDS. Main IDS contains incidents resulting in higher severity outcomes and provides more case

- specific detail. This system stores incident data for death, major and moderate incidents, and it in cludes information about the location, date and nature of the incident. Main IDS incidents involving only one pesticide are considered to provide more certain information about the potential effects of exposure from the pesticide. Aggregate IDS contains incidents resulting in less severe human incidents (minor, unknown, or no effects outcomes). These are reported by registrants only as counts in what are aggregate summaries.

7 Available: http://www.epa.gov/PR_Notices/pr95

- 3.htmlMethoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 40 of 52 For the Main IDS, from January 1, 2007 to December 11, 2012, there were no inci dents reported for methoxyfenozide only in the database. There were three incidents reported involving more than one chemical. Overall, there are few incidents involving methoxyfenozide reported to IDS. In Aggregate IDS, from January 1, 2007 to December 11, 2012, there were two reported incidents involving methoxyfenozide

.

The NIOSH SENSOR database covers 11 states from 1998

- 2009, although reporting varies from state to state. Cases of pesticide

- related illnesses are ascertained from a variety of source s, including: reports from local Poison Control Centers, state Department of Labor workers’ compensation claims when reported by physicians, reports from State Departments of Agriculture, and physician reports to state Departments of Health. Although both occupational
and non

- occupational incidents are included in the database, SENSOR focuses on occupational pesticide incidents. The SENSOR data system is accessible to participating states and EPA, and
includes more detailed follow

- up regarding the specific s of identified incidents, including physician’s reports when available.

A query of SENSOR

- Pesticides 1998

- 2009 identifies 12 cases involving methoxyfenozide stemming from 10 events. One case was moderate in severity and the remaining 11 cases were
low i n severity. Only two of these 12 cases involved a single active ingredient (methoxyfenozide only) and ten involved multiple active ingredients. The two cases with the single active ingredient resulted from one non

- occupational drift event that occurred i n Texas in 2008. Two cases were exposed to drift in their backyard after the pecan trees next door were sprayed with Intrepid 2F using a mist blower. Both cases experienced (low severity) dermal and ocular symptoms. Ten of the 12 cases include product

- specific information and all 10 of these cases involved Intrepid 2F.

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

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

1 1 .0 References

D4 2528 5

. Methoxyfenozide. Petition to Establish Permanent Tolerances, and Associated Section 3 Registration, for Residues Resulting from Use of the Insecticide o n Chives; and to
Convert Stone Fruit Group 12 (Except Fresh Prune Plums) to Stone Fruit Group 12

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

- 12 . Summary of Analytical Chemistry and Residue Data. W. Drew

, 31 March 2015

.

D429009. Methoxyfenozide. Addendum to D425285

- Petition to Establish Permanent Tolerances, and Associated Section 3 Registration, for Residues Resulting from Use of the
Insecticide o n Chives; and to Convert Stone Fruit Group 12 (Except Fresh Prune Plums) to Stone Fruit Group 12

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

- 12 . Summary of Analytical Chemistry and Residue Data. W. Drew, 09/08/ 2015.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 41 of 52 D422209

. Drinking Water Assessment for the IR

- 4 New Use Petition for the Use of Methoxyfenozide on Chives, Herb Subgroup 19A, Green Onion Subgroup 3

- 07B and Crop Group Conversions for Stone Fruit Group 12

- 12 (exce pt plum) and Tree Nut Group 14

- 12.” K.
Milians

, 12/09/2014

.

D416709. Drinking Water Assessment for the IR

- 4 New Use Petition for the Use of Methoxyfenozide on Pineapple. I. Negrón

- Encarnación, 12/19/2013.

D406608. Methoxyfenozide. Human Health Assessment Scoping Document in Support of Registration Review. L.Hansen , 05/10/2013.

D 4 26657

. Methoxyfenozide. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment as Part of the Methoxyfenozide Registration Review and for the Section 3 Registration on Chives; Crop Group Conversions for Stone Fruit and Tree Nuts. E. Holman

, 09/08/2015

.

D 4 26658

. Methoxyfenozide. Occupational and Residential Exposure/Risk Assessment for Registration Review and to Support the Registration o f Proposed Use on Chives and Crop Group Expansions. Z. Figueroa

, 09/09/2015

.

D389739

. Methoxyfenozide. Human Health Risk Assessment to Support Proposed Uses on Root Vegetables and Citrus. M. Collantes, 02/27/12

.

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

.

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

M ethoxyfenozide: S ummary of Hazard and Science Policy Council (HASPOC) Meeting of March 29, 2012: Recommendation on the need for a 28

- day inhalation study. K. Rury and J. Van Alstine, 03/23/12

. TXR #0053782

.

Methoxyfenozide: Summary of Hazard and Science Policy Council ( HASPOC ) Meeting of April 30, 2015 : Re evaluation of the need for a rat 28

- day inhalation study

. J. Leshin, June 26,
2015. TXR # 0055054.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 42 of 52 A ppendix A

. Toxicology Profile and Executive Summaries

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

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

................................ ..................... yes
yes
yes
yes
yes
yes yes

yes
yes
yes
yes
yes

870.3100 Oral Subchronic (rodent)

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

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 28

- or 90

- Day Inhalation

................................ ................ yes
yes
yes

no no* yes

yes
yes

-

no

870.3700a Developmental Toxicity (rodent)

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

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

................................ ................................ . yes
yes
yes yes

yes
yes

870.4100a Chronic Toxicity (rodent)

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

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

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

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

................................ ................... yes
yes
yes
yes
yes yes

yes
yes
yes
yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes
yes
yes
yes yes

yes
yes
yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

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

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

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

................................ ................. no

no
yes
yes

no -

- yes
yes

-

870.7485 General Metabolism

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

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

................................ ............................. yes
yes
yes yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)

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

................................ .................. Six

- month Oral (dog)

................................ .................. no

no

no -

-

- * The required repeated dose inhalation toxicity study has been waived.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 43 of 52 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 LD 50 >5000 mg/kg, both sexes IV

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

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

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

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

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

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



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

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

Nonguideline 2

- week oral

range

- finding (rat) 44617722 (1995)

Acceptable/nonguideline 0, 5 0, 25 0, 10 00 , 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, 5 0, 25 0, 10 00 , 5000, 20,000 ppm in the diet

M: 0, 3.4

, 17.0

, 69.3, 353.4, 1368.8 mg/kg/d ay F: 0, 3.7

, 19.1

, 72.4, 379.3,
1531.2 mg/kg/d ay NOAEL = 69.3/72.4 mg/kg/day [M/F] LOAEL = 353.4 mg/kg/day [M/F] based on periportal hepatocellular hypertrophy and increased liver weight.
At 1368.8/1531.2 mg/kg/day: decreased RBC and Hg in females.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 44 of 52 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 decrea sed body weight gain.

Nonguideline 2

- week range

finding (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, r eticulocyte counts, erythrocyte morphology and methemoglobinemia) and increased spleen weights.

At ≥264.7 mg/kg/day, bilirubinemia

870.3150 90

- Day oral

toxicity (dog) 44617724 (1995)

Acceptable/guideline

0, 15, 50, 500 or 5000 ppm in the diet

M: 0, 0.6, 2.0, 21.4, 197.5 mg/kg/day;

F: 0, 0.6, 1.9, 20.4, 208.8 mg/kg/day NOAEL = 197.5/208.8 mg/kg/day [M/F] LOAEL >197.5/208.8 mg/kg/day [M/F](HDT).

870.3200 28

- Day dermal

toxicity (rat) 44517725 (1998)

Acceptable/guideline

0, 75, 300, 1000 mg/kg/day Systemic NOAEL = 1000 mg/kg/day Systemic LOAEL > 1000 mg/kg/day (HDT)

Local dermal NOAEL = 1000 mg/kg/day Local dermal LOAEL > 1000 mg/kg/day (HDT)

870.3700a Prenatal

developmental in (rat) 44638201 (1994)

Acceptable/guideline

0, 100, 300, 1000 mg/kg/day (gavage) Maternal NOAEL = 1000 mg/kg/day LOAEL >1000 mg/kg/day (HDT) Developmental NOAEL = 1000 mg/kg/day LOAEL >1000 mg/kg/day (HDT)Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 45 of 52 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

870.3700b Prenatal

developmental in (rabbit) 44617726 (1997)

Acceptable/guideline

0, 100, 300, 1000 mg/kg/day (gavage) Materna l NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day (HDT) Developmenta l NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day (HDT)

870.3800 Reproduction

and fertility
effects (rat) 44617727 (1997)

Acceptable/guideline

0, 200, 2000 or 20,000 ppm in diet

P1 males: 0, 15.4, 153.4 or 1551.9 mg/kg/day;

P1 females: 0, 17.9, 180.7, 1820.7 mg/kg/day Parental/Systemic NOAEL = 153.4/180.7 mg/kg/day [M/F]; LOAEL = 1551.9/1820.7 mg/kg/day [M/F]
based on increased absolute and relative liver weights and microscopic midzonal to periportal hepatocellular hypertrophy. Reproductive NOAEL = 1551.9/1820.7 mg/kg/day [M/F]; LOAEL > 1551.9/1820.7 mg/kg/day [M/F](HDT) Offspring NOAEL = mg/kg/day LOAEL > 1551.9/1820.7 mg/kg/day [M/F](HDT)

870.4100a Chronic toxicity

(rat) See 870.4300

870.4100b Chronic toxicity

(dog) 44617728 (1997)

Acceptable/guideline

0, 60, 300, 3000 or 30,000 ppm in diet

M: 0, 2.2, 9.8, 106.1, 1152.4 mg/kg/day

F: 0, 2.2, 12.6, 110.6, 1199.2 mg/kg/day NOAEL = 9.8/12.6 mg/kg/day [M/F] LOAEL = 106.1/110.6 mg/kg/day [M/F] based on mild hematological changes (decreased RBC parameters, slight methemoglobinemia) and increased serum bilirubin. Hematological
effects first observed at week 14.
At 1152.4/1199.2 mg/kg/day: bilirubinemia in
male s, 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 carcinoge nicityMethoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 46 of 52 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.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 47 of 52 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 O

demethylation 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

Immunotoxic ity LOAEL = not established

Systemic toxicity NOAEL = = 76.9 mg/kg/day

Systemic toxicity LOAEL = 324 mg/kg/day, based on increased liver weights.



### A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

– All Populations including Infants and Children and Females age 13

- 49

An acute reference dose for methoxyfenozide was not selected. An appropriate toxicity dose and endpoint were not identified that could be attributed to a single exposure. Decreased hindlimb grip strength in male rats in the acute neurotoxicity study was only observed at the limit dose of 2000 mg/kg on the day of dosing.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 48 of 52 A.3.2 Chronic Reference Dose (cRfD )

Study Selected: Chronic Feeding

- Rat and Dog (co

- critical studies)
MRID Nos.: 44617731 (ra t) and 44617728 (dog)
Executive Summar ies : See Appendix A .4 of D407285 , Guideline [§ 870.3150 (dog study) and
870.3500 (rat study) ] Dose and Endpoint for Risk Assessment: NOAEL = 10.2 mg/kg/day (rat study) based on hematological changes (decreased RBC counts, hemoglobin concentrations, and/or hematocrit in males and females), liver effects (increased liver weights in males; periportal hepatocellular hypertrophy in males and females), histopathological changes in the thyroid (increased follicular cell hypertrophy, altered colloid in males) and possible adrenal toxicity (increased adrenal weights in males and females) seen at the LOAEL = 411 mg/kg/day

. Supported by the co

- critical chronic dog NOAEL = 9.8 mg/kg/day, bas ed 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 bil irubin 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 hematolo gical, 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 f or inter

- and
intra

- species variability).

A.3.3 Incidental Oral Exposure (Short

- Term)

An incidental oral exposure dose and endpoint was selected for potential exposure resulting from spray drift. Methoxyfenozide may be used on ornamental plants in a residential setting. However, postapplication incidental oral exposure from direct contact with treated ornamental plants is not expected since the extent to which young children engage in prolonged play or other activities involving such areas is low. T herefore only postapplication incidental oral exposure due to spray drift was assessed.

Study Selected: T wo

- week range

- finding study for the subchronic dietary study in the dog
MRID No. : 44617722 Executive Summary : See Appendix A .4 of D407285 , Guidel ine [§ 870.3150] Dose and Endpoint for Risk Assessment: NOAEL = 16.8 mg/kg/day based on hematological changes seen at LOAEL = 90.8 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factors: The dog 2

- week dietary range

- finding study was selected be cause 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 dosesMethoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 49 of 52 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 circumstan ce 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
NOA EL 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 effect s, because no offspring toxicity was observed in the reproductive toxicity study. A combined UF of 100x was utilized (10x each to account for inter

and intra

- species variability).

A.3.4 Dermal Exposure (Short

- and Intermediate

- Term )

A dose and endpoint for dermal exposure were not selected, based on the lack of toxicity in the rat dermal exposure study and a dermal absorption study demonstrating low (about 2%) absorption of methoxyfenozide in the 80WP formulation. An oral study was not selected because the appropriate studies either showed no toxicity at any dose tested, or the parameters affected in oral studies (e.g., hematologic changes) were examined but showed no treatment

related changes in the dermal study.

A.3.5 Inhalation Exposure (Sho rt

- and Intermediate

- Term)

Study Selected: T wo

- week range

- finding study for the subchronic dietary study in the dog
MRID No. : 44617722 Executive Summary : See Appendix A .4 of D407285 , Guideline [§ 870.3150] Dose and Endpoint for Risk Assessment: NOAEL = 16.8 mg/kg/day based on hematological changes seen at LOAEL = 90.8 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factors: No short

- term or subchronic inhalation toxicity studies were available; an oral study was therefore selected for route

- to

- route extrapolation. The dog 2

- week dietary range

- finding study was selected because it is of an appropriate duration and it identified the most sensitive dose and endpoint for this exposure scenario (see detailed description and rationale under Incident al Oral Exposure, above). The study is protective of potential developmental effects, because no developmental or offspring toxicity was observed in any of the available developmental and reproductive toxicity studies. Although a repeated

- dose inhalation toxicity study is not available, the oral study is considered adequately protective, based on the conservative endpoint selected, low vapor pressure of methoxyfenozide, low application rate for current use patterns, and low acute inhalation toxicity; a 10x UF DB 

### is therefore not required. Absorption following inhalation exposure is considered to be equivalentMethoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 50 of 52 to oral absorption (100%). A combined UF of 100x was utilized (10x each to account for inter

and intra

- species variability).Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 51 of 52 Appendix B. Physical/Chemical Properties

.

TABLE B.1. Physicochemical Properties of Methoxyfenozide.

Parameter Value Reference Molecular Weight 368.47 D231303; H. Podall; 19 M ay 1997

Melting point/range ( oC ) 206.1

- 208

pH 7.0 Density (g/ cm 3 ) 0.740 ± 0.0081 Water solubility (mg/L at 20oC) 3.3 Solvent solubility (g/L at 20oC) N

- heptane 1.87 Xylene 3.38 1,2

- dichloroethane 36.72
Methanol 192.92
2

- Propanol 50.22 Vapor pressure ( 25oC ) 1.33 x 10

- 5 Pa (1 x 10

- 7 mm Hg) Dissociation constant, pK
a None

Octan ol/water partition coefficient ( Log [ K OW ] ) 3.72 ± 0.04

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

– rev. 4 ; 7 October 2004



### Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. 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 requiremen ts. 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/handler

exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.Methoxyfenozide Human Health Risk Assessment DP Barcode 422208



### Page 52 of 52 Appendix D. Summary of Special Local Need (SLN) Registrations for Methoxyfenozide

Based on the scoping document, t here are a number of Special Local Need (SLN), also known as FIFRA Sec. (24c) registrations, for methoxyfenozide insecticide (see Table D.1). The SLN uses, application rates and equipment are covered by the assessment presented above. Occupational

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

Table D.1

. Special Local Need (SLN) Registrations for Methoxyfenozide Insecticide

. SLN No. and Parent Reg. No. % AI of
Parent Use Site Single Appl. Rate
and Method Comments

MS060014, 62719

- 442

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

- 442 CA060026, 62719

- 442 LA060011, 62719

- 442

CA060013, 62719

- 442 22.6 F Alfalfa for seed productions 0.25 lb ai/A; ground; aerial Maximum of
1lb ai/A/season;
maximum of 60,000 Acres

CA070015, 62719

- 442 22.6F Citrus (non

- bearing) 0.18 lb ai/A; ground/aerial Maximum of 4 applications
per year to avoid
resistance development

FL100001, 62719

- 442 22.6F Citrus crop group 10 0.25 lb ai/A; ground Maximum of
1 lb
ai/A/season

WY120005, 62719

- 442 22.6F Beans, dried type; sugar beet 0.25 lb ai/A; aerial Low volume

spray

concentrate