UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### MEMORANDUM

Date: May 10, 2013 OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION



### SUBJECT: Methoxyfenoz ide

. Human Health Assessment Scop ing Document in Support of Registration Review.



### PC Code: 121027 

### Decision No. : 474445 

### Petition No.: NA

Risk 

### Assessment Type : NA


### TXRNo.: NA


### MRIDNo.: NA



### FROM: Christina Swartz, Chemist
William T. Drew, Chemist 

### DP Barcode: D408668 

### Registration No.: NA 

### Regulatory Action: Regi strat ion Review Scoping Document 

### Case No.: 7431 

### CAS No

. : 161050-58-4
40 

### CFR: § 180.544

Linnea J. Han sen, Ph.D.

, Biologist
Risk Assessment Branch II
Health Effects Division (7509P)
Office of Pesticide Programs



### THROUG H: Jess Rowland

, Acting Associate Direct or

# ~ Dana Vogel

, Associate Dire ctor**~~,i~ --** **z___­** Health Effects Division (7509P)
Office of Pesticide Programs



### TO: Bonnie Adler, Chemical Review Manager
Pesticide Re-Evaluation Division (75 08P)
Office of Pesticide Progr ams

Attached is the Health Effects Division's (HED) human h ea lth risk assessment sco ping document for th e insecticide methoxyfenozide to support registration review.

Page 1 of34Executive Summary

The Health Effects Di vision Methoxyfenozide Ri sk Assessment Team h as eva lua ted the d atabase
and th e most recent human health ris k assessments for the insectici d e methoxyfenozide

. HED performed thi s evaluat i o n i n order to determine th e scope of work necessary to supp ort the
establ i she d tole ran ces and existing registrations. The primary source of information for this
eval u a ti on was the most recent human health ris k assessment written for the c hemical (Memo,

D 388978, M. Co ll antes 

### et al., 23 Ma y 2012).

Methoxyfenozide was ftr s t registe red for u se on cotton and app l es (pome fruit crops) in 2000. It
i s a n in sect growth regulator [IGR] for use on target pests of l arvae of de s tructive lepidopteran

s peci es

. Methoxyfenozide is a diacylhydrazine insecticide, which i s mod era tely systemic
throu g h the roo t syste m , but not through l eaves. T he in sect icidal mode of action consists of
prematur e induction of molting whic h kills the tar ge t in sect, and it i s ef f ec tive as bo t h a s tomach
and contact in sect i c ide.

S ub sequent registrations were allowed for methoxyfenozide use on numerous c ro ps: bush berries, ci l antro l eaves, brassica (cole) leafy vegetab l es, leaves of root and tuber vegetables,

c i trus fruit, cotton, cranberry, cucurbit vegetables

, fruit i ng vegetab l es, g l obe arti choke, grape , grass (forage, fodder, and hay), green o nion s, legume vegetables, foliage of legume vegeta bl es,
nongrass (forage, fod d e r , straw, and hay), pe anu t

, pome fruits, p o m eg r anate, popco rn , root vegetables, soy bean

, s pearmin t, peppermint

, stone fruits

, straw berry

, tree fruits

, tree nuts, and
tuberous and corm vegetables (exce pt pot ato ). In addition, i t is r egis t e r e d for use on ornamenta l
herbaceous p l ants, including ornamental woo d y shr u bs and vines, ornamental an d/o r sha d e trees, recreational areas/parks, and institutions (outdoor).

The toxicology database for methoxyfenoz i de is co n sidered comp l ete in accordance with the Part
158 Data Requirements for conventional pest ici de active ingredients. A ltho ugh a 28 -d ay inh alat ion toxicity s tudy i s not available

, the HED Hazard Science Policy Committee (HASPOC)
ha s determined that the study i s not requir e d for methoxyfenozide ba se d on weight of evidence considerations, including the available toxicity data and th e potential for exposure to methoxyfenozide via the inhalation route (TXR #0 05 3 782

, 4/17/1 2). No new toxicity data are bein g r e qu este d during registration review

, and th e r efo r e HED do es not anticipate updating the
ha zard c har acte ri zatio n database unles s new information (either n ew GLP data or literature

stu di es) is identifted during regi s tration review.

The toxico l ogy studies with methoxyfenozide ind i cate that t h e main target organs in the rat and dog we r e t h e liver

, th yroid and red blood ce ll s (RBC). The most co n s i sten t fmdin gs across species and studies were d ecreased red blood cell parameters and inc r eased liver

, thyroid,
ad r enal and s p l ee n weig ht s. Ma ny of the available s hort-term o r s u bc hroni c to xicity studies

s h owed li tt l e or no tox i c it y. In c r eases in thyroid and a dr enal we i ghts were o b served in the rat chronic ora l study. Thy r oid weights were al so increased i n the dog fo ll owi n g chronic exposure , b u t no accompanying histopathology was observe d.

Tox i cologica l test in g in di ca te s that methoxyfenozide is not neurotox ic or immunotoxic; it ha s been categor i ze d as " not lik e l y" to be carcinogenic to hu mans. There i s no evidence of

Page 2 of34

### Page 3 of 34

qualitative or quantitative susceptibility of the developing fetus or offspring, based on the developmental and reproductive toxicity study results. Therefore, based on the completeness of the database, the lack of susceptibility, the lack of neurotoxicity and the conservative nature of the exposure assessment, HED has previously recommended that the required 10X Food Quality Protection Act (FQPA) Safety Factor to be reduced to 1X.

Based on the registered use patterns and the subm itted toxicity data, endpoints for risk assessment were selected for chronic dietary and short

- and intermediate

- term inhalation exposures. There were no single dose effects in the database, and no toxicity via the dermal route. Although methoxyfenozide could be used in residential home gardens, post

- application exposure to children via the oral route is considered to be extremely low and was not assessed. Since inhalation risks were assessed using the endpoint and dose from an oral study, HED
assumed in halation toxicity would be equivalent to oral toxicity for the purpose of route

- to

- route extrapolation. The endpoint selected for chronic dietary risk assessment was liver and thyroid effects observed in the chronic/carcinogenicity study in the rat; the b lood effects seen in the dog study were considered co

- critical. For inhalation risk assessment, the endpoint selected was blood effects seen in a range

- finding study in the dog.

The residue chemistry database supporting the registered uses is complete. Acceptable studies are available depicting the metabolic fate of methoxyfenozide in target crops, rotational crops, and livestock. The main distinction between study results was that although methoxyfenozide does not undergo extensive metabolism in primar y crops, it is highly metabolized in livestock and rotational crops. Acceptable analytical methods are available to enforce the established tolerances, and the tolerance expression for methoxyfenozide listed in 40CFR §180.544 is appropriate

. Some toleran ce levels may need to change if HED determines that such changes are
needed in order to attain harmonization with CODEX and/or other international maximum residue levels (MRLs). However, no tolerance changes, in terms of the residues of concern and the tolerance expression are anticipated during registration review.

T he dietary exposure database is adequate to support the registrat ion review of methoxyfenozide,
and no risks of concern have been identified. No new dietary assessments are likely to be needed during registration review. It is unlikely that a new drinking water assessment will be required for registration review ; h owever, i f the estimated drinking water concentrat ions (EDWCs) a re revised

, HED may conduct a new dietary exposure assessment.

In the most recent human health risk assessment HED assessed potential inhalation exposure for residential handlers treating ornamentals in and around home gardens, and the resul ting risk
estimates were not of concern. This use on ornamentals is the only potential source of residential

exposure. A post

- application exposure and risk assessment was not conducted due to the lack of
hazard via the dermal route ; in addition, children ’s incidental oral post

- application exposure to treated ornamentals was considered to be negligible, and was not quantitatively assessed

. No additional residential exposure and risk assessments are anticipated during registration review.
When combined wit h exposure from food and water, residential handlers ’ aggregate risk estimates were not of concern. In addition, chronic aggregate exposure from food and wa ter resulted in risk estimates that were not of concern.

### Page 4 of 34

Prior to the most recent (2012) risk asse ssment conducted for methoxyfenozide, no dermal or inhalation endpoints and doses were selected, and therefore quantitative occupational handler and post

- application risk assessments were not considered necessary. In the most recent

assessment , HED contin ued to conclude that a dermal assessment was not needed due to the lack of toxicity via the dermal route; however, in the absence of a route

- specific inhalation toxicity study, HED selected an inhalation endpoint from an oral toxicity study , and quantitati vely assessed inhalation exposure for occupational handlers. No risks of concern were identified for the use patterns assessed in the most recent risk assessment. In addition, in order to prepare for HED’s HASPOC determination on the need for an inhalati on toxicity study, HED calculated risks for all uses on the registered labels using current assumptions with respect to body weight and unit exposures . There were no chemical

- specific data available to assess handlers’ inhalation exposure, so HED relied o n surrogate data generated by various task forces, and the
estimated risks were not of concern. During registration review, HED will update the occupational handler calculations as necessary with current policies, and will incorporate the results in the p reliminary risk assessment.

A quantitative post

- application exposure assessment was not completed due to the lack of dermal toxicity. Chemical

- specific dislodgeable foliar residue (DFR) data have not been submitted, but

are not needed due to the lack of an endpoint for dermal risk assessment. During registration review, HED will consider the impact of new policies and procedures, such as addressing volatilization exposure

, as well as the potential for exposure from spray drift. However, no risk
issues a re expected and no additional data are needed at this time

.

The Agency is currently considering proposed new uses of methoxyfenozide, and some of the review work expected during registration review as described above may be completed in conjunction with assessing the new uses.

Introduction

This document summarizes HED’s evaluation of the data available for assessing human health risk from exposure to the insecticide methoxyfenozide, as well as any data needed to support registration review. Methoxyfeno zide is a diacylhydrazine insecticide used on a variety of crops for control of armyworms and other lepidopterous pest species. Methoxyfenozide mimics the action of the molting hormone of lepidopterous larvae, causing the larvae to undergo an incomplete a nd premature molt, which ultimately results in their death. Methoxyfenozide is currently registered to Dow AgroSciences. In conducting this evaluation, HED has considered the most recent human health risk assessment (D388978; M

. Collantes; 23 May 2012), HED and OPPIN/PRISM databases, open literature (via Google Scholar) and the latest Agency science policies and risk assessment methodologies.

The structur e of methoxyfenozide, as well as the chemical names and other identifiers can be
found in the chemica l identity table attached to this document (Attachment 1)

. The registered formulations, active ingredient levels, use sites, application methods, and uses that were
evaluated in previous assessments a re summarized in Attachment 3

.

### Page 5 of 34

Hazard Identification/ Toxicology

The toxicological database is considered complete for methoxyfenozide, and includes the required subchronic studies, dermal toxicity and dermal penetration studies, chronic toxicity and carcinogenicity studies, developmental and reproductive to xicity studies, immunotoxicity and neurotoxicity studies, as well as rat metabolism and the required mutagenicity/genotoxicity battery (Attachment 5)

. Although a 28

- day inhalation toxicity study has not been submitted, HED has determined that this study i s not required for methoxyfenozide based on a weight of evidence (WOE) approach that considered all of the available hazard and exposure information (TXR # 0053782 , 4/17/12)

.

In general, the short

- term or subchronic toxicity studies on methoxyfenozide sho wed little or no toxicity. When toxicity was observed, the main target organs were the liver, thyroid and red blood cells. The effects of methoxyfenozide on the blood in the rat and the dog are consistent with those of other hydrazine compounds. Mild an emia was observed in both species following chronic dietary exposure, along with methemoglobinemia and red blood cell (RBC) structural abnormalities. Increased platelets were also observed. An increase in the cellularity of rib and
sternum bone marrow in the dog

, seen along with macrophage pigmentation in the liver and spleen, may be an indicator of systemic toxicity . The available data suggest that a compensatory mechanism for the RBC effects may occur over time, based on the effects observed at two wee ks 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.

Liver effects observed in the rat and dog included i ncreased liver weight and periportal hypertrophy. These findings were observed in the rat following two

- week, subchronic or chronic
diet ary exposure, in the dietary reproductive toxicity study, and in the dog following chronic

exposure. Certain thyroid and adrenal effects observed in the rat in a 2

- week study were not seen after subchronic durations of exposure. However, t hyroid hypertr ophy 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 expos ure, but there was no accompanying histopathology.

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

Acute and subchronic oral neurotoxicity studies in the rat did not show evidence of potential neurotoxicity. No clinical signs of toxicity or neurohistopathology were observed in othe r guideline studies. No maternal or developmental effects were observed in either the rat or rabbit oral developmental toxicity studies. In the rat two

- generation reproductive toxicity study, parental effects were limited to increased liver weight and mi croscopic periportal hypertrophy

, and n o offspring or reproductive toxicity was observed. The immunotoxicity study demonstrated liver effects consistent with those seen in other studies, but there was no evidence of an impact on the immune system.

### Page 6 of 34

Dermal effects were not observed in the rat fol lowing a 28

- day exposure period, and 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% wettabl e powder (WP) formulation product. There was no evidence of carcinogenicity in the submitted studies, and n o mutagenic or clastogenic potential was observed in the battery of genotoxicity studies on methoxyfenozide. Based on these findings, methoxyfenozi de is classified as “not likely to be carcinogenic to humans” (2005 Agency revised carcinogenicity assessment guidelines).

There were no single dose effects observed in the toxicity database that would be appropriate for acute dietary risk assessment. Fo r chronic dietary risk assessment, HED selected the endpoint
and dose from co

- critical studies, the rat chronic/carcinogenicity and dog chronic studies. Hematological effects were observed in both st udies, with similar no

- observed

- adverse

- effect

levels (N OAELs). In the rat, periportal liver hypertrophy, thyroid hypertrophy and altered colloid and increased adrenal weight were also observed at the lowest

- observed

- adverse

- effect

level ( LOAEL )

. The selected NOAEL and LOAEL are protective of all other toxici ty in the database, and are also protective of hematological and other effects observed in the dog and rat

two

- week range

- finding studies. A dermal endpoint for risk assessment was not selected based on the lack of dermal toxicity, and a lack of concern for developmental and reproductive toxicity.
For short

- and intermediate

- term inhalation exposure and ris k assessment, HED relied on the hematological effects and increased spleen weight observed in a 2

- week range

- finding study in the dog. The endpoint and dose selected are considered to be conservative but protective.

Based on both hazard and exposure cons iderations, including the completeness of the database, the lack of susceptibility in the required developmental and reproductive toxicity studies, the lack of neurotoxicity, and the conservative nature of the exposure assessment, HED has previously

recomm ended reducing the required 10X Food Quality Protection Act (FQPA) safety factor (SF) to 1X, and this conclusion is not expected to change during registration review.

Conclusions for Hazard Identification/Toxicology

The toxicology database for methoxyfen ozide is complete , and no new data are being
recommended to support registration review. Although not anticipated, any potential changes in doses and endpoints for risk assessment as a result of new information, changes in HED science policies or risk ass essment methodologies may lead to additional work on the hazard characterization and endpoint selection for methoxyfenozide during registration review.

Dietary Exposure

As stated above, methoxyfenozide is registered for use on a wide variety of crops, an d permanent tolerances have been established (40CFR §180.544) ranging from 0.02 ppm to 160 ppm in plant commodities and from 0.02 ppm to 0.40 ppm in livestock commodities. In addition, tolerances are established for inadvertent residues in rotational crop commodities based on findings of
detectable residues in extensive rotational crop field trials which were needed based on the persistence of methoxyfenozide in soil, and due to subsequent uptake by rotational corps

. The residue definition in primary crop s, for both tolerance enforcement and risk assessment, is

### Page 7 of 34

methoxyfenozide. However, in rotational crops and livestock, additional metabolites are included in both the tolerance expression and for the purpose of risk assessment.

The residue definition in milk and ruminant tissues (other than liver and kidney) is parent compound; in ruminant liver and kidney the residue definition is methoxyfenozide and its RH

141,518 metabolite. The residue definition in poultry meat (muscle) and fat is parent methoxyfeno zide; however, in eggs, poultry liver and meat byproducts, it includes methoxyfenozide and its metabolite, RH

- 141,518.

In rotational crops, a number of additional metabolites have been included for risk assessment

purposes . B ased on the residue profiles in the relevant rotational crops, for enforcement

purposes , only the parent is regulated in high

- moisture crops, whereas additional metabolites are included in the tolerance expression for low moisture rotational crops. A dditional metabolites
included for both risk assessment and tolerance enforcement were considered to be of potentially similar toxicity to the parent compound based on the presence of the hydrazide linkage. For those metabolites for which an adequate enforcement analytical method is avail able, the metabolites were quantified and included in the tolerance. For additional residues of concern for the dietary risk assessment

, the confined and field rotational crop study results were used to develop adjustment factor s to account for the additional residues.

Acceptable analytical methods are available to enforce tolerances for residues of methoxyfenozide in primary and rotational crops, and in livestock commodities. In the most recent risk assessment and associated Federal Register notic e, the tolerance expression for methoxyfenozide (primary crops, livestock, and rotational crops) was revised to reflect the required coverage and compliance statements. Therefore, no tolerance changes, in terms of the
residues of concern and the tolerance expression, are anticipated during registration review.

In the most recent assessment, HED used the Dietary Exposure Evaluation Model (DEEM

- FCID Version 2.03) to conduct the chronic dietary (food and drinking water) risk assessment for methoxyfenozide. Th e model incorporates consumption data from the USDA’s Continuing Survey of Food Intakes by Individuals taken between 1994 and 1996 along with a supplemental children’s survey taken in 1998. The chronic analysis was based on tolerance

- level residues,

ass ume d 100% crop treated, and u s e d both empirical and default processing factors ; in addition, exposure from drinking water was considered as described below

. The chronic dietary risk estimates were not of concern, even with the conservative model inputs us ed. Although the dietary model has since been updated with new consumption information from the National Health and Nutrition Examination Survey (NHANES), known as “What We Eat in America” (WWEIA), no risks of concern are expected with the use of the newe r consumption information. The dietary assessment to be conducted in conjunction with proposed new uses will incorporate the updated consumption data , and will also be included in the methoxyfenozide registration
review risk assessment

.

The Environmental Fate and Effects Division (EFED) provided modeled estimates of residues in drinking water , estimated drinking water concentrations (EDWCs), which were used in the most

recent chronic dietary risk assessment. HED’s past risk assessment s incorrectly stated that parent and two metabolites/degradates were modeled . However, as noted in EFED’s documents

,

### Page 8 of 34

very little degradation of the parent compound is expected, and only residues of the parent methoxyfenozide were included in their modeled estimates. During registration review, or during the review of pending new uses, HED will ensure the residues of concern clearly state that parent methoxyfenozide is the only residue of concern in drinking water sources. In addition, HED will evaluate whether updated EDWCs are needed during registration review. However, in conjunction with the evaluation of pending new uses, HED plans to assess chronic dietary exposure using updated EDWCs and the new dietary model. T herefore HED considers it unlikely that a new dietary assessment will be needed during registration review.

Conclusions for Dietary Exposure: The dietary exposure database is adequate to support the existing registrations and tolerances. No new residue chemistry data are required. A new dietary

exposure assessment is not anticipated during registration review ; however, if a new assessment is needed it will be conducted using the most up

- to

- date consumption information and dietary
model version . Finally, no chronic dietary risk estimates were of concern for methoxyfenozide, even though conservative assumptions were used in the dietary model. Therefore, no dietary risk concerns are anticipated during registration review.

Residential Expo s u re

The Intrepid 2F label indicates that methoxyfenozide exposure in residential settings can be
incurred during and following application to trees, shrubs, foliage plants and flowers grown in commercial nurseries and greenhouses, Christmas tree farms, outdoor landscape areas, parks, recreational areas, institutional gro unds and “residential property”. Since methoxyfenozide is

not a restricted use pesticide, HED conducted a residential handler exposure assessment to be protective of potential homeowner exposure . Homeowners were assessed for use of hand held equipment or a back

- pack sprayer using the 2012 Residential Standard Operating Procedures (SOPs). The residential handler risk estimates associated with the use on ornamentals were not
of concern.

A quantitative residential post

- application risk assessment was not c onducted for adults based on the absence of toxicity via the dermal route. In addition, incidental oral exposure for children is expected to be negligible from the use on ornamental trees and shrubs. Methoxyfenozide is not
used on ornamental turf.

Based on the Agency ’ s current practices, a quantitative post

- application inhalation exposure assessment was not performed for methoxyfenozide

, primarily becau se of it s vapor pressure (1.0
x 10 - 7 

### mm Hg) and application rate

. However, volatilization of pesticides may be a potential 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
Fe deral Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the

proces s of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency ’ s risk assessments. If new policies or procedur es are put into place,

### Page 9 of 34

the Agency may revisit the need for a quantitative post

- application inhalation exposure
assessment for methoxyfenozide

.

Spray Drift

Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) might occur as a result of applications of methoxyfenozide . The Agency is in the process of evaluating these types of exposures and might, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate these post

- application exposures into the Agency’s risk assessments. The need for spray drift and volatilization risk assessment for methoxyfenozide will be examined during registration review

.

Combined Residential Exposure

The only quantitatively assessed r esidential scenario for methoxyfenozide consists of adult handlers exposed via the inhalation route. As noted above, the risks were not of concern.

Conclusions for Residential Exposure

Although there are no products registered for use specifically by homeowners, HED has assessed residential handlers’ inhalation exposure and risk in order to protective of homeowners who may purchase the product and use it on home garden ornamentals. Expo sure and risk estimates were assessed in accordance with the 2012 Residential SOPs, and no additional residential exposure and risk assessments are anticipated during registration review.

Aggregate Risk Assessment

In the most recent risk assessment HED provided updated aggregate exposure and risk estimates, including the inhalation exposure for adult residential handlers, and exposure from food and water after methoxyfenozide is applied to growing crops. Due to the lack of an acute endpoint,
there were no acute aggregate risks associated with methoxyfenozide uses. Chronic aggregate risk estimates were equivalent to the chronic dietary risks, and were not of concern. Short

- term aggregate exposure and risk included inhalation exposure estimates for resid ential handlers, as well as the background levels of exposure from food and water, and these risk estimates were not
of concern.

Conclusions for Aggregate Assessment

HEDs previous conclusions regarding aggregate risks are not expected to change during

re gistration review. Additional food uses are currently under review in the Agency, as part of a joint review with PMRA, and these new uses may impact the aggregate risk estimates based on additional exposure through food and drinking water. During registr ation review, these newly proposed uses will be incorporated into the preliminary risk assessment, but no risk concerns are expected.

### Page 10 of 34

Occupational Exposure and Risk

Sec tion 3 and Sec tion 24 (c) registrations for methoxyfenozide are listed in Attachment 3

. There are essentially only 2 end

- use products, but there are several special local need ( SLN ) [ Section 24(c) ] labels based on the flowable concentrate (FlC) end use product, Intrepid 2F (Reg. No.
62719

- 442). Methoxyfenozide may be applied using aerial, groundboom, airblast, and hand

- held spray equipment. The personal protective equipment ( PPE) required for handlers consists of a single layer of clothing (long sleeve shirt, long pants, and socks plus shoes) and chemical resistant gloves. The res tricted entry interval (REI) for methoxyfenozide is 4 hours.

The agricultural and ornamental uses of methoxyfenozide result in short

- term (1

- 30 days) and
intermediate

- term (1

- 6 months) occupational exposures. For risk assessments conducted prior to 2012, endpoints and doses were not selected for dermal or inhalation exposure assessments. Therefore, these exposures were not quantitatively assessed. In 2012, HED re

- affirmed its previous conclusion that there is no hazard via the dermal route . I n the absence of a route

specific inhalation toxicity study, HED selected an inhalation dose and endpoint from a subchronic oral toxicity study. In conjunction with the uses that were evaluated at the time, HED
conducted a quantitative inhalation exposure and risk assessment.

Occupational Handler Exposure

The registrant has not submitted chemical

- specific exposure data to estimate handler exposures.
In the absence of chemical

- specific data, i t is HED policy to use th e best available data to assess handler exposure s . Sources of such generic (surrogate) handler data include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA )

.

As stated above, m ost of the handler exposures resulting from a gricultural uses of methoxyfenozide have not been evaluated quantitatively in Agency memoranda, due to the lack of endpoints for risk assessment prior to 2012. When HED conducted screening calculations for a variety of methoxyfenozide uses , application rates and application equipment, no inhalation risks of concern were identified for occupational handlers at the baseline level of personal protection. During registration review, HED will capture these screening calculations for the

purpose of the preliminary risk assessment.

Occupational Post

- application Exposure

In the absence of toxicity via the dermal route, no quantitative dermal post

- application risk assessment is required for the agricultural and non

- agricultural uses of methoxyfenozide. The REI on registered labels is considered appropriate based on the toxicity of the technical ingredient. Although HED would typically require dislodgeable foliar residue (DFR) studies based on the existing use pattern, no studies are re quired due to a lack of toxicity via the dermal

route.

### Page 11 of 34

A quantitative post

- application inhalation exposure as sessment was not performed for methoxyfenozide b ased on the Agency's current practices

. However, there are potential sources of inhalation exposu re to workers performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and re

- suspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and inp ut on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meeting s/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for methoxyfenozide

.

Although a quantitative post

- application inhalation exposure assessment was not performed for methoxyfenozide

, the handler assessment to be conducted during registration rev iew is considered protective of potential post

- application exposure exposures expected for workers.

Conclusions for Occupational Exposure and Risk

U pdated occupational handler exposure assessments will be needed during registration review, based on the selection of an inhalation dose and endpoint for risk assessment. Although these exposures have not been formally assessed in past risk assessments, HED has completed screening estimates of the risk associated with representative crop scenarios, application rates
and equipment , and there were no risks of concern identified. The screening estimates should be captured in the preliminary risk assessment to support registration review, and should include the most recent recommendations with respect to unit exposures and risk assessment methodology. As necessary, an inhalation post

- application risk assessment could be conducted in accordance with the development of relevant HED policies for risk assessmen t (e.g., spray drift, or volatilization).

Public Health and Pesticide Epidemiology Data

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

- Pesticides (SENSOR) databases were consulted for

pe sticide incident data on the active ingredient methoxyfenozide (PC Code : 121027 ) (D408715, E. Evans and S. Recore, January 31, 2013)

. The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to methoxyfenozide exposure.

OPP’s IDS includes reports of alleged human health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Ro denticide Act (FIFRA) Section 6(a) (2) reports

### Page 12 of 34

from registrants, other fed eral and state health and environmental agencies

, and individual consumers. Since 1992, OPP has compile d these reports in IDS. The IDS contain s reports from across the U.S. and most incidents have all relevant product information recorded. Reports
submitt ed to the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report.

IDS records incidents in one of two modules: Main IDS and Aggregate IDS. Main IDS contains incidents resulting in higher severity outcomes and provide s more case

- specific detail. This system stores incident data for death, major and moderate incidents, and it includes information about the location, date and nature of the incident. Main IDS incidents involving only one pesticide are considered to prov ide 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 i n what are aggregate summaries

.

For the M ain IDS, from January 1, 200 7 to December 11 , 2012

, there were no incidents reported
for methoxyfenozide only in the database. There were three incidents reported involving more than one chemical. Overall, there are few incidents involving m ethoxyfen o zide reported to IDS.
In A ggregate IDS , from January 1, 200 7 to December 11 , 2012

, there were two reported
incident s involving methoxyfenozide

.

Th e NIOSH SENSOR database covers 11 states from 1998

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

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

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

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

.

A query of SENSOR

- Pesticides 1998

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

- occupational drift event that occurred in Texas in 2008. T wo

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.

Ba sed 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 in cident information and if a concern is triggered, additional analysis may be included in the preliminary risk assessment for registration review.

### Page 13 of 34

Tolerance Assessment and International Harmonization

The currently established tolerance expression for methoxyfenozide is adequate, and includes both coverage and compliance statements for enforcement purposes. Adequate analytical
methods are available for enforcement of the tolerances. The residues of concern for tolerance
enforcement and risk assessment are described in the table below:

Summary of M ethoxyfenozide Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.

Matrix Residues I ncluded in Risk
Assessment Residues I ncluded in Tolerance Expression

Plants Primary Crop s Parent methoxyfenozide Parent methoxyfenozide

Rotational Crop s ( High Moisture ) 1 

### Parent methoxyfenozide and

metabolites, RH

- 151,055, RH

152,072, and RH

- 117,236, RH

152,067, RH

- 131,157 and RH

152,071 Parent methoxyfenozide

Rotational Crop s (Low Moisture ) 2 

### Parent methoxyfenozide and

metabolites, RH

- 151,055, RH

152,072, and RH

- 117,236

, RH

152,067

, RH

- 131,157 and RH

152,071 Parent methoxyfenozide and
metabolites RH

- 151,055

, RH

152,072

, and RH

- 117,236

Livestock Ruminant Milk,

Meat and Fat Parent methoxyfenozide Parent methoxyfenozide

Ruminant Liver
and Other Meat Byproducts Parent methoxyfenozide and

metabolite RH

- 141,518 Parent methoxyfenozide and
metabolite RH

- 141,518

Poultry Meat and
Fat Parent methoxyfenozide Parent methoxyfenozide

Poultry Eggs,
Liver and Other Meat Byproducts Parent methoxyfenozide and

metabolite RH

- 141,518 Parent methoxyfenozide and
metabolite RH

- 141,518

Drinking Water Parent methoxyfenozide Not a pplicable

1. High

- moisture rotational crops with established tolerances include potatoes and bulb
onions ( subgroup 3

- 07A ).
2. Low

- moisture rotational crops include non

- grass a nimal feed straw (group 18); cereal

g rain forage, fodder and straw ( group 16 ) except corn ; and h erb s and spice s ( group 19 )

exce pt coriander leaves

.

T he residue definition s for methoxyfenozide are not harmonized between EPA, Canada’s PMRA
and Codex

. Codex has established MRLs for methoxyfenozide, defined as the parent compound

, in all commodities

. Mexico adopts US methoxyfenozide tolerances and/or Codex MRLs for its export purposes. Canada has established MRLs for methoxyfenozide; the residue definition is the parent compound in cr ops and most livestock commodities . For livestock kidney and liver,

### Page 14 of 34

the residue defi nition is methoxyfenozide and RH

- 141,518. Despite the differences in the expressions, many of the established tolerance levels are harmonized with Canada and/or Codex.

EPA is in the process of looking for opportunities to harmonize its tolerances with Ca nada’s and/or Codex’s MRLs whenever possible , and some of these changes may be made prior to the completion of the preliminary risk assessment for registration review

. This includes
harmoniz ation of recommended tolerances for proposed new uses, and where possible

, revision
of existing tolerances concurrent ly with the establishment of new tolerances . A comparison of the existing EPA tolerances to PMRA and Codex MRLs can be found as Attachment 2

.

During registration review, HED will harmonize tolerances with Canadian and Codex MRLs to the extent possible.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk

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

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water cons umption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pest icide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to sm aller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary

exposures and risks based on home use of pesticide products for adult applicators and postapplication activitie s for toddlers, youths, and adults entering or playing on treated areas 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 exp osure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Endocrine Disruptor Screening Program

As required by FIFRA and 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, neurotoxici ty, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturati on, 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

### Page 15 of 34

taxonomic groups. As part of methoxyfenozide’s most recent registration decision, 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), methoxyf enozide is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

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

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

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

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

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

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Methoxyfenozide is not among the group of 58 pesticide active ingredients on the initial list to be
screened under the EDSP. Accordin gly, as part of registration review, EPA will issue future
EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for methoxyfenozide

. For further information on the status of the EDSP, the policies and procedures, the list of 67 che micals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Cumulative Risk Assessments

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to methoxyfenozide and any other substances and methoxyfenozide does not appea r to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that methoxyfenozide has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts t o determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

Human Studies

Past methoxyfenozide risk assessments rely in part on data from studies in wh ich adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation

exposure. These data, which include studies from the Pesticide Handlers Exposure Database

### Page 16 of 34

Version 1.1 (PHED 1.1); the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re

- entry Task Force (ARTF) database; and other registrant

- submitted exposure monitoring studies, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler

exposure

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

- app

- exposure

- data.html.

Data Requirements

None.

R eferences

Evans, E and Recore, S., D408715 , 1/31/13. Methoxyfenozide : Review of Human Incidents

.

Collantes, M. D388978, 5/23/12. Methoxyfenozide. Human Health Risk Assessment to Support Proposed Uses on Root Vegetables and Citrus.

Drew, W.T., D401250, 5/1/2012. Methoxyfenozide

. Addendum to Summary of Analytical Chemistry and Residue Data, D396397.

Holman, E. D401252, 5/1/12. Methoxyfenozide. Revised Chronic Aggregate Dietary Exposure and Risk Assessment for the Section 3 Registration on Root Vegetables and Citrus

– Addition of Rotational Crop Tolerances.

Van Alstine, J. TXR No. 0053782 , 4/17/12. Methoxyfenozide: Summary of Hazard and Scien ce Policy Council ( HASPOC ) Meeting of March 29, 2012 : Recommendation on the need for a 28

- day inhalation study

.

Drew, W.T., D396397, 3/2/12. Methoxyfenozide. Petition to Establish Permanent Tolerances (Associated with Section 3 Registration) for Residu es Resulting from Food/Feed Uses of the Insecticide on Citrus Fruits (Crop Group 10

- 10), and Root Vegetables, Except Sugar Beet (Crop Subgroup 1B). Summary of Analytical Chemistry and Residue Data

.

Collantes, M., D 389739

, 2/27/12. Methoxyfenozide: Occu pational and Residential Exposure Assessment for New Uses on Root Vegetables and Citrus.

Hanson, B. D374178, 5/4/10. Methoxyfenozide

– Special Local Need (SLN): The Florida Department of Agriculture and Consumer Services is requesting that a SLN, FL

- 1000 01, be established for Florida for use on Citrus Fruits (Crop Group 10).

Rate, D., D 357983, 7/22/09. Methoxyfenozide. Human Health Risk Assessment for Proposed Section 3 Uses on Dried Pea and Bean Subgroup 6C (Except Soybean), Pomegranate, Popcorn,
and Citrus Crop Group 10 (Regional Use ), and Conditional Registrations for Uses and/or Tolerances on Leaf Vegetables, Rotational Crops, Stone Fruits, and Poultry Commodities

.

### Page 17 of 34

Cutchin, W., D340540, 1/10/08. Methoxyfenozide. Human Health Risk Assessment for
P roposed Use on Sweet Potato, Blueberry, Dry Bean, Grass, Peanut, Green Onion, Avocado, Guava, Alfalfa and Clover.

Hanson, B. D 355027, 11/20/08. Methoxyfenozide. Human Health Risk Assessment for Proposed Section 18 Use on Grain Sorghum.

Cutchin, W. D322831, 4/25/06. Methoxyfenozide. Human Health Risk Assessment for Proposed Use on Soybeans.

Cutchin, W., D309334 , 11/9/04. Methoxyfenozide : Addendum to the Human Health Risk
Assessment for Section 3 Registrations on Mint, Strawberries, Papaya, Root Vegetables, Edible Podded Legumes, and Succulent Shelled Peas and Beans to include Coriander and Dill.

Cutchin, W., D297368 , 8/23/04. Methoxyfenozide : Human Health Risk Assessment for Section
3 Registrations on Mint, Strawberries, Papaya, Root Vegetable s, Edible Podded Legumes, and
Succulent Shelled Peas and Beans.

Clock

- Rust, M. D291304, 11/24/03. M ethoxyfenozide : Human Health Risk Assessment for Requested Section 18 Emergency Exemption for the Use of Methoxyfenozide in/on Grain Sorghum in Louisiana

.

Nelson, M. D285242 , 2/4/03. Methoxyfenozide: Supplemental Human Health Risk Assessment
for: PP# 2E06441 ( Cranberry ); PP# 3E06527 ( Cucumber and Summer Squash ); PP# 3E06534 ( Cantaloupe ); PP# 3E06528 ( Blackeyed and Southern Pea ); PP# 3E06533 (Okra and Turnip
G reens ).

Wassell, W. D258155 , 8/20/ 9 9. PP# 8F5004 & PP#8F5006 Methoxyfenozide on Cotton and the
Pome Fruit Crop Group. Human Health Risk Assessment for New Reduced

- Risk Insecticide.

Attachment s Attachment 1. Chemical Identity Table
Attachment 2 . International Residue Limit Status
Attachment 3

. Methoxyfenozide Products and Use Sites
Attachment 4

. Methoxyfenozide Endpoint Selection Tables Attachment 5. Methoxyfenozide Toxicity Profile s

### Page 18 of 34

Attachment 1

. Methoxyfenozide Chemical Identity Table

Chemical Identity

Chemical structure

Common name Methoxyfenozide
Chemical Class Diacylhydrazine
PC Code 121027 Company experimental name RH

- 2485
Molecular formula C 22 H 28 N 2 O 3 Molecular weight 368.47 Vapor Pressure (25C) 1.33 x 10 - 5 Pa (1 x 10 - 7 mm Hg)
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 Registration Review Case No. 7431
End

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

- 442)

### Page 19 of 34

Attachment 2 . International Residue Limit (IRL) Status

Methoxyfenozide (PC Code 121027; Date of Request 01

- 29

- 2013) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 2

40 CFR § 180.544

(a) General. (1) methoxyfenozide (3

- methoxy

- 2

- methylbenzoic acid 2

- (3,5

- dimethylbenzoyl)

- 2

- (1,1

- dimethylethyl) hydrazide) All food crops; livestock fat, meat and meat byproducts:
3

- methoxy

- 2

- methylbenzoic acid, 2

- (3,5

- dimethylbenzoyl)

- 2

- (1,1

- dimethylethyl)hydrazide Methoxyfenozide.
The residue is fat

soluble, but is
not classed as fat

soluble with respect
to its distribution in
milk.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)
US Canada Mexico 1 Codex 2

Acerola 0.4 Almond, hulls 25 50

Animal feed, nongrass, group 18, forage 50.0

Animal feed, nongrass, group 18, hay 150.0

Apple, wet pomace 7.0 7 apple pomace, dry Artichoke, globe 3.0
Avocado 0.6 0.7 Bean, dry, seed 0.24 0.5 5 cowpea (dry) Beet, sugar, roots 0.50 0.3 sugar beet Brassica, head and stem, subgroup 5A 7.0 3 broccoli 7 cabbage, head Brassica, leafy greens, subgroup 5B 30 30 mustard greens

Bushberry subgroup 13

- 07B 3.0 4 blueberries
Canistel 0.6 Cattle, fat 0.50 0.1 0.2 mammalian fats (except milk fats) Cattle, meat 0.02 0.1 0.2 meat (from
mammals other than marine mammals) (fat) Citrus, oil 100 Coriander, leaves 30 Corn, field, forage 15 Corn, field, grain 0.05 0.02 (*) maize Corn, field, refined oil 0.20 Corn, field, stover 125 60 maize fodder (dry) dry wt Corn, pop, grain 0.05 Corn, pop, stover 125 Corn, sweet, forage 30

### Page 20 of 34

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 2
Corn, sweet, kernel plus cob
with husks removed 0.05 0.02 (*)

Corn, sweet, stover 60 Cotton, gin byproducts 35 Cotton, undelinted seed 2.0 7 cotton seed Cranberry 0.5 0.7 Feijoa 0.4 Fruit, citrus, group 10

- 10 3.0 10 Australian (desert limes, finger limes, round limes), brown river finger limes, calamondin, citrus citron, citrus hybrids, grapefruits, Japanese summer grapefruit kumquats, lemons, limes, Mediterranean Mandarin, Mount White lime, New
Guinea wild lime oranges, pummelos, Russell River lime, Satsuma mandarins sweet limes, tachibana orange, tahiti lime, tangelos,

t angerines, tangors

, trifolia te oranges, uniq fruits

100 citrus oil 0.7 citrus fruits

Fruit, pome, group 11 1.5 1.5 apples, crabapples, loquats, mayhaws, oriental pears, pears, quinces 2 pome fruits

Fruit, stone, group 12, except plum, prune, fresh 3.0 2 stone fruits

Goat, fat 0.50 0.1 0.2 mammalian fats (except milk fats) Goat, meat 0.02 0.1 0.2 meat (from
mammals other than marine mammals) (fat) Grain, aspirated fractions 2.0 Grape 1.0 1 Grape, raisin 1.5 2 dried grapes (=currants, raisins and sultanas) Grass, forage, fodder and hay, group 17, forage 18.0

Grass, forage, fodder and hay, group 17, hay 30.0

Guava 0.4 Hog, fat 0.1 0.1 0.2 mammalian fats (except milk fats)

### Page 21 of 34

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 2
Hog, meat 0.02 0.1 0.2 meat (from
mammals other than marine mammals) (fat) Horse, fat 0.50 0.1 0.2 mammalian fats (except milk fats) Horse, meat 0.02 0.1 0.2 meat (from
mammals other than marine mammals) (fat)
Jaboticaba 0.4 Leaf petioles subgroup 4B 25 15 celery, lettuce,
head 30 lettuce, leaf Leafy greens subgroup 4A 30 Longan 2.0 Lychee 2.0 Mango 0.6
Milk 0.10 0.05 milks Nut, tree, group 14 0.10 0.1 tree nuts 0.03 peanut
Okra 2.0 Onion, green, subgroup 3

- 07B 5.0 5 Beltsville bunching onions, elegans hosta, fresh (Chinese chive leaves, chive leaves), fresh onions, fritillaria leaves, green onions, kurrats, lady's leek, leeks, macrostem onions,
shallot leaves tree onion tops, Welsh onion tops, wild
leeks Papaya 0.6 1
Passionfruit 0.4 Pea and bean, succulent shelled, subgroup 6B 0.2 0.3 peas, she ll ed (succulent seeds) Pea, blackeyed, seed 4.0 Pea, dry seed 2.5 Pea, southern, seed 4.0

Peanut 0.02 0.02 0.03 Peanut, hay 55.0 Peanut, oil 0.04 0.04 peanut oil (refined) 0.1 peanut oil,
edible Peppermint, tops 7.0
Pistachio 0.10 Plum, prune, fresh 0.30 2 prunes Pomegranate 0.6 Poultry, fat 0.02 Poultry, meat 0.02 0.01 (*)
Pulasan 2.0
Rambutan 2.0

### Page 22 of 34

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 2
Sapodilla 0.6 Sapote, black 0.6 Sapote, mamey 0.6 Sheep, fat 0.50 0.1 0.2 mammalian fats (except milk fats) Sheep, meat 0.02 0.1 0.2 meat (from
mammals other than marine mammals) (fat) Soybean, aspirated grain
fractions 160

Soybean, forage 30 Soybean, hay 80 Soybean, hulls 2.0 Soybean, seed 1.0 Spanish lime 2.0 Spearmint, tops 7.0 Star apple 0.6
Starfruit 0.4 Strawberry 1.5 2 Turnip, greens 30 Vegetable, cucurbit, group 9 0.3 Vegetable, foliage of legume, except soybean, subgroup 7A 35

Vegetable, fruiting, group 8 2.0 2 peppers, tomato 20 peppers chili,
dried Vegetable, leaves of root and tuber, group 2 30 7 radish leaves (including radish tops) Vegetable, legume, edible podded, subgroup 6A 1.5 0.3 beans, shelled; peas, shelled (succulent seeds)
2 common bean (pods and/or immature seeds) Vegetable, root, except sugar beet, Subgroup 1B 0.90 0.5 carrot
0.4 radish Vegetable, tuberous and corm, except potato, subgroup 1D 0.02 0.02 sweet potato

Wax jambu 0.4



### US [40 CFR §180.572(a)(2)] Canada Mexico 1 

### Codex 2

### Page 23 of 34

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 2
(2) sum of methoxyfenozide [3

- methoxy

- 2

- methylbenzoic acid 2

- (3,5

- dimethylbenzoyl)

- 2

- (1,1

- dimethylethyl) hydrazide] and its glucuronide metabolite (β

- D

- Glucopyranuronic acid, 3

- [[2

- (1,1

- dimethylethyl)

- 2

- (3,5

- dimethylbenzoyl)

- hydrazino]carbonyl]

- 2

- methylphenyl

- ), calculated as the stoichiometric equivalent of methoxyfenozide. Livestock: kidney and liver
3

- methoxy

- 2

- methylbenzoic acid, 2

- (3,5

- dimethylbenzoyl)

- 2

- (1,1

- dimethylethy l)hydrazide, including the metabolite β

D

- glucopyranuronic acid, 3

- {[2

- (1,1

- dimethylethyl)

- 2

- (3,5

- dimethylbenzoyl)

- hydrazino]carbonyl}

- 2

- methylphenyl



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)
US Canada Mexico 2 

### Codex 3

Cattle, liver 0.40 0.1 0.1 edible offal (mammalian) Cattle, meat byproducts, except liver 0.10 0.1 meat byproducts of
cattle 0.1 kidney of cattle Egg 0.02 0.01 Goat, liver 0.40 0.1
0.1 edible offal (mammalian) Goat, meat byproducts, except liver 0.10 0.1 meat byproducts of goats 0.1 kidney of goats Hog, liver 0.1 0.1
0.1 edible offal (mammalian) Hog, meat byproducts, except
liver 0.02 0.1 meat byproducts of hogs 0.1 kidney of hogs Horse, liver 0.40 0.1
0.1 edible offal (mammalian) Horse, meat byproducts, except liver 0.10 0.1 meat byproducts of
horses 0.1 kidney of horses Poultry, liver 0.10 0.01 (*) poultry
edible offal Poultry, meat byproducts, except liver 0.02

Sheep, liver 0.40 0.1
0.1 edible offal (mammalian) Sheep, meat byproducts, except liver 0.10 0.1 meat byproducts of sheep 0.1 kidney of sheep


### MRL s With No US Equivalent

P eanut, fodder 80

Completed: : M. Negussie; 02/04/2013

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.



### (b) Section 18 emergency exemptions. Time

- limited tolerances specified in the following table are established for residues of the insecticide methoxyfenozide, including its metabolites and degradates, in or on the specified agricultural commodities, resulting from use of the pesticide

### Page 24 of 34

pursuant to FFIFRA section 18 emergency exemptions. Compliance with the tolerance levels specified in the following table is to be determined by measuring only methoxyfenozide [benzoic acid, 3

- methoxy

- 2

- methyl

- , 2

- (3,5

- dimethylbenzoyl)

- 2

- (1,1

- dimethylethyl)hydrazide]. The expired tolerances will be revoked on the date specified in the table.

Commodity Parts per million Expiration/revocation date

Sorghum, forage 30.0 12/31/12

Sorghum, grain 0.05 12/31/12

Sorghum, stover 60.0 12/31/12



### (d) Indirect or inadvertent tolerances. (1) Tolerances are established for the indirect or inadvertent residues of the insecticide methoxyfenozide, including its metabolites and degradates, in or on the raw agricultural commodities in the following table, when present
therein as a result of the application of methoxyfenozide to growing crops as listed in paragraph (a) of this section. Compliance with the tolerance levels specified in the following table is to be determined by measuring only methoxyfenozide [3

- methoxy

- 2

- methylbenzoic acid 2

- (3,5

- dimethylbenzoyl)

- 2

- (1,1

- dimethylethyl) hydrazide].

Commodity Parts per
million

Onion, bulb, subgroup 3

- 07A 0.10

Potato 0.02



### (2) Tolerances are established for the indirect or inadvertent residues of the insecticide methoxyfenozide, including its metabolites and degradates, in or on the raw agricultural commodities in the following table, when present therein as a result of the application of methoxyfenozide to growing crops as listed in paragraph (a) of this section. Compliance with the
tolerance levels specified in the following table is to be determined by measuring only the sum of methoxyfenozide [3

- methoxy

- 2

- methylbenzoic acid, 2

- (3,5

- dimethylbenzoyl)

- 2

- (1,1

- dimethylethyl) hydrazide] and the following metabolites (all calculated as the stoichio metric equivalent of methoxyfenozide): free phenol of methoxyfenozide [3,5

- dimethylbenzoic acid N

tert

- butyl

- N ′

- (3

- hydroxy

- 2

- methylbenzoyl) hydrazide], the glucose conjugate of the phenol [3,5

- dimethyl benzoic acid N

- tert

- butyl

- N ′

- [3 (β

- D

- glucopyranosyloxy )

- 2

- methylbenzoyl]

- hydrazide]

and the malonylglycosyl conjugate of the phenol [3,5

- dimethyl benzoic acid N

- tert

- butyl

- N ′

- [3 (β

- D

- 6

- malonyl

- glucopyranosyl

- 1

- oxy)

- 2

- methylbenzoyl]

- hydrazide].

Commodity Parts per
million

Animal feed, nongrass, group 18, straw 8.0

Grain, cereal, forage, fodder and straw group 16, except corn 6.0

### Page 25 of 34 Commodity Parts per
million

Herb and spice, group 19, except coriander, leaves 4.5

### Page 26 of 34

Attachment 3

. Methoxyfenozide Products and Use Sites

Methoxyfenozide is registered for use on numerous agricultural crops; both ground and aerial application methods are allowed on registered labels, and a variety of hand

- held e quipment can also be used

.

Table 3. 1

. Methoxyfenozide Sec. 3 Product Formulations of Methoxyfenozide Insecticide

. Registered products & Formul. Types % AI Use Sites and Applicable ORE Reviews Application equipment Comments

62719

- 437
Technical 9 8

. 2 NA NA

62719

- 438 Intrepid WSP
MUP 80 A pples, Crabapples, Loqu at. M ayh a w, Pears including Oriental, Quince , Cotton
0.05 to 0.4 lb ai/A Ground, aerial Allow 14 days
between applications

62719

- 442 Intrepid 2F 22.6 Bushbernes (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)

, Okra

, Globe artichoke, Grape, Grass Forage Fodder, and Hay (Crop Group 17)

, Green Onion (Subgroup 3

- 07B)

, Legume Vegetables (Succulent or Dried) (Crop Group 6)

, Foliage of Legume Vegetables (Except Soybean) (Subgroup 7A ), Nongrass Forage, Fodder, Straw and Hay (Crop Group 18 ), Ornamentals

, Pome Fruits (Crop Group 11)

, Pomegranate

, Popcorn

, Root Vegetables (Subgroups 1A, 1B) , Soybean, Spearmint, Peppermint, Stone Fruits (Crop Group 12), Strawberry, Tree Nuts (Crop Group 14) and Pistachios, Tropical Tree Fruits, a nd Tuberous and Corm Vegetables (Except Potato) (Subgroup 1D) aerial, chemigation and ground equipment (airblast), ground boom,
hand held equipment (backpack

sprayer, manually

pressurized
handwand and hand gun), and
hose

- end

sprayer Up to 0.25 lb

ai/A for single application;
1.0 lb
ai/A/seasonal

max imum

Various Pre

harvest
intervals (PHIs) are allowed, ranging from 1 to 30 days.

There are no
rotational
restrictions for crops on the label; all
others have a
7

- day plant

back
restriction.
Abbre viations used: AI = active ingredient, WSP = water soluble package

, MUP = Manufacturing Use Product, F = Flowable Concentrate

.



### There are a number of Special Local Need ( SLN ) also known as FIFRA Sec. (24c) registrations
for methoxyfenozide insecticide (Table 2). These SLN sites have been reviewed but occupational exposures were not quanti tatively assessed due to a lack of endpoints for both dermal and inhalation assessment prior to 2102. However, HED has conducted screening
calculations for relevant use rates an d equipment, and did not identify risks of concern.

### Page 27 of 34

Table 3. 2

. 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

### Page 28 of 34

Attachment 4

. Methoxyfenozide Endpoint Selection Table s.

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

Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQPA

Safe ty 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 = 10 x

UF H = 10 x 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, 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 and
increased serum bilirubin

. Incidental Oral
Short

- Term (1

- 30 days) There are no residential uses for methoxyfenozide that would result in significant postapplication

incidental exposure to children.

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

Term (1

- 6 months) NOAEL =

16.8 mg/kg/day UF A =10x

UF H =10x Residential LOC for

MOE = 100 Two

- week oral range

- finding study

dog

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

.

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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF =

### Page 29 of 34

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 Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

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 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 animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable

### Page 30 of 34

Attachment 5: Methoxyfenozide

– Toxicity Profiles

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



### 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.

### Page 31 of 34

Subchronic, Chronic and Other Toxicity Profile

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

870.3100 90

- Day oral

toxicity (mouse) 44617723 (1995)

Acceptable/guideline

0, 70, 700, 2500, 7000 ppm in the diet

M: 0, 11.9, 112.5, 428.2, 1149.3 mg/kg/day;

F: 0, 17.4, 165.1, 589.4, 1742.1 mg/kg/day NOAEL = 428.2/589.4 mg/kg/day [M/F]
LOAEL = 1149.3/1742.1 mg/kg/day [M/F] based on decreased body weight gain.

Nonguideline 2

- week 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, i ncreased Heinz body count, reticulocyte counts, erythrocyte morphology and methemoglobinemia) and increased spleen weights.

At ≥264.7 mg/kg/day, bilirubinemia

870.3150 90

- Day oral

toxicity (dog) 44617724 (1995)

Acceptable/guideline

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

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

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

870.3200 28

- Day dermal

toxicity (rat) 44517725 (1998)

Acceptable/guideline

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

870.3700a Prenatal

developmental in (rat) 44638201 (1994)

Acceptable/guideline

0, 100, 300, 1000 mg/kg/day (gavage) Maternal NOAEL = 1000 mg/kg/day LOAEL >1000 mg/kg/day (HDT) Developmental NOAEL = 1000 mg/kg/day LOAEL >1000 mg/kg/day (HDT)

### Page 32 of 34

Subchronic, Chronic and Other Toxicity Profile

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

870.3700b Prenatal

developmental in (rabbit) 44617726 (1997)

Acceptable/guideline

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

870.3800 Reproduction

and fertility
effects (rat) 44617727 (1997)

Acceptable/guideline

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

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

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

870.4100a Chronic toxicity

(rat) See 870.4300

870.4100b Chronic toxicity

(dog) 44617728 (1997)

Acceptable/guideline

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

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

F: 0, 2.2, 12.6, 110.6, 1199.2 mg/kg/day NOAEL = 9.8/12.6 mg/kg/day [M/F] LOAEL = 106.1/110.6 mg/kg/day [M/F] based on mild hematological changes (decreased RBC parameters, slight methemoglobinemia) and increased serum bilirubin. Hematological
effects first observed at week 14. At 1152.4/1199.2 mg/kg/day: bilirubinemia in males, increased abs/rel liver and thyroid weights, increased cellularity of sternum and rib marrow, increased pigmented macrophages in liver and spleen.

870.4200 Carcinogenicity

(rat) 44617731 (1998)

Acceptable/guideline

0, 200, 8000 or 20,000 ppm in diet

M: 0, 10.2, 411 or 1045 mg/kg/day

F: 0, 11.9, 491 or 1248 mg/kg/day NOAEL = 10.2/11.9 mg/kg/day [M/F] LOAEL = 411/491 mg/kg/day [M/F] based on hematological changes (decreased RBC parameters), periportal liver hypertrophy, thyroid hypertrophy and altered colloid; possibly increased adrenal weight.

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

progress ive glomerulonephropathy, tissue
mineralization.

no evidence of carcinogenicity

### Page 33 of 34

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.

### Page 34 of 34

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 metabol ism 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
Immunotoxicity LOAEL = not established
Systemic toxicity NOAEL = = 76.9 mg/kg/day
Systemic toxicity LOAEL = 324 mg/kg/day, based on increased liver weights.