UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: May 10, 2013 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Methoxyfenozide. Human Health Assessment Scoping 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: Registration Review 

Scoping Document 

Case No.: 7431 

CAS No.: 161050-58-4 

40 CFR: § 180.544 

Linnea J. Hansen, Ph.D., Biologist 

Risk Assessment Branch II 

Health Effects Division (7509P) 

Office of Pesticide Programs 

THROUGH: Jess 

Dana 

Rowland

Vogel, Associate 

, Acting Associate 

Director 

Direct

~~,i~

or ~ --z___­

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Bonnie Adler, Chemical Review Manager 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

Attached is the Health Effects Division's (HED) human health risk assessment scoping document for the 

insecticide methoxyfenozide to support registration review. 

Page 1 of34 
Executive Summary 

The Health Effects Division Methoxyfenozide Risk Assessment Team has evaluated the database 

and the most recent human health risk assessments for the insecticide methoxyfenozide. HED 

performed this evaluation in order to determine the scope of work necessary to support the 

established tolerances and existing registrations. The primary source of information for this 

evaluation was the most recent human health risk assessment written for the chemical (Memo, 

D388978, M. Collantes et al., 23 May 2012). 

Methoxyfenozide was ftrst registered for use on cotton and apples (pome fruit crops) in 2000. It 

is an insect growth regulator [IGR] for use on target pests of larvae of destructive lepidopteran 

species. Methoxyfenozide is a diacylhydrazine insecticide, which is moderately systemic 

through the root system, but not through leaves. The insecticidal mode of action consists of 

premature induction of molting which kills the target insect, and it is effective as both a stomach 

and contact insecticide. 

Subsequent registrations were allowed for methoxyfenozide use on numerous crops: 

bush berries, cilantro leaves, brassica (cole) leafy vegetables, leaves of root and tuber vegetables, 

citrus fruit, cotton, cranberry, cucurbit vegetables, fruiting vegetables, globe artichoke, grape, 

grass (forage, fodder, and hay), green onions, legume vegetables, foliage of legume vegetables, 

nongrass (forage, fodder, straw, and hay), peanut, pome fruits, pomegranate, popcorn, root 

vegetables, soybean, spearmint, peppermint, stone fruits, strawberry, tree fruits, tree nuts, and 

tuberous and corm vegetables (except potato). In addition, it is registered for use on ornamental 

herbaceous plants, including ornamental woody shrubs and vines, ornamental and/or shade trees, 

recreational areas/parks, and institutions (outdoor). 

The toxicology database for methoxyfenozide is considered complete in accordance with the Part 

158 Data Requirements for conventional pesticide active ingredients. Although a 28-day 

inhalation toxicity study is not available, the HED Hazard Science Policy Committee (HASPOC) 

has determined that the study is not required for methoxyfenozide based on weight of evidence 

considerations, including the available toxicity data and the potential for exposure to 

methoxyfenozide via the inhalation route (TXR #0053782, 4/17/12). No new toxicity data are 

being requested during registration review, and therefore HED does not anticipate updating the 

hazard characterization database unless new information (either new GLP data or literature 

studies) is identifted during registration review. 

The toxicology studies with methoxyfenozide indicate that the main target organs in the rat and 

dog were the liver, thyroid and red blood cells (RBC). The most consistent fmdings across 

species and studies were decreased red blood cell parameters and increased liver, thyroid, 

adrenal and spleen weights. Many of the available short-term or subchronic toxicity studies 

showed little or no toxicity. Increases in thyroid and adrenal weights were observed in the rat 

chronic oral study. Thyroid weights were also increased in the dog following chronic exposure, 

but no accompanying histopathology was observed. 

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

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

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 submitted 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 inhalation toxicity would be equivalent to oral toxicity for the purpose of route-to-route 

extrapolation. The endpoint selected for chronic dietary risk assessment was liver and thyroid 

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

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

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 primary 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 tolerance 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.

The dietary exposure database is adequate to support the registration 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; however, if the estimated drinking water concentrations (EDWCs) are

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 resulting 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 with exposure from food and water, residential handlers’ aggregate risk 

estimates were not of concern. In addition, chronic aggregate exposure from food and water 

resulted in risk estimates that were not of concern.
Page 4 of 34

Prior to the most recent (2012) risk assessment 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 continued 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 quantitatively 

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 inhalation 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 on 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 preliminary 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 are 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. Methoxyfenozide 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 and 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 structure of methoxyfenozide, as well as the chemical names and other identifiers can be 

found in the chemical 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 are 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 toxicity 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 is 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 showed 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 anemia 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 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.

 

Liver effects observed in the rat and dog included increased liver weight and periportal 

hypertrophy. These findings were observed in the rat following two-week, subchronic or chronic 

dietary 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, thyroid hypertrophy and altered colloid and 

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

severity of chronic progressive glomerulonephropathy was increased. Thyroid weights were 

increased in the dog following chronic exposure, but there was no accompanying histopathology.

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

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

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

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

neurotoxicity. No clinical signs of toxicity or neurohistopathology were observed in other 

guideline studies. No maternal or developmental effects were observed in either the rat or rabbit 

oral developmental toxicity studies. In the rat two-generation reproductive toxicity study, 

parental effects were limited to increased liver weight and microscopic periportal hypertrophy, 

and no 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 following 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% wettable powder (WP) formulation 

product. There was no evidence of carcinogenicity in the submitted studies, and no mutagenic or 

clastogenic potential was observed in the battery of genotoxicity studies on methoxyfenozide. 

Based on these findings, methoxyfenozide is classified as “not likely to be carcinogenic to 

humans” (2005 Agency revised carcinogenicity assessment guidelines).

There were no single dose effects observed in the toxicity database that would be appropriate for 

acute dietary risk assessment. For 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 studies, with similar no-observed-adverse-effectlevels (NOAELs). In the rat, periportal liver hypertrophy, thyroid hypertrophy and altered 

colloid and increased adrenal weight were also observed at the lowest-observed-adverse-effectlevel (LOAEL). The selected NOAEL and LOAEL are protective of all other toxicity 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 risk 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 considerations, 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 

recommended 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 methoxyfenozide 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 assessment 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, and 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 crops, 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 RH141,518 metabolite. The residue definition in poultry meat (muscle) and fat is parent 

methoxyfenozide; 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. Based 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. Additional 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 available, 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 factors 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 notice, 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. The 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, 

assumed 100% crop treated, and used 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 used. 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 newer 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 assessments 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. Therefore 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 Exposure

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 grounds 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 conducted 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 because of its 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 

Federal 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 

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

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

exposure into the Agency’s risk assessments. If new policies or procedures are 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 residential 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. Exposure 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 residential 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 

registration 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 registration 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

Section 3 and Section 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 restricted 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. In the absence of a routespecific 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, it is HED policy to use the best available data to assess 

handler exposures. 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, most of the handler exposures resulting from agricultural 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 required due to a lack of toxicity via the dermal 

route.
Page 11 of 34

A quantitative post-application inhalation exposure assessment was not performed for 

methoxyfenozide based on the Agency's current practices. However, there are potential sources 

of inhalation exposure 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 input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency 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 review is 

considered protective of potential post-application exposure exposures expected for workers.

Conclusions for Occupational Exposure and Risk

Updated 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 assessment (e.g., spray drift, or 

volatilization).

Public Health and Pesticide Epidemiology Data

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

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

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

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

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

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

methoxyfenozide exposure. 

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

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports 
Page 12 of 34

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

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

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

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

the report. 

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

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

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

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

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

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

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

counts in what are aggregate summaries. 

For the Main IDS, from January 1, 2007 to December 11, 2012, there were no incidents reported 

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

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

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

incidents involving methoxyfenozide.

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

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

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

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

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

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

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

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

physician’s reports when available.

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

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

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

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

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

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

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

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

involved Intrepid 2F. 

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

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

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

if a concern is triggered, additional analysis 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 Methoxyfenozide Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression.

Matrix Residues Included in Risk 

Assessment

Residues Included in 

Tolerance Expression

Plants Primary Crops Parent methoxyfenozide Parent methoxyfenozide

Rotational Crops

(High Moisture)

1

Parent methoxyfenozide and 

metabolites, RH-151,055, RH152,072, and RH-117,236, RH152,067, RH-131,157 and RH152,071

Parent methoxyfenozide

Rotational Crops

(Low Moisture)

2

Parent methoxyfenozide and 

metabolites, RH-151,055, RH152,072, and RH-117,236, RH152,067, RH-131,157 and RH152,071

Parent methoxyfenozide and 

metabolites RH-151,055, RH152,072, 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 applicable

1. High-moisture rotational crops with established tolerances include potatoes and bulb 

onions (subgroup 3-07A).

2. Low-moisture rotational crops include non-grass animal feed straw (group 18); cereal 

grain forage, fodder and straw (group 16) except corn; and herbs and spices (group 19) 

except coriander leaves.

The residue definitions 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 crops and most livestock commodities. For livestock kidney and liver, 
Page 14 of 34

the residue definition 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 Canada’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 

harmonization of recommended tolerances for proposed new uses, and where possible, revision 

of existing tolerances concurrently 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 consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures and risks based on home use of pesticide products for adult applicators and

postapplication activities 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 exposure 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, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 
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), 

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

Program (EDSP). 

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

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

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

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

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

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

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

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

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

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

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

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

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

chemicals, which contains 58 pesticide active ingredients 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. Accordingly, 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 chemicals, 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 appear 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 to determine which chemicals have a 

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

policy statements released by EPA’s 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 which 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/handlerexposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

Data Requirements

None.

References

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 Science 

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 Residues 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., D389739, 2/27/12. Methoxyfenozide: Occupational 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-100001, be 

established for Florida for use on Citrus Fruits (Crop Group 10).

Rate, D., D357983, 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 

Proposed Use on Sweet Potato, Blueberry, Dry Bean, Grass, Peanut, Green Onion, Avocado, 

Guava, Alfalfa and Clover.

Hanson, B. D355027, 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 Vegetables, Edible Podded Legumes, and 

Succulent Shelled Peas and Beans.

Clock-Rust, M. D291304, 11/24/03. Methoxyfenozide: 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 

Greens).

Wassell, W. D258155, 8/20/99. PP# 8F5004 & PP#8F5006 Methoxyfenozide on Cotton and the

Pome Fruit Crop Group. Human Health Risk Assessment for New Reduced-Risk Insecticide.

Attachments

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 Profiles
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 C22H28N2O3

Molecular weight 368.47

Vapor Pressure (25C) 1.33 x 10-5Pa (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)

CH3 O

N

H

N

O

CH3

CH3

H3C CH3

H3C O

CH3
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 Mexico1 Codex2

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 fatsoluble, but is

not classed as fatsoluble with respect 

to its distribution in 

milk.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex2

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 Mexico1 Codex2

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, 

tangerines, tangors, 

trifoliate 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 Mexico1 Codex2

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, shelled 

(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 Mexico1 Codex2

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 Mexico1 Codex2
Page 23 of 34

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

(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-

dimethylethyl)hydrazide,

including the metabolite βD-glucopyranuronic acid, 3-

{[2-(1,1-dimethylethyl)-2-

(3,5-dimethylbenzoyl)-

hydrazino]carbonyl}-2-

methylphenylCommodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

Cattle, liver 0.40 0.1 0.1 edible offal 

Cattle, meat byproducts, (mammalian)

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

MRLs With No US Equivalent

Peanut, 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 stoichiometric 

equivalent of methoxyfenozide): free phenol of methoxyfenozide [3,5-dimethylbenzoic acid Ntert-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 equipment 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 98.2 NA NA

62719-438

Intrepid WSP

MUP

80

Apples, Crabapples, Loquat. Mayhaw, 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, and Tuberous and 

Corm Vegetables (Except Potato) (Subgroup 1D)

aerial, 

chemigation 

and ground 

equipment 

(airblast), 

ground boom, 

hand held 

equipment 

(backpack 

sprayer, 

manuallypressurized 

handwand and 

hand gun), and 

hose-end 

sprayer

Up to 0.25 lb 

ai/A for single 

application; 

1.0 lb 

ai/A/seasonal 

maximum

Various Preharvest 

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 plantback 

restriction.

Abbreviations 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 quantitatively 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 and 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. Rateand Method Comments

MS060014, 62719-442

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

CA060026, 62719-442

LA060011, 62719-442

CA060013, 62719-442 22.6 F Alfalfa for seed 

productions 0.25 lb ai/A; ground; aerial

Maximum of 

1lb 

ai/A/season; 

maximum of 

60,000 Acres

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

Maximum of 

4 applications 

per year to 

avoid 

resistance 

development

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

Maximum of 

1 lb 

ai/A/season

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

sugar beet 0.25 lb ai/A; aerial

Low volume 

spray 

concentrate
Page 28 of 34

Attachment 4. Methoxyfenozide Endpoint Selection Tables.

Summary of Toxicological Doses and Endpoints for Methoxyfenozide for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(All Populations, 

including Infants 

and Children

and Females 13-

49 years of age)

No hazard was identified for a single oral exposure.

Chronic Dietary 

(All 

Populations)

NOAEL= 10.2

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 1

Chronic RfD = 

0.10

mg/kg/day

cPAD = 0.10

mg/kg/day

Co-critical studies:

Combined oral chronic 

toxicity/carcinogenicity-rat

LOAEL = 411/491 mg/kg/day [M/F] 

based on hematological changes,

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 ShortTerm (1-30 

days) or 

Intermediateterm (1-6 

months)

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

Inhalation ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL =

16.8

mg/kg/day

UFA=10x

UFH=10x

Residential LOC for 

MOE = 100

Two-week oral range-finding studydog

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 = 
Page 29 of 34

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

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (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 ShortTerm (1-30 

days) or 

IntermediateTerm (1-6 

months)

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

Inhalation 

Short-Term (1-

30 days) and 

IntermediateTerm (1-6 

months)

NOAEL =

16.8

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

Two-week oral range-finding study-dog

LOAEL = 90.8 mg/kg/day based on 

hematological changes (decreased RBC 

parameters, increased Heinz body count, 

reticulocyte counts, erythrocyte 

morphology and methemoglobinemia) and 

increased spleen weights.

Cancer (oral, 

dermal, 

inhalation)

Classification: not likely to be carcinogenic to humans.

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

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

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

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

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

concern. N/A = not applicable
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 LD50 >5000 

mg/kg, both sexes

IV

870.1100 Acute oral [mouse] 44144416 LD50 >5000 

mg/kg, both sexes

IV

870.1200 Acute dermal [rat] 44144418 LD50 >2000 

mg/kg, both sexes

III

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

both sexes

IV

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

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

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

Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Nonguideline 2-week oral 

range-finding 

(rat)

44617722 (1995)

Acceptable/nonguideline

0, 50, 250, 1000, 5000, 

20,000 ppm in the diet

[note: mg/kg/day 

equivalents not calculated; 

see 90-day oral rat for 

mg/kg/day]

NOAEL = 250 ppm (approximately 17.0/19.1 

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

LOAEL = 1000 ppm (approximately 69.3/72.4 

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

based on thyroid gland hypertrophy/hyperplasia 

in males and females, and increased adrenal 

hypertrophy of zona fasciculata in females.

At ≥5000 ppm, increased abs/rel liver and 

adrenal weights, hepatocellular hypertrophy

870.3100 90-Day oral 

toxicity (rat)

44617722 (1995)

Acceptable/guideline

0, 50, 250, 1000, 5000, 

20,000 ppm in the diet

M: 0, 3.4, 17.0, 69.3, 

353.4, 1368.8 mg/kg/day

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

1531.2 mg/kg/day

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

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

periportal hepatocellular hypertrophy and 

increased liver weight.

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

and Hg in females.
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 rangefinding (dog)44617724 (1995)

Acceptable/nonguideline

0, 300, 3500, 15,000 or 

30,000 ppm in the diet (2 

animals/sex/dose)

M: 0, 11.7-14.7, 141.6-

167.6, 264.7-370.4, 571.4-

631.7, 1113.7-1337.0 

mg/kg/day;

F: 0, 13.3-16.8, 90.8-

184.8, 285.9-336.8, 582.3-

630.9, 1092.6-1169.1 

mg/kg/day

NOAEL = 11.7-14.7/13.3-16.8 mg/kg/day 

[M/F]

LOAEL = 141.6-167.6/90.8-184.8 mg/kg/day 

[M/F], based on hematological changes 

(decreased RBC parameters, increased Heinz 

body count, reticulocyte counts, erythrocyte 

morphology and methemoglobinemia) and 

increased spleen weights.

At ≥264.7 mg/kg/day, bilirubinemia 

870.3150 90-Day oral 

toxicity (dog)

44617724 (1995)

Acceptable/guideline

0, 15, 50, 500 or 5000 

ppm in the diet

M: 0, 0.6, 2.0, 21.4, 197.5 

mg/kg/day;

F: 0, 0.6, 1.9, 20.4, 208.8 

mg/kg/day

NOAEL = 197.5/208.8 mg/kg/day [M/F]

LOAEL >197.5/208.8 mg/kg/day [M/F](HDT).

870.3200 28-Day dermal 

toxicity (rat)

44517725 (1998)

Acceptable/guideline

0, 75, 300, 1000 

mg/kg/day

Systemic NOAEL = 1000 mg/kg/day

Systemic LOAEL > 1000 mg/kg/day (HDT)

Local dermal NOAEL = 1000 mg/kg/day

Local dermal LOAEL > 1000 mg/kg/day 

(HDT)

870.3700a Prenatal 

developmental in 

(rat)

44638201 (1994)

Acceptable/guideline

0, 100, 300, 1000 

mg/kg/day (gavage)

Maternal NOAEL = 1000 mg/kg/day

LOAEL >1000 mg/kg/day (HDT)

Developmental NOAEL = 1000 mg/kg/day

LOAEL >1000 mg/kg/day (HDT)
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)

Maternal NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day (HDT)

Developmental NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day (HDT)

870.3800 Reproduction 

and fertility 

effects

(rat)

44617727 (1997)

Acceptable/guideline

0, 200, 2000 or 20,000 

ppm in diet

P1 males: 0, 15.4, 153.4 

or 1551.9 mg/kg/day; 

P1 females: 0, 17.9, 

180.7, 1820.7 mg/kg/day

Parental/Systemic NOAEL = 153.4/180.7 

mg/kg/day [M/F];

LOAEL = 1551.9/1820.7 mg/kg/day [M/F] 

based on increased absolute and relative liver 

weights and microscopic midzonal to periportal 

hepatocellular hypertrophy.

Reproductive NOAEL = 1551.9/1820.7 

mg/kg/day [M/F];

LOAEL > 1551.9/1820.7 mg/kg/day 

[M/F](HDT)

Offspring NOAEL = mg/kg/day

LOAEL > 1551.9/1820.7 mg/kg/day 

[M/F](HDT)

870.4100a Chronic toxicity

(rat)

See 870.4300

870.4100b Chronic toxicity 

(dog)

44617728 (1997)

Acceptable/guideline

0, 60, 300, 3000 or 30,000 

ppm in diet

M: 0, 2.2, 9.8, 106.1, 

1152.4 mg/kg/day

F: 0, 2.2, 12.6, 110.6, 

1199.2 mg/kg/day

NOAEL = 9.8/12.6 mg/kg/day [M/F]

LOAEL = 106.1/110.6 mg/kg/day [M/F] based 

on mild hematological changes (decreased 

RBC parameters, slight methemoglobinemia) 

and increased serum bilirubin. Hematological 

effects first observed at week 14.

At 1152.4/1199.2 mg/kg/day: bilirubinemia in 

males, increased abs/rel liver and thyroid 

weights, increased cellularity of sternum and 

rib marrow, increased pigmented macrophages 

in liver and spleen.

870.4200 Carcinogenicity

(rat)

44617731 (1998)

Acceptable/guideline

0, 200, 8000 or 20,000 

ppm in diet

M: 0, 10.2, 411 or 1045 

mg/kg/day

F: 0, 11.9, 491 or 1248 

mg/kg/day

NOAEL = 10.2/11.9 mg/kg/day [M/F]

LOAEL = 411/491 mg/kg/day [M/F] based on 

hematological changes (decreased RBC 

parameters), periportal liver hypertrophy, 

thyroid hypertrophy and altered colloid; 

possibly increased adrenal weight.

At 1045/1248 mg/kg/day: decreased survival 

in males, decreased body weight in females, 

increased abs/rel liver weight, chronic 

progressive glomerulonephropathy, tissue 

mineralization.

no evidence of carcinogenicity
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 metabolism were Odemethylation and oxidative hydroxylation 

followed by conjugation with glucuronic acid. 

870.7600 Dermal 

penetration (rat)

44638202 (1998)

Acceptable/guideline

Mean dermal absorption at 10 and 24 hrs was 

2% using an 80WP formulation.

870.7800 Immunotoxicity 

(female rat)

48592601 (2011)

Acceptable/guideline

0, 76.9, 324 or 1076 

mg/kg/day in the diet 

(ppm not indicated)

Immunotoxicity NOAEL = 1076 mg/kg/day

Immunotoxicity LOAEL = not established

Systemic toxicity NOAEL = = 76.9 mg/kg/day

Systemic toxicity LOAEL = 324 mg/kg/day, 

based on increased liver weights.