UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 517/2013 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Pymetrozine. Human Health Assessment Seeping Document in Support of 

Registration Review 

PC Code: 101103 

Decision No.: 474077 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: D408387 

Registration No.: 100-91 2 and 100-913 

Regulatory Action: Registration Review 

Case No.: 7474 

CAS No.: 123312-89-0 

40 CFR: § 180.556 

FROM: Douglas Dotson, Ph.D., Chemist 4Q /)~ Karlyn Middleton, Toxicologist ~p·~/2.. _. _ Risk Assessment Branch II ~ ~-

Kelly 

Risk Assessment 

Lowe, Environmental 

Branch I 

Scientist ?~ 

CJ ~ 

Health Effects Division (7509P) 

Office of Pesticide Programs 

THROUGH: Christina Swartz, Branch Chief 

Risk Assessment Branch II 

Jess Rowland, Acting Associate Director ~a~J2---- Dana Vogel, Associate Director . ' .....-

Health Effects Division (7509P) ,·• C · · ... ~ 

Office of Pesticide Programs 

TO: Steven Snyderman, Chemical Review Manager 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

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

for pymetrozine to support registration review. 

1 of2Lj 
Pymetrozine Registration Review Seeping Document 

Executive Summary 

The Health Effects Division Pymetrozine Registration Review Team has evaluated the database 

and the most recent human health risk assessment for the insecticide pymetrozine. HED 

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

established tolerances and existing registrations during registration review. The primary source 

of information for this evaluation was the most recent human health risk assessment (D371299, 

C. Swartz and E. Scollon, 4/2/201 0). 

Pymetrozine, 4,5-dihydro-6-methyl-4-[ (E)-(3 -pyridinylmethylene )amino] -1 ,2,4-triazin-3(2H)-

one, is a selective insecticide and a member of the chemical class known as pyridine 

azomethines. It is currently registered for the control of a variety of sucking insect pests such as 

aphids and whiteflies. It is registered for use on a number of agricultural crops, including 

asparagus, head and stem Brassica, Brassica leafy greens, cotton, hops, pecans, turnips, fruiting 

vegetables, cucurbit vegetables, leafy vegetables, tobacco, and tuberous and corm vegetables. In 

addition, it is currently registered for use on ornamentals, including landscape ornamentals, 

groundcovers, and ornamental plants in greenhouses. 

The toxicology database for pymetrozine is complete except for subchronic inhalation and 

immunotoxicity studies that are required in accordance with the 2007 revised 40CFR Part 15 8 

Toxicology Data requirements. HED's Hazard and Science Policy Council (HASPOC) has 

determined that a subchronic inhalation toxicity study is not required because the oral Point of 

Departure (POD) used for assessing inhalation risk is based on the most sensitive endpoint 

observed in the most sensitive population subgroup (i.e, an inhalation study will not yield a 

lower POD) (TXR No. 0056567). Pymetrozine has a unique insecticidal mode of action in that it 

is a feeding inhibitor. The chemical affects the mechanism by which an aphid inserts its stylus 

into the plant tissue. The cellular mode of action of pymetrozine is not described, but is believed 

to be related to some aspect of neuroregulation or actual effect on the nerve-muscle interaction. 

The toxicity database indicates that the liver is the primary target organ following dosing with 

pymetrozine in rats and mice. In the dog, anemia and associated increases in bilirubin appeared 

to be a primary effect, although liver and skeletal effects were also seen. Pymetrozine is 

considered positive for liver tumors in both rats and mice. In accordance with the EPA Proposed 

Guidelines for Carcinogen Risk Assessment (April 10, 1996), the Cancer Assessment Review 

Committee (CARC) classified pymetrozine as a "likely human carcinogen" and recommended 

quantification of cancer risk using a cancer potency factor. Pymetrozine was not mutagenic or 

genotoxic in the submitted studies. 

There is no evidence (qualitative or quantitative) of increased susceptibility following in utero 

and/or pre-/post-natal exposure in adequate developmental toxicity studies in rats or rabbits, or in 

a two-generation reproduction study in rats. Quantitative susceptibility was observed in the 

developmental neurotoxicity (DNT) study in rats in which brain morphometric changes in rat 

pup brains were observed at a dose that did not cause maternal toxicity; however, the degree of 

concern is low because: 1) these effects were seen at the low dose indicating that the LOAEL is 

near the threshold dose for this effect; and 2) the LOAEL is used as the POD with the 1 Ox FQPA 

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Pymetrozine Registration Review Scoping Document

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Safety Factor retained in the form of a LOAEL to NOAEL factor (UFL). Thus there are no 

residual uncertainties for the overall risk assessment.

There was inconsistent evidence of neurotoxicity in the acute, subchronic, and developmental 

neurotoxicity (DNT) studies. 

In the most recent human health risk assessment for pymetrozine (D371299, C. Swartz, 

04/02/2010), endpoints were selected for acute and chronic dietary, as well as occupational 

short-, and intermediate-term dermal and inhalation exposure. For all anticipated exposures, the 

endpoint and POD were selected from the DNT study in rats. A 10x Food Quality Protection 

Act Safety Factor (FQPA SF) was retained to account for the lack of a NOAEL (no observed 

adverse effects level), based on the use of the pup LOAEL (lowest observed adverse effects 

level) for endpoint (brain morphometric changes) and dose selection, and for the observed 

quantitative susceptibility in the study. Therefore, a total uncertainty factor of 1000x (10x

FQPA, 10x intraspecies, and 10x interspecies) was applied.

Pymetrozine has low acute toxicity in lethality studies, being classified as III or IV in the acute 

oral, dermal, inhalation, and irritation studies, and is regarded as a slight sensitizer. 

The residue chemistry database is adequate to support current registration review requirements. 

Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the 

residue, and processing data are available to support the registered uses. Adequate methods are 

available for enforcement of the currently established tolerances. During registration review, the 

tolerance expression should be updated to include both coverage and compliance statements.

The dietary exposure database is adequate to support current registration requirements. The last 

risk assessment provided acute, chronic, and cancer dietary exposure estimates that are below 

HED’s level of concern for all population subgroups (D371299, C. Swartz and E. Scollon, 

4/2/2010). Cancer dietary risk estimates were 1.8 x 10-6. As part of registration review, HED 

anticipates performing revised dietary exposure analyses to reflect current Agency policy and 

potentially updated drinking water estimates.

The residential exposure database is adequate to support registration review for pymetrozine. 

There is the potential for residential handler and post-application exposures from the registered 

use on ornamentals. A residential handler assessment has not been conducted and will need to 

be included in the registration review assessment reflecting updated doses and endpoints for risk 

assessment, HED’s Residential SOPs, and current policies. Previous residential post-application 

assessments, which assessed incidental oral exposures, relied on default assumptions for 

dislodgeable foliar residues (DFR) available following treatments. Chemical-specific DFR data 

are available to assess exposure to residues following pymetrozine treatments. These studies will 

be reviewed during registration review, and updated residential post-application exposure 

assessments will be required reflecting updated doses and endpoints for risk assessment, the 

available chemical-specific DFR data, and HED’s Residential SOPs. 

The occupational exposure database is adequate to support registration review for pymetrozine. 

Updated occupational handler assessments will be required during registration review reflecting 
Pymetrozine Registration Review Scoping Document

Page 4 of 24

updated doses and endpoints for risk assessment. In addition, for the handheld equipment 

applications to ornamentals scenario, the currently registered rate is higher than that previously 

assessed and will need to be updated during registration review. Updated occupational postapplication assessments will also need to be conducted with updated doses and endpoints for risk 

assessment. In addition, two chemical-specific DFR studies available for pymetrozine will need 

to be evaluated during registration review for use in the occupational post-application 

assessments. Both occupational handler and post-application assessments will need to 

incorporate recent updates to HED’s exposure policies, including unit exposures for handler 

scenarios, updates to post-application transfer coefficients, and assumptions for body weights. 

 

The only data deficiency identified for pymetrozine is the required immunotoxicity study 

[870.7800]. During registration review, the tolerance expression for pymetrozine should be 

revised to reflect the residues of concern for both coverage and compliance purposes. HED 

anticipates performing revised dietary, residential (handler dermal and inhalation exposure, and 

post-application dermal and incidental oral exposure), and aggregate assessments that reflect 

current Agency policies, the updated dietary model, and potential revised drinking water 

estimates. In addition, both residential and occupational assessments will need to be updated 

with the use of chemical-specific DFR data as well as the use of current policies and updated 

endpoints and doses for risk assessment.

Introduction

HED evaluated the most recent human health risk assessment for pymetrozine in association 

with updates to its toxicity, exposure, and usage databases to determine if sufficient data are 

available, and if further updates are needed, to support registration review. The most recent 

human health risk assessment was performed in 2010 when HED updated a previous risk 

assessment because of comments submitted by the Natural Resources Defense Council 

(D371299, C. Swartz and E. Scollon, 4/2/2010).

Pymetrozine, 4,5-dihydro-6-methyl-4-[(E)-(3-pyridinylmethylene)amino]-1,2,4-triazin-3(2H)-

one, is a selective insecticide and a member of the chemical class known as pyridine 

azomethines. It is currently registered for the control of a variety of sucking insect pests such as 

aphids and whiteflies. It is registered for use on a number of agricultural crops, including 

asparagus, head and stem Brassica, Brassica leafy greens, cotton, hops, pecans, turnips, fruiting

vegetables, cucurbit vegetables, leafy vegetables, tobacco, and tuberous and corm vegetables. In 

addition, it is currently registered for use on ornamentals, including landscape ornamentals, 

groundcovers, and ornamental plants in greenhouses. Tolerances for pymetrozine are established 

in 40 CFR §180.556. These tolerances range from 0.02 ppm for pecans and tuberous and corm 

vegetables to 6.0 ppm for hop, dried cones. The tolerance is established in terms of the parent 

insecticide only.

The structure, the chemical names, and other identifiers can be found in the chemical identity 

table in Attachment 1.
Pymetrozine Registration Review Scoping Document

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Hazard Identification/Toxicology

Pymetrozine has a unique insecticidal mode of action in that it is a feeding inhibitor. It affects 

the mechanism by which an aphid inserts its stylus into the plant tissue. The cellular mode of 

action of pymetrozine is not described, but is believed to be related to some aspect of 

neuroregulation or actual effect on the nerve-muscle interaction. 

The toxicology database for pymetrozine is complete except for a subchronic inhalation toxicity

study and an immunotoxicity study that are required in accordance with the 2007 revised 40CFR 

Part 158 Toxicology Data requirements. HED’s HASPOC determined that the inhalation 

toxicity study is not needed because it would not result in a lower POD than that currently used 

in the overall risk assessment (TXR No. 0056567). Therefore, the immunotoxicity study is the 

only outstanding data gap. OPP has published the findings of an independent retrospective 

analysis of 170 immunotoxicity studies submitted to the Agency. The retrospective analysis 

suggests that the submitted immunotoxicity studies have not yet resulted in PODs that are lower 

than the PODs selected from other available guideline experimental toxicology studies. As a 

result, the currently available immunotoxicity studies have not impacted the Agency’s risk 

assessments. HED is in the process of developing a guidance document on data waiver 

considerations. In the interim, HED recommends that immunotoxicity studies continue to be 

required for registration and registration review chemicals.

In the available toxicology studies for pymetrozine, the liver was the primary target organ in rats

and mice, as evidenced by hepatocellular hypertrophy, increases in both absolute and relative 

liver weights, and liver pathology. Other effects in rats included decreases in body weight, 

increases in bilirubin, evidence of leukocytosis, and changes in spleen weight. Changes were 

seen in kidney, testis, ovary, brain, and heart weights, but these changes were not accompanied 

by pathological changes. Cholesterol and phospholipid levels were increased. In mice, 

additional effects included hemosiderosis and extramedullary hematopoiesis. In the dog, anemia 

and associated increases in bilirubin appeared to be a primary effect, although liver weight 

increases, intrahepatic bile duct hyperplasia, and skeletal muscle hypertrophy were also evident.

Pymetrozine is classified as a “likely human carcinogen” and the CARC recommended that 

quantification of risk be estimated by a cancer potency factor of 0.0119 (mg/kg/day)-1for 

combined liver tumors (benign hepatomas and/or carcinomas) in male and female mice and 

female rats. Pymetrozine is not considered to be mutagenic or genotoxic.

There is no evidence (qualitative or quantitative) of increased susceptibility following in utero

and/or pre-/post-natal exposure in adequate developmental toxicity studies in rats or rabbits, and 

in a two-generation reproduction study in rats. In the developmental toxicity studies, maternal 

toxicity consisted of decreased body weight and body weight gain and an associated decrease in 

food consumption for both the rat and rabbit. At dose levels higher than those producing 

maternal toxicity, there were indications of skeletal anomalies in the rat. In the rabbit, skeletal 

abnormalities were evident at the same dose that caused comparable maternal toxicity. 

Additional effects included reduced litter size and increased post-implantation loss. In the multigeneration reproduction study in rats, effects in pups (body weight changes and delayed eye 
Pymetrozine Registration Review Scoping Document

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opening) were seen at the same dose as comparable maternal toxicity (body weight changes, 

decreased food consumption, and liver, spleen, and thymus effects.

Quantitative susceptibility was observed in the rat DNT study. The maternal LOAEL was 38.7 

mg/kg/day based on complete litter losses, with a NOAEL for this effect of 8.1 mg/kg/day. The 

offspring LOAEL was the lowest dose tested of 8.1 mg/kg/day based on changes in pup brain 

morphometrics. However, HED’s degree of concern for the effect is low because: 1) this effect 

was seen at the low dose, indicating that the LOAEL is near the threshold dose for this effect; 

and 2) the LOAEL is used as the POD with the 10x FQPA Safety Factor retained in the form of a 

LOAEL to NOAEL factor (UFL). Thus, there are no residual uncertainties for the overall risk 

assessment.

Finally, neurotoxicity was observed in the acute, subchronic, and developmental neurotoxicity 

studies. In the acute study, a transient decrease in the body temperature and decreased activity in 

the functional observational battery (FOB) and motor activity assessments were evident. 

Excessive head movement and sniffing as well as tiptoe gait were observed in the subchronic 

study. Changes in brain morphometrics were observed in all dose groups examined in the DNT. 

Although indications of neurotoxicity were present, they were not consistent between the acute, 

subchronic, and DNT studies.

Pymetrozine demonstrated low toxicity in acute lethality studies, being classified as III or IV in 

the acute oral, dermal, inhalation, and irritation studies. Pymetrozine is regarded as a slight 

sensitizer. 

In the most recent human health risk assessment for pymetrozine (D371299, C. Swartz and E. 

Scollon, 04/02/2010), endpoints were selected for acute and chronic dietary, as well as 

occupational short-, and intermediate-term dermal and inhalation exposure. For all anticipated 

exposures, the endpoint and POD were selected from the DNT study in rats. Morphometric 

changes in the brains of female and male pups were observed at the LOAEL of 8.1 mg/kg/day in 

the absence of maternal toxicity. A 10x FQPA SF was retained to account for the lack of a 

NOAEL for the morphometric effects. Therefore, a total uncertainty factor of 1000x (10x

FQPA, 10x intraspecies, and 10x interspecies) was applied.

Conclusions for Hazard Identification/Toxicology

The toxicology database for pymetrozine is mostly complete. However, an immunotoxicity 

study is not available and should be submitted during registration review. No significant 

changes are anticipated for the endpoints, doses, and safety factors used in the most recent 

human health risk assessments for pymetrozine.

Dietary Exposure

The residue chemistry database is adequate to support current registration review requirements

(D250386, D. Dotson, 11/19/2001). Adequate metabolism (crops, livestock, and rotational 

crops), storage stability, magnitude of the residue, and processing data are available to support 

the registered uses. Adequate methods are available for enforcement of the currently established 
Pymetrozine Registration Review Scoping Document

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tolerances. No residue chemistry data deficiencies were cited in the previous risk assessment for 

pymetrozine.

In the 2010 risk assessment, HED conducted acute, chronic, and cancer dietary exposure 

analyses for all currently registered food uses (D371299, C. Swartz and E. Scollon, 4/2/2010). 

Although some refinements were used in the assessments, overall, the acute, chronic, and cancer 

assessments reflected conservative estimates of dietary exposure. The chronic and cancer 

analyses incorporated percent crop treated (PCT) estimates for most of the more heavilyconsumed commodities, including potatoes, peppers, and tomatoes; however, 100 PCT was 

assumed for numerous commodities for which usage data were not available. The dietary risk 

estimates included modeled surface water residue estimates provided by the Environmental Fate 

and Effects Division (EFED; D283937, 10/5/2004, J. Wolf and L. Shanaman). Drinking water 

residues included the parent pymetrozine as well as one degradate, CGA-359009. Acute and 

chronic dietary risk estimates were below HED’s level of concern for the general U.S. population 

and all population subgroups. In the acute assessment, the most highly exposed population 

subgroup was children 1-2 years old, which used 54% of the aPAD. The general US population 

used 35% of the aPAD. In the chronic assessment, the most highly exposed population subgroup 

was all infants, which used 9% of the cPAD. The general US population used 3% of the cPAD. 

The cancer risk estimate for the general US population was 1.8×10-6. Residues in drinking water

were the greatest contributor to overall dietary exposure. HED anticipates conducting a new 

dietary exposure and risk assessment with updated PCT estimates from the Biological and 

Economic Analysis Division (BEAD). At that time, the most current version of the dietary 

model will be used.

Conclusions for Dietary Exposure

No new data are needed to assess potential dietary exposure and risk for pymetrozine. However, 

HED anticipates performing a new dietary exposure assessment during registration review. The 

most current drinking water models will be used for this assessment. In addition, the most 

current version of the dietary model will be used, along with any potential changes in endpoints 

and doses for risk assessment. Finally, HED might need to incorporate updated PCT estimates in 

accordance with Agency policies regarding the use of anticipated residues for dietary risk 

assessment.

Residential Exposure

Pymetrozine is currently registered for use on ornamentals including landscape ornamentals, 

groundcovers, and ornamental plants in greenhouses. The initial registration for these uses was 

for the product, Endeavor (EPA Reg. No. 100-913), a 50% ai water-dispersible granule (WDG). 

The 1999 assessment for this use (D259881, M. Collantes, 9/24/1999) included residential postapplication scenarios only (incidental oral exposures/risk estimates), and no risks of concern 

were identified (non-cancer margins of exposure (MOEs) ≥ 900, and cancer risk estimates that 

were ≤ 1x10-6). As the product was intended for professional applicators only, a residential 

handler assessment was not conducted. During registration review, HED will conduct a 

residential handler assessment for ornamentals, because the product is not a restricted-use 

product (RUP), and a homeowner could potentially apply it in a residential setting.
Pymetrozine Registration Review Scoping Document

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HED’s Residential SOPs have been revised (February 2012) and include updates to exposure 

factors such as body weights; therefore, a revised residential exposure assessment using the 

updated Residential SOPs will be needed during registration review. In addition, since the last 

residential assessment was performed, new endpoints and doses for risk assessment have been 

selected. For residential handlers, HED will consider residential handlers treating ornamentals 

with various types of hand held equipment, and, in addition, a post-application dermal exposure 

and risk assessment will be needed for adults and children contacting treated gardens and trees. 

The scenarios are shown in detail in Attachment 6.

In accordance with the updated Part 158 data requirements (2007), DFR studies are required 

when a pesticide has residential or occupational uses that could result in post-application dermal 

exposure. There are two chemical-specific DFR studies available for pymetrozine on roses and 

lettuce. These studies will need to be reviewed during registration review for use in the 

residential post-application assessment.

Spray Drift

Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) might

occur as a result of applications of pymetrozine. 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 

pymetrozine will be examined during registration review.

Conclusions for Residential Exposure

The residential exposure database is adequate to support the registration review process for 

pymetrozine. There is the potential for residential handler and post-application exposures from 

the registered use on ornamentals. A residential handler assessment has not been conducted and 

will need to be included in the registration review assessment, using the latest doses and 

endpoints for risk assessment, HED’s residential SOPs, and current policies. Previous residential 

post-application assessments, which assessed incidental oral exposures, relied on default 

assumptions for dislodgeable foliar residues (DFR) available following treatments. Chemicalspecific DFR data are available to assess exposure to residues following pymetrozine treatments. 

These studies will be reviewed during registration review, and updated post-application exposure 

assessments will be required under registration review based upon updated doses and endpoints 

for risk assessment, revisions to HED’s Residential SOPs, and the available chemical-specific 

DFR data.

Aggregate Risk Assessment

The most recent aggregate risk assessment was performed in conjunction with the 2010 risk 

assessment (D371299, C. Swartz and E. Scollon, 4/2/2010). For aggregate risk assessment, risk 

estimates resulting from food, drinking water, and residential uses are usually combined. As no 

residential uses were identified for pymetrozine at the time, only acute, chronic, and cancer 

aggregate risk assessments were conducted. The acute, chronic, and cancer aggregate risk 
Pymetrozine Registration Review Scoping Document

Page 9 of 24

assessments consisted of dietary exposures from food and drinking water only. The acute and 

chronic risk estimates were not of concern for the general U.S. population or any of the 

population subgroups. The cancer aggregate risk estimate for the general US population was 

1.8×10-6. 

 

Conclusions for Aggregate Exposure and Risk

During registration review, updated aggregate assessments are likely to be needed to incorporate 

the potential for short-term residential exposures following use of pymetrozine in residential 

gardens. If aggregate assessments are needed, they will include any potential updates to 

exposure from food and drinking water.

Occupational Exposure 

Occupational handler and post-application exposures are expected based on the registered 

agricultural/commercial uses of pymetrozine. Attachment 5 provides a summary of the 

occupational use pattern. The current registrations include several special local need (SLN)

registrations. The products registered for pymetrozine are all water dispersible granules (WDG)

or dry flowables (DF). The application rates per area treated range from 0.086 – 0.31 lb ai/A for 

agricultural crops and ornamentals, and the rate per volume is 0.002 lb ai/gal for ornamentals. 

Occupational Handlers

There is the potential for dermal and inhalation exposure of occupational handlers from the 

currently registered use pattern of pymetrozine. In all past risk assessments, no chemicalspecific data were available with which to assess potential exposure of pesticide handlers; 

therefore, occupational handler assessments were based primarily on surrogate unit exposures 

from the Pesticide Handlers Exposure Database (PHED). Previous risk calculations were based 

on the maximum application rates and the assumption of maximum area treated per day or 

gallons handled. Handler’s exposure and risk were calculated assuming the use of baseline 

clothing (long pants, a long-sleeved shirt, no chemical-resistant gloves, and no respirator) and 

with personal protective equipment (PPE) when necessary (e.g., chemical-resistant gloves, 

respirators, and engineering controls). 

In previous assessments (M. Collantes, 9/24/1999, D259881; M. Collantes, 8/13/2001, D273635; 

Z. Figueroa, 12/1/2004, D308992) non-cancer inhalation exposure and risk were estimated for 

occupational handlers. Cancer risk was also estimated for handlers. No quantitative dermal risk 

assessments were required because no adverse effects were noted at the highest dose tested. 

There were no non-cancer risk estimates of concern (all MOEs ≥ 100), and all cancer risk 

estimates were less than 10-4.

Updated occupational handler assessments will be required during registration review to reflect 

updated doses and endpoints for risk assessment. In addition, for the handheld equipment 

application to ornamentals scenario, the currently registered rate is higher than that previously 

assessed and will need to be updated during registration review. Additionally, there have been 

several updates to HED’s exposure policies since the previous reviews were performed. These 
Pymetrozine Registration Review Scoping Document

Page 10 of 24

updates include revisions to default exposure data used for handler scenarios and assumptions for 

body weights. Thus, these scenarios will need to be updated in the registration review 

assessment to be sure they are assessed using current policies and recommended toxicity and 

exposure data.

Occupational Post-Application

There is the potential for post-application dermal exposure for workers conducting activities 

following applications of pymetrozine to agricultural crops and ornamentals. As noted above, 

however, a quantitative non-cancer dermal post-application assessment was not required because

no hazard was identified at the highest dose tested in a 28-day dermal toxicity study. In previous 

assessments (M. Collantes, 9/24/1999, D259881; M. Collantes, 8/13/2001, D273635; Z. 

Figueroa, 12/1/2004, D308992) post-application dermal cancer risk only was estimated for 

workers. The dermal cancer risk estimates are all less than 10-4. 

Updated non-cancer and cancer occupational post-application assessments will need to be 

conducted with updated doses and endpoints for risk assessment. The previous cancer 

assessments were conducted using default assumptions for DFR following applications. There 

are two chemical-specific DFR studies available for pymetrozine on roses and lettuce. These 

studies will be reviewed during registration review for use in the occupational post-application 

assessments. Additionally, there have been several revisions to HED’s exposure policies since 

the previous reviews were performed. These revisions include updates to post-application 

transfer coefficients and assumptions for body weights. Thus, these scenarios will need to be

updated in the registration review assessment to be sure they are assessed using current policies 

and recommended toxicity and exposure data.

Conclusions for Occupational Exposure

The occupational exposure database is adequate to support the registration review for 

pymetrozine. An updated occupational handler exposure assessment will be needed to reflect 

updated doses and endpoints for risk assessment, and to assess the currently registered rate for 

applications to ornamentals using handheld equipment. In addition, post-application assessments 

will need to be conducted to reflect updated doses and endpoints for risk assessments and to 

incorporate updated transfer coefficients and activity data. In addition, two chemical-specific 

DFR studies were submitted and will be reviewed to support any post-application risk 

assessments. Any scenarios that need to be updated in the registration review assessment will 

incorporate the updated body weight assumptions and other relevant updates to HED’s data and 

policies for occupational exposure and risk assessment.

Public Health and Pesticide Epidemiology Data

HED used OPP’s 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 to determine the 

number and severity of incidents that resulted from pymetrozine exposure (Memo, D408569, S. 

Recore, 2/5/2013). IDS records incidents in one of two modules: the Main IDS and the 
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Aggregate IDS. The Main IDS contains incidents resulting in higher severity outcomes and 

provides more detail than the Aggregate IDS. The Aggregate IDS contains incidents resulting in 

less severe human incidents. For the Main IDS, from January 1, 2007 to December 11, 2012,

there was one incident reported for the single chemical only in the database. There was one

additional incident reported involving more than one chemical. These incidents were classified 

as moderate severity. Overall, few incidents involving pymetrozine were reported to IDS. In the 

Aggregate IDS from January 1, 2007 to December 11, 2012, there was one reported incident

involving pymetrozine. This incident was classified as minor severity. A query of SENSORPesticides 1998-2009 identified two cases stemming from one event. This event involved 

exposure to multiple active ingredients. The event occurred in Oregon in 2001. Both cases were 

low in severity.

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

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

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

if a concern is triggered, additional analysis will be included in the registration review risk 

assessment.

Tolerance Assessment and International Harmonization

Tolerances for residues of pymetrozine in or on agricultural commodities are established in 

40CFR §180.556. During registration review, the tolerance expression should be revised as 

follows: Tolerances are established for residues of pymetrozine, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified below is to be determined by measuring only pymetrozine, 1,2,4-triazin-3(2H)-one,4,5-

dihydro-6-methyl-4-[(3-pyridinylmethylene)amino].

The Codex Alimentarius Commission (Codex) has not established maximum residue limits 

(MRLs) for pymetrozine. Canada and the U.S. have established MRLs (tolerances) for many of 

the same commodities. These tolerances and MRLs are established at the same levels. Mexico 

adopts U.S. tolerances and/or Codex MRLs for its export purposes. As there are no Codex 

MRLs for pymetrozine, Mexico’s MRLs are equivalent to the U.S. tolerances. As a result, there 

are currently no harmonization issues between the U.S. and either Canada or Mexico. The 

international residue limit status sheet can be found in Attachment 7. 

Environmental Justice

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

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

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

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP 

typically considers the highest potential exposures from the legal use of a pesticide when 

conducting human-health risk assessments, including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S., and 

people who might be exposed when harvesting crops. Should these highest exposures indicate 
Pymetrozine Registration Review Scoping Document

Page 12 of 24

potential risks of concern, OPP further refines the risk assessments to ensure that the risk 

estimates are based on the best available information.

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 might be 

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

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

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

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

taxonomic groups. As part of pymetrozine’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), pymetrozine 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. Pymetrozine 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 callins, requiring the submission of EDSP screening assays for pymetrozine. 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 pymetrozine and any other substances, and pymetrozine does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this action, therefore, EPA has not 
Pymetrozine Registration Review Scoping Document

Page 13 of 24

assumed that pymetrozine has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a common mechanism 

of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements 

released by EPA’s Office of Pesticide Programs concerning common mechanism determinations 

and procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Human Studies

Past pymetrozine 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. Many such studies, involving exposure to many different pesticides, comprise generic 

pesticide exposure databases such as PHED, the Outdoor Residential Exposure Task Force 

(ORETF) Database, and the Agricultural Reentry Task Force (ARTF) Database. EPA has 

reviewed all the studies supporting these multi-pesticide generic exposure databases, and has 

found no clear and convincing evidence that the conduct of any of them was either 

fundamentally unethical or significantly deficient relative to the ethical standards prevailing at 

the time the research was conducted. All applicable requirements of EPA’s Rule for the 

Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no 

regulatory barrier to continued reliance on these studies.

Additional Information from Literature Sources

A pymetrozine literature search did not reveal information that would impact the current risk 

assessment.

Risk Assessment Updates, Data Deficiencies, and Label Revisions

The following data deficiency was identified for pymetrozine:

Toxicology

An immunotoxicity study (870.7800) is required to support registration review. The 

immunotoxicity study is a new requirement for both food and non-food uses under 40 CFR Part 

158 Data Requirements for Pesticides. 

EPA anticipates conducting the following risk assessment updates during registration review:

Toxicology: 

A reevaluation of the toxicity endpoint/dose selection, along with the FQPA SF, based on 

submitted studies and any outstanding data.

Residue Chemistry:

The tolerance expression should be revised to reflect the residues of concern for both 

coverage and compliance purposes.
Pymetrozine Registration Review Scoping Document

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Dietary Exposure:

Revised dietary exposure analyses might be required to reflect current Agency policy, 

updated PCT estimates, updated dietary exposure models, and potentially updated 

drinking water estimates.

Occupational/Residential Exposure: 

Review of available chemical-specific dislodgeable foliar residue (DFR) studies will be 

conducted during registration review.

HED anticipates conducting revised occupational and residential exposure assessments to 

reflect the use of current policies and updated endpoints and doses for risk assessment.

References

Memoranda Relevant to Registration Review

Author Barcode Date Title

C. Swartz,

E. Scollon

D371299 4/2/2010 Pymetrozine. Updated Aggregate Human Health Risk Assessment

J. VanAlstine TXR No. 

0056567

3/20/2013 Pymetrozine: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting on January 23, 2013: Recommendations on 

Data Requirements for a Subchronic Inhalation Study.

D. Dotson D250386 11/19/2001 PP#s 8F4984, 8F5031, and 0F6141. Tolerance Petitions for the Use 

of Pymetrozine on Cotton, Hops, Pecans, Leafy Vegetables (Except 

Brassica Vegetables), Head and Stem Brassica, Leafy Brassica 

Greens, Turnip Greens, Cucurbits, and Fruiting Vegetables. 

Evaluation of Residue Chemistry and Analytical Methodology

C. Swartz D372578 4/2/2010 Pymetrozine – Acute, Chronic and Cancer Combined Dietary

(Food + Drinking Water) Exposure and Risk Assessments

M. Collantes D259881 9/24/1999 PP#8F4929. Occupational and Residential Exposure Risk 

Assessment for Pymetrozine on Fruiting Vegetables, Cucurbits, 

Potatoes, Tobacco, Ornamentals and Non-bearing Fruit, Nut and 

Christmas Trees

M. Collantes D273635 8/13/2001 Occupational Exposure Assessment for Section 3 Registration of 

Pymetrozine to Cotton, Hops, Leafy Vegetables, Head/Stem 

Brassica, and Leafy Brassica Greens

Z. Figueroa D308992 12/1/2004 Pymetrozine: Occupational Exposure Assessment for Proposed 

Section 3 Registration for Use on Asparagus

J. Wolf

L. Shanaman

D283937 10/5/2004 EFED Water Assessment/Environmental Risk Assessment for 

Pymetrozine New Use: Asparagus

S. Recore D408569 2/5/2013 Prallethrin: Review of Human Incidents
Pymetrozine Registration Review Scoping Document

Page 15 of 24

Attachments

Attachment 1. Chemical Identity Table

Attachment 2. Toxicology Data Requirements

Attachment 3. Pymetrozine Endpoint Selection Table

Attachment 4. Toxicity Profile Table

Attachment 5. Pymetrozine Use Pattern Summary

Attachment 6. Residential Handler and Post-Application Scenarios that Might Need to be 

Assessed/Reassessed During Registration Review of Pymetrozine

Attachment 7. International Residue Limit Status

Attachment 1. Chemical Identity Table

Pymetrozine Nomenclature

Chemical Structure

Empirical Formula C19H24O3

Common Name Pymetrozine

Company Experimental 

Name

CGA-215944

IUPAC Name (E)-4,5-dihydro-6-methyl-4-(3-pyridinylmethyleneamino)-1,2,4-triazin3(2H)-one

CAS Name (E)-4,5-dihydro-6-methyl-4-[(3-pyridinylmethylene)amino]-1,2,4-triazin3(2H)-one

CAS Registry Number 123312-89-0

End-use Product/EP Fulfill® (EPA Reg. No. 100-912; 50% ai WDG)

Endeavor® (EPA Reg. No. 100-913; 50% ai WDG)

Chemical Class Pyridine Azomethine

Known Impurities of 

Concern

None
Pymetrozine Registration Review Scoping Document

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Attachment 2. Toxicology Data Requirements

The requirements (40 CFR 158.340) for pymetrozine residential and occupational use are shown 

below. Use of the new guideline numbers does not imply that the new (1998) guideline 

protocols were used.

Test Technical

Required Satisfied

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

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

870.3200 21/28-Day Dermal..........................................................

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

870.3465 90-Day Inhalation...........................................................

yes

yes

no

yes

no

yes

yes

yes

 no1

---

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

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

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

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

no

yes

yes

yes

yes

yes

yes

yes

yes

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

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

870.5375 Mutagenicity—Structural Chromosomal Aberrations....

870.5395 Mutagenicity—Mammalian Erythrocyte Micronucleus.

870.5550 Mutagenicity—Unscheduled DNA Synthesis................

870.5915 Mutagenicity—In Vivo Sister Chromatid Exchange

yes

yes

yes

no

no

no

yes

yes

yes

yes

yes

--

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

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

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

870.6200b 90 Day Neurotox. Screening Battery (rat)......................

870.6300 Develop. Neuro ..............................................................

no

no

yes

yes

yes

---

---

yes

yes

yes

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

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

yes

no

yes

yes

870.7800 Immunotoxicity................................................ yes no

1 Requirement fulfilled by 21/28 day study.
Pymetrozine Registration Review Scoping Document

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Attachment 3. Toxicity Endpoint Summary Tables

Toxicological Doses and Endpoints for Pymetrozine for Use in Dietary and Non-Occupational Human Health 

Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(All Populations)

LOAEL = 8.1 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF/

UFLOAEL = 10X

Acute RfD = 8.1 

mg/kg/day

aPAD = 0.008 

mg/kg/day

Developmental Neurotoxicity (Rat)

LOAEL = 8.1 mg/kg/day, based on 

morphometric changes in the brains of 

female pups on PND 12 and male pups on 

PND 63.

Chronic Dietary 

(All Populations)

LOAEL = 8.1 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF/ 

UFLOAEL = 10X

Chronic RfD = 8.1 

mg/kg/day

cPAD = 0.008 

mg/kg/day

Developmental Neurotoxicity (Rat)

LOAEL = 8.1 mg/kg/day, based on 

morphometric changes in the brains of 

female pups on PND 12 and male pups on 

PND 63.

Cancer (oral, 

dermal, 

inhalation)

Classification: “likely human carcinogen.” A cancer potency factor of 0.0119 (mg/kg/day)-1 was 

calculated for pymetrozine based on male mouse liver benign hepatoma and/or carcinoma 

combined tumors.

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). UFLOAEL = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor.

PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.

Summary of Toxicological Doses and Endpoints for Pymetrozine 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- (1-30 days) 

and IntermediateTerm (1-6 

months)

LOAEL = 8.1 

mg/kg/day

DAF = 1%

UFA = 10X

UFH = 10X

UFLOAEL = 10X

Occupational LOC for 

MOE = 1000

Developmental Neurotoxicity (Rat)

LOAEL = 8.1 mg/kg/day, based on 

morphometric changes in the brains of 

female pups on PND 12 and male pups on 

PND 63

Inhalation 

Short- (1-30 days) 

and IntermediateTerm (1-6 

months)

LOAEL = 8.1 

mg/kg/day

IAF=100%

UFA = 10X

UFH = 10X

UFLOAEL = 10X

Occupational LOC for 

MOE = 1000

Developmental Neurotoxicity (Rat)

LOAEL = 8.1 mg/kg/day, based on 

morphometric changes in the brains of 

female pups on PND 12 and male pups on 

PND 63

Cancer (oral, 

dermal, 

inhalation)

Classification: “likely human carcinogen”. A cancer potency factor of 0.0119 (mg/kg/day)-1 was 

calculated for pymetrozine based on male mouse liver benign hepatoma and/or carcinoma 

combined tumors.

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). UFLOAEL = use of a LOAEL to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of 

concern.
Pymetrozine Registration Review Scoping Document

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Attachment 4. Toxicity Profile Table 

Toxicity Profile of Pymetrozine Technical

Study Type MRID No. Results

870.3100

Subchronic Feeding (rats)

44024939 (1992) 

Acceptable/Guideline 

0, 50, 500, 5000 ppm 

(0/0, 3.4/3.6, 

32.5/33.9, 360/370 

mg/kg/day [M/F])

LOAEL = 360/370 mg/kg/day based primarily on decreased 

body weight and liver effects (increased weight and 

centrilobular hypertrophy in males). Other effects included 

leukocytosis, bilirubinuria (females) and decreased urine 

volume (males), increased relative liver and spleen weights, 

calcification of kidneys (males), and atrophy of the thymus in 

both sexes.

NOAEL = 32.5/33.9 mg/kg/day

870.3100

Subchronic Feeding 

(Mouse - Dose rangefinding study)

44024938 (1992)

Acceptable/Nonguideline 0, 1000, 3000, 

7000 ppm (0, 143, 

429, 1002 mg/kg/day)

LOAEL (males & females) = 143 mg/kg/day (LDT) based on 

increased liver weight and increased focal cell necrosis in 

hepatic parenchyma 

NOAEL (males & females) = Not established

870.3151

Subchronic Feeding 

(Beagle dogs)

44572201 (1992) 

Acceptable/Guideline 

0, 100, 500, 2500 ppm 

(0, 3.1, 14, 54 

mg/kg/day)

LOAEL = 14 mg/kg/day based on liver pathology (bile duct 

proliferation in both sexes and hepatocyte necrosis in females), 

skeletal muscle atrophy, and lymphocytic infiltration in several 

organs. 

NOAEL = 3.12 mg/kg/day

870.3200 

28-Day Dermal Toxicity 

(Sprague-Dawley rats)

44024942 (1993) 

Acceptable/Guideline

0, 10, 100, 1000 

mg/kg/day (6 hrs/day, 

5 days/week for 4 

weeks)

Systemic/Dermal Irritation LOAEL > 1000 mg/kg/day 

Systemic/Dermal Irritation NOAEL = 1000 mg/kg/day 

870.4100

Chronic Feeding 

(beagle dog)

44024943 (1994)

Acceptable/Guideline 

0, 20, 200, 1000 ppm 

(0, 0.57, 5.33, 27.8 

mg/kg/day) 

LOAEL = 27.8 mg/kg/day based primarily on myopathy and 

anemia. Additional effects included Liver effects included 

inflammatory cell infiltration in the liver (males), cholesterol, 

phospholipids, hemosiderosis, decreased testis weight and 

increased liver weight.

NOAEL = 5.33 mg/kg/day. 

An equivocal increase in liver weight at 5.33 mg/kg/day did not 

show related pathology or dose response and was considered 

adaptive and not toxicological.
Pymetrozine Registration Review Scoping Document

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870.4200 Carcinogenicity 

(mouse)

44024944 (1995) 

Acceptable/Guideline 

0, 10, 100, 2000, 5000 

ppm (0, 1.2, 12, 250, 

675 mg/kg/day)

LOAEL = 250 mg/kg/day based on liver weight and hepatocyte 

hypertrophy, hemosiderosis and extramedullary hematopoiesis

NOAEL = 12 mg/kg/day

At ≥ 250 mg/kg/day, increased incidences of benign liver 

hepatomas and/or carcinomas combined in both sexes. 

83-3a:

Developmental Toxicity 

(Sprague-Dawley rat)

44024948 (1992)

Acceptable/Guideline 

0, 30, 100, 300 mg/kg 

Maternal LOAEL = 100 mg/kg/day based on reduced body 

weight gain and food consumption

Maternal NOAEL = 30 mg/kg/day

Developmental LOAEL = 300 mg/kg/day based on increased 

skeletal anomalies including delayed ossification of digits and 

dumbbell shaped thoracic vertebral centers

Developmental NOAEL = 100 mg/kg/day

870.3700

Developmental Toxicity 

(Russian rabbits)

44024949 (1992)

Acceptable/Guideline 

0, 10, 75, 125 mg/kg 

Maternal LOAEL = 75 mg/kg/day based on decreased body 

weight and body weight gain

Maternal NOAEL = 10 mg/kg/day

Developmental LOAEL = 75 mg/kg/day based on skeletal 

anomalies including increased incidences of 13th ribs, fused 

sternebrae, and delayed ossification of digits

Developmental NOAEL = 10 mg/kg/day 

870.3800

Reproductive Toxicity 

(Sprague-Dawley rat)

44024950 (1993)

Acceptable/Guideline 

0, 20, 200, 2000 ppm 

(0/0, 1.4/1.6, 

13.9/16.0, 136.9/151.6 

mg/kg/day [M/F])

Parental /Systemic LOAEL = 13.9/16.0 mg/kg/day based on 

increased liver weight and hepatocellular hypertrophy

Parental/Systemic NOAEL = 1.4/1.6 mg/kg/day

Offspring LOAEL = 136.9/151.6 mg/kg/day based on decreased 

pup weight and delay in eye opening on both F1 and F2 litters

Offspring NOAEL = 13.9/16.0 mg/kg/day

Reproductive LOAEL ≥ 136.9/151.6 mg/kg/day Reproductive 

NOAEL > 136.9/151.6 mg/kg/day 

870.4300

Combined Chronic 

Feeding and 

Carcinogenicity (SpragueDawley rat)

44024951 (1995)

Acceptable/Guideline 

0, 10, 100, 1000, 3000 

ppm (0/0, 0.38/0.45, 

3.76/4.48, 38.5/46.3, 

123.4/148.3 

mg/kg/day [M/F]) 

LOAEL = 38.5/46.3 mg/kg/day based on hepatocellular 

hypertrophy in males. 

NOAEL = 3.76/4.48 mg/kg/day

Increased incidence of benign liver hepatomas and/or 

carcinomas combined at 1000 and 3000 ppm in females 

870.5100

Gene Mutation -

Salmonella & E. Coli

44024952 (1991)

Acceptable/Guideline 

312.5 to 5000 μg/plate

Non-mutagenic (±) activation in Salmonella and E. coli.
Pymetrozine Registration Review Scoping Document

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870.5300

Gene Mutation - HGPRT 

with V79 cells 

44024954 (1991)

Acceptable/Guideline

5.21 to 333.3 μg/mL

Non-mutagenic up to the solubility limit (±) activation.

870.5375

In vitro cytogenetics assay 

in CHO cells

44024953 (1991)

Acceptable/Guideline

2.58 to 330 μg/mL

Not clastogenic up to the solubility limit of the test substance.

870.5395

Micronucleus Assay in 

Mice

44024955 (1991)

Acceptable/Guideline

0, 1000, 2000, 4000 

mg/kg

No clastogenic response at any dose or sacrifice time.

870.5550

Unscheduled DNA 

Synthesis in Primary Rat 

Hepatocytes

44024956 (1991)

Acceptable/Guideline

2.78 to 300 μg/mL

No evidence of induced UDS.

870.6200 

Acute Neurotoxicity 

(Sprague-Dawley rats)

44411317 (1997) 

Acceptable/Guideline 

0, 125, 500, 2000 

mg/kg

LOAEL = 125 mg/kg based on decreases in body temperature, 

FOB changes, and decreased motor activity (males) related to 

decreased activity 

NOAEL < 125 mg/kg

870.6200

Subchronic neurotoxicity 

(Sprague-Dawley rats)

44411318 (1997) 

Acceptable/Guideline 

0, 500, 1000, 3000 

ppm (0/0, 35/41, 

68/81, 201/224 

mg/kg/day [M/F])

LOAEL = 201 mg/kg/day based on decreased weight and 

stereotypy (excessive head movement and sniffing) in males 

and tiptoe gait in females

NOAEL = 68 mg/kg/day

870.6300

Developmental 

Neurotoxicity

(Wistar-derived rat)

46170301 (2003)

Acceptable/Nonguideline

0, 100, 500, 2500 ppm 

(0/0, 8.1/16.8, 

38.7/82.6, 173.1/NA 

mg/kg/day 

[gestation/lactation])

Maternal LOAEL = 38.7 mg/kg/day based on complete litter 

losses

Maternal NOAEL = 8.1 mg/kg/day

Offspring LOAEL = 8.1 mg/kg/day based on morphometric 

changes in the brains of female pups on PND 12 and male pups 

on PND 63.

Offspring NOAEL < 8.1 mg/kg/day
Pymetrozine Registration Review Scoping Document

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870.7485

Metabolism and 

Pharmacokinetics 

(Sprague-Dawley rat)

44024957 (1993)

44517720

Absorption and excretion studies were conducted after a single 

low dose iv injection (0.5 mg/kg); single low (0.5 mg/kg) and 

high (100 mg/kg) oral doses; 14 daily low (0.5 mg/kg) or high 

(100 mg/kg) oral doses followed by a single low (0.5 mg/kg) 

oral dose; and after a single high oral dose with the chemical 

labeled at different site. Both the oral and iv doses had similar 

urine values at 24 hours. 7 days post-dosing: recovered 

radioactivity in urine (56.3-80.3%), expired air (0.2-1.4%), 

tissues (0.3-3.8%), feces (15.4-38.9%), and cage washes (0.2-

0.7%). Both sexes excreted more via the kidneys after a high 

dose (M/F: 72.5%/78.3%) than after a low dose (M/F: 56.3%/ 

62.1%). Twelve urinary and fecal metabolites were recovered 

after a high dose and were isolated and characterized. There 

was a relatively high level of unchanged test material in the 

urine, which suggests metabolic saturation at the high dose of 

100 mg/kg. Three major metabolic pathways: oxidation of 

methyl substituent at triazine ring, which is further oxidized to 

corresponding carboxylic acid, oxidation at methylene group 

within the triazine ring, and cleavage of the bridge between the 

two rings to give rise to several single ring metabolites. No 

indication that conjugated metabolites formed. Maximum 

blood concentrations attained at 15 minutes (0.3 ppm) and at 4 

hours (60 ppm) following low and high oral dosing, 

respectively. Calculated half life times (t1⁄2) for the depletion of 

radiolabel from all the tissues ranged from 1 to 2 hours at 0.5 

mg/kg dose (both labels) and from 2 to 11 hours at the 100 

mg/kg dose, with the pyridine label having a relatively longer t1⁄2

than the triazine label. Details: see summaries of toxicology 

studies.

870.7600

Dermal absorption (rat)

44024958 (1996)

Acceptable/Guideline

0, 0.007, 0.040, 0.375 

mg/cm2(CMC)

After 10 hours of dermal application, the percent of dose 

absorbed was 0.01%, 0.01% and <0.005% for the low-, midand high-dose groups, respectively.
Pymetrozine Registration Review Scoping Document

Page 22 of 24

Attachment 5. Summary of Occupational/Residential Registered Uses for Pymetrozine

Use Site Occupational/ 

Residential Use

Application 

Equipment

Max App 

Rate

(lb ai/A)

Assessed previously?

Product: Fulfill® (EPA Reg. No. 100-912; 50% ai WDG)

Alfalfa grown for seed 

(only found on SLNs: ID-000010, 

MT-030008, NV-000004, OR040005, UT-000010, WA-000016)

Occupational

Aerial, 

Groundboom 0.086

Covered by cotton 

assessment

(ORE memo: D273635)

Asparagus Aerial, 

Groundboom 0.086 Yes (ORE memo: D308992)

Brassica (Cole) Crops Aerial, 

Groundboom 0.086 Yes(ORE memo: D273635)

Cotton Aerial, 

Groundboom 0.086 Yes(ORE memo: D273635)

Cucurbit Vegetables Aerial, 

Groundboom 0.086 Yes(ORE memo: D259881)

Fruiting Vegetables Aerial, 

Groundboom 0.086 Yes(ORE memo: D259881)

Hops Airblast 0.188 Yes

(ORE memo: D273635)

Leafy Vegetables (includes SLN 

WA-000017)

Aerial, 

Groundboom 0.086 Yes(ORE memo: D273635)

Pecan Aerial, 

Groundboom 0.125 Yes(RA memo: D279321) 

Potatoes (and other Tuberous Root 

and Corm Vegetables)

Aerial, 

Groundboom, 

Chemigation

0.17 Yes

(RA memo: D321672) 

Root vegetables (SLNs: OR-040005, 

WA-000017)

Aerial, 

Groundboom 0.086

Covered by potatoes 

assessment 

(RA memo: D321672)

Tobacco Groundboom 0.086 Yes

(ORE memo: D259881)

Tomato (SLNs: FL-030004, FL040006)Aerial, 

Groundboom

0.047 lb 

ai/100,000 

plants

Covered by fruiting 

vegetables assessment

(ORE memo: D259881)

Product: Endeavor® (EPA Reg. No. 100-913; 50% ai WDG)

Landscape ornamentals, field grown 

ornamentals, container grown 

ornamentals, nonbearing fruit and 

nut trees in nurseries, Christmas 

trees, groundcovers, ornamental 

plants in greenhouses, lath- and 

shadehouses, and interiorscapes

Occupational and 

Residential

Airblast, 

Groundboom, 

Backpack, 

Manuallypressurized 

Handwand, 

Mechanicallypressurized 

Handgun

0.31 lb ai/A Yes

(ORE memo: D259881)

0.002 lb 

ai/gal

No

(ORE memo: D259881 –

assessed at 0.0008 lb ai/gal)
Pymetrozine Registration Review Scoping Document

Page 23 of 24

Attachment 6. Residential Handler and Post-Application Scenarios 

Residential Handler Scenarios for Pymetrozine 

Handler activity Formulation Application Equipment

Mixer/loader/applicator 

(M/L/A)

Water-dispersible granule 

(WDG)

Manually-pressurized handwand

Hose-end sprayer

Backpack sprayer

Residential Post-Application Scenarios for Pymetrozine 

Exposure Route Lifestage Activity

Dermal Adults Contact with previously treated gardens and 

Children (6 < 11 years old) trees
Pymetrozine Registration Review Scoping Document

Page 24 of 24

Attachment 7. International Residue Limit Status

Pymetrozine (101103)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

US Canada Mexico2 Codex

40 CFR 180.556:

Plants: Pymetrozine: 1,2,4-triazin3(2H)-one, 4,5-dihydro-6-methyl4-[(3-pyridinylmethylene) amino]

4,5-dihydro-6-methyl-4-[(3-

pyridinylmethylene)amino]

-1,2,4-triazin-3(2H)-one

None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Asparagus 0.04

Brassica, head and stem, 

subgroup 5A 0.5

0.5 broccoli, Brussels sprouts, cabbages cauliflower, 

Chinese broccoli, Chinese mustard cabbages, kohlrabi, 

(napa) Chinese cabbages

Brassica, leafy greens, 

subgroup 5B 0.25 0.25 (bok choy) Chinese cabbages, brocolli raab, collards, kale, mustard greens, mustard spinach, rape leaves

Cotton, gin byproducts 2.0

Cotton, undelinted seed 0.3

Hop, dried cones 6.0 6 hops (dried)

Pecan 0.02 0.02 pecan nuts

Turnip, greens 0.25

Vegetable, fruiting, group 8 0.2 0.2 bell peppers, eggplants. ground cherries, non-bell 

peppers, pepinos, pepper hybrids, tomatillos, tomatoes

Vegetable, cucurbit, group 9 0.1

0.1 balsam apples, balsam pears, cantaloupes, chayote fruit, 

Chinese cucumbers, Chinese waxgourds, citron melons, 

cucumbers, edible gourds and muskmelons (other than those 

listed in this item) pumpkins, summer squash, watermelons, 

west Indian gherkins, winter squash

Vegetable, leafy, except 

brassica, group 4 0.6

0.6 Amaranth, arugula, cardoon, celery, celtuce, Chinese 

celery, corn salad, dandelion leaves, dock, edible leaved 

chrysanthemum, endives, fresh chervil leaves, fresh 

Florence fennel leaves and stalks, fresh parsley leaves, 

garden cress, garden pursiane, garland chrysanthemum, 

head lettuce, leaf lettuce, malabar spinach, New Zealand 

spinach, orach, radicchio, rhubarb, spinach, swiss chard, 

upland cress, winter purslane

Vegetable,tuberous and 

corm, subgroup 1C 0.02

0.02 arracacha, arrowroot, cassava roots, chayote roots, 

Chinese artichokes, chufa, edible canna, ginger roots, 

Jerusalem artichokes, lerens, potatoes, sweet potato roots, 

tanier corms, taro corms, turmeric roots, true yam tubers, 

yam bean roots

MRLs With No US Equivalent

Lemons 0.2

Mandarins 0.2

Oranges 0.2

Completed: M. Negussie; 1/31/2013

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

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