UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C

. 20460

MEMORANDUM

Date: 517/2013 O F F I CE OF CHEM I CAL SAF E TY
AND POL L UTION PREVENTION

SUBJECT: Pymetrozine. Human H ealth Assessme nt 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: Re g i stration Review

Case No.: 7474

CAS No.: 123312-89-0

40 CFR: 

### § 180.556

FROM: Doug l as Dot so n, Ph.D

. , Chemist 

# 4Q**/)~** Karlyn Middleton, Toxicolo gist**~p·~/2..** 

## _. _ Risk Assessment Branch II

### ~**~-** Kelly Lowe

, Environmental Sc i entist**?~ ~**  Risk Assessment Branch I 

### CJ

Health Effects Division (7509P)

Office of P est icide Program s

THRO UGH: Chris t ina Swartz, Branch Chief

Risk Assessme nt Bran ch 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 R eview Manager

P estic ide Re-Evaluation Division (7508P)

Office of Pesticide Program s

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

for pymetrozine to support registration review.

1 of2LjPymetrozine Registrati on Review Seeping Document

Executive Summary

The Health Effects Division Pymetrozine Regi s tration Review Team ha s eval uated the database

and the most recent human health risk assessment for the insecticide pymetrozine. HED performed this evaluation in order to determin e the scope of work necessary to support the

established tolerance s and existing registration s 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 -p yridiny lmethylene )amino] -1 ,2,4-triaz in- 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 in sec t pests such as aphids and whiteflies. It is registered for use on a number of agricultural crops, including

asparagus, head and s tem Brassica, Brassica leafy greens, cotton, hop s, pecans, turnips, fruiting vegetables, cucurbit vegetables, leafy vegetables

, tobacco, and tuberou s and corm vegetables. In addition, it is currently registe red 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 sens itive population subgroup (i.e, an inhalation study will not yield a lower POD ) (TXR No. 0056567). Pymetro zine has a unique insecticidal mode of action in that it

is a feeding inhibit or. The chemical affects the mechanism by which an aph id inserts its sty lu s into the plant tissue. The cellular mode of action of pymetrozine is not described, but i s 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 th e 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 rat s and mice. In accordance with the EPA Proposed

Guidelines for Carcinogen Risk Assessment (Apri l 10, 1996), the Cancer Assessment Re view
Committee (CARC) class ified pymetrozin e as a " lik ely human carcinogen" and recommended quantification of cancer ri sk using a cancer potency factor. Pymetro zine was not mutagenic or genotoxic in the submitted stud ies.

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 neur otoxici ty (DNT) study in rats in which brain morph ometri c 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 d ose for this effect; and 2) the LO AEL is used as the POD with the 1 Ox FQP A

Page 2 of24

### Pymetrozine Registration Review Scoping Document

Page 3 of 24 S afety F actor retained in the form of a LOAEL to NOAEL factor (UF L 

### ). Thus there are no
residual uncertainties for the overall risk assessment.

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

n eurotoxicity (DNT) studies.

I n the most recent human health risk assessment for pymetrozine ( D371299

, C

. Swartz,
04/02 /20 10) , endpoints were selected for acute and chronic dietary, as well as occupational
short

- , and intermediate

- term dermal and inhalation exposure. For all anticipat ed exposures, the endpoint and POD were selected from the DNT study in rats. A 10 x 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 1000 x (10 x FQPA, 10 x intraspecies, and 10 x inters pecies) 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 adequat e to support current r egistration r eview 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
avail able 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 registra tion 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 wer e 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 registr ation 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 exposure s , relied on default assumptions fo r d islodgeable foliar residue s ( 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 resident ial 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 regist ration 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, t he current ly registered rate is higher than that previously
assessed and will need to be updated during registration review

. Updated occupational post

application assessments will also need to be conducted with updated doses and endpoints for risk

assessment. In addition, t wo chemical

- specific DFR studies available for pymetrozine will need
to be evaluated during registration review for use in the occupational post

- application

assessment s

. 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 deficienc y identified for pymetroz ine is the required immunotoxicity study [870.7800]. During registration review, t he tolerance expression for pymetrozine should be revised to reflect the residues of concern for both coverage and compliance purposes. HED anticipates performing r evised d ietary, residential (handler dermal and inhalation exposure, and
post

- application dermal and incidental oral exposure)

, and aggregate assessments t hat reflect current Agency policies, the updated dietary model

, and potential revised drinking water
estimate s. 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 p ymetroz i n e 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 revi ew. The most r ecent human health risk assessment was performed in 20 10 when HED updated a previous risk assessment because of comments submitted by the Natu ral 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(2 H )

- 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, tobac co, a nd tuberous and corm vegetables. In addition, it is currently registered for use on ornamentals, including l andscape ornamentals, groundcovers, and o rnamental plants in greenhouses

. Tolerances for pymetrozine are established
i n 40 CFR §180.55 6. The se tolerance s 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 A ttachment 1

.

### Pymetrozine Registration Review Scoping Document

Page 5 of 24 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 interactio n.

The toxicology database for pymetrozine is complete except for a subchronic inhalation toxic ity study and an immunotoxicity study that are re quir ed in accordance with the 2007 revised 40CFR Part 158 Toxicology Data requirements. HED’s HASPOC determi ned that the inhalation toxicity study i s not needed because it would not result in a lower POD than th at currently used in the overall risk assessment ( TXR No. 0056567)

. The refore

, the immunotoxicity study is the only outstanding data gap

. OPP has publi shed the findings of an independent retrospective analysis of 170 immunotoxicity studies submitted to the Agency. The retrospective analysis
suggest s that the submitted immunotoxicity studies have not yet resulted in PODs that are lower
than the PODs sele cted 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
consi derations. 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 sp leen 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 i s 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) - 1 

### for combined liver tumors (benign hepatomas and/or carcinomas) in male and female mice and
fema le rats. Pymetrozine is not considered to be mutagenic or gen otoxic.

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 r abbits, 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, ther e 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 t he multi

generation reproduction study in rats

, effects in pups (body weight changes and delayed eye

### Pymetrozine Registration Review Scoping Document

Page 6 of 24 opening) were seen at the same dose as comparable maternal toxicity ( body weight changes,
d ecreased food consumption, and liver , spleen

, and thymus effects

.

Quantitative susceptibility was observed i n 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

, indicat ing that the LOAEL is near the threshold dose for this effect ; and 2) the LOAEL is used as the POD with the 10 x FQPA S afety F actor retained in the form of a LOAEL to NOAEL factor (UF L 

### ). Thus

, there are no residual uncertainties for the overall risk

assessment.

Finally, neurotoxicity was observed in the acute, subchronic, and developmental n eurotoxicity 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 w ere evident

. E xcessive head movement and sniffing as well as tiptoe gait were o bserved in the subchronic study . C hanges in brain morphometrics were observed in all dose groups examined in the DNT. Although indications of neurotoxicity were present, the y were not consistent between the acute, subchronic, and DNT studies.

Pymetrozin e 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.

I n the most recent human health risk assessment for pym etrozine ( D371299

, C

. Swartz and E.
Scollon , 04/02 /20 10) , 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. M orphometric 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 10 x FQPA SF was retained to account for the lack of a
NOAEL for the m orphometric effects

. Therefore, a total uncertainty factor of 1000 x (10 x FQPA, 10 x intraspecies, and 10 x 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

. N o 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 r egistration r eview requirements (D250386, D. Dotson, 11/19/2001) . Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue

, and proce ssing data are available to support the registered uses. Adequate methods are available for enforcement of the currently established

### Pymetrozine Registration Review Scoping Document

Page 7 of 24 tolerances. No residue chemistry data deficiencies were cited in the previous risk assessment for pymetrozine.

In the 20 10 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 assessment s , overall, the a cute

, chron ic

, and cancer

assessments reflected conservative estimates of dietary exposure. T he chronic and cancer analyses incorporated percent crop treated ( PCT ) estimates for most of the more heavily

consumed commodities, including potatoes, peppers, and tomatoes ; however, 100 P CT was assumed for numerous commodities for which usage data were not available. The d ietary 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, t he 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 a PAD. 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 wa s 1.8 ×10 - 6



### . R esidues in dri nking water were the greatest contributor to overall dietary exposure. HED anticipates conduct ing a new dietary exposure and risk assessment with updated PCT estimates from the Biological and Economic Analysis Division (BEAD). At that time, the most curr ent 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 p ymetroz in e . However, HED anticipates performing a new dietary exposure assessment during registrati on review . T he 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 m ight need to incorporate updated PCT estimates in accordance with Agency policies regarding the use of anticipated residues for dietary ris k

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

- di spersible granule (WDG). The 1999 assessment for this use (D259881, M. Collantes, 9/24/ 1999) included residential post

application scenarios only (incidental oral exposures/risk estimates)

, and no risks of concern were identified (non

- cancer margins of ex posure ( 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 asse ssment for ornamentals, becaus e 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

Page 8 of 24 HED’s Residential SOPs have been revised (February 2012) and includ e updates to exposure factors such as body weights ; therefore , a revised residential exposure assessment using the updated Residential SOPs will be needed during r egistration review . In addition, since the last
residential assessment was performed, new end points 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 assessm ent 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), D FR studies are required when a pesticide has residentia l 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 r egistration review for use in the

res idential 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 typ es 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 r egistration 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 r egistration revie w assessment, using the latest doses and endpoints for risk assessment, HED’s r esidential SOPs

, and current policies. Previous residential
post

- application assessments

, which assessed incidental oral exposures

, relied on default assumptions for dislodgeab le 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 post

- application exp osure

assessments will be required under r egistration 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 combine d. As n o residential uses were identified for pymetrozine at the time, only acute, chronic

, and cancer aggregate risk assessments were conducted. T he acute , chronic, and cancer aggregate risk

### Pymetrozine Registration Review Scoping Document

Page 9 of 24 assessment s consisted of dietary exposures from food and drink ing 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 Exp osure and Risk

During registration review, updated aggregate assessment s are likely to be need ed 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 . At tachment 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 o f oc cupational handlers from the currently registered use pattern of pymetrozine . In all past risk assessments, no chemical

specific data were available with which to assess potential exposure o f 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 assum ption 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,

resp irators, and engineering controls).

In p revious assessments ( M. Collantes

, 9/24/ 1999 , D 259881 ; M. Collantes, 8/13/ 2001 , D 273635 ; Z. Figueroa

, 12/1/ 2004

, D308992 ) non

- cancer inhalation exposure and risk were estimate d for occupational handlers . C ancer risk was also estimate d for handlers. No quantitative dermal risk assessments were required becaus e 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

e stimates were less than 10 - 4



### .

U pdated 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 , t h e current ly registered rate is higher than that previously
assessed and will need to be updated during r egistration 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 includ e 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 p revious assessments (M. Collantes, 9/24/ 1999, D259881; M. Collantes, 8/13/ 2001, D273635; Z. Figueroa, 1 2/1/ 2004, D308992) post

- application dermal cancer risk only was estimate d for
workers. The dermal cancer risk estimates are all less than 10 - 4



### .

Updated non

- cancer and cancer occupational post

- application assessments wi ll 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 o n roses and lettuce. These
studies will be reviewed during r egistration review for use in the occupational post

- application

assessment s

. Additionally, there have been several revisions to HED’s exposure policies since the previous reviews were performed. These revisions in clud e updates to post

- appli cation
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 po licies
and recommended toxicity and exposure data.

Conclusions for Occupational Exposure

The occupational exposure database is adequate to support the r egistration review for pymetrozine. An updated occupational handler exposure assessment will be neede d to reflect updated doses and endpoints for risk assessment, and to assess t he current ly registered rate for applications to ornamentals using handheld equipment

. In addition, post

- application assessments
will need to be conducted to reflect updated dose s a nd endpoints for risk assessments and to incorporate updated transfer coefficients and activity data . In addition, t wo chemical

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

- application risk

assessments. Any scenarios th at n eed 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 p ymetrozine exposure (Memo, D 408569 , S. Recore, 2/ 5 /201 3 ). IDS records incidents in one of two modules: the Main IDS and the

### Pymetrozine Registration Review Scoping Document

Page 11 of 24 Aggregate IDS. The Main IDS contains incidents resulting in hig her severity outcomes and provides more detail than the Aggregate IDS. The Aggregate IDS contains incidents resulting in
less severe human incidents

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

, there was one incident reported for the sin gle 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 p ymetrozine were reported to IDS. In the

A ggregate ID S from January 1, 200 7 to December 11 , 2012

, there was one reported incident involving p ymetrozine

. This incident was classified as minor severity. A query of SENSOR

Pesticides 1998

- 2009 identifie d 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 bo th 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 includ ed in the registration review risk

assessment.

Tolerance Assessment and International Harmonization

T olerance s for residues of pymetrozine in or on agricultural commodities are established in 40CFR §180. 556

. During registration review, the tolerance exp ression should be revised as
follow s: 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) ha s not established maximum residue limits ( MRLs ) for pymetrozine

. Canada and the U.S. ha ve established MRLs ( tolerances ) for many of
the same commodities. These tolerances and MRLs are established at the same levels. M exico 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

Potent ial 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

- Incom e 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 lim ited 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 furthe r 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, neurotoxici ty, 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 matur ation, 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), pymetrozi ne 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 wildli fe 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 batte ry 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 caus ed 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 c all

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. P ymetroz in e 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 p ymetrozine

. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, futu re 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 effec ts 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 i n 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 O utdoor 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 Subjec ts 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 p ymetrozine literature search did not reveal information that would impact th e current risk

assessment.

Risk Assessment Updates, Data Deficiencies, and Label Revisions

The following data deficienc y w as identified for pymetrozine :

Toxicology

A n immunotoxic ity study ( 870.7800 ) is requ ir ed to support registration review. The
immunotoxic ity stud y is a new requirement for both food and non

- food uses under 40 CFR Part
158 Data R equirements for Pesticides.

EPA anticipates conducting the following risk assessment updates during r egistration r eview :

Toxicology:

A r eevaluat ion 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 purpose s.

### Pymetrozine Registration Review Scoping Document

Page 14 of 24 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 r egistration r eview. HED anticipates conducting revised occupational and residential exposure assessments to
reflect the use of current policies and up dated endpoints and doses for risk assessment.

R eferences

Memoranda Relevant to Registration Review
Author Barcode Date Title C. Swartz,
E. Scollon D 371299 4 / 2 /20 10 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 An alytical Methodology

C. Swartz D372578 4 / 2 /20 1 0 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 D 283937 10/5 /20 04 EFED Water Assessment/Environmental Risk Assessment for Pymetrozine New Use: Asparagus

S. Recore D 408569 2 / 5 /201 3 Prallethrin : Review of Human Incidents

### Pymetrozine Registration Review Scoping Document

Page 15 of 24 Attachment s

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

. Intern a tional Residue Limit Status

Attachment 1

. Chemical Identity Table

P ymetroz in e Nomenclature

Chemical Structure

Empirical Formula C 1 9 H 2 4 O 3
Common N ame Pymetrozine
Company E xperimental

N ame CGA

- 215944

IUPAC N ame ( E )

- 4,5

- dihydro

- 6

- methyl

- 4

- (3

- pyrid in ylmethyleneamino)

- 1,2,4

- triazin

3(2 H )

- one

CAS N ame ( E )

- 4,5

- dihydro

- 6

- methyl

- 4

- [(3

- pyrid in ylmethylene)amino]

- 1,2,4

- triazin

3(2 H )

- one

CAS Registry Number 1 2331 2

- 89

- 0

End

- use P roduct/EP Fulfill® (EPA Reg. No. 100

- 912; 50% ai WDG) Endeavor® (EPA Reg. No. 100

- 913; 50% ai WDG)

Chemical Class Pyrid i ne A zomethine
Known Impurities of
Concern None

### Pymetrozine Registration Review Scoping Document

Page 16 of 24 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

no 1

---

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

Page 17 of 24 Attachment 3

. Toxicity Endpoint S ummary Table s

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 Population s ) LOAEL = 8.1

mg/kg/day UF A = 10X

UF H = 10X

FQPA SF /

UF L OAEL = 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 UF A = 10X

UF H = 10X

FQPA SF /

UF L OAEL = 10X Chronic RfD = 8.1

mg/kg/day

c PAD = 0.0 0 8 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 b ased on male mouse liver benign hepatoma and/or carcinoma
combined tumor s.

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

- response data and used to
mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor.

UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L OAEL = 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 Intermediate

Term (1

- 6 months) LOAEL = 8.1

mg/kg/day

DAF = 1% UF A = 10X

UF H = 10X

UF LOAEL = 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 Intermediate

Term (1

- 6 months) LOAEL = 8.1

mg/kg/day

IAF=100% UF A = 10X

UF H = 10X

UF L OAEL = 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 b ased on male mouse liver benign hepatoma and/or carcinoma
combined tumor s. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to

ma rk the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor.

UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L OAEL = use of a LOAEL to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of

concern.

### Pymetrozine Registration Review Scoping Document

Page 18 of 24 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 rela tive 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 range

finding study) 44024938 (1992) Acceptable/Nonguide

line 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 ly mphocytic 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

Page 19 of 24 870.4200 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 liv er 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 13 th 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 (Sprague

Dawley 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 male s.

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

Page 20 of 24 870.5300
Gene Mutation

- HGPRT
with V79 cells 44024954 (1991) Acceptable/Guideline 5.21 to 333.3 μg/m L 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/m L 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/m L 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/k g

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/Nonguide

line 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 N OAEL < 8.1 mg/kg/day

### Pymetrozine Registration Review Scoping Document

Page 21 of 24 870.7485
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 ho urs. 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 th e 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 betw een 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. C alculated half life times (t 1⁄2 ) 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 t 1⁄2 than the triazi ne label. Details: see summaries of toxicology
studies.

870.7600 Dermal absorption (rat) 44024958 (1996) Acceptable/Guideline 0, 0.007, 0.040, 0.375 mg/cm 2 (CMC) After 10 hours of dermal application, the percent of dose absorbed was 0.01%, 0.01% and < 0.005% for the low

- , mid

and 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, OR

040005, 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: D 321672)

Root vegetables ( SLN s: OR

- 040005,
WA

- 000017 ) Aerial,
Groundboom 0.086 Covered by potatoes

assessment (RA memo: D 321672)

Tobacco Groundboom 0.086 Yes (ORE memo: D259881)

Tomato (SLNs: FL

- 030004

, FL

040006 ) 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, Manually

pressurized Handwand, Mechanically

pressurized 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

trees Children (6 < 11 years old)

### 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 Mexico 2 Codex

40 CFR 180.556:

Plants: Pymetrozine: 1,2,4

- triazin

3(2H)

- one, 4,5

- dihydro

- 6

- methyl

4

- [(3

- pyridinylmethylene) amino] 4,5

- dihydro

- 6

- methyl

- 4

- [(3

- pyridinylmethylene)amino]

- 1,2,4

- triazin

- 3(2 H

)

- one None



### Commodity 1 

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

US Canada Mexico 2 

### 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 h ops (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 mel ons, 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 lettuc e, 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 

### MRL s 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.