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



### MEMORANDUM

Date: 14-JAN-2015 OFFICE OF C HEMICAL SAFETY A N D POLLUTION PREVENTION



### SUBJECT: Spiromes i fen. Human Health Assessment Seeping Document in Support of Registration Review.

PC Cod e: 024875 DP Barcode: D42 243 8 Decision No

. : 494562 Registration No.: N/A Petition No.: N/ A Regulatory Action: Registra t ion Review Seepi n g Document Risk Assessment Type: N/ A Case No.: 744 2 TXR No.: N / A CAS No.: 283594-90-1 MRID N o.: N / A 40 CFR: §180.607



### FROM: Sarah 

### J. 

## Levy, Chemist 

# ,2 cvJ_ () 

# \.jl

# ~ 

# i2

Anwar Y. Dunbar, Ph.D.

, Pharmacoligi{t 

# O v _.r ;_ _,//

James S. Miller, Environmental Health Scientist**_.; ~**  

### . ..._.

,**-- ~**  

### Risk Assessment Branch I (RA Bl) Health Effects Division (HED, 7509P)

TO: Julia Stokes

, Chemical Review Manager Pesticide Re-Evaluation Division (PRD) (75 08P )

Attached is HED's human health risk assessment seeping document for spiromesifen to support Registration Review.

Page 1 of25Spiromesifen Registration Review Human Health Assessment Scoeing Document 

### Table of Co n tents 

### Executive Summary

........................ . .. .. ................. .. ......... .. .. .... ....................................................... 3 1.0 Int ro duc t ion

....................................................................................................... .. .. .. .. .. .. ...... ..... 4 2.0 Hazard Characterization/ Ass essm en t

......... ..... ... . ... . .. .. .. .. .. .. .. ..... .. ......................... .......... ........ 4 3 .0 R e sidue Chemistry

........................................................... ...... ............................. .. . ... .. .. .. ......... 6 4.0 Dietary Expos ur e .

...... ........ ...... .. ............. ......................... ...... ............................................ .. .. .. 7 5.0 Residential Exposure

.................... .. ..... .. .. .. .. .. ............. .............. .. .. ......... .. .. .. .. .. .. .. .. .. .. .. .. .. ........ 8 6.0 Aggregate -Ri sk Assessment

. .. ................................................................................................. 9 7.0 Occupational Expos u re

......... .. ..... .. ............................ .. .. .. ........................................ .. .............. 9 8.0 Pub li c H ealth and Pesticide Epidemiology Data

................................................................... I 0 9.0 Tolerance Assessment and International H armonizat i on

...................................................... 10 10.0 Environmental Justice

..................................................................................................... .. ... 11 11 .0 Cumulative

................................. .. .. .. .. . ....... . ... .. ........ .. .. .. ...... .. ..... ... . ... ................ ........ ..... .. .. . 11 12.0 Human Studies

.......... . ..... .................... ............................ ..... ................................................ 11 13.0 Risk Assessment Updates, Data D efi ciencies, and Label Rev isions

. .. ................... .......... ... 1 1 14.0 References

...................................... . .................................... .. ..................... . .......... ........... .... 12 Attachment 1 : C h emica l Identity Tabl e

............................................................. . ......................... 13 Attachment 2: Spiromesifen Acute, S u bc hr onic, Chronic, and Other Toxicity Profile

.............. 14 Attachment 3: Spiromesifen Endpoint Selection Table (from 2012 Risk Assessment)

.............. 21 Attachment 4 : Summary of Registered Uses

......................... .. .......................... . ......................... 22 Attachm en t 5: Spiromesifen Int e rnation al Residue L im it Status Sheet.

........... . .. .. .. .. .. .. .. ........ .. . 23

Page 2 of25Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 3 of 25 

### Executive Summary

HED has prepared a scoping document to support the Registration Review of spiromesifen ( 2

-
oxo

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4 .4]non

- 3

- en

- 4

- yl 3,3

- dimethylbutanoate)

. Spiromesifen is a tetronic acid insecticide/miticide used for control of a broad spectrum of mite pests and whiteflies. Currently, spiromesifen is used on agricultural commodities

, as well as on ornamentals

, including in residential areas

. There are no pending Pesticide Registration Improvement Act ( PRIA ) actions for spiromesifen

. The most recent risk assessment was a request for tolerance in/on tea which included an updated residential exposure assessment ( Memo, S. Levy et al. , 18

- JUL

- 2012; D396338). Prior to the 2012 assessment, the most recent human health risk assessment was conducted in conjunction with a request for the use of Oberon ® 

### 2 Soluble Concentrate (SC) Insecticide/Miticide [a 2 pound (lb) act ive ingredient (ai)/gallon SC formulation of spiromesifen] and Oberon ® 

### 4 SC Insecticide/Miticide (a 4 lb ai/gal SC formulat ion) on grain sorghum and wheat.

HED has evaluated the status of the human health risk assessments for spiromesifen to determine whe ther sufficient data are available and whether any updates are needed to support Registration Review. HED has considered all available data and human health risk assessments for spiromesifen with respect to its toxicity, exposure, and usage databases, and the most updated Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review.

The toxicity database for spiromesifen is complete and adequate to support the current registrations, as spe cified by the 2007 revised 40 CFR Toxicology Data Requirements. No additional data are required . HED does not anticipate the need to revise the toxicological endpoints, points of departure, or safety factors for spiromesifen during Registration Review.

The residue chemistry database is complete and 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 su pport the registered uses. Adequate methods are available for enforcement of the currently established tolerances.

The dietary

- exposure database for spiromesifen is adequate to support current registration requirements. The most recent risk assessment provided an un refined chronic dietary (food + drinking water) exposure estimates that are below HED’s level of concern (LOC) for the general U.S. population and all population subgroups (Memo, S. Levy

, 18

- JUL

- 201 2 ; D40 2968 ). HED notes that the 201 2 chron ic dietary assessment did not incorporate ground water estimated drinking water concentrations (EDWCs) modeled using the Pesticide Root Zone Model for GroundWater (PRZM

- GW). The Provisional Cranberry Model was used to generate EDWCs. Furthermore, the 201 2 chronic dietary assessment did not utilize the latest dietary exposure model or consumption database. Since this dietary assessment, HED adopted use of Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID, ver. 3.16)

, which us es food consumption data from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) from 2003 through 2008. The impacts of using these models to estimate dietary exposure of spiromesi fen
may be examined during Registration Review.

A n u p dated residential exposure assessment was conducted for the 2012 s piromesifen risk
assessment (Memo, S. Levy et al. , 18

- JUL

- 2012; D396338) to reflect updates to HED’s 2012Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 4 of 25 

### Residential Standard Operating Procedures (SOPs) and policy changes for body

- weight assumptions ; therefore
, an updated residential exposure assessment will not be needed to support Registration Review. The need for spray drift and volatilization r isk assessment for spiromesif en may be examined during Registration Review.

There is sufficient information available to assess aggregate exposure. However, a new aggregate risk assessment may be required during Registration Review if a revised dietary exposure analys i s is required

. The occupational exposure database is adequate to support the Registration Review process for spiromesifen. The most recent occupational handler and post

- application exposure assessment did not identify risks of concern ; however , the handler assessment is not reflective of all current exposure policies ( Memo, J. Van Alstine et al. , 10

- NOV

- 2010; D383723)

. Therefore, during Registration Review, updated occupational handler assessments may be conducted to reflect all currently registered uses, u sing current occupational/residential exposure (ORE) policies.

No data deficiencies were identified for spiromesifen ; however, several risk assessment updates
may need to be completed during Registration Review (see Section 13 for more details).

1.0 Introduction

Spiromesifen is a tetronic acid insecticide/miticide used for control of a broad spectrum of mites and whiteflies. Spiromesifen is currently registered for use on a variety of crops and ornamentals as well as for use in homeowner/residential settings . The current registrations also include special local need (SLN) registrations on greenhouse and nursery ornamentals. There are no pending PRIA actions for spiromesifen. The most recent human health risk assessment w as performed in 201 2

, for a tolerance in/on tea which included an updated residential exposure
assessment ( Memo, S. Levy et al. , 18

- JUL

- 2012; D396338 ).

2.0 Hazard Characterization/Assessment

Spiromesifen is a member of the tetronic acid class of acaricides/insecticides which ar e primarily acaricides but also have insecticidal uses at higher doses. The postulated mode of action of tetronic acids involves inhibition of lipid biosynthesis, which inhibits the younger insects’ ability to develop through the various growth stages and the ability to reproduce in adults. Some of the toxic effects noted for spiromesifen in mammalian systems include decreased triglyceride levels and body

- weight decrements that are consistent with a mode of action involving inhibition of lipid biosynthesi s.
Spiromesifen administered to rats via oral gavage was rapidly absorbed into the systemic circulation. The fraction absorbed, however, was about 43%. Repeated dosing at the low dose of 2 mg/kg or single dosing with a high dose of 500 mg/kg bw prolonge d absorption. Approximately 35

- 40% was excreted in the urine and 53

- 57% was recovered in the feces. Greater excretion of the radiolabel in feces (90%) and a corresponding lesser excretion in the urine (9%), were noted at 500 mg/kg bw, further suggesting saturation of absorption. In single and repeated 2

- mg/kg bw treatment regimens, it was noted that females experienced less systemic exposure to the test material than males. The highest areas of concentration throughout the body at 1 hour post

- dose were the gastrointestinal tract, bladder, and blood within the heart. At 48 hours post

- dosing, observable levels of radioactivity were present only in theSpiromesifen Registration Review Human Health Assessment Scoping Document

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Page 5 of 25 

### gastrointestinal tract, kidneys, and bladder, and were quite low at 72 hours post

- dose

. The predominant species recovered in the feces was the parent chemical.

The critical effects following oral administration of spiromesifen in mammals were loss of body weight, adrenal effects (discoloration, decrease in fine vesiculation, the presence of cytoplasmic

eo sinophilia in zona fasciculata cells), thyroid effects (increased thyroid

- stimulating hormone (TSH) , increased thyroxine binding capacity, decreased T3 and T4 levels, colloidal alteration, and thyroid follicular cell hypertrophy), liver effects (increased alkaline phosphatase, alanine transaminase , and decreased cholesterol and triglycerides), and splee n effects (atrophy, decreased spleen cell count, and increased macrophages). The most sensitive species was the rat with no significant sex

- dependent differences in sensitivity noted. Therefore, the grea ter systemic exposures noted in male rats did not r esult in any noticeable differences in sensitivity in females

. In the developmental and multi generation reproductive studies, there was no evidence of increased quantitative or qualitative sensitivity for fetuses or offspring

. Maternal effects noted in the rat and rabbit prenatal developmental toxicity studies were decreased body

- weight gain and food consumption. In the rabbit study, an increase in the number of late resorptions at the high dose tested of 250 mg/kg bw/day was also reported. No develop mental effects were noted up to the highest doses tested in either study. In the rat two

- generation reproductive toxicity study, the reported parental effects consisted of decreased spleen weights (relative and absolute) and a decreasing number of ovarian follicles at dose levels that also caused pup body

- weight decrements during lactation.

Because spleen effects were seen in several toxicity studies, specialized immunotoxicity studies were performed in rats and mice. The results of these studies did not reveal any immunotoxicity

specific effects. Those observed were consistent with the effects reported to other studies in the database; decreases in body weight and spleen weights. There was no evidence of neurotoxicity in either the acute or subchronic neurotoxicity study.

In a 28

- day dermal toxicity study in rats, there were no adverse effects reported (local or systemic) at the highest dose tested of 1000 mg/kg bw/day. Dermal application of spiromesifen to monkeys resulted in limited absorption (abs orbed fraction estimated at 3.3%) after an 8

- hour
exposure.

T he effects following inhalation exposure to spiromesifen consisted of clinical signs (tremors, clonic

- tonic convulsions, reduced activity, bradypnea, labored breathing, vocalization, avoidance

r eaction, giddiness, piloerection, limp, emaciation, cyanosis, squatted posture, apathy and salivation), and gross pathology (dark red areas or foci in the lungs and bloated stomachs and pale livers)

. D ecrease d spleen weights (absolute and relative to body weight and brain weight) were also reported at the highest exposure concentration tested in both sexes.

There is no evidence of carcinogenic potential for spiromesifen based on the results of carcinogenicity studies via the oral route in either the rats or mice resulting in the carcinogenicity classification of “not likely” to be carcinogenic to humans (1999 Proposed Carcinogenicity Guidelines). Genotoxicity studies including mutagenicity did not demonstrate any genotoxic potential resulting from sp iromesifen exposure.

Conclusions: The toxicity database for spiromesifen is complete and adequate to support the current registrations, as specified by the 2007 revised 40 CFR Toxicology Data Requirements.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 6 of 25 

### No additional data are required

. HED does not anticipate the need to revise the toxicological endpoints, points of departure, or safety factors (FQPA SF was reduced to 1X for the last action ) for spiromesifen during Registration Review. Since the last action for spiromesifen, HED has updated its meth odologies for identifying inhalation risks of concern. For future actions, inhalation risk assessments using the current hazard data may be updated for consisten cy with
current policies.

3.0 Residue Chemistry

Spiromesifen tolerances have been established under 40 CFR §180.607(a)(1) for the combined residues of spiromesifen and its enol metabolite, calculated as the parent compound equivalents, in/on various primary crop commodities. Tolerances have been establ ished under 40 CFR §180.607(a)(2) for the combined residues of spiromesifen and its metabolites containing the enol and 4

- hydroxymethyl (4

- hydroxy

- 3

- [4

- (hydroxymethyl)

- 2,6

- dimethylphenyl]

- 1

- oxaspiro[4.4]non

- 3

- en

- 2

- one) moieties, expressed as parent equival ents, in/on livestock commodities. Time

- limited tolerances have been established under 40 CFR §180.607(b) for the combined residues of spiromesifen and its enol metabolite, expressed as parent equivalents, in/on soybean forage, hay

, and seed (set to expir e on 31

- DEC

- 2014). Under 40 CFR §180.607(d), tolerances for the inadvertent or indirect combined residues of spiromesifen, its enol metabolite, and its metabolites containing the 4

- hydroxymethyl moiety, calculated as the parent compound equivalents, have been established for rotational crops alfalfa ; barley ; sugar beet ; oat ; vegetable, bulb, grou p 3

- 07 ; and wheat commodities.

The nature of the residue in plants and livestock is adequately understood based on acceptable metabolism studies conducted on lact ating goats, laying hens, lettuce, cotton, tomato, and confined rotational crops. Based on these studies, the residues of concern in plants (primary and rotational) and livestock commodities are as follows (Memo, K. Martin, et al. , 17

- FEB

- 2005; D300469):

Primary crops: spiromesifen and its enol metabolite. BSN 2060

- 4

- hydroxymethyl (free and conjugated) is a residue of concern in leafy vegetables (risk assessment only) Rotational crops: spiromesifen, its enol metabolite, and its metabolites containing t he 4

- hydroxymethyl moiety Livestock: spiromesifen and its metabolites containing the enol and 4

- hydroxymethyl moieties


### A high

- performance liquid chromatography (HPLC)/tandem mass

- spectrometry (MS/MS) method ( BS001

- P09

- 01 ) is suitable for the enforcement o f tolerances for residues of spiromesifen and BSN 2060

- enol in/on primary and rotational crop commodities. The validated limit of quantitation (LOQ) is 0.01 ppm for each analyte. Additional HPLC/MS/MS methods were submitted for determining residues of sp iromesifen, BSN 2060

- enol, and BSN 2060 4

- hydroxymethyl in livestock tissue and milk (Method 110878) and for determining residues of BSN 2060 4

- hydroxymethyl and the BSN 2060 4

- hydroxymethyl conjugates in rotational crops grown in soil treated with spirome sifen (Method 110333).

Adequate multiresidue method (MRM) data for spiromesifen and its enol and 4

- hydroxymethyl metabolites were previously submitted. Spiromesifen was completely recovered using multiresidue method Protocols D, E, and F, for the analy sis of non

- oily and fatty commodities. The methods were not found to be suitable for the determination of the enol and 4

- hydroxymethyl metabolites, and are, therefore, not suitable for tolerance enforcement

. The potential for secondary transfer of spirom esifen residues of concern to meat and milk exists because there are livestock feedstuffs associated with the registered spiromesifenSpiromesifen Registration Review Human Health Assessment Scoping Document

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Page 7 of 25 

### uses. Tolerances on meat (cattle, goat, horse, and sheep) and milk commodities have been established (40 CFR §180.607 ). The livestock dietary burdens previously calculated reflect the most recent guidance from HED (OPPTS 860.1000 Supplement, Table 1 Feedstuffs, 30

- JUN

2008) concerning revisions of feedstuff percenta ges and constructing maximum reasonable dietary burdens (MR DBs) (Memo, J. Van Alstine, 10

- NOV

- 2010; D383905 ). The current tolerance levels for cattle goat, horse, and sheep commodities (fat, meat, and meat byproducts) and milk (milk and milk fat) remain appropriate

. Based on the results of adequate hen and rumin ant metabolism studies and low dietary burden s , HED previously stated that there is no reasonable expectation of finite residues (180.6(a)(3)) and thus no tolerances are required at this time for poultry or swine commodities (Memo, G. Kramer, et al. , 18

- FEB

- 2005; D308837). This conclusion remains adequate; however, if additional uses are proposed in the future which increase the poultry or swine MRDB, then this conclusion will be reevaluated.

Adequate field trial data are available to support the all registered use s of spiromesifen . An adequate number of trials were conducted in the appropriate geographical regions using the appropriate formulation s applied at the maximum use rate s . These studies are also supported by adequate storage stability d ata and processing data.

There are adequate field rotational crop data to support the established tolerances for the inadvertent or indirect combined residues of spiromesifen, its enol metabolite, and its metabolites containing the 4

- hydroxymethyl moiet y in/on the rotational crop commodities of alfalfa, barley, sugar beet, bulb vegetables (crop group 3

- 07), oat, and wheat.

The following rotational crop restrictions are specified for formulations of spiromesifen: (i) immediate plantback for cotton, fi eld corn, popcorn , sweet corn, fruiting vegetables, leafy vegetables, cucurbits, tuber vegetables (potatoes), and strawberry; (ii) 30

- day plantback interval (PBI) for alfalfa, barley, oat, sugar beets, bulb vegetables (crop group 3

- 07), and wheat; and (ii i) 12

- month PBI for all other crops

.

Conclusions : The residue chemistry database is adequate to support current Registration Review data requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the resi due, and processing data are available to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances.

4.0 Dietary Exposure

A c hronic aggregate dietary (food + drinking water) exposure and risk assessment w as conducted for the 2012 risk assessment for spiromesifen using DEEM

- FCID, ver. 2.03

, which incorporates consumption data from the U.S. Department of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 19 96 and 1998

. An unrefined, chronic dietary exposure assessment was conducted assuming tolerance

- level residues [except for leafy

- green and leafy

- Brassica vegetable subgroups (4A, 4B, and 5B), spearmint and peppermint tops and oil, and tea where residues w ere adjusted to include BSN 2060

- 4

- hydroxymethyl, which is also a residue of concern for risk assessment for these commodities ], DEEM 7.81 default processing factors, and 100% crop treated (%CT). Drinking water was incorporated directly into the dietary

a ssessment using the chronic concentration for surface water generated by the Provisional Cranberry Model. The chronic dietary risk assessment shows that for all included commodities, the chronic dietary risk estimates are not of concern to HED [i.e., <100 % chronic population

- adjusted dose (cPAD)]. For the general U.S. population, the risk for food and water utilizes 53% of the cPAD. The chronic dietary risk estimate for the highest reported exposedSpiromesifen Registration Review Human Health Assessment Scoping Document

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Page 8 of 25 

### population subgroup, all infants (<1 year old), is 78% o f the cPAD.

HED note s that the 2012 chronic dietary assessment did not utilize the latest dietary exposure model or consumption database. Since this dietary assessment, HED adopted use of DEEM

FCID Version 3.16, which uses food consumption data from the USDA NHANES/WWEIA
survey from 2003 through 2008. Furthermore, the asses sment did not incorporate ground water EDWCs modeled using PRZM

- GW. The impacts of using th e s e model s to estimate ground water concentrations of spiromesifen will need to be considered during Registration Review.

Conclusions: The dietary

- exposure database is adequate to support current registration requirements. In the most recent risk assessment, chronic dietary exposures were not of concern to HED. Howe ver, as part of Registration Review, a revised dietary

- exposure analysis may be required to reflect the most recent dietary

- exposure models and potential revised EDWCs (specifically, use of PRZM

- GW)

.

5.0 Residential Exposure

Spiromesifen is registered f or use in residential settings; and, based on this registered use pattern, there is a potential for residential handler exposure to spiromesifen. The registered products Forbid ® 

### 4F Ornamental Insecticide/Miticide (EPA Reg. No. 432

- 1279) and BSN 2060 480SC (EPA Reg. No. 432

- 1280) contain 4 lb ai/gallon. The maximum application rate according to the registered labels is 4 fl oz/100 gallons or 0.00125 lb ai/gallon. The Forbid label contains a statement that the product is “For professional use only”; howeve r, this statement does not prevent use by a homeowner since the identified use sites on the label include areas around residential buildings

. The BSN 2060 480SC label contains no such statement. Both products will be assessed for potential residential ha ndler exposures.

For spiromesifen, dermal and inhalation handler exposure is expected; however, only inhalation exposure and risk estimates were quantified since no hazard was identified via the dermal route (i.e., no dermal point of departure was selecte d). The quantitative inhalation exposure/risk assessment developed for residential handlers is based on the following scenarios : mixer /loader/applicator using a manually pressurized handwand; hose

- end sprayer; backpack
sprayer ; and a sprinkler can application. The unit exposures, area treated

, and / or amount handled were taken from HED’s 2012 Residential SOPs. a 

### The Summary of Residential Handler Non

Cancer Exposure and Risk Estimates for spiromesifen detailed no risk estimates of concern for any potential exposure scenarios, with the lowest margin of exposure (MOE) being 130,000. See memorandum (Memo, S. Levy et al ., 18

- JUL

- 2012; D396338) for details.

Postapp lication dermal exposure is anticipated, but not quantitatively assessed because no dermal hazard was identified via the dermal route (i.e., no dermal point of departure was selected).

Spray Drift and Volatilization : Residential bystander exposures resulting f rom off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of spiromesifen . The potential for spray drift may be quantitatively evaluated for each pesticide during the Registration Review process that ensures that all uses for that pesticide may be considered concurrently. The approach is outlined in the revised (2012) SOPs for Residential Risk Assessment

– Resi dential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

-

a Residential SOPs (http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htm l)Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 9 of 25 

### occupational exposure to drift.

In terms of volatilization, the agency has developed a Volatiliz ation Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

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

- specific inhalation toxicological studies) or further analyses are required for specific chemicals.

Conclusions : An updated residential exposure assessment was conducted in 2012 for spiromesifen and therefore an update during Registration Review is not antic i pated

. The need for spray drift and volatilization ris k assessment for spiromesifen may be examined during Registration Review.

6.0 Aggregate

- Risk Assessment

The most recent aggregate

- risk assessment was performed in conjunction with the 2012 HED human health risk assessment (Memo, S. Levy et al. , 18

- JUL

- 2012; D396338). In the assessment it was noted that a chronic aggregate exposure risk assessment was performed by incorporating the drinking water directly into the dietary

- exposure assessment for the chronic exposure scenario. Short

- , intermediate

- , and long

- term aggregate

- risk assessments were not performed because there are no dermal toxicity concerns for spiro mesifen and HED does not expect post

- application incidental oral exposure to occur from the residential uses registered for spiromesifen. Short

- term adult post

- application inhalation exposure could not be aggregated with dietary food and drinking water ex posure because a short

- term oral endpoint was not available. Acute and cancer aggregate

- risk assessments were not performed because an appropriate endpoint was not available to determine the aRfD for the general population or any population subgroup, and spiromesifen is classified as “Not likely to be Carcinogenic to Humans,” respectively.

A chronic aggregate (food + drinking water) risk assessment was conducted for spiromesifen. The chronic dietary

- exposure risk estimates are not of concern to HED for t he general U.S. population and all population subgroups. Therefore, the chronic aggregate risk for spiromesifen is not of concern for the general U.S. population or any population subgroups.

Conclusions: There is sufficient information available to ass ess aggregate exposure. However, a new aggregate risk assessment may be required during Registration Review if a revised dietary exposure analys i s is required

.

7 .0 Occupational Exposure

Spiromesifen is registered for use in/on a variety of crops; and , based on this registered use pattern, there is a potential for occupational handler and post

- application exposure to spiromesifen. The most recent occupational exposure assessment for spiromesifen was conducted in 2010 (Memo, A. Nowotarski

, 26

- JUL

- 2010; D 375387 ). See A ttachment 4 for a summary of the registered use patterns. Handler exposure is expected to be short

- and intermediate

- term based on information provided on registered labels (e.g., two applications/season with an RTI of 14 days). Spiromesifen registered labels require mixers, loaders, and other handlers to wear long

- sleeved shirt and long pants, chemical

- resistant gloves, and shoes plus socks. The labels also require applicators to wear long

- sleeved shirt and long pants, and shoes plus socks.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 10 of 25 

### Occupational Handlers : There is the potential for dermal and inhalation exposure to occupational handlers from the currently registered use pattern of spiromesifen. In the most recent exposure assessment for spiromesifen (Memo, J. Van Als tine et al. , 10

- NOV

- 2010; D383723), inhalation assessments were conducted for mixers/loaders, applicators and flaggers for aerial , chemigation and groundboom applications of a soluble concentrate formulation. Since no short

- or intermediate

- term dermal po ints of departure were selected, dermal exposures and risks were not quantitatively assessed. The maximum application rate is 0.25 lb ai/A, and applications can be made using aerial, groundboom and chemigation equipment, depending on the use site. Inhala tion risk estimates were not of concern (i.e., MOEs ≥ 100) with baseline protection.

Based on a review of the registered labels and the most recent exposure assessment (Memo, J. Van Alstine et al. , 10

- NOV

- 2010; D383723), HED has conducted occupational han dler assessments for most of the occupational handler scenarios anticipated for the registered uses of spiromesifen. However, the scenarios were not assessed based on current ORE SOPs and policies ; therefore
, a n updated assessment may be required during Registration Review.

Occupational Post

- Application

Dermal : Typically, it is possible for agricultural workers to have post

- application exposure to pesticide residues during the course of typical agricultural activities. However

, s ince no short

- or intermediate

- term dermal points of departure were selected, dermal exposures and risks were not quantitatively assessed ; therefore

, a dislodgeable

- foliar residue (DFR) study will not be needed.

Conclusions : The occupational exposure da tabase is adequate to support the Registration Review process for spiromesifen. The most recent occupational handler and post

- application exposure assessments did not identify risks of concern ; however

, the occupational handler assessment is not reflective of current exposure policies

. Therefore , during Registration Review, updated occupational assessments may be conducted to reflect all currently registered uses, using current ORE policies.

8.0 Public Health and Pesticide Epidemiology Data

The Agency has reviewed the available incident data for spiromesifen (Memo, E. Evans and S. Recore, 23

- OCT

- 2014; D 422439 ) and concluded that based on the low frequency and low severity of incident cases of spiromesifen reported to either the OPP Incident Data System (IDS) or Sentinel Event Notification System for Occupational Risk (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 an d if a concern is triggered, additional analysis will be included in the risk assessment.

9 .0 Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR § 180. 607 ) are summarized in Attachment 5. There

are no Codex or Mexican m aximum residue limits (MRLs) established for residues of spiromesifen

. The U.S. tolerance levels are harmonized with the corresponding Canadian MRL s in all commodities except as follows : tea, dry (the U.S. tolerance value is lower); and tomat o, paste; the fat, meat, and meat byproducts of cattle, goat, horse, and sheep

, as well as milk and milk fat (the U.S. tolerance values are higher). The tolerance expressions are harmonized forSpiromesifen Registration Review Human Health Assessment Scoping Document

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Page 11 of 25 

### primary crops, but not for livestock commodities or rotationa l crops. Harmonization of tolerances/MRLs will be considered during Registration Review.

10 .0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the
most recent spiromesifen human healt h risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations b



### . ” The OPP typically considers the highest potential exposures from the legal use of a p esticide 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 may be exposed when harvesting crops. Should these highest exposures indicate potential risks of conc ern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

11.0 Cumulative

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 for spiromesifen and any other substances; and spiromesifen does not appear to produce a toxic metabolite produced by other substances. For the purposes of this toleran ce action, therefore, EPA has assumed that spiromesifen does not have 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 cumula tive 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 h ttp://www.epa.gov/pesticides/cumulative/.

1 2

. 0 Human Studies

Past spiromesifen 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 the Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF) Database, and the Agricultural R eentry 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 significa ntly 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.

1 3 .0 Risk Assessment Updates, Data Deficiencies, and Label Revisions

No data deficiencies were identified for spiromesifen . EPA notes the following risk assessment updates will need to be completed durin g Registration Review:

b http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdfSpiromesifen Registration Review Human Health Assessment Scoping Document

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Page 12 of 25 

### o Toxicology:

o None.

o Residue Chemistry/Dietary Exposure:

o A revised dietary

- exposure analysis may be required to reflect the most recent dietary

- exposure models and potential revised EDWCs (specifically, use of PRZM

- GW).

o Occupational/Residential Exposure:

o Updated occupational handler assessments may be conducted using current ORE policies to reflect all currently registered uses and maximum application rates, using current ORE policies.

o The need for spray drift and volati lization risk assessment for spiromesifen may be examined during Registration Review.

1 4 .0 References

Memoranda Relevant to Registration Review. Author Barcode Date Title S. Malak D298191 29

- APR

- 2004 A. Nowotarski D375387 26

- JUL

- 2010 Spiromesifen: Occupational and Residential Exposure/Risk Assessment for Proposed Use on Sorghum and Wheat. K. Martin, et al. D300469 17

- FEB

- 2005 Spiromesifen: Human Health Risk Assessment for Proposed Uses on Alfalfa; Barley; Corn; Cotton; Strawberry; Sugarbeet; Tomato; Vegetables ( Brassica , head and stem subgroup; Brassica , leafy subgroup; cucurbit group; fruiting group; leafy greens subgroup (except Brassica ); tuberous and corm subgroup); Wheat. G. Kramer D308837 18

- FEB

- 2005 Spiromesifen in/on Strawberry, Tub erous and Corm Vegetables, Brassica Vegetables, Leafy Greens Vegetables (except brassica), Fruiting Vegetables, Cucurbit Vegetables, Field Corn and Cotton. PP# 3F6537. Summary of Analytical Chemistry and Residue Data. J. Van Alstine, et al. D383905 10

- NOV

- 2010 Spiromesifen: Revised Summary of Analytical Chemistry and Residue Data for Use on Grain Sorghum and Wheat. J. Van Alstine, et al. D383723 10

- NOV

- 2010 Spiromesifen: Revised Human

- Health Risk Assessment for Proposed Section 3 Uses on Grain Sorghum and Wheat. S. Levy, et al

. D396338 18

- JUL

- 2012 Spiromesifen: Human

- Health Risk Assessment for Request for Tolerance without U.S. Registration in/on Tea. S. Levy D402968 18

- JUL

- 2012 Spiromesifen. Chronic Aggregate Dietary (Food + Drinking Water) Exposure and Risk Assessment for Request for Tolerance without U.S. Registration in/on Imported Tea

. E. Evans and S. Recore D422439 23

- OCT

- 2014 Spiromesifen : Tier I Review of Human Incidents

.



### Attachments:

Attachment 1: Chemical Identity Table. Attachment 2: Spiromesifen Acute, Subchronic, Chronic, and Other Toxicity Profile. Attachment 3: Spiromesifen Endpoint Selection Table. Attachment 4: Summary of Register ed Uses

. Attachment 5: Spiromesifen International Residue Limit Status Sheet.

cc: S. Levy (RAB1) RDI: RAB1 ( 11 / 12 /1 4 ) , D. Vogel ( 11/19/14 ) S. Levy :S1095 3 :PY

- S:(703)305

- 07 83 :7509P:RAB1Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 13 of 25 

### Attachment 1: Chemical Identity Table

.

Table A .1. Test Compound Nomenclature Spiromesifen. Compound Chemical Structure

Common name Spiromesifen Company experimental name BSN 2060

IUPAC name 3

- mesityl

- 2

- oxo

- 1

- oxaspiro[4.4]non

- 3

- en

- 4

- yl 3,3

- dimethylbutyrate CAS name 2

- oxo

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

- 4

- yl 3,3

- dimethylbutanoate CAS # 283594

- 90

- 1 End

- use products 2 lb ai/gal (240 g ai/L) SC formulation; (Oberon ® 240 SC)

Table A .2. Physicochemical Properties of the Technical Grade Test Compo und Spiromesifen. Parameter Value Reference
Melting point Crystal modification 1: 98.7°C Crystal modification 2: 96.7°C

Memo, S. Malak, 29

- APR

2004, D298191; MRID 45854501 pH 5.19 (2% suspension in 0.1% NaCl) Density 1.13 g/mL Water solubility (20°C) 0.13 mg/L (constant from pH 4 to pH 9)

Solvent solubility (mg/L at 20°C) Acetone: >250 g/L Acetonitrile: >250 g/L Ethyl Acetate: >250 g/L Dichloromethane: >250 g/L

n

- Heptane: 23 g/L 1

- Octanol: 60 g/L 2

- Propanol: 110 g/L Xylene: >250 g/L Vapor pressure at 25°C 1 x 10

- 5 Pa (7.5 x 10

- 8 mmHg)
Dissociation constant (pK a ) No acid or base properties between pH 2 and pH 12 Octanol/water partition coefficient Log(K OW ) 4.55 at 20°C
UV/visible absorption spectrum Molar absorption coefficient 23,360 L/mol cm at 214 nm (neutral)Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 14 of 2 5 

### Attachment 2: Spiromesifen Acute, Subchronic, Chronic , and Other Toxicity Profile

.

Table B .1. Acute Toxicity of Spiromesifen.

Guideline No. Study Type MRID # Results Toxicity Category 81

- 1 Acute oral

— rat 45819514 LD 50 = 2000 mg/kg III 81

- 2 Acute dermal

— rat 45819521 LD 50 = 2000 mg/kg III 81

- 3 Acute inhalation

– rat 45819522 LC 50 = 4.873 mg/l IV 81

- 4 Acute eye irritation

— rabbit 45819525 Not an irritant IV 81

- 5 Acute dermal irritation

— rabbit 45819524 Not an irritant IV

81

- 6 Skin sensitization

— guinea pig 45819518 Potential moderate contact sensitizer Not applicable

Table B .2. Subchronic, Chronic, and Other Toxicity Profile. Guideline Number/ Study Type MRID Number (year)/

Doses/Classification Results

870.3050 28

- day oral (mouse) 45819523 (1999)

0, 1000, 3500, or 7000 ppm M: 0, 202.6, 720.0, and 1292.3 mg/kg/day F: 0, 269.6, 699.2, and 1706.0 mg/kg/day Acceptable/nonguideline NOAEL was not established. LOAEL (M/F) = 202.6/269.6 mg/kg/day based on decreased body

- weight gain (↓25% in M; ↓41%F). Note: In this study, only three animals were used and some of 90

- day oral toxicity guideline parameters were not measured.

870.3050 28

- day oral toxicity (mouse) 45854505 (1998)

0 or 5000 ppm M: 0 and 444.3 mg/kg/day (males only tested) Acceptable/nonguideline NOAEL was not established. LOAEL (M/F) = 444.3 mg/kg/day based on decreased body

weight gain (↓51%) and increase in a lkaline phosphatase. Note: In this study, only one dose was used and some of 90

- day oral toxicity guideline parameters were not measured. 870.3100 90

- day oral toxicity (mouse) 45819526 (1999)

0, 140, 700, or 3500 ppm M: 0, 21.7, 104.5, and 589.3
mg /kg/day F: 0, 35.3, 190.5, and 1010.3 mg/kg/day Unacceptable/guideline NOAEL was not established. LOAEL = 21.7/35.3 mg/kg/day based on gross (discolored) and microscopic (decrease in fine vesiculation, and the
pres ence of cytoplasmic eosinophilia in zona fasciculata cells) changes in the adrenal glands in both sexes. Note: Some of the guideline parameters were not measured.

870.3150 14

- week oral toxicity (rat) 45819515 (2000)

0, 100, 500, or 3000 ppm M: 0, 6.3, 31.7, and 204.0 mg/kg/day F: 0, 7.7, 36.6, and 232.1 mg/kg/day Acceptable/guideline NOAEL (M/F): 31.7/7.7 mg/kg bw/day. The LOAEL (F): 36.6 mg/kg bw/day based on thyroid effects (increased TSH, thyroxine bin ding capacity, and
t hyroid follicular cell hypertrophy), kidney effects (mineralization), and liver effect (increased ALP). LOAEL (M): 204.0 mg/kg bw/day based on thyroid effect (colloidal alteration, thyroid follicular cell hypertrophy, decreased T 3 and T 4 , and increased TBC and TSH), kidney effects (Hyalin droplets), and liver effects (increase in ALP and ALAT). 870.3100 14

- week oral toxicity (mouse) 45819601 (2001)

0, 20, or 80 ppm M: 0, 3.2, and 11.5 mg/kg/day F: 0, 5.1, and 20.3 mg/kg/day Unacceptable/nonguideline NOAEL = (M/F) = 11.5/20.3 mg/kg/day. LOAEL was not established. Note: In this study, only two doses were used and some of 90

- day oral toxicity guideline parameters were not measured.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 15 of 25 Table B .2. Subchronic, Chronic, and Other Toxicity Profile. Guideline Number/ Study Type MRID Number (year)/

Doses/Classification Results

870.3100 28

- day oral toxicity (rat) 45854507 (2000)

0, 100, 500, or 5000 ppm F: 0, 10.9, 53.4, and 536.3 mg/kg/day (only females tested) Acceptable/nonguideline NOAEL = 53.4 mg/kg/day. LOAEL = 536.3 mg/kg/day based on clinical signs (piloerection, reduced motility, spastic gait, discolored feces, and increased reactivity when touched), decrease in body

weight gain (↓53% of controls), and food consumption, hematology (thromboplastin time increase), clinical chemistry (increased aspart ate amino transferase and alanine aminotransferase), liver enzyme (increased aldrin epoxidase and epoxide hydrolase), increased spleen and lymph node cell proliferation, organ weights (increased brain, heart and kidneys, decrease in weights in the ovaries, spleen, and thymus), gross pat hology (thin appearance, discolored adrenal glands, and white mucous in the duodenum and jejunum ), and microscopic findings (vacuolation of the superficial mucosal cells in the jejunum and duodenum, increased follicular cell hypertrophy in the thyroid, in distinct corticomedullary junction in the thymus, and cytoplasmic changes in the adrenal glands). Note: some of 90

- day oral toxicity guideline parameters were not measured. 870.3150 90

- day oral toxicity (dog) 45819614 (2001)

0, 20, 50, 250, or 2000 ppm 0, 0.75, 1.85, 9.2, and 71 mg/kg/day Acceptable/guideline NOAEL = 9.2 mg/kg/day. LOAEL = 71 mg/kg/day (the highest dose tested or HDT) based on clinical chemistry (increased ALP) and liver h istopathology.

Note: This study is acceptable when combined with MRID 45819623. 870.3150 90

- day oral toxicity (dog) 45819623 (2001)

0, 3000 or 5000 ppm M: 0, 98.4, and 172.5 mg/kg/day F: 0, 102.8, and 170.8 mg/kg/day Acceptable/guideline NOAEL was not established. LOAEL = 98.4 mg/kg/day based on increase in alkaline phosphatase and liver histopathology (cytoplasmic changes).

Note: This study is acceptable when combined with MRID 45819614. 870.3200 21/28

- day dermal toxicity (rat) 45819603 (2001)

0, 100, 300, or 1000 mg/kg/day Acceptable/guideline NOAEL = 1000 mg/kg/day (HDT). LOAEL was not established.

870.3465 5

- day inhalation toxicity (rat) 45819605 (2000)

0, 2.9, 20.7, and 134.2 mg/l/day Acceptable/nonguideline NOAEL = 20.7 mg/kg/day (0.0794 mg/l/day). LOAEL = 134.2 mg/kg/day (0.5143 mg/l/day) based on the clinical signs (tremors, clonic

- tonic convulsions, reduced activity, bradypnea, labored breathing, vocalization, avoidance reaction, giddiness, piloerection, limp, emaciation, cyanosis, squatted posture, apathy, and salivation), gross pathology (dark red areas or foci in the lungs, bloated stomachs, and pale liver) and decreased spleen weigh ts.

Note: No histopathology. 870.3465 30

- day inhalation toxicity (rat) 45819622 (2001)

0, 0.0050, 0.0246, or 0.0809 mg/l/day; 0, 1.3, 6.4, or 21.1 mg/kg/day Acceptable/nonguideline NOAEL = 21.1 mg/kg/day (0.0809 mg/l/day, HDT). LOAEL not established; however, LOAEL from 5

- day study can be used since both studies have the same NOAEL.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 16 of 25 Table B .2. Subchronic, Chronic, and Other Toxicity Profile. Guideline Number/ Study Type MRID Number (year)/

Doses/Classification Results

870.3700a Prenatal developmental in (rat) 45819612 (2001)

0, 10, 70, or 500 mg/kg/day Acceptable/guideline Maternal NOAEL = 10 mg/kg/day. LOAEL = 70 mg/kg/day based on decreased body

- weight gain (↓15%) and reduced food consumption. Developmental NOAEL  500 mg/kg/day (HDT). LOAEL >500 mg/kg/day. 870.3700b Prenatal developmental in (rabbit) 45819604 (2000)

0, 5, 35, or 250 mg/kg/day Acceptable/guideline Maternal NOAEL = 5 mg/kg/day. LOAEL = 35 mg/kg/day based on body

- weight loss and reduced food consumption. Developmental NOAEL  250 mg/kg/day. LOAEL >250 mg/kg/day. 870.3800 Reproduction and fertility effects (rat) 45819619 (2002)

0, 30, 120, or 500 ppm M (P 0 ): 0, 2.2, 8.8, and 37 mg/kg/day F (P 0 ): 0, 3.3, 14.2, and 64 mg/kg/day M (F 1 ): 0, 3.3, 13.2, and 76 mg/kg/day F (F 1 ): 0, 4.6, 18.0, and 91 mg/kg/day Acceptable/guideline Parental/Systemic NOAEL (M/F) = 2.2/3.8 mg/kg/day. LOAEL (M/F) = 8.8/13.2 mg/kg bw/day based on significantly decreased spleen weight (absolute and relative in parental females and F 1 males) and significantly decr eased growing ovarian follicles in females. Reproductive NOAEL (M/F) = 37/64 mg/kg/day (HDT). LOAEL = not established. Offspring NOAEL = 2.2 mg/kg/day. LOAEL = 8.8 mg/kg/day based on pup body

- weight decrements (↓13.6) during lactation.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 17 of 25 Table B .2. Subchronic, Chronic, and Other Toxicity Profile. Guideline Number/ Study Type MRID Number (year)/

Doses/Classification Results

870.3800 Reproduc tion and fertility effects (rat) 45854511 (2001) invalid

0, 30, 120, or 500 ppm M (P 0 ): 0, 2.6, 10.2, and 46 mg/kg/day F (P 0 ): 0, 3.3, 14.7, and 56 mg/kg/day M (F 1 ): 0, 3.1, 13.6, and 58 mg/kg/day F (F 1 ): 0, 4.7, 20.5, and 86 mg/kg/day Not graded due to flaws. Parental/Systemic NOAEL = 13.6 (M) and 20.5 (F) mg/kg/day. Parental LOAEL = 58 (male F 1 ) and 86 mg/kg/day (female F 1 ) based on body

- weight decrements (as high as 9% in lactating P females, at 8% and 9% at the end of the premating period at week 12 in 500 ppm F 1 adult males and females, respectively). Additional findings in parent rats included slight i ncreases in incidences of histopatholog y in thyroid gland (general increases, usually not statistically significant, of follicular cell hyperplasia and colloidal alteration in both sexes of both generations), adrenal cortex [increased incidence of “decreased vacuolation” in the zona glomerulosa (highly significant, but limited to P females only)], and possibly liver (decreased incidence of “decreased periportal fat content,” only in P females). Although there was no consistent relative organ weight alteration across generations, a 9% decreased relative kidney weight in P males was consistent with findings of the replacement study, and might represent a minor treatment effect. The parental systemic NOAEL is 120 ppm (13.6 mg/kg/day in males and 20.5 mg/kg/day in females).

Reproductive NOAEL (M/F ) = 58/86 (F) mg/kg/day (HDT). LOAEL (M/F) >58/86 mg/kg/day (HDT).

Offspring NOAEL = 20.5 mg/kg/day. LOAEL = 86 mg/kg/day based on pup body

- weight decrements during lactation (decrements compared to
concurrent contr ols at lactation day 21 for 500

- ppm pup s were: 21% for F 1 males, 18% for F 1 females, 13% for F 2 males and 24% for F 2 females). Sexual maturation criteria (preputial separation or vaginal opening) were unaffected in this study, in contrast to the results of the replacement study. This may ref

lect the comparatively small body

- weight decrements in pups in this study (about two to three day body

- weight gain delays at 500 ppm in either generation in this study, compared to about eight days in the replacement study).

Note: invalid study, cannot be used due to colony contamination. 870.4100a Chronic toxicity (rat) 45819621 (2001)

0, 50, 125, 300, or 800 ppm M: 0, 2.6, 6.5, 15.9, and 42.4 mg/kg/day F: 0, 3.0, 7.6, 19.3, and 51.7 mg/kg/day Acceptable/guideline NOAEL (M/F) = 15.9/19.3 mg/kg/day. LOAEL (M/F) = 42.4/51.7 mg/kg/day based on increase in T 3 hormone in males, gross pathology (enlarged liver in males, dilated uterus, and discolored adrenal gland in females ) and histopathology (adr enal cytoplasmic eosinophilia, metritise, thyroid colloidal alteration in female, and thyroid follicular cell hypertrophy in both males and females). 870.4100b Chronic toxicity (dog) 45819620 (2002)

0, 50, 400, or 4000 ppm M: 0, 1.4, 11.5, and 109 mg/kg/day F: 0, 1.4, 10.8, and 117 mg/kg/day Acceptable/guideline NOAEL (M/F) = 11.5/10.8 mg/kg/day. LOAEL (M/F) = 109/117 mg/kg/day based on increase in alkaline phosphatase and liver histopathology (cytoplasmic changes, inclusions, an d vacuoles).Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 18 of 25 Table B .2. Subchronic, Chronic, and Other Toxicity Profile. Guideline Number/ Study Type MRID Number (year)/

Doses/Classification Results

870.4200 Carcinogenicity (rat) 45819624 (2001)

0, 50, 125, 300, or 800 ppm M: 0, 2.5, 6.1, 14.8, and 40.0 mg/kg/day F: 0, 3.3, 8.2, 19.5, and 53.5 mg/kg/day Acceptable/guideline NOAEL (M/F) = 14.8/19.5 mg/kg bw/day. LOAEL (M/F) = 40.0/53.5 mg/kg bw/day based on clinical signs (palpable masses, vaginal bleeding, and pallor), gross necropsy (discolored area in the lungs and nodules/dilation of uterus), histopathology (osseus metaplasia and granulomatous inflammation of the lungs in the males, liver necrosis, endometritis/metritis, endometrial hyperplasia of the cervix uteri, and colloidal alteration of the thyroid gland in females), and increased TSH in females.

No evidence of carcinogenicity. 870.4200 Carcinogenicit y (mouse) 45819625 (2001)

0, 20, 140, 1000, or 2000 ppm M: 0, 3.3, 22, 157, and 335 mg/kg/day F: 0, 3.8, 30, 200, and 401 mg/kg/day Acceptable/guideline NOAEL (M/F) = 3.3/3.8 mg/kg/day. LOAEL (M/F) = 22/30 mg/kg/day based on gross (enlarged adrenal gland in males) and microscopic changes (cytoplasmic eosinophilia, ceroid deposits, and diffuse fatty changes of the adrenal cortex and pancreatic amyloidosis in both sexes).

No evidence of carcinogenicity. Gene Mutation 870.[5100] In Vitro bacteria gene mutation 45819516 (1997)

0, 16, 50, 158, 500, 1581, or 5000  g/plate Acceptable/guideline Negative

Cytogenetics 870.5300 In Vitro mammalian gene mutation (V79) 45819520 (1999)

1, 2.5, 5, 10, 15, 20, or 25
 g/mL (

- activation) 10, 20, 35, 50, 65, 80, or 95
 g/mL (+ activation) Acceptable/guideline Negative

870.5375 In Vitro mammalian cytogenetics (V79) 45819517 (1997)

0, 40, 60, and 80  g/mL (with metabolic activation) 0, 10, 20, and 40  g/mL without metabolic activation) Acceptable/guideline Negative

870.5395 In Vivo mammalian cytogenetics micronucleus (mouse) 45819519 (1999)

0, 100, 200, or 400 mg/kg Acceptable/guideline Negative

870.6200a Acute neurotoxicity screening battery 45819606 (2001)

0, 200, 700, or 2000 mg/kg Acceptable/guideline NOAEL = 2000 mg/kg/day. LOAEL = not established.

870.6200b Subchronic neurotoxicity screening battery 45819607 (2002)

0, 100, 500, or 2000 ppm M: 0, 6.4, 31.8, and 122.7 mg/kg/day F: 0, 7.9, 38.3, and 149.3 mg/kg/day Acceptable/guideline NOAEL (M/F) = 31.8/38.3 mg/kg/day. LOAEL (M/F) = 122.7/149.3 mg/kg/day based on decreased body w eight and food consumption.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 19 of 25 Table B .2. Subchronic, Chronic, and Other Toxicity Profile. Guideline Number/ Study Type MRID Number (year)/

Doses/Classification Results

870.7485 Metabolism and pharmacokinetics (rat) 45819403 (2000)

2 and 500 mg/kg Acceptable/guideline For a single dose of 2 mg/kg, 39% of the administered dose was excreted in the urine and 55 to 57% in the feces with 88 to 90% of the dose being eliminated within the first 24 hours. Approximately 43% of the orally administered dose is absorbed. Treatment with multiple doses of 2 mg/kg did not affect the ratio of radiolabel excreted in the urine and fece s. Concentrations of residual radioactivity in the tissues were quite low at 72 hours post

- dose. Treatment with 500 mg/kg of the test material resulted in a much lower percentage of the administered dose being excreted in the urine (7 to 9%) with the rem ainder recovered in the feces. Following a single dose of 2 mg/kg, the test material was rapidly if incompletely absorbed with the C max value in the blood achieved within one to two hours post

- dose. Treatment with multiple doses of 2 mg/kg or a single do se of 500 mg/kg delayed the T max to three to four hours and six hours, respectively. The C max values and the concentration versus time curves [AUC(t)] indicated a disproportionately lower increase in the uptake of the radiolabel into the blood between the 2

- and 500

- mg/kg treatments. At 500 mg/kg, these values were approximately 80% less than would be predicted by a proportionately linear increase. The data confirmed the reduced percentage of radiolabel that was absorbed at the 500

- mg/kg treatment level in the excretion

balance profile. In the two 2

- mg/kg treatment regimens, the C max and AUC(t) values for the females were less than those of the males with values ranging from 66 to 86% for C max and 43 to 55% for AUC(t) in comparison to the males. These data indicated that the females experienced less of an exposure to the test material than did the males. The whole

body autoradiograms qualitatively demonstrated the distribution of the radioact ivity throughout the body. The highest areas of concentration at one hour post

- dose were the gastrointestinal tract, bladder, and blood within the heart. Overall tissue distribution appeared to be the highest at four hours post

- dose with a progressive de cline over the time

course of the study. At 48 hours post

- dose, observable levels of radioactivity were present only in the gastrointestinal tract, kidneys, and bladder. The test material was initially metabolized to the keto

- enol by loss of the dimethyl butyric acid moiety. Both the phenyl and cyclopentyl rings were hydroxylated and the methyl groups on the phenyl ring were ultimately oxidized to a carboxylic acid. These metabolites were largely recovered in the bile and urine. The predominate moiety r ecovered in the feces was the unmetabolized test material. No conjugation with either glucuronic acid or sulfate was observed. 870.7600 Dermal penetration (monkey) 45819828 (2002)

Acceptable/nonguideline Intravenous injection resulted in excretion of the radiolabel mainly via urine: urine (54.32%), fe ces (13.08%), and cage debris/rinse (26.57%). Excretion was rapid in that 70% of the dose was excreted within 24 hours. Dermal application of spiromesifen resulted in limited ab sorption after eight

hour exposure (3.3%), which a large portion was recovered from urine and cage debris/rinse showing that it is poorly absorbed through the skin layers. 870.7800 45819608 (2001) NOAEL (M/F) = 52.8/45.7 mg/kg/day.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 20 of 25 Table B .2. Subchronic, Chronic, and Other Toxicity Profile. Guideline Number/ Study Type MRID Number (year)/

Doses/Classification Results

4

- week immunotoxicity (rat) 0, 100, 500, or 3000 ppm

M: 0, 9.6, 52.8, and 291.6 mg/kg/day F: 0, 10.7, 45.7, and 288.6 mg/kg/day Acceptable/guideline LOAEL (M/F) = 291.6/288.6 mg/kg/day based on mortality (females), clinical signs (both sexes), and de creased body weights and body

- weight gains (both sexes).

Treatment did not significantly alter the IgM antibody

forming cell response to the T cell

- dependent antigen, sheep erythrocytes. 870.7800 Immunotoxicity (Plaque

- forming cell assay) (mouse) 45819615 (2001)

0, 100, 500, or 3500 ppm M: 0, 30.5, 162.5, and 1226.6 mg/kg/day F: 0, 47.9, 278.7, and 1510.2 mg/kg/day Acceptable/guideline NOAEL = 500 ppm (equivalent to 162.5/278.7 mg/kg/day M/F). LOAEL = 3500 ppm (equivalent to 1226.6/1510.2 mg/kg/day M/F, exceeds limit dose) based on decreased body weights and body

- weight gains (↓38%) in males and decreased water consumption and spleen weights in both

sexes.

Under conditions of this study, no immunotoxicity (as detected by plaque forming cells) was observed.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 21 of 25 

### Attachment 3: Spiromesifen Endpoint Selection Table (from 201 2 Risk Assessment)

.

Table C.1 . Summary of Toxicological Doses and Endpoints for Use in Spiromesifen Risk Assessments.
Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF* and LOC for Risk Assessment Study and Toxicological Effects

Acute Dietary (females 13 to 49 years old) Not applicable None An endpoint of concern attributable to a single dose was not identified. An aRfD was not

established. Acute Dietary (general population) Chronic Dietary (all populations) NOAEL = 2.2 mg/kg/day

UF = 100X (for inter

- and intra

species extrapolation)

FQPA SF = 1X cRfD = cPAD = 0.022 mg/kg/day

cPAD = 0.022 mg/kg/day FQPA SF = 1X Two

- generation reproduction study in rats.

The parental systemic LOAEL: 8.8 mg/kg bw/day based on significantly decreased spleen weight (absolute and relative in parental females and F 1 males) and significantly decreased growing ovarian

follicles in femal es.

Dermal Short (1 to 30 days) and Intermediate

- Term (1 to 6 months) None No dermal, systemic, or developmental toxicity

concerns.

Inhalation Short

- Term (1 to 30 days) and Intermediate

Term (1 to 6 months) Rat Inhalation NOAEL = 0.081 mg/L LOC < 30

(3X interspecies and 10X intraspecies extrapolations ) Subchronic (30

- day) inhalation toxicity study

in rats & 5

- day inhalation toxicity study in rats.

LOAEL (5

- day) = 134.2 mg/kg/day based on the clinical signs (tremors, clonic

- tonic convulsions, reduced act ivity, bradypnea, labored breathing, vocalization, avoidance reaction, giddiness, piloerection, limp, emaciation, cyanosis, squatted posture, apathy, and salivation), gross pathology (dark red areas or foci in the lungs, bloated stomachs, and pale liver), and decreased spleen weights. HEC = 0.06 mg/L HED = 1.42 mg/kg bw/day

Cancer (oral, dermal, inhalation) Classification: “N ot likely to be carcinogenic to humans.”

* FQPA SF = FQPA Safety Factor; LOAEL = lowest

- observed adverse

- effect level; LOC = level of concern; NA = not applicable; NOAEL = no

- observed adverse

- effect level; PAD = population

- adjusted dose (a = acute, c = chronic); RfD = reference dose; (a = acute, c = chronic); MOE = margin of exposure; UF = uncertainty factor ; HEC = human

- equivalent concentration; HED = human

- equivalent dose. HEC = rat NOAEL*(daily duration adjustment)*weekly daily duration adjustment *RDDR* = 0.081 mg/L*(6 hr/4 hr)*(1)*0.488 = 0.06 mg/L. HED = HEC* human

- specific conversion factor*daily duration = 0.06 mg/L*6.0 L/hr/kg*4 hr = 1.42 mg/kg bw/day.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 22 of 25 

### Attachment 4: Summary of Registered Uses

.

Table D .1. Summary of Registered Uses for Spiromesifen.

Crop/Use Site Product (Formulation) Application

Method Maximum

App Rate (lb/ai/A) REI

(hours)
Agricultural Crops Apple EC Ground 0.11 24 Caneberry subgroup 13

- 07A DF/WDG, WP Ground 0.135 12 Corn, field and pop DF/WDG, WP Ground, aerial 0.135 12 Cotton DF/WDG, WP Ground, aerial 0.045 12 EC 24 Cucumber (greenhouse) 1 PRL Fogger 0.056 2 Cucurbit vegetables (Crop Group 9) DF/WDG, WP Ground, aerial 0.135 12 Eggplant (greenhouse) 1 PRL Fogger 0.056 2 Hops DF/WDG, WP Ground 0.18 12 Low growing berry (subgroup 13

- 07G) DF/WDG, WP Ground 0.135 12 Mint (peppermint and spearmint) DF/WDG, WP Ground, aerial 0.18 12 Mint (peppermint and spearmint; greenhouse) 1 PRL Fogger 0.056 2

Pepper and Eggplant (Subgroup 8

- 10B) DF/WDG, WP Ground 0.135 12 Pear EC Ground 0.11 24 Pepper (greenhouse) 1 PRL Fogger 0.056 2 Pome fruit (Crop group 11) DF/WDG, WP Ground 0.135 12 Pome fruit (apple and pear; greenhouse) 1 PRL Fogger 0.056 2 Pumpkin (greenhouse) 1 PRL Fogger 0.056 2 Small fruit vine climbing, except fuzzy kiwifruit (Subgroup 13

- 07F) DF/WDG, WP Ground 0.135 12

Squash (greenhouse) 1 PRL Fogger 0.056 2 Stone fruit (Crop Group 12) DF/WDG, WP Ground 0.135 12 Stone fruit (except plum; greenhouse) 1 PRL Fogger 0.056 2 Strawberry EC Ground 0.11 24 Tree nuts (Crop Group 14) DF/WDG, WP Ground 0.135 12 Tree nuts (almonds and pecans; greenhouse) 1 PRL Fogger 0.056 2 Tropical and Sub

- tropical Fruit (Inedible Peel) DF/WDG, WP Ground, aerial 0.135 12 Tomato (Greenhouse

- grown) 1 DF/WDG Boom sprayer, handwand (high and low pressure), backpack 0.125 12

PRL Fogger 0.056 2 Non

- agricultural Crops Christmas trees DF/WDG, WP Ground, aerial 0.135 12 Non

- bearing fruit trees DF/WDG, WP Ground 0.135 12 Ornamentals (greenhouse) 1 PRGS Aerosol, fog or fumigation 24

PRL Total release 0.056 2 WDG Ground 0.1 12 24(c) Alfalfa WP Ground, aerial 0.135 12 Carrot (including tops) WP Ground, aerial 0.135 12 1. Registered for use on these crops grown in greenhouse s

.Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 23 of 25 

### Attachment 5: Spiromesifen International Residue Limit Status Sheet.

Table E.1. Summary of US and International Tolerances and Maximum Residue Limits

. 

### Residue Definition : US Canada Mexico 1 

### Codex 40 CFR 180.607 the sum of spiromesifen [2

- oxo

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

4

- yl 3,3

- dimethylbutanoate] and 4

- hydroxy

3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

- 2

- one, calculated as the stoichiometric equivalent of spiromesifen Plants (except barley, sugar beets and wheat ): 2

- oxo

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

3

- en

- 4

- yl 3,3

- dimethylbutanoate, including the metabolite 4

- hydroxy

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

- 2

- one None



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

### Codex Bean, dry 0.02 0.02 Dry (adzuki beans, beans, blackeyed peas, broad beans, catjang seeds, chickpeas, cowpea seed, guar seeds, kidney beans, lablab beans, lima beans, moth beans, mung beans, navy beans, pink beans, pinto beans, rice beans, southern peas, tepary beans, urd beans) 0.02 grain lupin Bean, edible podded 0.80 0.8 edible podded (jackbeans, moth beans, runner beans, snap beans, soybeans, sword beans, wax beans, yardlong beans) Bean, succulent 0.10 0.1 succulent shelled (blackeyed peas, broad beans, cowpeas, lima beans, southern peas Berry and small fruit, low growing berry, subgroup 13

- 07G 2.0 2 strawberries

Brassica, head and stem, subgroup 5A 2.0 2 broccoli, brussels sprouts, cabbages, cauliflowers, Chinese broccoli, Chinese mustard cabbages, kohlrabies, napa Chinese cabbages Brassica, leafy greens, subgroup 5B 12 12 bok choy Chinese cabbages, broccoli raab, collards, kales, mustard greens, mustard spinach, rape leaves Corn, field, forage 5.0 Corn, field, grain 0.02 0.02 Corn, field, stover 8.0 Corn, pop, grain 0.02 Corn, pop, stover 4.0 Corn, sweet, forage 17 Corn, sweet, kernel plus cob with husks removed 0.02

Corn, sweet, stover 12 Cotton, gin byproducts 15 Cotton, undelinted seed 0.50 Cowpea, forage 30 Cowpea, hay 86 Leaf petiole subgroup 4B 6.0Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 24 of 25 Leafy greens subgroup 4A 12 12 amaranth, arugula, corn salad, dandelion leaves, dock, edible leaved chrysanthemum, endives, fresh chervil leaves, fresh parsley leaves, garden cress, garden purslane , garland chrysanthemum, head lettuce, leaf lettuce, Malabar spinach, New Zealand spinach, orach, radicchio, spinach, upland cress, winter purslane Pea, dry, seed 0.20 Peppermint, tops 45 Spearmint, tops 45 Tea, dry 40 60 tea (dried leaves) Tomato, paste 0.80 0.6 Vegetable, cucurbit, group 9 0.10 0.1 balsam apples, balsam pears, cantaloupes, chayote fruit, Chinese cucumbers, Chinese waxgourds, citron melons, edible gourds, muskmelons (other than those listed in this item) pumpkins, summer squash, watermelons, west Indian gherkins, winter squash

0.2 cucumbers Vegetable, fruiting, group 8 0.45 0.45 bell peppers, eggplants. ground cherry, non

- bell peppers, pepinos,
pepper hybrids, tomatillos, tomatoes (except cherry tomatoes) 0.6 cherry tomatoes 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, true yam tubers, turmeric roots, yam bean roots sum of spiromesifen [2

- oxo

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

4

- yl 3,3

- dimethylbutanoate] and its metabolites cont aining the 4

- hydroxy

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

- 2

- one and 4

- hydroxy

- 3

- [4

- (hydroxymethyl)

- 2,6

- dimethylphenyl]

- 1

- oxaspiro[4.4]non

- 3

- en

2

- one moieties, calculated as the stoichiometric equivalent of spiromesifen All livestock commodities, barley, sugar beets and wheat: 2

- oxo

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

3

- en

- 4

- yl 3,3

- dimethylbutanoate, including the metabolites 4

- hydroxy

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

- 2

- one and 4

- hydroxy

- 3

- [4

- (hydroxyme thyl)

- 2,6

- dimethylphenyl]

- 1

- oxaspiro[4.4]

non

- 3

- en

- 2

- one 

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

### Codex 2 Cattle, fat 0.10 0.05 Cattle, meat 0.02 0.01 Cattle, meat byproducts 0.20 0.05 Goat, fat 0.10 0.05 Goat, meat 0.02 0.01 Goat, meat byproducts 0.20 0.05 Horse, fat 0.10 0.05 Horse, meat 0.02 0.01Spiromesifen Registration Review Human Health Assessment Scoping Document

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Page 25 of 25 Horse, meat byproducts 0.20 0.05 Milk 0.01 0.005 Milk, fat 0.25 0.1 Sheep, fat 0.10 0.05 Sheep, meat 0.02 0.01 Sheep, meat byproducts 0.20 0.05

Completed: M. Negussie; 09/15/14

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

(b) Section 18 emergency exemptions. Time

- limited tolerances specified in the following table are established for residues of the insecticide/miticide spiromesifen, including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of spiromesifen [2

- oxo

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

- 4

- yl 3,3

- dimethylbutanoate] and 4

- hydroxy

3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

- 2

- one, calculated as the stoichiometri c equivalent of spiromesifen, in or on the specified agricultural commodities, resulting from use of the pesticide pursuant to FIFRA section 18 emergency exemptions. The tolerances expire and are revoked on the date specified in the table.

Commodity ppm E xpiration/revocation date Soybean, forage 30 12/31/14 Soybean, hay 86 12/31/14 Soybean, seed 0.02 12/31/14

(d) Indirect or inadvertent residues. Time

- limited tolerances are established for the inadvertent or indirect residues of the insecticide/miticide spiromesifen, including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified belo w is to be determined by measuring only the sum of spiromesifen [2

- oxo

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

- 4

- yl 3,3

- dimethylbutanoate] and its metabolites containing the 4

- hydroxy

- 3

- (2,4,6

- trimethylphenyl)

- 1

- oxaspiro[4.4]non

- 3

- en

- 2

- one and 4

- hydroxy

- 3

- [4

- (hydroxymethyl)

- 2,6

- dimethylphenyl]

- 1

- oxaspiro[4.4]non

- 3

- en

- 2

- one moieties, calculated as the stoichiometric equivalent of spiromesifen, in the following rotational crop commodities:

Commodity ppm Canada (MRL) Alfalfa, forage 1.5 Alfalfa, hay 3.0 Barley, grain 0.03 0.03 Barley, hay 0.25 Barley, straw 0.15 Beet, sugar, roots 0.03 0.03 Beet, sugar, tops 0.20 Oat, forage 0.20 Oat, grain 0.03 Oat, hay 0.25 Oat, straw 0.25 Vegetable, bulb, group 3

- 07 0.09 Wheat, forage 0.20 Wheat, grain 0.03 0.03 Wheat, hay 0.15 Wheat, straw 0.25