UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 14-JAN-2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

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

Registration Review. 

PC Code: 024875 DP Barcode: D422438 

Decision No.: 494562 Registration No.: N/A 

Petition No.: N/ A Regulatory Action: Registration Review Seeping Document 

Risk Assessment Type: N/ A Case No.: 7442 

TXR No.: N/A CAS No.: 283594-90-1 

MRID No.: 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 (RABl) 

Health Effects Division (HED, 7509P) 

TO: Julia Stokes, Chemical Review Manager 

Pesticide Re-Evaluation Division (PRD) (7508P) 

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

Registration Review. 

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Spiromesifen Registration Review Human Health Assessment Scoeing Document 

Table of Contents 

Executive Summary ............................. .............................. ............................................................. 3 

1.0 Introduction ......................................................................................................... .... .... ............. 4 

2.0 Hazard Characterization/ Assessment ................. .... ... .... .... .... .................................................. 4 

3.0 Residue Chemistry ................................................................................................ .... ............... 6 

4.0 Dietary Exposure ..................................................................................................................... 7 

5.0 Residential Exposure .................................................................... ........... ................ .... ............ 8 

6.0 Aggregate-Risk Assessment .................................................................................................... 9 

7.0 Occupational Exposure ............................................................................................................ 9 

8.0 Public Health and Pesticide Epidemiology Data ................................................................... I 0 

9.0 Tolerance Assessment and International Harmonization ...................................................... 10 

10.0 Environmental Justice .......................................................................................................... 11 

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

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

13.0 Risk Assessment Updates, Data Deficiencies, and Label Revisions ................................... 11 

14.0 References ............................................................................. ............................................... 12 

Attachment 1: Chemical Identity Table ....................................................................................... 13 

Attachment 2: Spiromesifen Acute, Subchronic, Chronic, and Other Toxicity Profile .............. 14 

Attachment 3: Spiromesifen Endpoint Selection Table (from 2012 Risk Assessment) .............. 21 

Attachment 4: Summary of Registered Uses ............................................................................... 22 

Attachment 5: Spiromesifen International Residue Limit Status Sheet. ................ .... ................. 23 

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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) active ingredient (ai)/gallon SC formulation of spiromesifen] and Oberon® 4 SC 

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

HED has evaluated the status of the human health risk assessments for spiromesifen to determine 

whether 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 specified 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 support 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 unrefined 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-2012; D402968). HED 

notes that the 2012 chronic 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 2012 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 uses 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 spiromesifen 

may be examined during Registration Review. 

An updated residential exposure assessment was conducted for the 2012 spiromesifen risk 

assessment (Memo, S. Levy et al., 18-JUL-2012; D396338) to reflect updates to HED’s 2012 
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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 risk assessment for spiromesifen

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 analysis 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, using 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 was

performed in 2012, 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 are 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 biosynthesis.

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 prolonged 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 the 
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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 

eosinophilia 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 spleen 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 greater 

systemic exposures noted in male rats did not result 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 developmental 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 immunotoxicityspecific 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 (absorbed fraction estimated at 3.3%) after an 8-hour 

exposure.

The effects following inhalation exposure to spiromesifen consisted of clinical signs (tremors, 

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

reaction, 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). Decreased 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 spiromesifen 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. 
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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 methodologies for identifying inhalation risks of concern. For future actions, 

inhalation risk assessments using the current hazard data may be updated for consistency 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 established 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 equivalents, 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 expire 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, group 3-07; and wheat commodities.

The nature of the residue in plants and livestock is adequately understood based on acceptable 

metabolism studies conducted on lactating 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 the 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 of 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 spiromesifen, 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 spiromesifen (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 analysis 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 spiromesifen residues of concern to meat and milk exists 

because there are livestock feedstuffs associated with the registered spiromesifen 
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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-JUN2008) concerning revisions of feedstuff percentages and constructing maximum reasonable 

dietary burdens (MRDBs) (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 

ruminant metabolism studies and low dietary burdens, 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 uses of spiromesifen. An 

adequate number of trials were conducted in the appropriate geographical regions using the 

appropriate formulations applied at the maximum use rates. These studies are also supported by 

adequate storage stability data 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 moiety 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, field 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 (iii) 

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 residue, 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 chronic aggregate dietary (food + drinking water) exposure and risk assessment was 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 1994-1996 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 were 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 

assessment 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 exposed 
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population subgroup, all infants (<1 year old), is 78% of the cPAD.

HED notes 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 DEEMFCID Version 3.16, which uses food consumption data from the USDA NHANES/WWEIA 

survey from 2003 through 2008. Furthermore, the assessment did not incorporate ground water 

EDWCs modeled using PRZM-GW. The impacts of using these models 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. However, 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 for 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”; however, 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 handler 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 selected). 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 NonCancer 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. 

Postapplication 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 from 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 – Residential 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.html)
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occupational exposure to drift.

In terms of volatilization, the agency has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the 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 anticipated. The need 

for spray drift and volatilization risk 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 spiromesifen 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 exposure 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 the 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 assess aggregate exposure. However, a 

new aggregate risk assessment may be required during Registration Review if a revised dietary 

exposure analysis 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; D375387). See Attachment 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. 
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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 Alstine 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 points 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. Inhalation 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 handler 

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, an 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, since 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 database 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; D422439) 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 and 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 maximum residue limits (MRLs) established for residues of 

spiromesifen. The U.S. tolerance levels are harmonized with the corresponding Canadian MRLs 

in all commodities except as follows: tea, dry (the U.S. tolerance value is lower); and tomato, 

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 for 
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primary crops, but not for livestock commodities or rotational 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 health risk assessment, in accordance with U.S. Executive 

Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and 

Low-Income Populationsb.” The OPP typically considers the highest potential exposures from 

the legal use of a pesticide when conducting human health risk assessments, including, but not 

limited to, people who obtain drinking water from sources near agricultural areas, the variability 

of diets within the U.S., and people who may be exposed when harvesting crops. Should these 

highest exposures indicate potential risks of concern, 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 tolerance 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 cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

12.0 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 Reentry Task 

Force (ARTF) Database. EPA has reviewed all the studies supporting these multi-pesticide 

generic exposure databases, and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentally unethical or significantly deficient relative to the ethical 

standards prevailing at the time the research was conducted. All applicable requirements of 

EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied, and there is no regulatory barrier to continued reliance on these studies.

13.0 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 during Registration Review:

 

b http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf
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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 volatilization risk assessment for spiromesifen may

be examined during Registration Review.

14.0 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, Tuberous 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 Registered Uses.

Attachment 5: Spiromesifen International Residue Limit Status Sheet.

cc: S. Levy (RAB1)

RDI: RAB1 (11/12/14), D. Vogel (11/19/14)

S. Levy:S10953:PY-S:(703)305-0783:7509P:RAB1
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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 Compound Spiromesifen.

Parameter Value Reference

Melting point Crystal modification 1: 98.7°C 

Crystal modification 2: 96.7°C

Memo, S. Malak, 29-APR2004, 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 (pKa)

No acid or base properties between pH 2 and 

pH 12

Octanol/water partition coefficient Log(KOW) 4.55 at 20°C

UV/visible absorption spectrum Molar absorption coefficient 23,360 L/mol 

cm at 214 nm (neutral)

CH3 H3C CH3

O O

O

O

CH3 H3C

CH3
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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 LD50 = 2000 mg/kg III

81-2 Acute dermal—rat 45819521 LD50 = 2000 mg/kg III

81-3 Acute inhalation–rat 45819522 LC50 = 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 bodyweight gain (↓51%) and increase in alkaline 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 

presence 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 binding capacity, and 

thyroid 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 T3 and T4, 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.
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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 bodyweight gain (↓53% of controls), and food consumption, 

hematology (thromboplastin time increase), clinical 

chemistry (increased aspartate aminotransferase 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 pathology (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, indistinct 

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 

histopathology.

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 weights.

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.
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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 (P0): 0, 2.2, 8.8, and 37 

mg/kg/day

F (P0): 0, 3.3, 14.2, and 64 

mg/kg/day

M (F1): 0, 3.3, 13.2, and 76 

mg/kg/day

F (F1): 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 F1 males) and significantly decreased 

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.
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Table B.2. Subchronic, Chronic, and Other Toxicity Profile.

Guideline 

Number/

Study Type

MRID Number (year)/

Doses/Classification Results

870.3800

Reproduction and 

fertility effects (rat)

45854511 (2001) invalid 

0, 30, 120, or 500 ppm

M (P0): 0, 2.6, 10.2, and 46 

mg/kg/day

F (P0): 0, 3.3, 14.7, and 56 

mg/kg/day

M (F1): 0, 3.1, 13.6, and 58 

mg/kg/day

F (F1): 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 F1) and 86 mg/kg/day (female 

F1) 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 F1 adult males and 

females, respectively). Additional findings in parent rats 

included slight increases in incidences of histopathology 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 controls at lactation day 21 for 500-ppm pups 

were: 21% for F1 males, 18% for F1 females, 13% for F2

males and 24% for F2 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 reflect 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 

T3 hormone in males, gross pathology (enlarged liver in 

males, dilated uterus, and discolored adrenal gland in 

females) and histopathology (adrenal 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, and vacuoles).
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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

Carcinogenicity 

(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 weight and food consumption. 
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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 feces. 

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 remainder recovered in the feces. Following a 

single dose of 2 mg/kg, the test material was rapidly if 

incompletely absorbed with the Cmax value in the blood 

achieved within one to two hours post-dose. Treatment with 

multiple doses of 2 mg/kg or a single dose of 500 mg/kg 

delayed the Tmax to three to four hours and six hours, 

respectively. The Cmax 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 excretionbalance profile. In the two 2-mg/kg treatment regimens, the 

Cmax and AUC(t) values for the females were less than those 

of the males with values ranging from 66 to 86% for Cmax

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 wholebody autoradiograms qualitatively demonstrated the 

distribution of the radioactivity 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 decline over the timecourse 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 dimethylbutyric 

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 recovered 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%), feces (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 absorption after eighthour 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.
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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 decreased body 

weights and body-weight gains (both sexes).

Treatment did not significantly alter the IgM antibodyforming 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. 
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Attachment 3: Spiromesifen Endpoint Selection Table (from 2012 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 intraspecies 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 F1 males) and 

significantly decreased growing ovarian 

follicles in females.

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 IntermediateTerm (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 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 weights.

HEC = 0.06 mg/L

HED = 1.42 mg/kg 

bw/day

Cancer (oral, dermal, 

inhalation)

Classification: “Not 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.
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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 greenhouses.
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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 Mexico1 Codex

40 CFR 180.607

the sum of spiromesifen [2-oxo-3-(2,4,6-

trimethylphenyl)-1-oxaspiro[4.4]non-3-en4-yl 3,3-dimethylbutanoate] and 4-hydroxy3-(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]non3-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 Mexico1 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 6.0
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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-en4-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-en2-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]non3-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-

(hydroxymethyl)-2,6-

dimethylphenyl]-1-oxaspiro[4.4]

non-3-en-2-one

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

US Canada Mexico1 Codex2

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 0.01
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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-hydroxy3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-2-one, calculated as the stoichiometric 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 Expiration/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 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 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