UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: 28-0CT-2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Spirotetramat. Human Health Risk Assessment for the Proposed Use on Citrus 

Trees Grown in Residential Areas. 

PC Code: 39220 I 

Decision No.: 495325 

Petition No.: NA 

OP Ba rcode: 0424088 

Registration No.: 432-RLUE 

Regula tory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical/Aggregate Case No.: 7452 

TXR No.: NA CAS No.: 203313-25-1 

MRIO No.: NA 40 CFR: § 180.641 

FROM: Kelly M. Lowe, Environmental Scientist 

Monique M. Perron, Sc.D., Toxicologis ~ 

Risk Assessment Branch I (RAB I) 

Health Effects Division (HED; 7509P) 

THROUGH: G Charles 

F 

Smith

Kr , Branch PhD 

Chief S . CC::

h . 

_ ~ .......~e.-,,,s;~S::.:2Z=:~~s..s:~-. .. ,_...--- - eorge . amer, .. , eruor em1st ~a_ 

RABl/HED (7509P) ~ -

TO: Rita Kumar 

Registration Division (RD; 7505P) 

The 1-IED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from the proposed 

Section 3 registration use of the active ingredient (ai) spirotetramat (cis-3-(2,5-dimethlyphenyl)-

8-methoxy-2-oxo-1-azaspiro[ 4.S]dec-3-en-4-yl-ethyl carbonate]) on citrus trees grown in 

residential areas. When registered, this will be the first residential use of spirotetramat. 

A summary of the findings and an assessment of human health risk resulting from the proposed 

and registered uses of spirotetramat are provided in this document. The risk assessment and 

occupational exposure and residential assessment was provided by Kelly Lowe (RAB 1 ); the 

hazard characterization and endpoint selection by Monique Perron (RAB 1 ); and the drinking 

water exposure assessment by Jose Melendez of the Environmental Fate and Effects Division 

(EFED). 

The most recent human health risk assessment for spirotetramat was for a proposed use on 

turfgrass (Memo, K. Lowe el al., 16-0CT-2014; 04 13575). 

Page I of26 
Spirotetramat Human Health Risk Assessment 0424088 

Table of Contents 

1.0 

2.0 

2.1 

2.2 

2.3 

Executive Sum1nary .......................................................................................................................... 3 

HED Recommendations ................................................................................................................... 5 

Tolerance Considerations ......................................................................................................... 5 

International Hannonization ..................................................................................................... 5 

Label Recommendations .......................................................................................................... 5 

3.0 

3.1 

3.2 

3.3 

3.4 

Introduction ...................................................................................................................................... 6 

Chemical Identity ..................................................................................................................... 6 

Physical/Chern ical Characteristics ........................................................................................... 6 

Pesticide Use Pattern ................................................................................................................ 6 

Anticipated Exposure Pathways ............................................................................................... 7 

3.5 Consideration of Environmental Justice ................................................................................... 7 

4.0 Hazard Characterization and Dose-Response Assessment.. ............................................................. 8 

4.1 

4.2 

4.2.1 

4.3 

4.4 

4.4.1 

4.4.2 

4.4.3 

4.4.4 

4.5 

4.5.1 

4.5.2 

4.5.3 

4.5.4 

Toxicology Studies Available for Analysis .............................................................................. 8 

Absorption, Distribution, Metabolism, and Excretion (ADME) .............................................. 8 

Denna I Absorption ............................................................................................................... 8 

Toxicological Effects ................................................................................................................ 9 

Safety Factor for Infants and Children (FQPA SF) ................................................................ 10 

Completeness of the Toxicology Database ......................................................................... I 0 

Evidence of Neurotoxicity .................................................................................................. I 0 

Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ..................... I 0 

Residual Uncerta inty in the Exposure Database ................................................................. I 0 

Toxicity Endpoint and Point of Departure Selections ............................................................ I I 

Dose-Response Assessment ............................................................................................... 11 

Recommendation for Combini ng Routes of Exposures for Risk Assessment... ................. 11 

Cancer Classification and Risk Assessment Recommendation .......................................... 12 

Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment 

12 

5.0 

5.1 

Dietary Exposure and Risk Assessment ......................................................................................... 13 

Dietary Risk Assess1nent ........................................................................................................ 13 

5.1. I Description of Residue Data Used in Dietary Assessment.. ............................................... 13 

5.1.2 Percent Crop Treated Used in Dietary Assessment.. .......................................................... 13 

5.1 .3 Acute Dietary Risk Assessment ......................................................................................... 13 

5.1 .4 Chronic Dietary Risk Assessment ...................................................................................... 13 

5. 1.5 Cancer Dietary Risk Assessment.. ...................................................................................... 14 

5.1.6 Summary Table .................................................................................................................. 14 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................................. 14 

6.1 Residential Handler Exposure ................................................................................................ 14 

6.2 Residential Post-Application Exposure .................................................................................. 1 S 

6.3 Residential Risk Estimates for Use in Aggregate Assessment ............................................... 15 

7 .0 Aggregate Exposure/Risk Characterization .................................................................................... 16 

7. I Acute Aggregate Risk ............................................................................................................. 16 

7.2 Short- and Intermediate-Term Aggregate Risks ..................................................................... 16 

7.3 Chronic Aggregate Risk ......................................................................................................... 17 

8.0 Cumulative Exposure/Risk Characterization .................................................................................. 17 

9.0 Occupational Exposure/Risk Characterization ............................................................................... 17 

9.1 Short- and Intermediate-Term Handler Risk .......................................................................... 17 

9.2 Short- and Intermediate-Term Post-Application Risk ............................................................ 19 

Appendix A. Toxicology Profile and Executive Summaries ..................................................................... 20 

Appendix B. Physical/Chemical Properties ............................................................................................... 26 

Appendix C. Review of Human Research ................................................................................................. 26 

Page 2 of26 
Spirotetramat Human Health Risk Assessment D424088

Page 3 of 26

1.0 Executive Summary

Background: Spirotetramat is a tetramic acid derivative (ketoenol) and is active against sucking 

insects in a variety of plants. It is systemic (xylem and phloem mobile) and can control hidden 

pests and protect new shoots.

Permanent tolerances for the combined residues of spirotetramat and its metabolites BYI 08330-

enol, BYI 08330-ketohydroxy, BYI 08330-enol-Glc, and BYI 08330-mono-hydroxy, calculated 

as spirotetramat equivalents, are currently established in/on a variety of crops (40 CFR 

§180.641). 

Bayer CropScience has proposed a new use of spirotetramat on citrus trees grown in residential 

areas. When registered, this would be the first residential use of spirotetramat. The proposed 

end-use product is 14ACP703 SC Insecticide/Miticide (EPA Reg. #432-xxxx), which contains 2 

lb ai/gallon or 22.4% ai. The proposed label allows for up to 2 foliar spray applications (with a 

21-day retreatment interval) per year using handheld sprayers at a maximum single application 

rate of 10 fl oz/A (0.156 lb ai/A), 4.25 fl oz/100 gal (0.066 lb ai/100 gal) or 0.23 fl oz/1000 ft2

(0.0036 lb ai/1000 ft2). 

There are no proposed or HED-recommended tolerances associated with the proposed residential 

citrus tree use of spirotetramat. 

Hazard Assessment: The thyroid and thymus glands were target organs in oral subchronic and 

chronic toxicity studies in the dog, which was the most sensitive species. Lower circulating 

levels of thyroid hormones were seen in both sexes. Males exhibited the effect at a lower dose 

than females. The only histopathological change in the thyroid was a reduction in follicle size in 

the high-dose group, a possible indication of reduced amount of colloid. There were no 

correlative changes in thyroid weight, thyroid histopathology, or thyroid-stimulating hormone 

(TSH) in either sex. In all dog studies, there were decreases in thymus weights described 

microscopically as involution. Although the toxicology database for spirotetramat shows effects 

in the thymus gland in dogs, the results of the immunotoxicity study in rats does not indicate any 

functional deficits in immune function indicating that the thymus involution is secondary to the 

thyroid effects rather than a direct effect on the immune system. 

In rats, the testes were the target organ following subchronic and chronic exposure to 

spirotetramat. In a subchronic study, abnormal spermatozoa and hypospermia in the epididymis, 

decreased testicular weight, and testicular degeneration and vacuolation were observed in males 

at a relatively high dose (616 mg/kg bw/day). These effects proved to be reversible in most 

animals after cessation of treatment. Following 12 or 24 months of oral exposure, abnormal 

sperm or spermatid degeneration in the testes and germ cell exfoliated debris in the epididymis 

were observed in male rats at the high dose (~400 mg/kg bw/day). The effects on male 

reproduction are most likely due to the enol metabolite of spirotetramat, which has been shown 

in an investigative study to cause spermatotoxicity, abnormal sperm, and Sertoli cell vacuolation.

Other effects reported in rats were associated with the kidney. In the carcinogenicity study, kidney 

toxicity consisted of decreased organ weight and tubular dilation in both sexes. Similar kidney 

toxicity (decreased organ weight and histopathology) was also observed in parental animals of the F1

generation in the two-generation rat reproduction toxicity study along with male reproductive 

toxicity that is consistent with the subchronic and chronic studies in adult rats. Additionally, body 

weight decrements were observed in parental animals and offspring. 
Spirotetramat Human Health Risk Assessment D424088

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In an acute neurotoxicity (ACN) study in rats, the only evidence of neurotoxicity was decreased 

motor and locomotor activity which occurred at relatively high-dose levels (≥200 mg/kg bw) 

with no confirmatory findings of neurological pathology. A recently submitted subchronic 

neurotoxicity (SCN) study in rats does not display any neurotoxic effects up to the highest dose 

tested.

There was evidence of increased qualitative susceptibility in the rat developmental study with 

reduced fetal weight and increased incidences of malformations and skeletal deviations observed 

in offspring at the limit dose, while maternal effects at the same dose were limited to body 

weight decrements. There was no evidence of increased quantitative or qualitative susceptibility 

to offspring following pre- or postnatal exposure to spirotetramat in the rabbit developmental or 

two-generation reproduction studies. 

Consistent with previous risk assessments for spirotetramat, the spirotetramat risk assessment 

team recommends that the 10X Food Quality Protection Act Safety Factor (FQPA SF) be 

reduced to 1X for all exposure scenarios, as discussed in Section 4.4.

Exposure/Risk Assessment Characterization: A revised dietary assessment is not needed for 

this registration request since tolerances are not required based on the proposed residential citrus 

tree use. The proposed use pattern is identical to the registered agricultural use pattern, and is, 

therefore, not expected to result in residues higher than the current tolerances. In addition, the 

estimated drinking water concentrations (EDWCs) used in the previous dietary risk assessment 

still represent the highest estimated drinking water exposure scenarios. 

Since the proposed use represents the first residential use of spirotetramat, a summary of the 

most recent dietary assessment has been included in this risk assessment for the purposes of the 

aggregate assessment. Acute and chronic risk assessments were previously conducted for dietary 

exposure using the Dietary Exposure Evaluation Model software with the Food Commodity 

Intake Database (DEEM-FCID) Version 3.16, which uses food consumption data from the U.S. 

Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, 

What We Eat in America, (NHANES/WWEIA) from 2003 through 2008. The acute and chronic 

assessments directly incorporated drinking water estimates. Assumptions for the acute 

assessment included tolerance-level residues for all foods, DEEM 7.81 default processing factors 

(where provided), and 100% crop-treated (CT). Assumptions for the chronic dietary assessment 

included average field trial residues for some commodities, tolerance-level residues for the 

remaining commodities, and 100% CT. Some empirical processing factors were used in the 

chronic assessment along with DEEM 7.81 default processing factors (where provided). All 

dietary exposure and risk estimates were not of concern. A cancer dietary assessment was not 

conducted because spirotetramat is classified as “not likely to be carcinogenic to humans.”

There are no existing residential uses of spirotetramat. There is the potential for residential 

short-term handler inhalation exposure from the proposed use. The residential handler exposure 

and risk estimates indicate that the short-term inhalation margins of exposure (MOEs) are not of 

concern to HED (i.e., MOEs ≥ 100). While residential post-application exposure may potentially 

occur for adults entering treated areas, there is no dermal point of departure (POD) for 

spirotetramat therefore a quantitative assessment was not conducted.

Acute, short- and intermediate-term, and chronic aggregate assessments were included in this 

risk assessment. A cancer aggregate assessment was not performed because spirotetramat is 
Spirotetramat Human Health Risk Assessment D424088

Page 5 of 26

classified as “not likely to be carcinogenic to humans.” Acute and chronic aggregate risks are 

made up only of dietary sources; therefore, the exposure estimates provided in the dietary 

exposure analysis represent acute and chronic aggregate exposure, respectively. Since the shortand intermediate-term endpoint and POD are the same, the short-term assessment is protective of 

intermediate-term exposure. The short-term aggregate risk assessment includes dietary and nondietary sources of exposure. All potential exposure pathways were assessed in the aggregate risk 

assessment as a conservative, health-protective measure. No aggregate risk estimates exceed 

HED’s level of concern (LOC) for the scenarios listed above. 

Based on the proposed use pattern, there is potential for short- and intermediate-term 

occupational exposure to spirotetramat during mixing, loading, applying, and other handling 

tasks. Chronic exposure is not expected for the proposed agricultural uses. Occupational postapplication exposure is not anticipated since the use is on residential citrus trees, and 

professional applicators would not be expected to return to a residential area to perform functions 

associated with previously treated residential ornamentals. In addition, there is no dermal POD 

therefore, a dermal risk assessment is not necessary. The LOC for occupational inhalation 

exposures are for MOEs <100. For the proposed use, all occupational short- and intermediateterm handler inhalation MOEs were >100. 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. Please refer to Appendix C for a 

discussion of the human study data used in this risk assessment. 

2.0 HED Recommendations

There are no occupational, residential, or toxicology data deficiencies at this time for the 

proposed residential use on citrus trees, and HED recommends in favor of the proposed 

registration. 

2.1 Tolerance Considerations

Tolerances are not required for the proposed residential use of spirotetramat on citrus trees. 

2.2 International Harmonization

Since there are no proposed or HED-recommended tolerances, harmonization is not an issue for 

this registration request. 

2.3 Label Recommendations

The proposed label is adequate to allow evaluation of the proposed residential use. No label 

updates are required at this time. 
Spirotetramat Human Health Risk Assessment D424088

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3.0 Introduction

3.1 Chemical Identity

Table 3.1. Test Compound Nomenclature.

Compound

Chemical Structure

Common name Spirotetramat

Company experimental name BYI 08330

IUPAC name cis-4-(ethoxycarbonyloxy)-8-methoxy-3-(2,5-xylyl)-1-azaspiro[4.5]dec-3-en-2-one

CAS name cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl ethyl 

carbonate

CAS # 203313-25-1

End-use product/EP 14ACP703 SC Insecticide/Miticide (EPA Reg. #432-xxxx)

3.2 Physical/Chemical Characteristics

Spirotetramat is a systemic broad-spectrum tetramic acid insecticide (ketoenol class) that is 

applied as a preventative treatment during an early threshold of developing chewing insect 

population when sufficient leaf tissue is present for uptake and translocation to occur within 

agricultural crops. It is systemic (xylem and phloem mobile) and can control hidden pests and 

protect new shoots. Its vapor pressure is 1.5 x 10-8 Pa at 25oC. The mobility of spirotetramat is 

moderately high [partition coefficient (Kd) range 3.58-5.52 L/Kg, soil organic carbon partition 

coefficient (KOC) range 184-437 L/KgOC, moderately mobile, FAO 2000]. Spirotetramat is 

labile, especially under aerobic soil metabolism conditions. Nonetheless, its total residues are 

relatively persistent. A table of the physicochemical properties can be found in Appendix B. 

3.3 Pesticide Use Pattern

Bayer CropScience has submitted a draft label for 14ACP703 SC Insecticide/Miticide (EPA Reg. 

#432-RLUE). Information pertaining to the proposed end-use product is listed in Table 3.3. 

There are no required label changes at this time. 

Table 3.3.1. Summary of Proposed Directions for Use of Spirotetramat.

Applic. Timing, 

Type, and 

Equip.

Formulation 

[EPA Reg. No.] Applic. Rate (lb ai/A)

Max. No. 

Applic. per 

Year

Max. Yearly

Applic. Rate (lb 

ai/A)

Use Directions and 

Limitations

Residential Citrus Trees

Apply to fullsize mature 

trees

Foliar 

application 

using handheld

sprayers

Soluble 

Concentrate

[432-xxxx]

2 lb ai/gal

22.4% ai

10 fl oz/A = 0.156 lb ai/A

4.25 fl oz/100 gal = 0.066 lb 

ai/100 gal

0.23 fl oz/1000 ft2 = 0.0036 

lb ai/1000 ft2

2

20 fl oz/A = 0.32 

lb ai/A

Do not apply within 10 

days prior to bloom, 

during bloom, or until 

petal fall is complete.
Spirotetramat Human Health Risk Assessment D424088

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To ensure the residue levels on backyard citrus would not exceed those expected from the 

currently registered agricultural citrus use, the proposed residential use pattern was compared to 

the registered agricultural use pattern. The proposed and registered use patterns, in terms of 

maximum application rates and retreatment intervals, are identical as can be seen in Table 3.3.2

(from Memo, G. Kramer et al., D333437, 14-May-2008). It is, therefore, not anticipated that 

residue levels on backyard citrus would exceed the current tolerance levels.

Table 3.3.2. Summary of Registered Directions for Use of Spirotetramat on Agricultural Citrus.

Trade 

Names

Application 

Timing, 

Type, and 

Equipment

Applic. 

Rate 

(lb ai/A)

Maximum 

Number 

Applications 

per Season

Maximum 

Seasonal 

Application Rate 

(lb ai/A) 

PHI 

(days) Use Directions and Limitations

CITRUS (Crop Group 10)

BYI 8330 

OD 

MoventoTM

UltorTM

Ground & 

aerial 0.12-0.16 2 0.32 1

Minimum retreatment interval: 

21 days

Minimum spray volume: 15 

gallons per acre (GPA) ground, 

10 GPA aerial

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new use of 

spirotetramat on residential citrus trees. Humans may be exposed to spirotetramat in food and 

drinking water, since spirotetramat may be applied directly to growing crops and application may 

result in spirotetramat reaching surface and ground water sources of drinking water. Adults may 

be exposed to spirotetramat in residential settings when handling the product during application, 

and adults and children may be exposed when entering treated areas after application. In an 

occupational setting, applicators may be exposed while handling the pesticide prior to 

application, as well as during application. This risk assessment considers all of the 

aforementioned exposure pathways based on the proposed new use of spirotetramat, but also 

considers the existing registered uses as well, particularly for the dietary exposure assessment. 

3.5 Consideration of Environmental Justice

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

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

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

(http://www.archives.gov/federal-register/executive-orders/pdf/12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns, compiled by the USDA’s 

NHANES/WWEIA), are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 
Spirotetramat Human Health Risk Assessment D424088

Page 8 of 26

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Spirotetramat belongs to the class of cyclic ketoenol insecticides. The proposed insecticidal 

mode of action for these agents is based on inhibition of acetyl-CoA carboxylase, a key enzyme 

in fatty acid biosynthesis in eukaryotes and prokaryotes. Inhibition of lipogenesis, resulting in 

decreased lipid content (notably triglycerides and free fatty acids) in treated insects, hinders the 

ability of younger insects to develop and ultimately their ability to reproduce as adults. The 

mammalian toxicity database for spirotetramat does not indicate changes in plasma lipid 

parameters, such as plasma levels of triglycerides and cholesterol; therefore, it is unclear if this 

mode of action also operates in mammals.

4.1 Toxicology Studies Available for Analysis

The toxicology database for spirotetramat is adequate for characterization of its hazard, toxicity 

endpoint selection, and FQPA SF consideration. As part of the revised 40 CFR Toxicology Data 

Requirements, subchronic inhalation and SCN studies are necessary for registered uses; 

however, the Hazard and Science Policy Council (HASPOC) concluded using a weight-ofevidence approach that these studies are not required at this time (TXR# 0056480). Although the 

SCN study was not required according to HASPOC, a SCN study has been submitted and the 

results of the study incorporated into the current assessment.

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Absorption of orally administered spirotetramat in rats was rapid and nearly complete. In 

females, the time to maximum plasma levels (Tmax) at the low dose tested of 2 mg/kg bw was 

estimated to be ~10 minutes, while at the high dose of 100 mg/kg bw, it was prolonged to 42 

minutes. In males, Tmax was between 0.7 and 1 hour at both dose levels. The extent of 

absorption was 89-98% by 48 hours following single low (2 mg/kg bw) and high (100 mg/kg 

bw) gavage doses, as well as repeated low doses (2 mg/kg bw). Systemic exposure estimated by 

the area under the plasma concentration-time curve (AUC) was higher for male than female rats. 

At 2 mg/kg bw (single or repeated dosing), the AUC for males was about 60% higher than 

females and much greater at the high dose. Less than 0.2% of the administered dose was 

detected in the body at sacrifice and the highest concentrations were detected at similar levels in 

the liver and kidney. Spirotetramat was completely metabolized in the rat since no parent 

compound was detected in the excreta. The main metabolic reaction was cleavage of the ester 

group, which resulted in formation of the major metabolite BYI 08330-enol (53-87% of 

administered dose). All other identified metabolites could be derived from the primary enol 

metabolite. Male rats exhibited much higher rates of demethylation of BYI 08330-enol to BYI 

08330-desmethyl-enol (25-37%) when compared to female rats (5-10%). Excretion of 

radioactivity was relatively rapid with 88-95% of the administered dose eliminated via urine and 

2-11% via feces by 48 hours of exposure.

4.2.1 Dermal Absorption

There was no dermal hazard identified in the toxicological database for spirotetramat. As a 

result, a dermal absorption factor is not needed because a quantitative dermal assessment was not 
Spirotetramat Human Health Risk Assessment D424088

Page 9 of 26

performed (Section 4.5.1). An in vivo dermal penetration study in rats exists in the database that 

can be used to estimate a dermal absorption factor in the future if needed.

4.3 Toxicological Effects

The thyroid and thymus glands were target organs in oral subchronic and chronic toxicity studies 

in the dog, which was the most sensitive species. In subchronic dog studies, lower circulating 

levels of the thyroid hormones T3 and T4 were seen in both sexes. Males exhibited the effect at 

a lower dose than females. These differences are supported by data in the ADME studies 

showing that males achieve higher systemic exposures than their female counterparts. Decreases 

in T4 were also observed in a one-year study in dogs at a lower dose as compared to subchronic 

exposures. The only histopathological change in the thyroid was a reduction in follicle size in 

the high-dose group, a possible indication of reduced amount of colloid. There were no 

correlative changes in thyroid weight, thyroid histopathology, or TSH in either sex. In all dog 

studies, there were decreases in thymus weights described microscopically as involution (both 

sexes following subchronic exposure; only males in the one-year study). Although the 

toxicology database for spirotetramat shows effects in the thymus gland in dogs, the results of 

the immunotoxicity study in rats does not indicate any functional deficits in immune function. 

Thymus involution has been demonstrated to occur when hypothyroidism is induced in animals, 

so it is reasonable to conclude that the thymus involution in dogs was secondary to the thyroid 

effects rather than a direct effect on the immune system.

In rats, the testes were the target organ following subchronic and chronic exposure to 

spirotetramat. In a subchronic study, abnormal spermatozoa and hypospermia in the epididymis, 

decreased testicular weight, and testicular degeneration and vacuolation were observed in males 

at a relatively high dose (616 mg/kg bw/day). These effects proved to be reversible in most 

animals after cessation of treatment. Following 12 or 24 months of oral exposure, abnormal 

sperm or spermatid degeneration in the testes and germ cell exfoliated debris in the epididymis 

were observed in male rats at the high dose (~400 mg/kg bw/day). In an investigative study with 

the enol metabolite of spirotetramat, spermatotoxicity, abnormal sperm, and Sertoli cell 

vacuolation were observed in the testes-epididymides of treated animals. In conjunction with the 

ADME data, which indicates that the parent chemical is completely metabolized to the enol 

metabolite, these data support the conclusion that male reproductive toxicity in rats is likely due 

to the enol metabolite of spirotetramat.

Other effects reported in rats were associated with the kidney. Kidney toxicity in the carcinogenicity 

study consisted of decreased organ weight and tubular dilation in both sexes. Similar kidney toxicity 

(decreased organ weight and histopathology) was also observed in parental animals of the F1

generation in the two-generation rat reproduction toxicity study along with male reproductive 

toxicity that is consistent with the subchronic and chronic studies in adult rats. Additionally, body 

weight decrements were observed in parental animals and offspring. 

In the ACN study in rats, the only evidence of neurotoxicity was decreased motor and locomotor 

activity which occurred only at relatively high-dose levels (200 mg/kg bw) with no confirmatory 

findings of neurological pathology. A recently submitted SCN study in rats does not display any 

neurotoxic effects up to the highest dose tested.

There was evidence of increased qualitative susceptibility in the rat developmental study with 

reduced fetal weight and increased incidences of malformations and skeletal deviations observed 

at the limit dose, while maternal effects at this dose consisted of only body weight decrements. 
Spirotetramat Human Health Risk Assessment D424088

Page 10 of 26

There was no evidence of increased quantitative or qualitative susceptibility to offspring 

following pre- or postnatal exposure to spirotetramat in the rabbit developmental or twogeneration reproduction studies. 

4.4 Safety Factor for Infants and Children (FQPA SF)

The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all 

exposure scenarios based on the following considerations outlined in more detail in the sections 

below: (1) the toxicology database for spirotetramat is adequate for FQPA SF consideration; (2) 

spirotetramat is not considered neurotoxic in mammals; (3) evidence of qualitative susceptibility 

to offspring is protected for by selected endpoints; and (4) the exposure databases are sufficient 

and unlikely to underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The existing toxicology database for spirotetramat is complete for FQPA SF evaluation. The 

following acceptable studies are available for direct evaluation of neurotoxicity and pre- and 

post-natal sensitivity: developmental toxicity studies in rats and rabbits, one- and two-generation 

reproduction toxicity studies in rats, and neurotoxicity (acute and subchronic) studies in rats.

4.4.2 Evidence of Neurotoxicity

Although there is evidence of neurotoxicity in the ACN study (see section 4.3), concern is low 

since the effects are well-characterized with clearly established no-observed adverse-effect level 

(NOAEL)/lowest-observed adverse-effect level (LOAEL) values, the selected endpoints are 

protective of the observed neurotoxic effect, there are no neurotoxic effects seen in the SCN 

study after preliminary review, and the existing toxicological database indicates that 

spirotetramat is not a neurotoxic chemical.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no evidence of quantitative susceptibility of offspring following pre- or postnatal 

exposure. There is evidence of qualitative susceptibility in the rat developmental study (see 

Section 4.3); however, concern is low since effects were only seen at the limit dose, effects were 

seen in the presence of maternal toxicity, and selected endpoints are protective of the observed 

effects. 

4.4.4 Residual Uncertainty in the Exposure Database

The acute dietary food and drinking water exposure assessment utilizes tolerance-level residues, 

DEEM 7.81 default processing factors (where provided), and 100% CT information for all 

commodities. By using these screening-level assessments, actual exposures/risks will not be 

underestimated. The chronic dietary food and drinking water exposure assessment utilizes 

average field trial residues for some commodities, tolerance-level residues for the remaining 

commodities, and 100% CT. Some empirical processing factors were used in the chronic 

assessment along with DEEM 7.81 default processing factors (where provided). The chronic 

assessment is somewhat refined; however, since it is based on reliable data, it will not 

underestimate exposure/risk. The drinking water assessments utilize water concentration values 

from the watercress application scenario generated by the Tier 1 Rice Model v.1.0. The resulting 

screening-level EDWCs provide conservative, health-protective, high-end estimates of water 
Spirotetramat Human Health Risk Assessment D424088

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concentrations that will not likely be exceeded. The residential handler exposure assessments are 

based upon the residential SOPs, which are based upon reasonable worst-case assumptions and 

are not expected to underestimate risk. These assessments of exposure are not likely to 

underestimate the resulting estimates of risk from exposure to spirotetramat.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Tables 4.5.4.1 and 4.5.4.2 summarize the toxicological doses and endpoints selected for human 

health risk assessment. Since the last risk assessment, dermal and inhalation exposure endpoints 

have been updated. 

Acute Dietary Endpoint (General Population): The acute dietary endpoint was based on clinical 

signs and decreased motor activity observed in the ACN study at the LOAEL of 200 mg/kg bw 

(NOAEL = 100 mg/kg bw). This study is appropriate for the duration and route of exposure. 

The acute population-adjusted dose (aPAD) of 1.0 mg/kg bw/day is derived from the NOAEL of 

100 mg/kg bw and a 100-fold uncertainty factor (10X for interspecies extrapolation, 10X for 

intraspecies variation, and 1X for FQPA SF).

Chronic Dietary (All Populations): The chronic dietary endpoint was based on the thymus 

involution in males in the chronic dog study at the LOAEL of 20 mg/kg bw/day (NOAEL = 5 

mg/kg bw/day). This study is appropriate for the route and duration of exposure and is 

protective of all effects seen in the database following chronic exposure. The chronic 

population-adjusted dose (cPAD) of 0.05 mg/kg bw/day is derived from the NOAEL of 5 mg/kg 

bw/day and a 100-fold uncertainty factor (10X for interspecies extrapolation, 10X for 

intraspecies variation, and 1X for FQPA SF).

Dermal (Short- and Intermediate-Term): A dermal endpoint was not selected. Dermal endpoints 

were chosen in previous risk assessments; however, reevaluation of the toxicological database 

yielded no dermal hazard. Since there is no concern for enhanced quantitative 

sensitivity/susceptibility to offspring from spirotetramat exposure, the effects of concern in 

adults and offspring are adequately assessed in the dermal toxicity study where no adverse 

dermal or systemic effects were observed up to the limit dose.

Inhalation (Short- and Intermediate-Term): The 90-day oral toxicity study in dogs was selected 

to evaluate inhalation exposures (NOAEL = 32 mg/kg bw/day). The LOAEL of 72 mg/kg 

bw/day is based on depressed red blood cell parameters, thymus atrophy, and decreased food 

consumption. This study is appropriate for the duration of exposure and is protective of all 

effects seen in the database following subchronic exposure. The LOC for inhalation exposure 

scenarios is for MOEs <100 (10X for interspecies extrapolation, 10X for intraspecies variation, 

and 1X FQPA SF when applicable). Inhalation exposure is assumed to be equivalent to oral 

exposure. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

A dermal endpoint was not selected for spirotetramat; therefore, dermal and inhalation exposures 

do not need to be combined.
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4.5.3 Cancer Classification and Risk Assessment Recommendation

There is no evidence of carcinogenicity in chronic toxicity/carcinogenicity studies performed in 

rats and mice. Spirotetramat has been classified as “not likely to be carcinogenic to humans” 

based on lack of evidence for carcinogenicity in rodent studies. Spirotetramat was also negative 

for mutagenicity and clastogenicity in in vivo and in vitro assays. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Dietary and 

Non-Occupational Human Health Risk Assessments. 

Exposure Scenario POD Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for 

Risk Assessment

Study and Relevant 

Toxicological Effects

Acute Dietary (General 

Population, including 

Infants and Children)

NOAEL = 

100

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

aRfD = aPAD = 1.0 

mg/kg/day

Acute neurotoxicity (rat)

LOAEL = 200 mg/kg based on 

clinical signs and decreased 

motor activity in males.

Chronic Dietary (All 

Populations)

NOAEL = 5

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

cRfD = cPAD = 0.05 

mg/kg/day

Chronic toxicity (dog)

LOAEL = 20 mg/kg/day based 

on thymus involution in males.

Dermal

Short- and 

Intermediate- Term (1-

30 days and 1-6 

months)

In a dermal toxicity study in rats, no adverse effects were observed up to the limit dose. Since 

there is no evidence of increased quantitative susceptibility, a dermal assessment is not needed.

Inhalation

Short- and 

Intermediate- Term (1-

30 days and 1-6

months)

NOAEL = 32

mg/kg/day 

Inhalation 

assumed

equivalent to 

oral.

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential LOC for 

MOE =100

90-Day oral toxicity (dog)

LOAEL = 72 mg/kg/day [F] 

based on depressed RBC 

parameters (red blood cell count, 

hemoglobin level and 

hematocrit), thymus atrophy and 

decreased food consumption.

Cancer (Oral, Dermal, 

Inhalation)

Classification: “not likely to be carcinogenic to humans” based on lack of evidence of 

carcinogenicity in rats and mice.

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among 

members of the human population (intraspecies), FQPA SF = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = 

lowest-observed adverse-effect level, RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, LOC = level of concern.

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Occupational 

Human Health Risk Assessments.

Exposure Scenario POD Uncertainty Factors LOC for Risk 

Assessment Study and Toxicological Effects

Dermal

Short- and 

Intermediate- Term (1-

30 days and 1-6 

months)

In a dermal toxicity study in rats, no adverse effects were observed up to the limit dose. Since there 

is no evidence of increased quantitative susceptibility, a dermal assessment is not needed.

Inhalation

Short- and 

Intermediate- Term (1-

30 days and 1-6

months)

NOAEL = 32

mg/kg/day 

Inhalation 

toxicity is 

considered 

equivalent to 

oral toxicity.

UFA = 10X

UFH = 10X

Occupational LOC for 

MOE =100

90-Day oral toxicity (dog)

LOAEL = 72 mg/kg/day [F] 

based on depressed RBC 

parameters (red blood cell count, 

hemoglobin level and 

hematocrit), thymus atrophy and 

decreased food consumption.

Cancer (oral, dermal, 

inhalation)

Classification: “not likely to be carcinogenic to humans” based on lack of evidence of 

carcinogenicity in rats and mice.

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among 

members of the human population (intraspecies), NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level, 

MOE = margin of exposure, LOC = level of concern.
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5.0 Dietary Exposure and Risk Assessment 

An overview of the metabolism and environmental degradation of spirotetramat can be found in 

the August 2012 human health risk assessment (Memo, J. Van Alstine, et al.; D399022). 

Additionally, a summary of the residues of concern can be found in the April 2013 human health 

risk assessment (Memo, J. Van Alstine et al.; D398509). An updated drinking water memo was 

provided by EFED (Memo, J. Meléndez, 7-MAY-2013; D410121); however the application rate 

for the proposed use on citrus trees is lower than the previously assessed watercress and banana 

and plantain application rates. Therefore, the recommended surface and ground water EDWCs 

are based on the previously assessed watercress and banana and plantain scenarios, and a revised 

dietary assessment is not required.

5.1 Dietary Risk Assessment

5.1.1 Description of Residue Data Used in Dietary Assessment

The proposed citrus tree use does not result in changes to the most recent dietary exposure 

assessment (Memo, J. Van Alstine, 26-MAR-2013; D398858); however, for the purposes of the 

aggregate assessment, this information is included in this risk assessment. Acute and chronic 

dietary-exposure (food plus water) and risk assessments were conducted using DEEM-FCID, 

Version 3.16, which uses food consumption data from the USDA’s NHANES/WWEIA survey 

from 2003 through 2008. The assessments were performed for the general U.S. population and 

all population subgroups. Assumptions for the acute assessment included tolerance-level 

residues for all foods, DEEM 7.81 default processing factors (where provided), and 100% CT. 

Assumptions for the chronic dietary assessment included average field trial residues for some 

commodities, tolerance-level residues for the remaining commodities, and 100% CT. Some 

empirical processing factors were used in the chronic assessment along with DEEM 7.81 default 

processing factors (where provided). Drinking water estimates were provided by EFED. The 

EDWC values were generated using the watercress use pattern and the Tier 1 Rice Model v.1.0. 

The resulting screening-level surface water EDWC estimate of 0.395 ppm was used for both the 

acute and chronic assessments. 

5.1.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary analyses assumed 100% CT for all commodities. 

5.1.3 Acute Dietary Risk Assessment

Acute dietary risk estimates (food and drinking water) are not of concern for the general 

population or any other population subgroup. The assessment was unrefined and the highest 

exposure estimate was for the population subgroup children 1-2 years old, which utilized 16% of 

the aPAD for spirotetramat. The acute exposure estimate for the general U.S. population utilized 

7% of the aPAD. A summary table of dietary exposure and risk for spirotetramat can be found 

in Section 5.1.6. 

5.1.4 Chronic Dietary Risk Assessment

Chronic dietary risk estimates (food and drinking water) are not of concern for the general 

population or any other population subgroup. The assessment was somewhat refined and the 

highest exposure and risk estimates were for the population subgroup children 1-2 years old, 
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which utilized 76% of the cPAD for spirotetramat. The chronic exposure estimate for the 

general U.S. population utilized 36% of the cPAD. A summary table of dietary exposure and 

risk for spirotetramat can be found in Section 5.1.6. Although further refinement to the analysis 

is not required at this time, future assessments could be refined through the use of additional 

average field trial values and translation of average field trial residues to other commodities 

using HED SOP 2000.1, additional empirical processing factors, incorporation of % CT data, or 

monitoring data. 

5.1.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not performed because spirotetramat was classified as “not 

likely to be carcinogenic to humans.”

5.1.6 Summary Table

Table 5.1.6. Summary of Dietary (Food and Drinking Water) Exposure Risk for Spirotetramat1.

Population Subgroup

Acute Dietary (95th Percentile) Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD Dietary Exposure(mg/kg/day) % cPAD

General U.S. Population 0.066115 7 0.017785 36

All Infants (<1 year old) 0.137642 14 0.036886 74

Children 1-2 years old 0.155241 16 0.038038 76

Children 3-5 years old 0.125606 13 0.030925 62

Children 6-12 years old 0.075624 8 0.019418 39

Youth 13-19 years old 0.046354 5 0.013149 26

Adults 20-49 years old 0.053000 5 0.016159 32

Adults 50-99 years old 0.050326 5 0.016494 33

Females 13-49 years old 0.052999 5 0.015902 32

1 The values for the highest exposed population for each type of risk assessment are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

A residential exposure assessment was provided in a HED memorandum dated 28-OCT-2015

(K. Lowe; D429878). There is the potential for residential short-term handler and postapplication dermal and inhalation exposure from the proposed use on residential citrus trees; 

however, a quantitative assessment was only conducted for residential handler inhalation 

exposure since a dermal POD has not been selected for spirotetramat. When registered, this will 

be the first residential use for spirotetramat.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct tasks related to applications and that 

exposures can vary depending on the specifics of each task. Residential handlers are addressed 

somewhat differently by HED as homeowners are assumed to complete all elements of an 

application without use of any protective equipment.

The quantitative exposure/risk assessment developed for residential handlers is based on the 

following scenarios: (1) mixing/loading/applying a liquid formulation using a manuallypressurized handwand, and (2) mixing/loading/applying a liquid formulation using a backpack 

sprayer.
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Maximum application rates, as outlined in Table 3.3, were used to assess residential handler 

exposure. Unit exposure values and estimates for area treated or amount handled and the 

algorithms used to estimate exposure and dose for residential handlers were taken from HED’s 

2012 Residential Standard Operating Procedures (SOPs)1. Although the product can be applied 

every 21 days, a maximum of two applications can only be made per year; therefore, only shortterm residential handler exposure was assessed. 

The residential handler exposure and risk estimates indicate that the short-term inhalation MOEs 

are not of concern to HED (i.e., MOEs >100). 

Table 6.1.1. Residential Handler Non-cancer Exposure and Risk Estimates for Spirotetramat.

Exposure Scenario Level of 

Concern

Inhalation Unit 

Exposure 

(mg/lb ai)

Maximum 

Application 

Rate1

Amount 

Handled 

Daily2

Inhalation

(LOC = 100)

Dose 

(mg/kg/day)3 MOE4

Mixer/Loader/Applicator

Manuallypressurized 

handwand 100

0.018 0.00066 5 0.00000074 43,000,000

Hose-end sprayer 0.0014 0.00066 11 0.00000013 250,000,000

Backpack sprayer 0.14 0.00066 5 0.0000058 5,500,000

1 Based on proposed label (EPA Reg. #432-xxxx).

2 Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

3

Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/gal) × Amount Handled (gallons/day) ÷ Body Weight (80 kg).

4

Inhalation MOE = Inhalation NOAEL (32 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

6.2 Residential Post-Application Exposure

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with spirotetramat. For the spirotetramat 

proposed use on residential citrus trees, there would be the potential for dermal exposure for 

adults and children; however, since there is no dermal POD, a quantitative assessment of dermal 

risk is not necessary and has not been conducted. Post-application inhalation exposure while 

performing activities in previously treated gardens or trees has not been quantitatively assessed 

due to the combination of low vapor pressure for spirotetramat (1.5 x 10-8 Pa at 25oC) and the 

expected dilution in outdoor air. 

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for spirotetramat.

 The recommended residential exposure for use in the adult aggregate assessment reflects 

handler inhalation exposure when using a backpack sprayer.

Table 6.3.1. Recommendations for the Residential Exposures for the Spirotetramat Aggregate Assessment.1

Lifestage Dose (mg/kg/day)2 MOE3

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Short-term Residential Handler

Adult 

(Backpack Sprayer) NA 0.0000058 NA 0.0000058 NA 5,500,000 NA 5,500,000

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

 

1 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Spirotetramat Human Health Risk Assessment D424088

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2 Dose = the highest dose for each applicable lifestage of all scenarios assessed from Table 6.1.1. 

3 MOE = the MOEs associated with the highest doses identified in Table 6.1.1. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

For spirotetramat, aggregate exposure risk assessments were performed for the following 

scenarios: acute aggregate exposure (food and drinking water), short- and intermediate-term 

aggregate exposure (food, drinking water, and residential exposure), and chronic aggregate 

exposure (food and drinking water). Spirotetramat is classified as “not likely to be carcinogenic 

to humans”; therefore, a cancer aggregate risk assessment was not performed.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure estimates from dietary 

consumption of spirotetramat (food and drinking water). The acute dietary exposure estimates 

are not of concern to HED (<100% aPAD) at the 95th exposure percentile for the general U.S. 

population and all other population subgroups (see Table 5.1.6). The dietary exposure 

assessment utilized tolerance-level residues, 100% CT information for all proposed agricultural 

uses, DEEM 7.81 default processing factors (where provided), and a Tier 1 surface water EDWC 

generated by the Tier 1 Rice Model v.1.0. 

7.2 Short- and Intermediate-Term Aggregate Risks

Short-term (1 to 30 day) and intermediate-term (1 to 6 months) aggregate risk assessments are 

necessary for adults since there is potential for handler exposure from the residential use of 

spirotetramat on citrus trees. Since the short-term assessment assumed no dissipation (i.e., dayzero residues) for the entire exposure duration (up to 30 days), and the short- and intermediateterm PODs are the same, the short-term assessment is expected to be protective of intermediateterm exposure durations. 

For the short-term aggregate risk assessment, potential residential exposures were combined with 

food and drinking water exposures. Specifically, the short-term aggregate assessment for adults 

combines dietary (food + drinking water) exposures with handler inhalation exposures resulting 

from the proposed use. See Table 6.3 for more information on the residential risk estimates that 

are recommended for use in the aggregate assessment for spirotetramat. 

The short-term residential exposure estimates were aggregated with the chronic dietary (food + 

drinking water) to provide a worst-case estimate of short-term aggregate risk for adults. As the 

short-term aggregate MOEs are greater than 100, risk estimates do not exceed HED’s LOC. 

Short-term aggregate MOEs are protective of intermediate-term exposure durations. 
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Table 7.2. Short- and Intermediate-Term Aggregate Risk Calculations for Spirotetramat.

Population

Subgroups

Short/Intermediate-Term Scenario

NOAEL

(mg/kg/day) LOC1 Max Exposure2(mg/kg/day)

Average Dietary 

Exposure

(mg/kg/day)

Residential 

Exposure3

(mg/kg/day)

Aggregate MOE

(dietary and 

residential)4

Adult 32 100 0.32 0.016494 0.0000058 1,900

1 The LOC (target MOE) includes 10X for interspecies extrapolation and 10X for intraspecies variation.

2 Maximum Exposure (mg/kg/day) = NOAEL/Target MOE.

3 Residential Exposure = Handler inhalation exposure for adults.

4 Aggregate MOE = [NOAEL ÷ (Avg. Dietary Exposure + Residential Exposure)]. 

7.3 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of spirotetramat (food and drinking water). The chronic dietary exposure 

estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all 

population subgroups (see Table 5.1.6). The dietary exposure assessment utilized average field 

trial residues for some commodities, tolerance-level residues for the remaining commodities, 

100% CT, some empirical processing factors, DEEM 7.81 default processing factors (where 

provided), and a Tier 1 chronic surface water EDWC generated by the Tier 1 Rice Model v.1.0. 

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to spirotetramat and any other substances and spirotetramat does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that spirotetramat has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

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

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

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

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

9.0 Occupational Exposure/Risk Characterization

An occupational exposure assessment of the proposed uses was provided in a HED 

memorandum dated 28-OCT-2015 (K. Lowe; D429878). For the proposed use sites, there is a 

potential for short- and intermediate-term occupational exposure to spirotetramat during mixing, 

loading, applying, and other handling tasks. Additionally, since the same endpoint and POD 

were selected for short- and intermediate-term durations, short-term exposure and risk estimates 

are considered to be protective of potential longer-term exposure and risk. Chronic exposure is 

not expected for the proposed agricultural uses. Occupational post-application exposure is not 

anticipated since the use is on residential citrus trees, and professional applicators would not be 

expected to return to a residential area to perform functions associated with previously treated 

residential ornamentals. 

9.1 Short- and Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 
Spirotetramat Human Health Risk Assessment D424088

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(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: (1) mixing/loading/applying a liquid formulation using a manuallypressurized handwand and (2) mixing/loading/applying a liquid formulation using a backpack 

sprayer. 

Maximum application rates, as outlined in Table 3.3, were used to assess occupational handler 

exposure. An estimate of 40 gallons handled/day was used in the occupational handler exposure 

calculations based on guidance in Science Advisory Council for Exposure (ExpoSAC) Policy 

9.1.

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include 

Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task 

Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or 

other registrant-submitted occupational exposure studies. Some of these data are proprietary 

(e.g., AHETF data), and subject to the data protection provisions of the Federal Insecticide, 

Fungicide, and Rodenticide Act (FIFRA). The standard values recommended for use in 

predicting handler exposure that are used in this assessment, known as “unit exposures,” are 

outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table2,” 

which, along with additional information on HED policy on use of surrogate data, including 

descriptions of the various sources, can be found at the Agency website3. 

For spirotetramat, based on the proposed uses, short- and intermediate-term exposures are 

expected since there is the potential for multiple applications at the maximum application rate. 

The proposed label is for use on residential citrus trees, and the product could be used by 

professional applicators for multiple clients. The label states that applications can be repeated up 

to two times per year at a 21-day interval. It should also be noted that for spirotetramat, both the 

short- and intermediate-term PODs are the same; therefore, estimates of short-term exposure/risk 

are protective of any repeated exposure for longer than 30 days. 

The proposed product label for this use recommends that applicators and other handler must 

wear protective eyewear, long-sleeved shirts and long pants, chemical-resistant gloves, and shoes 

plus socks.

The occupational handler exposure and risk estimates indicate that the short- and intermediateterm inhalation MOEs are not of concern to HED (i.e., MOEs >100) for the proposed uses on 

residential citrus trees. 

 

2 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

3 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Spirotetramat Human Health Risk Assessment D424088

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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Spirotetramat. 

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 

(μg/lb ai)1 Maximum 

Application Rate2

Amount Handled 

Daily3

Inhalation

(LOC = 100)

Mitigation Level Dose 

(mg/kg/day)4 MOE5

Mixer/loader/Applicator

Manually-pressurized 

handwand for foliar 

applications 

Residential 

Citrus trees

140

(baseline)

0.00066

40 0.0000463 690,000

Backpack sprayer for 

foliar applications

30

(baseline) 40 0.0000099 3,200,000

Mechanicallypressurized handgun for 

foliar applications

3.9

(baseline) 1000 0.0000321 1,000,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013); Level of mitigation: Baseline (longsleeved shirt, long pants, shoes plus socks).

2 Based on proposed label (EPA Reg. # 432-RLUE).

3 ExpoSAC Policy #9.1.

4

Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/gal) × Amount Handled 

(gal/day) ÷ BW (80 kg).

5

Inhalation MOE = Inhalation NOAEL (32 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

9.2 Short- and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). For the proposed use of spirotetramat, occupational post-application exposure 

is not anticipated since the use is on residential citrus trees. Professional applicators would not 

be expected to return to a residential area to perform functions associated with previously treated 

residential citrus trees. Therefore, a quantitative occupational post-application assessment was 

not conducted.

10.0 References

Previous Risk Assessments: J. Tyler, et al., 14-MAY-2008, D333437; J. Van Alstine, et al. 22-

DEC-2010, D368785; J. Van Alstine, et al. 02-AUG-2012, D399022; J. Van Alstine et 

al., 17-APR-2013; D398509

HASPOC Memo: K. Rury, 4-OCT-2012; TXR# 0056480

Drinking Water Memo: J. Meléndez, 7-MAY-2013; D410121

Dietary Memo: J. Van Alstine, 26-MAR-2013; D398858

Occupational and Residential Exposure Memo: K. Lowe, 28-OCT-2015; D429878

List of Appendices:

Appendix A. Toxicology Profile and Executive Summaries

Appendix B. Physical/Chemical Properties

Appendix C. Review of Human Research

cc: K. Lowe, M. Perron

RDI: RAB1 (17-JUL-2015), G. Kramer, (17-JUL-2015)

K. Lowe: S-10947: Potomac Yard 1 (PY1): (703)347-8989: 7509P: RAB1
Spirotetramat Human Health Risk Assessment D424088

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for spirotetramat are presented below.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21/28-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation

yes

yes

yes

no

no1

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction and Fertility Effects

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5400 Mutagenicity—Structural Chromosomal Aberrations

870.5500 Mutagenicity—Other Genotoxic Effects

yes

yes

yes

no

yes

yes

yes

-

870.6100a Acute Delayed Neurotox. (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neuroxicity. Screening Battery (rat)

870.6300 Develop. Neurotoxicity

no

no

yes

no

no

-

-

yes

yes

-

870.7485 General Metabolism

870.7600 Dermal Penetration

yes

yes

yes

yes

1 The HASPOC met on 04-OCT-2012 (TXR# 0056480) and concluded that a repeated-exposure inhalation toxicity study is not required for 

spirotetramat at this time. 
Spirotetramat Human Health Risk Assessment D424088

Page 21 of 26

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile – Spirotetramat Technical. 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral (rat) 46904527 LD50 >2000 mg/kg (F) III

870.1200 Acute dermal (rat) 46904529 LD50 >2000 mg/kg 

(M&F) III

870.1300 Acute inhalation (rat) 46904530 LC50 >4.183 mg/L 

(M&F) IV

870.2400 Primary eye irritation (rabbit) 46904531

Corneal opacity and iritis 

(grade 1); cleared by day 

8

II

870.2500 Primary dermal irritation (rabbit) 46904532 Negative IV

870.2600 Dermal sensitization (mouse) 46904565 Positive (LLNA) N/A

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

No. Study Type MRID No. (year)/ Classification/Doses Results

870.3100 28-Day oral toxicity 

(mouse)

46904536 (2001) Acceptable/nonguideline

0, 500, or 5000 ppm (equivalent to 

0, 136.5, or 1415 mg/kg bw/day 

[M])

NOAEL = 5000 ppm (1415 mg/kg/day [M]).

LOAEL not observed.

870.3100 90-Day oral toxicity 

(mouse)

46904539 (2005) 

Acceptable/guideline

0, 70, 350, 1700, or 7000 ppm 

(equivalent to 0/0, 12.8/16, 

59.6/72.4, 300/389, or 1305/1515 

mg/kg bw/day [M/F])

NOAEL = 7000 ppm (1305/1515 mg/kg/day [M/F]).

LOAEL not observed.

870.3100 28-Day oral toxicity 

(rat)

46904537 (1998) Acceptable/nonguideline

0, 500 or 5000 ppm (equivalent to 

0, 47.3, or 501.8 mg/kg bw/day [F])

NOAEL = 5000 ppm (501.8 mg/kg/day [F]).

LOAEL not observed.

870.3100 90-Day oral toxicity 

(rat)

46904538 (2005) 

Acceptable/guideline

0, 150, 600, 2500, or 10000 ppm 

(equivalent to 0/0, 9/11, 26/46, 

148/188, or 616/752 mg/kg bw/day 

[M/F])

NOAEL = 2500 ppm (148/188 mg/kg/day [M/F]).

LOAEL = 10000 ppm (616/752 mg/kg/day [M/F]), 

based on decreased body weight, abnormal 

spermatozoa and hypospermia in the epididymis, 

decreased testicular weight, and testicular 

degeneration and vacuolation in males, and alveolar 

macrophages in both sexes.

870.3150 28-Day oral toxicity 

(dog)

46904572 (2004)

Acceptable/non-guideline

0, 100, 400, 1600, or 6400 ppm 

(equivalent to 0/0, 3/3, 13/12, 

42/70, or 104/127 mg/kg/day 

[M/F])

NOAEL = 1600 ppm (42/70 mg/kg/day [M/F]).

LOAEL = 6400 ppm (104/127 mg/kg/day [M/F]) 

based on decreased thymus size and weight as well as 

decreased body weight and food consumption, which 

resulted in emaciation.

870.3150 90-Day oral toxicity 

(dog)

46904541 (2005) 

Acceptable/guideline

0, 150, 300, 1200, or 4000/2500 

ppm (equivalent to 0/0, 5/6, 9/10, 

33/32, or 81/72 mg/kg bw/day)

NOAEL = 1200 (32 mg/kg/day) [F] & 2500 ppm (81 

mg/kg/day) [M].

LOAEL = 2500 ppm (72 mg/kg/day) [F] based on 

decreased food consumption, depressed RBC 

parameters (red blood cell count, hemoglobin level. 

and hematocrit), and thymus atrophy.

870.3200 28-Day dermal toxicity 

(rat)

46904542 (2006)

Acceptable/guideline

0, 100, 300, or 1000 mg/kg bw/day 

(limit dose)

NOAEL = 1000 mg/kg/day.

LOAEL not established.

870.3700a Prenatal developmental 

(rat)

46904543 (2004)

Acceptable/guideline

0, 20, 140, or 1000 mg/kg bw/day

Maternal NOAEL = 140 mg/kg/day.

LOAEL = 1000 mg/kg/day based on impaired food 

consumption, transient body weight loss, and reduced 

final body weight.

Developmental NOAEL = 140 mg/kg/day.

LOAEL = 1000 mg/kg/day based on reduced fetal 

weight and increased incidences of malformations and 

skeletal variations.
Spirotetramat Human Health Risk Assessment D424088

Page 22 of 26

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

No. Study Type MRID No. (year)/ Classification/Doses Results

870.3700b Prenatal developmental 

(rabbit)

46904544 (2004)

Acceptable/guideline

0, 10, 40, or 160 mg/kg bw/day

Maternal NOAEL = 40 mg/kg/day.

LOAEL = 160 mg/kg/day based on sacrifice of 

animals in moribund condition and clinical signs

Developmental NOAEL = 160 mg/kg/day.

LOAEL not observed.

870.3800 1-gen. reproduction and 

fertility effects

(rat) – range finding

46904571 (2006)

Acceptable/non-guideline

0, 200, 500, 6000, or 10000 ppm 

(equivalent to 0/0, 10.5/12.8, 

27.8/31.4, 320.1/384.1, or 

537.9/645.7 mg/kg bw/day [M/F])

Parental/Systemic NOAEL = 500 ppm (27.8 and 

31.4 mg/kg bw/day [M/F]).

LOAEL = 6,000 ppm (320.1 and 384.1 mg/kg bw/day 

[M/F]) based on decreased terminal body weight (F1

males).

Reproductive NOAEL = 500 ppm (27.8 mg/kg 

bw/day [M]) and 10,000 ppm (645.7 mg/kg/day) [F].

LOAEL = 6,000 ppm (320.1 mg/kg bw/day [M]) 

based on decreased sperm motility and progression 

and increased abnormal sperm cells in the F1 males.

Offspring NOAEL = 500 ppm (27.8 and 31.4 mg/kg 

bw/day [M/F]).

LOAEL = 6,000 ppm (320.1 and 384.1 mg/kg bw/day 

[M/F]) based on decreased body weight during 

lactation in F1 pups.

870.3800 2-gen. reproduction and 

fertility effects

(rat)

46904546 (2006)

Acceptable/guideline

0, 250, 1,000, or 6,000 ppm 

(equivalent to 0/0, 17.2/20, 

70.7/82.5, or 419.3/484.7 mg/kg 

bw/day [M/F])

Parental/Systemic NOAEL = 1000 ppm (70.7/82.5 

mg/kg/day [M/F]).

LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) 

based on decreases in body weight (F1 males and 

females), and food consumption during lactation (Pand F1-generation females), and kidney 

histopathology and decreased kidney weights (F1

males and females).

Reproductive NOAEL = 1000 ppm (70.7 mg/kg/day) 

[M] & 6000 ppm (484.7 mg/kg/day) [F].

LOAEL = 6000 ppm (419.3 mg/kg/day) [M] based on 

abnormal sperm cells and decreased reproductive 

performance in the F1 males.

Offspring NOAEL = 1000 ppm (70.7/82.5 

mg/kg/day [M/F]).

LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) 

based on decreased body weight during lactation in 

both F1 and F2 generations.

870.4100 Chronic toxicity (1 year; 

dog)

46904548 (2006)

Acceptable/guideline

0, 200, 600, or 1800 ppm 

(equivalent to 0/0, 6/5, 20/19, or 

55/48 mg/kg/day [M/F])

NOAEL = 200 ppm (6 mg/kg/day) [M] & 1800 ppm 

(48 mg/kg/day) [F].

LOAEL = 600 ppm (20 mg/kg/day) [M] based on 

thymus involution [M] and not observed [F].

870.4100 Chronic toxicity

(1 year; rat)

46904547 (2005)

Acceptable/guideline

0, 250, 3500, or 7500/12000 ppm 

(M/F) (equivalent to 0/0, 13.2/18, 

189/255, or 414/890 mg/kg bw/day 

[M/F])

NOAEL = 250 ppm (13.2 mg/kg/day) [M] & 3500 

ppm (255 mg/kg/day) [F].

LOAEL = 3500 ppm (189 mg/kg/day)[M] based on 

dose-dependent increase in alveolar macrophages; & 

12000 ppm (890 mg/kg/day)[F] based on decreased 

body weight, alveolar macrophages, discoloration of 

the lung, and yellow/brown staining of the perigenital 

area and tail.

870.4200 Carcinogenicity

(rat)

46904549 (2006)

Acceptable/guideline

0, 250, 3500, or 7500/12000 ppm 

(M/F) (equivalent to 0/0, 12.5/16.8, 

169/229, or 373/823 mg/kg bw/day 

[M/F])

NOAEL = 250 ppm (12.5/16.8 mg/kg/day [M/F]).

LOAEL = 3500 ppm (169/229 mg/kg/day [M/F]) 

based on decreased kidney weight and renal tubular 

dilation.

No evidence of carcinogenicity.

870.4200 Carcinogenicity

(mouse)

46904550 (2006)

Acceptable/guideline

0, 70, 1700, or 7000/6000 ppm 

(M/F) (equivalent to 0/0, 10.9/13.7, 

263/331, or 1022/1319 mg/kg/day 

[M/F])

NOAEL = 7000/6000 ppm (1022/1319 mg/kg/day 

[M/F]).

LOAEL not observed.

No evidence of carcinogenicity.
Spirotetramat Human Health Risk Assessment D424088

Page 23 of 26

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

No. Study Type MRID No. (year)/ Classification/Doses Results

870.5100 Bacterial Gene 

Mutation

46904551 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 5000 

μg/plate +/- S9 activation

Negative.

870.5100 Bacterial Gene 

Mutation

46904552 (2002)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 5000 

μg/plate +/- S9 activation

Negative.

870.5300 Mammalian Gene 

Mutation

46904553 (2002)

Acceptable/guideline

0, 2.5, 5, 10, 20, 30, 40, 50, 60, 70, 

or 80 g/mL (-S9)

0, 20, 40, 60, 80, 92, 100, 108, 116, 

120, 124, 132, or 140 g/mL (+S9)

Negative.

870.5375 In vitro mammalian 

chromosome aberration

46904554 (2002)

Acceptable/guideline

0, 10, 12, 24, 30, 48, or 50 μg/mL (-

S9) 

0, 20, 40, or 80 μg/mL (+S9)

Weakly clastogenic at cytotoxic concentrations only.

870.5375 In vitro mammalian 

chromosome aberration

46904555 (2003)

Unacceptable/guideline

0, 30, 50, 70, 90, or 110 μg/mL (-

S9)

0, 40, 60, 80, 100, or 120 μg/mL 

(+S9)

N/A

870.5395 In vivo erythrocyte 

micronucleus assay 

(mouse)

46904556 (2002)

Acceptable/guideline

0, 125, 250, or 500 mg/kg bw

Negative.

870.5385 In vivo bone marrow 

chromosomal aberration 

assay (mouse)

46904558 (2003)

Acceptable/guideline

0, 125, 250, or 500 mg/kg bw

Negative.

870.5550 In vivo/in vitro UDS 

assay (rat hepatocytes)

46904557 (2003)

Acceptable/guideline

0, 1000, or 2000 mg/kg bw

Negative.

870.6200a Acute neurotoxicity 

screening battery

46904560 (2005)

Acceptable/guideline

0, 50, 100, 200, 500, or 2000 mg/kg 

bw

NOAEL = 100 mg/kg/day.

LOAEL = 200 mg/kg/day based on clinical signs 

(males and females) and decreased motor activity 

(males).

870.6200b Subchronic 

neurotoxicity screening 

battery

48958802 (2012)

Acceptable/guideline

0, 400, 2000, or 10,000 ppm

0, 22.6/28.3, 114/137, or 585/707 

mg/kg/day (M/F)

NOAEL = 585/707 mg/kg/day (M/F)

LOAEL = not established.

870.7485 Metabolism and 

pharmacokinetics

(rat)

46904504 (2006)

Acceptable/guideline

2 or 100 mg/kg bw (single)

2 mg/kg bw (repeat)

Absorption: 89-98% after 48 hours (no significant 

differences among low-dose, high-dose, and repeateddose tests).

Distribution: AUC0-∞ (measure of systemic exposure) 

slightly higher for males than females; <0.2% of 

administered dose detected in body 48 hours after 

sacrifice; highest equivalent concentrations detected 

in liver and kidney.

Metabolism: parent compound undetected in urine 

and feces of all tests; main metabolic reaction was 

cleavage of the ester group which resulted in 

formation of the primary metabolite BYI 08330-enol 

(53-87% of administered dose); all other identified 

metabolites could be derived from enol; male rats 

exhibited much higher rates of demethylation of BYI 

08330-enol to BYI 08330-desmethyl-enol (25-37%) 

vs. females rats (5-10%).

Excretion: 88-95% of administered dose eliminated 

via urine and 2-11% via feces within 48 hours.
Spirotetramat Human Health Risk Assessment D424088

Page 24 of 26

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

No. Study Type MRID No. (year)/ Classification/Doses Results

870.7485 Metabolism and 

pharmacokinetics

(rat)

46904561 (2006)

Acceptable/guideline

2 or 1000 mg/kg bw (single)

At 1000 mg/kg bw: Absorption and excretion less 

than low dose, with 27% of dose excreted in urine 

after 24 hours (18% in feces); plasma radioactivity 

slightly higher than in liver and kidney; these results 

are consistent with saturation of cellular transport 

mechanisms. Tissue radioactivity decreased from 1 to 

24 hours post dose. Metabolism profile qualitatively 

similar to that of the low-dose group; BYI 08330-enol 

was most prominent metabolite; similar to low-dose 

group, BYI 08330-desmethyl-enol levels greater in 

urine than in plasma and organs.

870.7600 In vivo dermal 

penetration

(rat)

46904563 (2006)

Acceptable/guideline 

100, 15, or 5 μg ai/cm2(OD150 

formulation)

Dermal absorption = 10%.

870.7800 Immunotoxicity

(rat)

48525901 (2011)

Acceptable/guideline

500, 2500, or 12,000 ppm 

(equivalent to 33, 164, or 795 

mg/kg/day)

The functional immunotoxicity NOAEL is 12,000 

ppm (equivalent to 795 mg/kg/day, the highest dose 

tested); the LOAEL was not established.

The systemic toxicity LOAEL for spirotetramat in 

male rats is 12,000 ppm (equivalent to 795 mg/kg 

bw/day) based on decreased body weights, lowered 

food consumption, lower thymus weight, and 

observations of atrophic thymus. The NOAEL for 

systemic toxicity is 2500 ppm (equivalent to 164 

mg/kg bw/day).

Special 

study

Male reproductive 

toxicity 

46904569 (2005)

Acceptable/non-guideline

1000 mg/kg bw/day (3, 10, 21, or 

41 days)

Primary testicular effects on or after day 10 were 

degeneration of round and elongating spermatids 

(stage 7-8 and 9-14, respectively), decreased sperm 

count, and increased numbers of aberrant/abnormal 

spermatozoa in the epididymis.

Table A.2.3. Toxicity Profile – Metabolites.

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses Results

Exploratory 

study

10-day gavage (enol 

metabolite)

46904601 (2006)

Acceptable/non-guideline

800 mg/kg bw/day

No treatment related effects; only limited parameters 

measured; histopathology not evaluated.

Special study 21-day gavage (enol 

metabolite)

47070901 (2006)

Acceptable/non-guideline

800 mg/kg bw/day

Clinical signs of toxicity and testicular/spermatotoxicity.

870.5100 Bacterial Gene 

Mutation

(ketohydroxy 

metabolite)

46904594 (2005)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 

5000 μg/plate +/- S9 activation

Negative.

870.7485 Metabolism and 

Pharmacokinetics (rat)

(ketohydroxy 

metabolite)

46904595 (2006)

Acceptable/guideline

2 mg/kg bw (single)

Absorption: ≥55% after 48 hours. 

Distribution: highest concentrations detected in GI tract, 

liver, and kidney; <0.2% of administered dose detected 

in body 48 hours post dose.

Metabolism: parent compound undetected in urine and 

trace amounts in feces; main metabolic reaction was 

oxidative demethylation of cyclohexyl-O-methyl group 

to form desmethyl-ketohydroxy metabolite (15% of 

administered dose); all other identified metabolites could 

be derived from desmethyl-ketohydroxy metabolite.

Excretion: 54% of administered dose eliminated via 

urine and 44% via feces within 48 hours.
Spirotetramat Human Health Risk Assessment D424088

Page 25 of 26

Table A.2.3. Toxicity Profile – Metabolites.

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses Results

870.5100 Bacterial Gene 

Mutation

(desmethylketohydroxy 

metabolite)

46904597 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 

5000 μg/plate +/- S9 activation

Negative.

870.5100 Bacterial Gene 

Mutation

(dihydroxy metabolite)

46904599 (2005)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 

5000 μg/plate +/- S9 activation

Negative.

870.7485 Metabolism and 

Pharmacokinetics (rat)

(enol glucoside 

metabolite)

46904602 (2006)

Acceptable/non-guideline

0.1 mg/kg bw (single; 1 rat)

Absorption: 54% after 48 hours.

Distribution: plasma concentrations peaked 4 hours post 

dose; 1% of administered dose detected in body 48 hours 

post dose.

Metabolism: parent compound detected in feces (21%); 

main metabolite was enol (64% of administered dose).

Excretion: 53% of administered dose eliminated via 

urine and 44% via feces within 48 hours.

870.5100 Bacterial Gene 

Mutation

(monohydroxy 

metabolite)

46904604 (2005)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, or 

5000 μg/plate +/- S9 activation

Negative. 
Spirotetramat Human Health Risk Assessment D424088

Page 26 of 26

Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of the Spirotetramat.

Parameter Value Reference

Melting point 142 °C EPA Chemical Fact Sheet for 

Spirotetramat, June 2008 pH 6.3

Density D4

20 = 1.22

Water solubility (20 oC) pH 4: 33.5 mg/L

pH 7: 29.9 mg/L

pH 9: 19.1 mg/L

Solvent solubility (20 oC) Solvent g/L

n-hexane 0.055

Dichloromethane >600

Dimethyl Sulfoxide 200-300

Toluene 60

Acetone 100-120

Ethyl acetate 67

Ethanol 44

Vapor pressure Extrapolated Values:

5.6 x 10-9 Pa (20 oC)

1.5 x 10-8 Pa (25 oC)

1.5 x 10-6 Pa (50 oC)

Dissociation constant, pKa 10.7 Included in MRID 47648203

Octanol/water partition coefficient, Log(KOW) pH 4: 2.51

pH 7: 2.51

pH 9: 2.50

EPA Chemical Fact Sheet for 

Spirotetramat, June 2008

UV/visible absorption spectrum Peak Maxima Molar Absorptivity 

 (nm) (1000 cm2/ mol)

 211 22.0 x 103 

 276 0.8 x 103

Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review 

pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website4. 

 

4 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html