### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON

, D

. C. 20460



### MEM O RAN D UM

D ATE: 28-0CT-2015 O FF ICE OF C HEMI CA L SA FE TY AND PO LLU T I O N PR E VEN T I O N



### SU B JECT: S p i r otet r a m at. Human H eal th Risk Assessment for the Proposed Use on C i trus Trees Grown i n Residential Areas.

PC Code : 39220 I
D ec i s i on No. : 495325
Pet i t i on No.: NA O P Ba r co d e: 0424088 Regis t rat i o n No.: 432-RLUE Reg ul a t ory Act i on : Section 3 Registration
Case No.: 7452 Risk Assess m e n t Type : Single Chemical/Aggregate TXR No.: NA CAS No.: 203313-25-1 40 CFR: § 180.641 MR IO No.: NA



### FROM: Kell y M. Lowe

, Environmental Scientist Monique M. Perron

, Sc.D

. ,**Toxicologis ~**  

### Risk Assessment Branch I (RAB I )
Hea l th Effects Division (HED; 7509P)



### THR O UG H : Charles S mith

, Branch Chief 

# C::

_

# ~ G F Kr 

### PhD 

## S

. C h

.**.......~e.-,,,s;~S::.:2Z=:~~s..s:~-.** 

## .. ,_... -- - - eorge

. amer,

.. , eruor**em1st ~a_**  

### RABl/HED (7509 P )**~** 

### -



### TO: Rita Kumar Registration Division 

### (RD; 7505P)

The 1-IED of the Offic e of Pesticide Programs (OP P ) is charged with estimat i ng the risk to human health from exposure to pesticides. The 

### RD of OPP ha s requested that HED eva l uate hazard and

ex posure data and conduct dietary

, occupational

, resident i a l

, and aggregate exposure

assessme nts
, as 

### needed

, to estimate the risk to human health that will result from the proposed Sectio n 3 registration use of the active ingredient (a i ) s pirotetramat (cis-3

- (2,5-d imethlyphenyl )

- 8-met h oxy -2

- oxo-1-azaspiro[ 4.S]dec

- 3-en-4-yl-ethyl carbonate]) on c i trus trees grown i n residential areas. When r eg i ste r e d

, 

### this will be the first residential use of sp i rotetramat.

A 

### su mmary of the findings and an assessm e nt of human health risk resu l t i ng from t h e proposed and registered uses of sp irotetramat are provided in t h is document. The risk assessment and occupational exposure a nd re s idential assessment was provided by Kelly Low e (RAB 1 ); the hazard characterization and endpoi nt selection by Mon i que Perron (RAB 1 ); and the drinking

wa t er exposure assessment by Jose Melendez of the Environmenta l Fate and Effects Di visio n (E FED).

The most recent human health risk assessment for sp i rotetramat was for a proposed use on turfgrass (M emo , K. Lowe el al., 

### 16-0CT-2014 ; 04 1 3575)

. Page I of26Spirotetramat Human H ealth Risk Assessment 0424088



### Table of Contents

1. 0
2. 0 2.1 2.2 2.3 Exec uti ve S um1 nary

.. . ... .. .. ..... .. . ........... . .. . ............. .. . .. .. .. . .. .. .. .. . ... .. .. ... . ... .. .. .. ... .. ... .. ... ... ... .. .... ............ 3 H E D R eco mm en d a ti o n s

........... .. .. .. . .. .. . ...... .. . .. .. .. . ... . .. ............. .. .. .. .. . ......................................... .. ..... 5 T o l erance Co n siderations

...... . ................ .. . .. .. .. .. . .. .. .. . ........... .. .. .. .. ... .. . ............... .. ... .. ................ 5 I nte rn at i onal H annonization

........................ ... .. . ...................... ... . ... .. . ................... .... .. . ............. 5 Labe l Recommendations

.............................. .. .. . ....................... . .... . ....................... .... .. .. ........... 5
3 .0 3. 1 3.2 3.3 3.4 I nt r od u ctio n

................................... . ...................... ... .. . .. . ................... ...... ... .. ... . .............. .... ... ... .... . .... 6

C h e mi ca l I de nti ty

.. .. .. ....... . ..... .. .. .. . .. .. .. ............. ............ .. ....... ...... ...................... . ...................... 6 P

hys i ca l/ C h e rn ica l C h arac t er i s ti cs

...... . ... .. .. .... ...... . ........... .. .. . ... .. .. .. .. .. ......... .. ... ... .. .... .............. 6 P

estic i de Use P attern

.. . ... .. .. .. ................ . ................................................................................... 6 A n tic i pated Exposu r e Pat h ways

.................. .. ........................................................................... 7 3.5 Co n sideration of Environ m e n ta l Ju stice

.. . .... ... .. . ................... . .. .... . .. ... . ............... .. .. .... ... . .......... 7 4

. 0 H azard Characte ri zat i on a n d D ose-Respo n se Assessme n t..

...... . ..... . ................... . ............................ 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 Toxico l ogy Stu di es Ava ila b l

e fo r A n a l ys i s

.... . .. .. .. . ....................... ... .. .. ................... ... ... .. .... .. ... 8 A b so rpti o n , Di s tribu t i o n , Meta b o l ism

, a nd Exc r e ti o n (A D ME)

.............................................. 8 D

e nn a I Abso r pt i o n

.. ... . .. .. . .............. . .. . .. .. .. . ...................... . ... . .. . ............................................. 8 Toxicological Effects

... .. .. .. ... . ............. . .. . .. .. .. .. . .. .. . ............... . ... .. .. .. ....................... .. .................. 9 Safety Factor for I nfants and Children ( F Q P A SF)

................................................................ 10 Com p leteness of the T ox i co l ogy Database

.......................... . .............................................. I 0
Ev i de n ce of Ne ur otox i c i ty

.................................................. . ....................... .. .... ... ............... I 0
Ev iden ce of Se n s iti v i ty/S u sce p t ibili ty i n th e D e v e l o pin g o r Y o un g A nimal

. ... ... ... ... ... ... .. I 0
R

es i d u a l Uncerta in ty i n t h e Expos ur e D a t a b ase

................................................................. I 0
T oxicity En d po i nt an d Po in t of Depa rtur e Se l ec ti ons

............................................................ I I D ose -R espon se Assess m ent

.................. .. . .. ......................... ... . ... ....................... .... ............. 11
R

ecom m enda ti o n fo r Co m bi ni ng R o ut es of Expos u res fo r Ri sk Asse ss ment...

.. . .... . ......... 11
Cance r C l ass ifi ca ti o n a n d Ri sk Assess m e n t R eco mm e n da ti o n

.. ............. ... ... ... .. .... .. .... ...... 1 2
S umm ary of P o int s o f D e p a rt u r e a nd T ox i c i ty E ndp o int s Us ed in H u m a n R is k Assess m e n t 12
5

. 0 5.1 Dietary Exposure and Ris k Assessmen t

......................................................................................... 13 Dietary R i sk Assess 1n ent

. ... . ............ . ...... .. .. .. ........................ .. ... . ... .. .................. .. ... ... .... . ........ 13 5.1. I D esc ripti o n of R es i due Data Used i n Di etary Assess m en t..

.. .. ... .. .. .. ................... .. .... .. ....... 13
5.1.2 Pe r ce nt Cro p T r ea t ed U se d i n D i etary Assess m ent..

... . .. ... .. .. ....... ... . ..... . ... .. ... .. .. .... ... ... ...... 13
5 .1 .3 Ac ut e Di e t ary Ri s k Assess m e n t

.. . .. .. .. .. ........ . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ... .. ................... ... .... .. ...... 1 3
5 .1 .4 C h ro ni c Di etary Risk Assess m en t

.............. .. .. .. .................................................................. 13
5. 1 .5 Cance r D ie t ary Ri sk Assessment..

........................................................................ .. ............ 14
5.1.6 Su mm ary T a bl e

...................................... .. ........................ .. .. ... .. .. ................. ... ... ... ... ... ....... 14
6.0 Res id ent i a l (No n -Occu p at i o n a l ) Exposu r e/

R is k C h aracte ri zat i o n

.... .. .. .. ... .. .................................. 14 6 .1 R es identi a l H a nd le r Ex p os ur e

.. .. .. .............. ........... ......................... .. ...................................... 14 6

. 2 R es idential P ost-App li c ati o n Ex p osu r e .

.. . ..... .. .. .. .. ............. .. . ... .. ... .. .. .. .. .............. .. .. .... .... . ...... 1 S 6.3 Res id e n t i a l Ri sk Esti mat es fo r Use in Aggregate Assessme n t

............................................... 15 7

. 0 Aggregate Expos ur e / R isk Ch ara cte r ization

...................................................................... .. ............ 16 7. I Acute Aggrega te Risk

... . ... . .................... . .. .. . .. .. .. ................. . ... .. .. .. ... . ................... . ... ... ............ 16 7.2 S h ort- a n d Int er m ediate-Te rm Aggregate Ris k s

.............. . ... . .. .. .. .. ... .. .. .. .............. .. .. .... ... .. ...... 16 7.3 C hr o ni c A ggregate Ri s k

........ .. .. ...... . ........ .. .. ..... .. ..... ................... . .... . ..................................... 17 8.0 C umul a ti ve Expos ur e/ Ri s k C hara c t e ri za ti o n

............ . ......................................... .. ... .. ... ... .. .... ... .. .... 17 9.0 Occu p at i o n a l Exposu r e

/ Ris k C h arac te ri za t io n

......................... . .. . ... ... .. .. .. .. .................. .... . .... .... .. ... 17 9.1 Short- and In termediate-Term H and l e r Ri sk

. . ......................... ... . .. ... .. ........... ....... .. ..... .. ......... 17 9.2 S h ort- a n d I ntermediate-Term Po s t -App l ication Risk

............ .. ... . ...................... .... .. ... ........... 19 Append i x A. Tox i co l ogy P rofi l e and Executive Summar i es

.................. . ... .. .. .. ..................... . .... ... ............ 20 Ap p e n d i x B. Ph ys i cal/C h em i cal P ropert i es

........ . .. .. . .. .. ..... ... . .............. . .. .. ... .. . .. ... . .... . .............. .... ... ... .... . ... 26 App e ndi x C. R ev ie w o f Hum a n R esea r c h

.. .. .. .. .. .... ... .. .............. .. .. ............... .. .. ... .. .. .................................. 26
Page 2 of26Spirotetramat 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

- h ydroxy, 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 p roposed label allows for up to 2 foliar spray applications (with a 21

- day r etreatment 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 ft 2 

### (0.0036 lb ai/1000 ft 2 

### ).

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 i n 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 in dicating 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, abnor mal 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 ce ssation 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 mal e 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 kid ney. In the carcinogenicity study, k idney 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 F 1 

### generation in t he 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

Page 4 of 26 

### In a n 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 subm itted 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 inc idences of malformations and skeletal deviations observed in offspring at the limit dose, while maternal effects at th e same dose were limited to body weight decrements. There was no evidence of increased quantitative or qualitative susceptibility to offs pring 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 registrati on request since tolera nces 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 additi on, t he 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 c onducted 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) fr om 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 asses sment. A cancer aggregate assessment was not performed because spirotetramat isSpirotetramat 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 short

and intermediate

- term endpoint and POD are the same, the short

- term assessment is protective of intermediate

- term exposure. The short

- term aggreg ate risk assessment includes dietary and non

dietary 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 conce rn (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 e xpected 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. In addition, there is no dermal POD therefore, a dermal risk assessment is not necessary. The LOC for occupational inhalation exposures are for MO Es <100. For the proposed use , all occupational short

- and intermediate

term handler inhalation MOEs were >100

.
This risk assessment relies in part on data from studies in which adult human subj ects 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 defi ciencies 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 resid ential 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

Page 6 of 26 

### 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 ne w shoots. Its vapor pressure is 1.5 x 10

- 8 

### Pa at 25oC. The mobility of spirotetramat is moderately high [partition coefficient (K d 

## ) range 3.58

- 5.52 L/Kg, soil organic carbon partition coefficient (K OC 

### ) range 184

- 437 L/Kg OC 

### , 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 full

size mature

trees

Foliar application using handheld
sprayer s 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 ft 2 = 0.0036 lb ai/1000 ft 2 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

Page 7 of 26 

### To ensure the residue levels on backyard citrus would not exceed those expected from the currently registered agricultural citrus use, the p roposed residential use pattern was compared to the registered agricultural use pattern. The proposed and registered use pattern s, 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 Movento TM Ultor TM 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 r equested 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 spirote tramat 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 appli cation . In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. T his risk assessment considers all of the aforementioned exposure pathway s based on the proposed new use of s pirotetramat, 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 consider ed 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 subgrou ps according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on pa tterns 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 categorize d 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 warran t. 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 considerat ions are currently in development as OPP has committed resources and expertise to theSpirotetramat 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 ultimat ely 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

- of

evidence approach that these studies are not required at this time (TXR# 005648 0). 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 ad ministered spirotetramat in rats was rapid and nearly complete. In females, the time to maximum plasma levels (T max 

### ) at the low dose tested of 2 mg/kg bw was estimated to be ~10 minutes, while at the h igh dose of 100 mg/kg bw, it was prolonged to 42 minut es. In males, T max 

### 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 esti mated 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 th e 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. Th e 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 exh ibited 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 notSpirotetramat 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 subchr onic 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 e ffects 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 reasonab le 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 ani mals 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. Ki dney 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 F 1 

### generation in the two

- ge neration 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 st udy 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 do es 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 qualit ative susceptibility to offspring following pre

- or postnatal exposure to spirotetramat in the rabbit developmental or two

generation reproduction studies.

4.4 Safety Factor for Infants and Children (FQPA SF)

The RAB1 risk assessment team recommends th at 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 c onsidered 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 Dat abase

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 reproductio n 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), con cern 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 n o 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 w as 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 utilize s 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 dr inking 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 de fault 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 waterc ress 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 waterSpirotetramat Human Health Risk Assessment D424088

Page 11 of 26 

### 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 exposur e 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): T he 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 se en 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 variati on, 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 o bserved 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 pa rameters, 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 <1 00 (10X for interspecies extrapolation

, 10X for intraspecies variation

, and 1X FQPA SF when applicable ). I n halation exposure is assumed to be equivalent to oral
exposure

.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

A der mal endpoint was not selected for spirotetramat ; therefore , dermal and inhalation exposures do not need to be combined.Spirotetramat Human Health Risk Assessment D424088

Page 12 of 26 

### 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

- Occup ational 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 UF A = 10X

UF H = 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 UF A = 10X

UF H = 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. UF A = 10X

UF H = 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, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), FQPA SF = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowe st

- 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 Ri sk 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. UF A = 10X

UF H = 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, he moglobin 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, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

- observed adverse

- effect l evel, MOE = margin of exposure, LOC = level of concern.Spirotetramat Human Health Risk Assessment D424088

Page 13 of 26 

### 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
prov ided 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 gro und 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 ci trus tree use does not result in changes to the most recent dietary exposure assessment (M emo, 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 consumpt ion 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 p rocessing 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 Mo del 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 sub group 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 child ren 1

- 2 years old,Spirotetramat Human Health Risk Assessment D424088

Page 14 of 26 

### 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 diet ary 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 o f average field trial residues to other commodit ies 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 becaus e 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 Spirotetramat 1

.

Population Subgroup Acute Dietary (95 th 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; D 429878 ). There is the potential for residential short

- term handler and post

application dermal and inhalation exposure from the proposed use on residential citrus trees; however, a quantitative assessment was only conducted for residential handler inhal ation 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 in volved 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 homeown ers 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 fo rmulation using a manually

pressurized handwand, and (2) mixing/loading/applying a liquid formulation using a backpack
sprayer.Spirotetramat Human Health Risk Assessment D424088

Page 15 of 26 

### Maximum application rates, as outlined in Table 3.3 , were used to assess residential handler exposure. Unit exposure values an d 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; t herefore, only short

term 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., MOE s > 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 Rate 1 Amount

Handled Daily 2 Inhalation

(LOC = 100)
Dose (mg/kg/day) 3 MOE 4

Mixer/Loader/Applicator Manually

pressurized 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 fo r 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 back pack sprayer.

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

Lifestage Dose (mg/kg/day) 2 MOE 3

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.htmlSpirotetramat Human Health Risk Assessment D424088

Page 16 of 26 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 h azard (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 perform ed 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 sp irotetramat (food and drinking water). The acute dietary exposure estimates are not of concern to HED (<100% aPAD) at the 95 th 

### 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 Interme diate

- 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 t he short

- term assessment assumed no dissipation (i.e., day

zero residues) for the entire exposure duration (up to 30 days), and the short

- and intermediate

term PODs are the same, the short

- term assessment is expected to be protective of intermediate

term 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.Spirotetramat Human Health Risk Assessment D424088

Page 17 of 26 Table 7.2. Short

- and Intermediate

- Term Aggregate Risk Calculations for Spirotetramat.

Population Subgroups Short /Intermediate

- Term Scenario

NOAEL (mg/kg/day) LOC 1 Max Exposure 2 (mg/kg/day) Average Dietary

Exposure (mg/kg/day) Residential

Exposure 3 (mg/kg/day) Aggregate MOE

(dietary and residential) 4
Adult 32 100 0. 32 0.016494 0.0000058 1 ,9 00

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 em pirical 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 fol lowed 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 mechani sm 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 provide d in a HED memorandum dated 28

- OCT

- 2015 (K. Lowe; D 429878 ). 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 exposu re 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 Interm ediate

- 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 requirementsSpirotetramat Human Health Risk Assessment D424088

Page 18 of 26 

### (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 manually

pressurized handwand and (2) mixing/loading/ap plying 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 calculati ons 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

- spe cific 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 i n this assessment, known as “unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 2



### , ” which, along with additional information on HED policy on use of surrogate data, including descriptions of the vari ous sources, can be found at the Agency website 3



### . For spirotetramat, based on the proposed use s , short

- and intermediate

- term exposures are expected since there is the potential for multiple applications at the maximum application rate. The proposed lab el 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 intermediate

term inhalation MOEs are not of concern to HED (i.e., MOE s > 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/pes ticides/science/handler

- exposure

- data.htmlSpirotetramat Human Health Risk Assessment D424088

Page 19 of 26 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 Rate 2 Amount Handled Daily 3 Inhalation

(LOC = 100)

Mitigation Level Dose (mg/kg/day) 4 MOE 5

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
Mechanically

pressurized 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: Baseli ne (long

sleeved 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) × Amou nt Handled (gal/day) ÷ BW (80 kg).

5 Inhalation MOE = Inhal ation 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 t reated with a pesticide (also referred to as re

entry 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

- 201 5 ; D 429878

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

- JU L

- 201 5 ), G. Kramer, ( 17

- JUL

- 2015 ) K. Lowe: S

- 10947 : Potomac Yard 1 (PY1): (703) 347

- 8989 : 7509P: RAB1Spirotetramat Human Health Risk Assessment D424088

Page 20 of 26 

### 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

no 1 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 LD 50 >2000 mg/kg (F) III

870.1200 Acute dermal (rat) 46904529 LD 50 >2000 mg/kg (M&F) III

870.1300 Acute inhalation (rat) 46904530 LC 50 >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/non

guideline 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/non

guideline 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 epididym is, 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 emaciati on.

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 P renatal 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 (F 1 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 F 1 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 F 1 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 (F 1 males and females), and food consumption during lactation (P

and F 1

- generation females), and kidney histopathology and decreased kidney weights (F 1 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 F 1 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 F 1 and F 2 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) Negat ive.

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 h ou rs (no significant differences among low

- dose, high

- dose, and repeated

dose tests). Distribution: AUC 0

- ∞ (measure of systemic exposure) slightly higher for males than females; <0.2% of administered dose detected in body 48 h ou rs after sacrifice; highest equivalent concentrations detected in liver and kidney. Metabolism: parent c ompound 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 derive d 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 h ou rs.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/cm 2 (O D150 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, an d 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 h ou rs. Distribution: highest concentrations detected in GI tract, liver, and kidney; <0.2% of administered dose detected in body 48 h ou rs 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 h ou rs.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 (desmethyl

ketohydroxy 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 h ou rs. Distribution: plasma concentrations peaked 4 h ou rs post dose; 1% of administered dose detected in body 48 h ou rs 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 h ou rs. 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 D 4 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, pK a 10.7 Included in MRID 47648203 Octanol/water partition coefficient, Log(K OW ) 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 cm 2 / mol) 211 22.0 x 10 3
276 0.8 x 10 3



### 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 website 4



### .

4 http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html