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

OFFICE OF CHEMICAL SAFETY AND
POLLUTION PREVENTION

MEMORANDUM

Date: February 02, 2011

SUBJECT: Spirotetramat; Response to comments on human health effects submitted by Mayra Quirindongo of the NRDC

PC Code: 39220 I

Decision No.: 406300

Petition No.: NA

Risk Assessment Type: NA

TXR No.: 0055644

MRID No.: NA

FROM Dana Vogel, Branch Chief Registration Action Branch 1

Health Effects Division (7509P)

TO: John Hebert

Risk Manager Registration Division (7505P)

I. CONCLUSIONS DP Barcode: D38637! Registration No.:

. 

### J 

### V.J

- 10 

### 'i 

### q Regulatory Action: NA

Case No.: NA

CAS No.: NA

40 CFR: NA
Ver.Apr.08

In a submission to the Agency, Ms. Quirindongo of the Natural Resources Defense Council

stated that spirotctramat presents risks of developmental, reproductive and neurological toxicity.

As stated in the Federal Register for July 9, 2008 (Volume 73, Number 132), EPA detennined

that reliable data show that the safety of infants and children would be adequately protected if the FQPA SF were reduced to 1X for spirotetramat. That decision was based on the available toxicity and exposure data. The Agency is regulating at a dose that is 100-200 times lower than

the doses at which toxicity of concern was seen and then applying the I DO-fold uncertainty factor

to the Point of Departure results in a margin of exposure of 10,000-20,000. Therefore, the Agency's assessment is highly protective of the developmental, reproductive and neurotoxic

effects observed with spirotetramat.

Page 1 of3 

# \Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 2 of 47 A summary of the findings and an assessment of human-health risk resulting from the proposed registered uses of spirotetramat are provided in this document. The risk assessment and dietary exposure assessment were provided by Julie Van Alstine (RAB1); the residue chemistry data review by George Kramer (RAB1); the hazard ch aracterization and endpoint selection by Robert Mitkus (RAB1); the occupationa l exposure assessment by Kelly Lowe (RAB1); and the drinking water exposure assessment by José Meléndez of the Environmenta l Fate and Effects Division (EFED). The most recent human-health risk assessment for spirotetramat was completed on 14- MAY-2008 (Memo, J. Tyler, et al. ; D333437).

Table of Contents
1.0 Executive Summary 3
2.0 Ingredient Profile 9
2.1 Summary of Proposed Uses 10
2.2 Structure and Nomenclature 11
2.3 Physical and Chemical Properties 13
3.0 Hazard Characterization/Assessment 13
3.1 Hazard and Dose-Response Characterization 13
3.2 FQPA Considerations 16
3.3 Hazard Identification and Toxicity Endpoint Selection 18
3.4 Endocrine Disruption 21
4.0 Public Health and Pesticide Epidemiology Data 22
5.0 Dietary Exposure/Risk Characterization 22
5.1 Pesticide Metabolism and Environmental Degradation 22
5.2 Dietary Exposure and Risk 29
6.0 Residential (Non-Occupational) Ex posure/Risk Characterization 31
6.1 Spray Drift 31
7.0 Aggregate Risk Assessments a nd Risk Characterization 31
7.1 Acute Aggregate Risk 32
7.2 Chronic Aggregate Risk 32
8.0 Cumulative Risk Charac terization/Assessment 32
9.0 Occupational Exposure/Risk Pathway 32
9.1 Short- and Intermediate-Term Handler Risk 33
9.2 Short-Term Post-application Risk 36
10.0 Data Needs and Label Recommendations 37
10.1 Toxicology 37
10.2 Residue Chemistry 38
10.3 Occupational Exposure 38 Appendix A. Toxicology Assessment 39 Appendix B. Tolerance Summary Table for Spirotetramat 47Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 3 of 47 1.0 Executive Summary

Bayer CropScience has submitted a Section 3 requestto register a 2 lb a.i./gal suspensionconcentrate (SC) formulation (Movento TM ; EPA Reg. No. 264-1050), a 1.25 lb a.i./gal SC formulation (Ultor TM ; EPA Reg. No. 264-1065), and a 1.25 lb a.i./gal oil-dispersion (OD) formulation (BYI 8330 OD; EPA Reg. No. 264-1051) of spirotetramat for use on cotton, legume vegetables including soybean (crop groups 6 and 7a ), and tropical fruit. Spirotetramat is a tetramic acid derivative (ketoenole ), and is active against sucking insects in vegetables, citrus, pome fruit, stone fruit, grapes, cotton, and ot her plants. It is systemic (xylem and phloem mobile) and can control hidden pests and protect new shoots.

Permanent tolerances for the combined residu es of spirotetramat and its metabolites BYI 08330- enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc , and BYI 08330-mono-hydroxy, calculated as spirotetramat equivalents, are currently esta blished in/on citrus, cucu rbit vegetables, fruiting vegetables, grapes, hops, leafy Brassica vegetables, leafy non- Brassica vegetables, pome fruit, tuberous and corm vegetables, stone fruit, and tree nuts (40 CFR §180.641) . Spirotetramat is being evaluated as part of a tril ateral joint review with Canada and Austria. The most recent human-health risk assessment for spirot etramat was completed on 14-MAY-2008 (Memo, J. Tyler, et al. ; D333437). There are currently no register ed or proposed residential uses for spirotetramat.

Hazard Assessment : The acute, short-term, and long-term toxicity of spirotetramat is well understood. Spirotetramat technical demonstrated moderate to low acute toxicity (Toxicity Category III or IV) via the oral, dermal, and inhalation routes. Sp irotetramat is non-irritating to the skin (Toxicity Category IV), although it is an irritant to the eyes (Toxicity Category II) and exhibits a skin-sensitization potential in animal s and humans. The thyroid and thymus glands were target organs in oral subchronic toxicity studies in the dog; whereas, the testesepididymides were the target organs following subchronic oral treatment of rats. Long-term toxicity studies reflected the short-term toxicol ogical profile of spirotetramat with the thymus and thyroid as target or gans following one-year oral exposure of dogs. Chronic exposure of rats to spirotetramat also reflected the subchronic patter n of testicular toxicity. No evidence of tumor formation was found following long-term studies of rodents, and spirotetra mat was also negative for mutagenicity and clastoge nicity in several standard in vivo and in vitro assays.

The reproductive and developmenta l toxicity potential of spirotetramat was tested in rats and rabbits. In addition to testicular histopat hology observed following subchronic and chronic exposure of rats to spirotetramat, male reprodu ctive toxicity was recorded in a 2-generation reproductive toxicity study. However, developmen t of the sexual organs of offspring (balanopreputial separation, vaginal opening) was unaffect ed. In an investig ative study designed to explore the time of onset of testicular toxicity in rats, decreased epididymal sperm counts were noted after 10 days of exposure. Similar eff ects were observed after re peated dosing with the enol metabolite of spirotetramat. Although reproduc tive effects manifested as testicular toxicity and sperm abnormalities in a 90-day rat study, in a two-generation reproductive toxicity study and in a special reproductive toxicity, the reprod uctive effects were seen at very high doses. Testicular toxicity was seen at 616 mg/kg/da y and the sperm abnormalities were seen at 419 mg/kg/day in the two generation reproduction st udy and at 1000 mg/kg/day (Limit Dose) in the special male reproductive toxicity study. Deve lopmental toxicity was not observed with spirotetramat in the absence of maternal toxicity in either the rat or rabbit.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 4 of 47 Dose Response Assessment and Food Qua lity Protection Act (FQPA) Decision : Consistent with the last risk assessment for spirotetramat (Memo, J. Tyler, et al., 14-MAY-2008; D333437), the spirotetramat risk assessment team recommends that the 10X FQPA Safety Factor (SF) be reduced to 1X based on the following:

• There was no evidence of increased susceptibi lity of offspring following pre- or postnatal exposure in any study. In the rat devel opmental toxicity study, toxicity to offspring
was observed at the same dose as maternal toxi city, which was also the limit dose. In the developmental toxicity study in the rabbit, only maternal toxi city was observed. In both reproductive toxicity studies, toxicity to offspring (decreased body weight) was observed at the same dose as parental toxicity. Therefore, no eviden ce of increased susceptibility of offspring was found across four relevant toxicity studies wi th spirotetramat.

• Spirotetramat does not operate by way of a neurotoxic mechanism of action in target
pests.

• Although a subchronic neurotoxicit y study is now required as part of the revisions to 40 CFR Part 158, the existing toxicological databa se indicates that sp irotetramat is not a
neurotoxic chemical in mammals. Clinical si gns of toxicity and decreased motor activity were observed in adult rats following a si ngle dose of spirotetramat in the acute neurotoxicity study in the rat; however, these effects only atta ined statistical significance at high doses and were not observed at the lim it dose in the acute oral toxicity study in
the rat.

• There is no concern for neurotoxicity with sp irotetramat in the developing animal based
on the fact that brain dilation in the one -year dog study is most likely a congenital anomaly (see section 3.1.2) that was not obser ved in any other study in the database, and
the fact that the stru cturally related Bayer compounds spirodiclofen and spiromesifen are
not neurotoxic in ad ults or young animals.

• Although the toxicology database for spirotetramat shows eff ects in the thymus gland, an organ of the immune system, this finding does not raise uncertainty given the lack of an immunotoxicity study. The endpoint select ed for risk assessment was based on accelerated thymus involution and hypothyroi d effects in the dog. Thymus involution has been demonstrated to occur when hypothyr oidism is induced in animals, so it is
reasonable to conclude that the thymus involution in thes e dogs was secondary to the thyroid effects, rather than a direct effect on the immune system. With respect to immunotoxicity, no immunotoxic eff ects were seen in rats or mice, the species in which immunotoxicity studies are conducted. Thus, HED does not believe that conducting a functional immunotoxicity study in any rodent species will re sult in a lower point of departure (POD) than that currently used for overall risk assessment. For this reason and
because the current POD is considered extremel y protective, a database uncertainty factor (UF DB ) is not needed to account fo r the lack of this study.

• There are no residual uncertainti es with respect to the exposur e database which will result in underestimation of exposure. The di etary food exposure assessment utilizes
recommended tolerance-level or average field-trial residues and 100% crop treated (CT) information for all proposed commodities. By using this screening-level assessment, the acute and chronic exposures/risks will not be underestimated. Additional residue data for tropical fruits are being requested. Howeve r, the recommended tolerances are based on exaggerated-rate data; the additional field trials will be used to determine whether these tolerances are being set at a level higher than necessary.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 5 of 47 • The dietary drinking water assessment (Tier 1 estimates) utilizes values generated by model and associated modeling parameters wh ich are designed to provide conservative, health-protective, high-end estimates of water concentrations.

• The registered and/or proposed uses of spir otetramat are not expected to result in residential exposures.

Risk assessments were conducted for the followi ng specific exposure scenarios listed below. The acute and chronic reference doses (aRfD a nd cRfD) were calculate d by dividing the NOAEL by 100 (10X for interspecies extrapolation and 10X for intraspecies variat ion). Since the FQPA SF has been reduced to 1X, the acute and chr onic population-adjusted doses (aPAD and cPAD) are equal to the aRfD and cR fD, respectively. A 100% oral-e quivalent inhalation-absorption factor is assumed. The level of concern (LOC) for occupational dermal and inhalation exposures are for margins of exposure (MOEs) <100.

Exposure
Scenario POD RfD, PAD, LOC for
Risk Assessment Study/Effect

Acute Dietary NOAEL =
100 mg/kg/day aRfD = aPAD =
1.0 mg/kg/day Acute neurotoxicity in rats (gavage)/Clinical signs (M&F) and decreased motor activity (M) seen at the lowest-observed-adverse-effect-level (LOAEL) of 200 mg/kg/day.

Chronic Dietary NOAEL = 5 mg/kg/day cRfD = cPAD = 0.05 mg/kg/day Chronic toxicity study in dogs (dieta ry)/Thymus involution seen at LOAEL of 20 mg/kg/day (M).

Short- and
Intermediateterm Dermal NOAEL = 10 mg/kg/day LOC for MOE <100 (occupational) Prenatal developmental study in rabbits/Late abortion [ ≥ gestation day (GD) 22], clinical signs, impaired food a nd water consumption, and body-weight
loss seen at maternal LOAEL of 40 mg/kg/day.

Short- and
Intermediateterm Inhalation NOAEL = 10 mg/kg/day LOC for MOE <100 (occupational) Prenatal developmental study in rabbits/Late abortion ( ≥ GD 22), clinical signs, impaired food and water consump tion, and body-weight loss seen at
maternal LOAEL of 40 mg/kg/day.

Residue Chemistry and Drinking Water Assessments: The residue chemis try and drinking water databases are adequate to assess potential human e xposure to spirotetramat. Adequate data have been submitted to determine the residues of concern in primary crops, rotational crops, and
livestock.

Adequate crop field trial data have been subm itted for the following proposed crops: cotton; soybean; edible-podded legume vegeta bles; succulent shelled peas a nd beans; dried shelled peas and beans (except soybeans), subgroup 6C; and fo liage of legume vegetables (except soybean) 7A. For these commodities, the data reflect the maximum rates and minimum preharvest intervals (PHIs) requested and ha ve sufficient geographic represen tation to support tolerances for the proposed uses. The submitted residue data for tropical fruit are not adequate to fulfill data requirements. The number and locations of the crop field trials for tropical fruit are in
accordance with OPPTS Guideline 860.1500. Howeve r, the available data will not support the proposed use pattern as the trials were conducted at a ~2X use rate. Field trial data were not submitted for pistachio and okra; however, the existing tree nut crop group tolerance may be translated to pistachio and the existing fruiting vegetable crop group tolerance may be translated to okra. All crop field trial studies are supporte d by adequate storage stability data. Adequate processing data indicate that sepa rate tolerances do not need to be established for cotton meal and hulls, soybean meal, and dried plum, prune. Ho wever, a separate tole rance is required for soybean aspirated grain fractions (AGF). Based on the proposed new uses, tolerances on eggs, poultry meat byproducts, and hog meat byproducts shoul d be established, and the tolerances for cattle, goat, horse, and sheep meat byproducts sh ould be increased (see Appendix B). HED has determined that high-performance liquid ch romatography with tandem mass spectrometrySpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 6 of 47 (HPLC-MS/MS) Methods 00857 and 00966 are suitable enforcement methods for plant and livestock commodities, respectively, since th e methods passed a successful petition method validation (PMV) by Agency chemists at the An alytical Chemistry Labor atory/Biological and Economics Analysis Division (ACL/BEAD; E-mail, C. Stafford to D. Vogel; 19-FEB-2008). The existing confined and field rotational cr op data are adequate to support the proposed rotational crop restrictions.

Drinking water monitoring data are not availabl e for spirotetramat. The effects of water treatment on the pesticide and de gradates is uncertain. Spirot etramat and its metabolites, BYI 08330-enol, BYI 08330-ketohydroxy, and BYI 08330- MA-amide, were highly mobile to moderately mobile, and low levels of binding ar e expected. It appear s that spirotetramat metabolites BYI 08330-enol and BYI 08330-ketohydroxy are of high concern because the parent and BYI 08330 degrade relatively fast in most e nvironments. EFED provided Tier 1 estimated drinking water concentrations (EDWCs) for surface and ground water which were generated using the FQPA Index Reservoir Screening T ool (FIRST) and Screen ing Concentration in Ground Water (SCI-GROW) models , respectively. New drinki ng water numbers were not calculated for the new uses of spirotetramat because the new use rates are similar to or lower than the previously assessed use rates in the 22-JAN-2008 EFED memo (J. Meléndez; D345275).

Dietary (Food and Drinking Wa ter) Exposure Estimates: Acute and chronic dietary exposure analyses were conducted using the Dietary Expo sure Evaluation Model-Food Commodity Intake Database (DEEM-FCID TM ; ver. 2.03) program, which incorpor ates consumption data from the United States Department of Agriculture’s (U SDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII), 1994-1996/1998. For acute and chronic dietary risk estimates, HED’s LOC
is for estimates that exceed 100% aPAD or cPAD, respectively.

The acute analysis assumed 100% CT and toleran ce-level residues for all foods. Empirical and

DEEM TM (ver. 7.81) default processing factors we re used for processed commodities. A conservative chronic dietary assessment assuming average field-trial residues, empirical and

DEEM TM (ver. 7.81) default processing factors, and 100% CT was also conducted. Drinking water was incorporated directly in the di etary assessment using the acute or chronic concentrations for surface water generated by th e FIRST model. The acute dietary exposure estimates (95 th percentile) are not of concern to HED (<100% of the aPAD) for the general U.S. population (4.8% of the aPAD) and all other pop ulation subgroups. The most highly exposed population subgroup is children 1-2 y ears old at 11% of the aPAD. The chronic dietary exposure estimates are not of concern to HED (<100% of the cPAD) for the general U.S. population (34% of the cPAD) and all populati on subgroups. The most highly exposed population subgroup is children 1-2 years old at 93% of the cPAD.

Aggregate Exposure Scenarios and Risk Conclusions : For the proposed uses, human-health aggregate risk assessments have been conducte d for the following exposur e scenarios: acute aggregate exposure (food + dri nking water), and chronic aggreg ate exposure (food + drinking water). Short- and intermediate-term aggregat e risk assessments were not performed because there are no registered or proposed residential uses for spirotetramat. A cancer aggregate risk assessment was not performed because spirotetramat is classified as “Not Likely to be Carcinogenic to Humans.” All aggregate exposure and risk es timates are not of concern to
HED for the scenarios listed above.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 7 of 47 Occupational Exposure Estimates : Handler exposure is expected to be short- or intermediateterm based on information provided on the pr oposed labels. In addition, the short- andintermediate-term toxicological endpoints are the same; therefore, the estimates of risk for shortterm duration exposures are prot ective of those for intermediate-term duration exposures. Longterm exposures are not expected, therefore, a long-term assessment was not conducted. No chemical-specific data were available with wh ich to assess potential exposure to pesticide handlers. The scenarios assessed for occupati onal handlers include mixi ng/loading liquids for aerial, chemigation, airblast and groundboom applic ations, applying sprays via aerial, airblast and groundboom equipment, and flagging for aerial a pplications. The estimates of exposure to pesticide handlers are based upon surrogate study data available in the Pesticide Handlers Exposure Database (PHED; August, 1998). For pe sticide handlers, HED presents estimates of dermal exposure for “baseline” (i.e., workers we aring a single layer of work clothing consisting of a long-sleeved shirt, long pants, shoes plus socks, and no protective gloves), as well as for “baseline” and the use of protective gloves or ot her personal-protective equipment (PPE), as might be necessary. The spirotetramat product labe ls direct applicators and other handlers to wear a long-sleeved shirt, l ong pants, protective eyewear, chem ical-resistant gloves and shoes plus socks. HED has determined that risks are not of concern (i.e ., MOEs >100), provided workers wear protective glove s as recommended on the label.

Post-application exposure is expected to be short-term based on information provided on the proposed labels. However, the short- and inte rmediate-term toxicological endpoints are the same; therefore, the estimates of risk for short- term duration exposures ar e protective of those for intermediate-term duration exposures. Since no post-application exposure data were submitted in support of this registration action, dermal e xposures during post-application activities were estimated using dermal transfer coefficients (TCs) from the Science Advisory Council for Exposure (ExpoSAC) Policy Number 3.1: Agricultur al TCs (August, 2000). All post-application scenarios resulted in MOEs greater than 100 on day 0 (12 hours after applica tion) and, therefore,
are not of concern to HED.

The acute toxicity categories for this chemical re quire a 24-hour restricted-entry interval (REI) under the Worker Protection Standard (WPS). The 24-hour REI, which appears on the proposed label, is adequate for th ese proposed use patterns.

Environmental Justice Considerations : Potential areas of environm ental 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 Ad dress Environmental Justice in Minority Populations and Low-Income Populations,” ( http://www.hss.energy.gov/nuclearsa fety/env/guidance /justice/eo12898.pdf ).

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-esta blished procedures. In line with OPP policy, HED estimates risks to population subgroups fr om pesticide exposures that ar e based on patterns of that subgroup’s food and water consumption, and activ ities in and around the home that involve pesticide use in a residential se tting. Extensive data on food consumption patterns are compiled by the USDA under CSFII and are used in pesticide risk assessments for all registered food uses of a pesticide. These data ar e analyzed and categor ized 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-diet ary exposures based onSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 8 of 47 home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas post-application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditi onal dietary patterns among specific subgroups.

Review of Human Research : This risk assessment relies in pa rt on data from studies in which adult human subjects were intent ionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, invo lving exposure to many different pesticides, comprise generic pesticide exposure databases su ch as PHED, the Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reen try Task Force (ARTF) databases. EPA has reviewed all the studies in these multi-pesticide generic exposure databases, and on the basis of
available evidence has found them to have been neither fundamentally une thical nor significantly
deficient relative to standards of ethical research conduct prevai ling when they were conducted. There is no regulatory barrier to continued reliance on thes e studies, and all applicable requirements of EPA’s Rule for the Protection of Huma n Subjects of Research (40 CFR Part 26)
have been satisfied.

Recommendations for Tolerances : Pending submission of revised Se ctions B and F, there are no residue chemistry, toxicology, or occupational exposure issues that would preclude granting an unconditional registration for the use of spirot etramat on the requested crops, except tropical fruit. The registration for tropical fruit s hould be made conditional pending submission of bridging residue studies.

The proposed uses and the submitted data support the following permanent tolerances for residues of the insecticide spirotetramat, includi ng its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of spirotetramat ( cis- 3-(2,5-dimethlyphenyl)-8-methoxy2-oxo-1-azaspiro[4.5]dec-3-en-4-yl-et hyl carbonate]) and its metabolites cis- 3-(2,5- dimethylphenyl)-4-hydroxy-8-methoxy- 1-azaspiro[4.5]dec-3-en-2-one, cis- 3-(2,5- dimethylphenyl)-3-hydroxy-8-methoxy- 1-azaspiro[4.5]decane-2,4-dione, cis- 3-(2,5- dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl beta-D-glucopyranoside, and

cis- 3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azas piro[4.5]decan-2-one, calculated as the stoichiometric equivalent of spirotetramat, in or on the following commodities:

Cotton, undelinted seed 0.30 ppm Avocado 0.60 ppm Cotton gin byproducts 10 ppm Black sapote 0.60 ppm Soybean seed 5.0 ppm Canistel 0.60 ppm Soybean forage 8.0 ppm Mamey sapote 0.60 ppm Soybean hay 16 ppm Mango 0.60 ppm Aspirated Grain Fraction 10 ppm Sapodilla 0.60 ppm Vegetables, legume, group 06, except soybean 2.5 ppm Star apple 0.60 ppm Vegetables, foliage of legume, except soybean, subgroup 07A 7.0 ppm Papaya 0.35 ppm

Okra 2.5 ppm Guava 2.5 ppm Pistachio 0.25 ppm Feijoa 2.5 ppm Lychee 13 ppm Jaboticaba 2.5 ppm Longan 13 ppm Wax jambu 2.5 ppm Spanish lime 13 ppm Starfruit 2.5 ppm Rambutan 13 ppm Passionfruit 2.5 ppmSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 9 of 47 Pulasan 13 ppm Acerola 2.5 ppm Persimmon 2.5 ppm White sapote 0.60 ppm

The proposed uses and the submitted data also support the following permanent tolerances for residues of the insecticide spirotetramat, includi ng its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of spirotetramat ( cis- 3-(2,5-dimethlyphenyl)-8-methoxy2-oxo-1-azaspiro[4.5]dec-3-en-4-yl-et hyl carbonate]) and its metabolite cis- 3-(2,5- dimethylphenyl)-4-hydroxy-8-met hoxy-1-azaspiro[4.5]dec-3-en-2 -one, calculated as the stoichiometric equivalent of spirotetramat, in or on the following commodities:

Cattle, meat byproducts 0. 20 ppm Eggs 0.02 ppm Goat, meat byproducts 0.20 ppm Hog, meat byproducts 0.02 ppm Horse, meat byproducts 0.20 ppm Poultry, meat byproducts 0.02 ppm Sheep, meat byproducts 0.20 ppm

Data Needs/Deficiencies

Toxicology

• Immunotoxicity study (new require ment under 40 CFR Part 158).

• Subchronic neurotoxicity study (new requirement under 40 CFR Part 158).

Residue Chemistry

860.1200 Directions for Use

• Field trial data are required for sugar apple (the representa tive crop for atemoya, custard apple, cherimoya, ilama, soursop, and birida). As these data have not been submitted, the spirotetramat labels should be revised to delete instructions for use on sugar apple, atemoya, custard apple, cherimoya , ilama, soursop, and birida.

860.1500 Crop Field Trials

• The submitted residue data for tropical fruit will not support the proposed use pattern as
the trials were conducted at a ~2X use rate . HED thus requests that the petitioner conduct bridging studies with lychee and guava (1 trial each with four samples per treatment regimen) in order to determine the relationship between resi dues resulting from the labeled use pattern and that used in the submitted field trials (MRID# 47648205). Based on this relationship, the submitted residue data will be adjusted and the appropriate
tolerances determined.

860.1550 Proposed Tolerances

• The petitioner is requested to submit a revi sed Section F specifying revised tolerance levels and commodity definitions in Appendix B (summarized above).

Occupational and Residential Exposure

• None.

2.0 Ingredient ProfileSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 10 of 47 Spirotetramat is a tetramic acid derivative (k etoenole) developed by Ba yer CropScience AG. This foliar insecticide is active against sucking in sects in vegetables, citrus, pome fruit, stone fruit, grapes, cotton, and other pl ants. It is systemic (xylem and phloem mobile) and can control hidden pests and protect new s hoots. Spirotetramat toleran ces are published in 40 CFR§180.641. Spirotetramat is being evaluated as part of a trilateral joint re view with Canada and Austria.

The petitioner has submitted draft labels for a Section 3 request to register a 2 lb a.i./gal SC formulation (Movento TM ; EPA Reg. No. 264-1050), a 1.25 lb a.i./gal SC formulation (Ultor TM ; EPA Reg. No. 264-1065), and a 1.25 lb a.i./gal OD formulation (BYI 8330 OD; EPA Reg. No. 264-1051) of spirotetramat for use on cotton, legu me vegetables including soybean (crop groups 6 and 7a), and tropical fruit. A summary of the proposed use patter ns on cotton, legume vegetables including soybean (crop groups 6 and 7a ), and tropical fruit is detailed in Table 2.1.

2.1 Summary of Proposed Uses

Table 2.1. Summary of Direct ions for Use of Spirotetramat.

Trade

Names Application Timing, Type, and Equipment Application

Rate (lb a.i./A) Maximum
Number Applications per Season Maximum
Seasonal Application

Rate (lb a.i./A) PHI (days) Use Directions and Limitations

Cotton

BYI 8330
OD

Movento TM

Ultor TM Ground &
aerial 0.04-0.08 4 0.16 21 Minimum RTI: 7 days

Minimum spray volume: 10 gallons per acre (GPA) ground, 5 GPA aerial

REI: 24 hours Soybean

BYI 8330
OD

Movento TM

Ultor TM Ground &
aerial 0.04-0.08 4 0.16 21 Minimum RTI: 7 days

Minimum spray volume: 10 GPA ground, 5
GPA aerial

REI: 24 hours Legume Vegetables (excluding soybean, dry)

BYI 8330
OD

Movento TM

Ultor TM Ground &
aerial 0.04-0.08 4 0.16 1 (ediblepodded, succulent)

7 (dry shelled) Minimum RTI: 7 days

Minimum spray volume: 15 GPA ground, 5
GPA aerial

REI: 24 hours
Tropical Fruit (Acerola, Atemoya, Avo cado, Birida, Black sapote, Canistel, Cherimoya, Custard Apple, Feijoa,

Jaboticaba, Guava, Llama ( sic ), Longan, Lychee, Mamey sapote, Ma ngo, Papaya, Passionfruit, Persimmon, Pulasan, Rambutan, Sapodilla, Soursop, Spanish lime, Star a pple, Starfruit, Sugar apple, Wax jambu, White sapote)

BYI 8330
OD

Movento TM

Ultor TM Ground &
aerial 0.13-0.16 3 0.40 1 Minimum RTI: 14 days

Minimum spray volume: 30 GPA ground, 10
GPA aerial

REI: 24 hours Additional Restrictions for all Crops:

Movento TM and Ultor TM must be tank-mixed with a spray adjuvant/additi ve. BYI 8330 OD may be tank-mixed with a spray adjuvant/additive. Use in enclosed structures, such as gree nhouses or planthouses, is not permitted unless specified otherwise by state-specific supplemental labeling. Rotational crop plantback intervals (PBIs): 30 days for all non-labeled crops.

HED Conclusions: The submitted use directions for Movento TM , Ultor TM , and BYI 8330 OD are adequate to allow evaluation of th e residue data relative to the pr oposed use. Field trial data are required for sugar apple (the re presentative crop for atemoya, cu stard apple, cherimoya, ilama, soursop, and birida). As these data have not been submitted, the spirotetramat labels should be revised to delete instructions for use on sugar apple, atemoya, custard apple, cherimoya, ilama, soursop, and birida.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 11 of 47 2.2 Structure and Nomenclature

Table 2.2. 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 Movento TM , UltorTM, BYI 8330 OD

Compound: BYI08330-enol Chemical Structure

Common name BYI08330-enol Company experimental name BYI08330-enol IUPAC name None provided

CAS name cis -3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one CAS # None provided

Compound: BYI08830- ketohydroxy Chemical Structure

Common name BYI08830-ketohydroxy Company experimental name BYI08830-ketohydroxy IUPAC name None provided

CAS name cis -3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,4-dione CAS # None providedSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 12 of 47 Compound: BYI08330-enol-Glc Chemical Structure

Common name BYI08330-enol-Glc Company experimental name BYI08330-enol-Glc IUPAC name None provided

CAS name cis -3-(2,5-dimethylphenyl)-8-methoxy-2-oxo -1-azaspiro[4.5]dec-3-en-4-yl beta-Dglucopyranoside CAS # None provided

Compound: BYI 08330-monohydroxy Chemical Structure

Common name BYI 08330-mono-hydroxy Company experimental name BYI 08330-mono-hydroxy IUPAC name None provided

CAS name cis -3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-one CAS # None provided

Compound: BYI 08330-enolGA Chemical Structure

Common name BYI 08330-enol-GA Company experimental name BYI 08330-enol-GA IUPAC name None provided

CAS name cis -3-(2,5-dimethylphenyl)-4-( β -D-glucopyranosyloxy)-8-methoxy-1-azaspiro[4.5]dec-3-

en-2-one CAS # None providedSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 13 of 47 2.3 Physical and Chemical Properties

Table 2.3. Physicochemical Properties of the Technical Grade Spirotetramat.

Parameter Valu e 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

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

Data from the following studies were used to evaluate the hazard pot ential of spirotetramat:

• Acute: One acute neurotoxicity study (rat), in ad dition to standard acu te toxicity battery.

• Subchronic: Six oral (mouse, rat, dog) and on e dermal (rat) toxicity studies.

• Long-term: Two oral toxicity (dog, rat) and two oral carcinogen icity (rat, mouse)
studies.

• Reproduction/developmental: Two developmental (rat, rabbit), one single-generation (rat), and one two-generation reproduction (rat) studies.

• Other: Eight genotoxicity screens ( in vivo / in vitro ), two disposition studies (rat), and

one in vivo dermal penetration study (rat).

The submitted acute, subchronic, and chronic studi es were sufficient to evaluate human hazard potential, and data qualit y is acceptable.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 14 of 47 3.1.2 Mammalian Toxicology

Spirotetramat is an insecticidal compound and belongs to the chemical class of cyclic ketoenols. In insects, spirotetramat is an inhibitor of acetyl-CoA carboxylase, which is a key enzyme in fatty acid biosynthesis in eukaryotes and prokary otes. The insecticidal mode of action of spirotetramat correlates with i nhibition of lipogenesis in treated insects, resulting in decreased lipid contents (notably trigly cerides and free fatty acids), i nhibition of the ability of younger insects to develop through the va rious growth stages, and ultimate ly culminating in a diminished capacity of the insects to reproduce as adults. Changes in plasma lipid parameters such as plasma triglycerides and plasma cholesterol were not observed in any animal study in the toxicology database for spirotetramat.

Absorption, Distribution, Me tabolism, and Excretion : Absorption of spirotetramat in the rat was 89-98% at 48 hours following single low (2 mg /kg bw) and higher (100 mg/kg bw) doses, as well as repeated low doses (2 mg/kg bw). Systemic exposure, as estimated by AUC 0- ∞ , was slightly higher for males than females. Less th an 0.2% of the administered dose was detected in the body 48 hours after sacrifice, and the highest equivalent concentr ations were detected in the liver and kidney. Spirotetramat was complete ly metabolized by 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 metabo lites could be derived from enol. Male rats exhibited much higher rates of demethylati on of BYI 08330-enol to BYI 08330-desmethyl-enol (25-37%) when compared to female rats (5-10 %). Spirotetramat was excreted quickly with 88-
95% of the administered dose eliminated via urine and 2-11% via feces within 48 hours of

exposure.

Absorption and excretion in anim als treated one time with 1000 mg/ kg bw was less than that at the lower doses, with 27% of dose excreted in urine after 24 hours and 18% in feces. Plasma radioactivity was slightly higher than that for liver and kidne y, thereby suggesting saturation of cellular transport mechanisms at this high dose. Tissue radioactiv ity decreased from 1 hour to 24 hours post dose. The metabolism profile was qualitativ ely similar to that of the low dose studies.Similar to the low-dose studies, BYI 08330-enol was the most prominent metabolite in the highdose study. Physiologically-based pharmacokinetic (PBPK) simulations with the enol metabolite suggest that repeated daily doses ≥ 300 mg/kg bw spirotetramat l eads to non-linear elimination kinetics, possibly due to sa turation of uptake processes in the liver and kidney.

Acute toxicity : Spirotetramat technical demonstrated moderate to low acute toxicity (Toxicity Category III or IV) via the oral, dermal, and inhalation routes. Sp irotetramat is non-irritating to the skin (Toxicity Category IV), although it is an irritant to the eyes (Toxicity Category II) and exhibits a skin-sensitization potential under the conditions of the guinea pig maximization test and the local lymph node assay, but not the Buehle r patch test. The sensitization potential of spirotetramat was supported by two cases of Type IV hypersensitivity that were reported in spirotetramat manufactur ing plant personnel.

Subchronic toxicity : A summary of the prechronic and chronic toxicity and genotoxicity databases for spirotetramat is found in Appendi x A.2. The thyroid and thymus glands were target organs in oral subchroni c toxicity studies in the dog. S ubchronic (90-day) exposure of dogs to spirotetramat was character ized by statistically significant d eclines in circulating thyroid hormones (T4) at ≥ 1200 ppm (32 mg/kg bw/day); decreased T3 was observed at the highest doseSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 15 of 47 tested only (2500 ppm; 72 mg kg bw/day). Howe ver, correlative changes in thyroid weight, thyroid histopathology, or thyroid-stimulating hormone (TSH) were not observed in either sex.

In rats, the testes were the target organ follo wing subchronic oral trea tment at a high dose. Abnormal spermatozoa and hypospermia in the ep ididymis, decreased testicular weight, and testicular degeneration and vac uolation were observed in males after 90 days of exposure at 10,000 ppm (616 mg/kg bw/day). Thes e effects proved to be revers ible in most animals after
cessation of treatment. It is not eworthy that the thyroid and thym us were unaffected in rats at any dose, while testicular hist opathology was unobserved in dogs. No adverse effects of any kind were observed in mice following oral exposure . Subchronic exposure of rats by the dermal route yielded no evidence of systemic toxicity.

Long-term toxicity : The thymus and thyroid were also target organs following one-year oral exposure of dogs to spirotetramat. Thymus involution and brain dila tion with dose-related severity were observed in one male each at 600 ppm (20 mg/kg bw/day) and 1800 ppm (55 mg/kg bw/day). Brain dilation has been observe d by veterinary patholog ists in up to 5% of Beagle dog colonies and is considered a c ongenital anomaly by Bayer CropScience. Brain dilation was not observed in any other study in the dog or in any other species tested with spirotetramat. For these reasons, and since br ain dilation was also obs erved sporadically in several other Bayer dog studies with other chemicals of varying dur ations (from f our weeks up to one year), this observation was considered to be an equivocal effect and not likely treatmentrelated. Declines in circulati ng thyroid hormone (T4) were observed in males and females at

≥ 600 ppm (20 mg/kg bw/day). Reduction in folli cle size, a possible i ndication of a reduced amount of colloid in the organ, and decreased T3 levels were observed in 1800-ppm males (55 mg/kg bw/day) only. Correlative changes in thyroi d weight or TSH were not observed in either sex. No morphological changes in the test es were observed in dogs at any dose.

In rats, abnormal sperm or sperma tid degeneration in the testes and germ cell exfoliated debris in the epididymis were observed in male rats at the high dose only (7500 ppm; 414 or 373 mg/kg bw/day) following 12 (not statistic ally significant) or 24 months of oral exposure. Other target organs in rats following exposure for 2 years were the kidney (both sexes) at mid and high doses and the liver (females) at the highest dose only. These results are consistent with the excretory and/or detoxification roles of the kidney and liver . Similar kidney toxicity was also observed at higher doses (419.3 or 484.7 mg/kg bw/day) in parental animals of the F 1 generation in the 2- generation reproductive toxicity st udy in rats. No adverse findi ngs were observed in mice up to the limit dose following long-term treatment with spirotetramat.

Carcinogenicity and Genotoxicity : Treatment-related increases in tumor incidence were not observed in either sex in rats or mice. Spir otetramat was also negative for mutagenicity and clastogenicity in several standard in vivo and in vitro assays.

Developmental Toxicity : Developmental toxicity in the absence of maternal toxicity was not
observed in either the rat or rabbit. In the rat, decreased body wei ght and food consumption
were observed in dams at the limit dose in a developmental toxicity study. Developmental toxicity (reduced fetal weight a nd increased incidences of malformations and skeletal deviations)
was also observed at the limit dose. The NOAEL was established at the next lower dose (140 mg/kg bw/day) in both dams and offspring. In the rabbit, developmen tal toxicity was not observed up to the highest dose tested (160 mg/kg bw/day). However, maternal toxicity wasSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 16 of 47 observed at ≥ 40 mg/kg bw/day, including a dose-depe ndent increase in abortion and other clinical signs of systemic t oxicity in affected animals.

Reproductive Toxicity : In addition to testicular hist opathology observed following subchronic and chronic exposure of male rats to spirotetramat, evidence of male reproductive toxicity was provided in the 2-generation repr oductive toxicity study. Abnormal sperm cells were reported in

F 1 -generation male rats treated with 6000 ppm (419 mg/kg bw/day) spirotetramat in the diet, and decreased reproductive performance was also obser ved in one of these males. Similar results were obtained in the 1-generati on reproductive toxicity range-fi nding study, in which decreased sperm motility and progression and increased abnor mal sperm cells in the epididymides were
observed in F 1 males at ≥ 6000 ppm (320 mg/kg bw/day). Devel opment of the sexual organs of offspring (balano-preputial sepa ration, vaginal opening) was unaff ected in either study, and no
treatment-related effects were observed at lower doses.

In an investigative study designed to explore the time of onset of testicular toxicity in rats, decreased epididymal sperm counts were observed after 10 days or more of treatment with 1000 mg/kg bw/day by gavage. Although the data dem onstrate that the decreased sperm counts were the result of repeated dosing w ith spirotetramat, it is noted that since sperm development is a lengthy process (approximately 8 weeks in rats and 10 weeks in humans), the decreased sperm counts may have resulted from single-dose toxic ity to an immature pr ecursor that did not manifest until 10 days later . However, while plausible, th is hypothesis is unproven in the
absence of additional mechanistic data. In a se cond investigative study, ma le rats were treated by gavage with the enol metabolite of spirotetra mat for 21 days at a dose of 800 mg/kg bw/day. Spermatotoxicity, abnormal sperm, and Sertoli cell vacuolation were obs erved in the testesepididymides of treated animals. Therefore, male reproductive toxicity in ra ts is likely due to the enol metabolite of spirotetramat.

Although reproductive effects manife sted as testicular toxicity and sperm abnormalities in a 90- day rat study, in a two-generation reproductive toxicity study and in a special reproductive toxicity, the reproductive effects we re seen at very high doses. Te sticular toxicity was seen at 616 mg/kg/day and the sperm abnormalities were s een at 419 mg/kg/day in the two generation reproduction study and at 1000 mg/kg/day (Limit Dose) in the special male reproductive toxicity study.

3.2 FQPA Considerations

Consistent with the last risk assessme nt for spirotetramat (Memo, J. Tyler, et al., 14-MAY-2008; D333437), the spirotetramat risk assessment team recommends that the FQPA SF be reduced to 1X for the following reasons:

• There was no evidence of increased susceptibi lity of offspring following pre- or postnatal exposure in any study. In the rat devel opmental toxicity study, toxicity to offspring
was observed at the same dose as maternal toxi city, which was also the limit dose. In the developmental toxicity study in the rabbit, only maternal toxi city was observed. In both reproductive toxicity studies, toxicity to offspring (decreased body weight) was observed at the same dose as parental toxicity. Therefore, no eviden ce of increased susceptibility of offspring was found across four relevant toxicity studies wi th spirotetramat.

• Spirotetramat does not operate by way of a neurotoxic mechanism and there is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 17 of 47 • Although a subchronic neurotoxicit y study is now required as part of the revisions to 40 CFR Part 158, the existing toxicological databa se indicates that sp irotetramat is not a neurotoxic chemical in mammals. The only clinical signs at a ny dose in the acute neurotoxicity study were staining of the fur or perianal region with urine and decreased motor activity. The urine staining that was id entified is not cons idered a neurotoxic effect and was likely due to a colored metabolit e that was excreted into the urine or feces or to a change in the pH of the urine due to an excreted me tabolite. The decreased motor activity observed is not considered eviden ce of neurotoxicity b ecause there were no effects on movement or gait or and there were no confirmatory findings of neurological pathology. Thus, both of these effects of ar e considered signs of general toxicity (malaise). Further, the effects seen in th e acute neurotoxicity st udy are not corroborated by any other study in the database. Although brain dilation was found in one dog in the one-year dog study, EPA concluded that this effect was most likely not caused by administration of spirotetramat given eviden ce showing this to be a congenital anomaly in the test species, and because there is no other evidence of br ain pathology in the database. Finally, the conclusion that spir otetramat is not a neurotoxic chemical is supported by the fact that the acute, subchr onic and developmental neurotoxicity studies available for structurally-related compounds (spirodiclofen and spiromesifen) do not
show evidence of neurotoxi city in adults or young.

• There is no concern for neurotoxicity with sp irotetramat in the developing animal based
on the fact that brain dilation in the one -year dog study is most likely a congenital anomaly (see section 3.1.2) that was not obser ved in any other study in the database, and
the fact that the stru cturally related Bayer compounds spirodiclofen and spiromesifen are
not neurotoxic in ad ults or young animals.

• There are no residual uncertainti es identified in the exposure databases. The dietary food exposure assessments were performed based on 100% CT and tolerance-level or average field-trial residues. The submitted residue data for tropical fruit is not appropriate for the proposed use pattern as the trials were conducte d at a ~2X use rate. The Agency is thus requesting that the petitioner conduct bridging studies with lychee and guava (1 trial each with four samples per treatment regimen) in order to determine the relationship between residues resulting from the labeled use pattern and that used in the submitted field trials. Based on this relationship, the submitted residue data will be adjusted and the appropriate
tolerances determined. As the recommended tolerances are based on exaggerated-rate field trial data, it is likely that any future ad justment of these tolerances will be to a lower level. This risk assessment is thus likely to over-estimate the dietary risk from spirotetramat residues in/on tropical fruit. Us e of tolerance levels based on exaggerated application rates in a risk assessment will te nd to overstate exposure even more than the overestimate usually supplied by use of the a ssumption of tolerance-level residues.

• The dietary drinking water assessment (Tier 1 estimates) utilizes values generated by model and associated modeling parameters wh ich are designed to provide conservative, health-protective, high-end estimates of water concentrations.

• The registered and/or proposed uses of spir otetramat are not expected to result in residential exposures.

Although the toxicology database for spirotetramat shows effects in the thymus gland, an organ of the immune system, this finding does not raise uncertainty given the lack of an immunotoxicity study. The endpoint selected for risk assessment was based on accelerated thymus involution and hypothyr oid effects in the dog. Th ymus involution has beenSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 18 of 47 demonstrated to occur when hypothyroidism is induced in animals, so it is reasonable to conclude that the thymus involut ion in these dogs was secondary to the thyroid effects, rather than a direct effect on the immune system. Th e dose at which these effects were observed is
considered a LOAEL because there was some co nsistency of dose and effect seen across the subchronic and chronic toxicity st udies. However, the effects occurred in relatively few animals and thus selection of this endpointis considered a very protectiv e POD; it is at least 10-fold lower than any other potential POD. With respect to imm unotoxicity, no immunotoxic effects were seen in rats or mice, the species in which immunotoxicity studi es are conducted. Thus, HED does not believe that conducting a functiona l immunotoxicity study in any rodent species will result in a lower POD than that currently us ed for overall risk assessment. For this reason and because the current POD is considered extremely protective, a UF DB is not needed to account for the lack of this study.

3.3 Hazard Identification and Toxicity Endpoint Selection

3.3.1 Acute Reference Dose (aRfD)

The aRfD for the general populat ion, including females 13-49 years of age, was established based on the NOAEL (100 mg/kg/day) from the acute neurotoxicity study in rats. The LOAEL of 200 mg/kg/day is based on clinic al signs of toxicity in males and females and decreased motor activity in males. This study and endpoint are th e most appropriate sing le-dose effects for the general population, including women of childbeari ng age. For reasons outlined in Section 3.2, the 10X FQPA SF has been reduced to 1X.

3.3.2 Chronic Reference Dose (cRfD )

The cRfD was established based on the NOAEL (5 mg /kg/day) from the 1-y ear toxicity study in the dog. The LOAEL of 20 mg/kg/day is based on thymus involution in males. The NOAEL of 5 mg/kg is the lowest in the database. In a ddition, the study duration is appropriate for the duration of exposure. For reas ons outlined in Section 3.2, the 10X FQPA SF has been reduced to

1X.

3.3.3 Incidental Oral Exposure ( Short- and Intermediate-Term)

No residential uses are proposed for the current acti on. Therefore, an endpoi nt for incidental oral exposure was not chosen.

3.3.4 Dermal Absorption

An in vivo dermal-penetration study was performed in the rat using the OD150 formulation. Dermal absorption was estimated to be 10%, ba sed on the directly absorbed dose and compound remaining at the dose site (including stratum co rneum) 168 hours following a 10-hour exposure. Compound retained in the stratum corneum wa s included in this calculation, because radioactivity in the feces increased over the 168-hour time period, which suggested that compound measured in the stratum corneum imme diately after the 10-hour exposure continued
to be absorbed.

3.3.5 Dermal Exposure (Short- and Intermediate-Term)Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 19 of 47 There are no registered or propos ed residential uses for spirotet ramat. The oral developmental toxicity study in the rabbit was considered the most relevant st udy for short- and intermediateterm dermal occupational exposure scenarios, beca use it is protective of potential exposure to pregnant workers. Dose-dependent systemic toxicity (including body we ight loss, decreased food consumption, clinical signs of toxicity, abortion) was observed in one dam at the LOAEL of 40 mg/kg bw/day (NOAEL = 10 mg/kg bw/day). The route of exposure of th is study is not ideal for these dermal exposure scenarios; however, th e NOAEL in this study is protective of potential systemic toxicity in pregnant workers.

3.3.6 Dermal Exposure (Long-Term)

There are no registered or proposed residential uses for spirotetra mat. The 1-year toxicity study in the dog was chosen for the long-term dermal occupational exposure scenario. The LOAEL of 20 mg/kg/day is based on thymus involution in males. The NOAEL of 5 mg/kg is the lowest in the database. Although the route of exposure is not ideal, the study duration is ideal for the duration of exposure.

3.3.7 Inhalation Exposure (Short- and Intermediate-Term)

There are no registered or propos ed residential uses for spirotet ramat. The effects of concern that are relevant to the selection of the short- and intermediate-term occupational inhalation doses are dose-dependent systemic toxicity (including body weight loss, decreased food consumption, clinical signs of toxicity, abortion) observed in one dam at 40 mg/kg bw/day (NOAEL = 10 mg/kg bw/day). The route of expo sure of this study is not ideal for these inhalation exposure scenarios; however, the NOA EL in this study is protective of potential toxicity to pregnant workers.

Based on the available toxicity da tabase and the Agency's current practices, the inhalation risk for spirotetramat was assessed using an oral t oxicity study. The Agency sought expert advice and input on issues related to this route-to-route extrapolation approach (i.e., the use of oral toxicity studies for inhalation risk assessment) from its Fede ral Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scien tific Advisory Panel (SAP) in December 2009. The Agency
received the SAP’s fina l report on March 2, 2010 ( http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine and develop new policies and procedures for conducting inhalati on risk assessments, in cluding route to route extrapolation of toxicity data. If any new polic ies or procedures are developed, then the Agency may revisit the need for an inhalation toxicity study for spirotetramat and/or a re-examination of the inhalation toxicity risk assessment.

3.3.8 Inhalation Exposure (Long-Term)

There are no registered or proposed residential uses for spirotetra mat. The 1-year toxicity study in the dog was chosen for the long-term inhalatio n occupational exposure scenario. The LOAEL of 20 mg/kg/day is based on thymus involution in males. The NOAEL of 5 mg/kg is the lowest in the database. Although the route of exposure is not ideal, the study dur ation is ideal for the duration of exposure. See section 3.3.7 for a disc ussion of the use of oral toxicity studies to
assess inhalation risk.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 20 of 47 3.3.9 Level of Concern for Margins of Exposure

There are no registered or proposed residential uses for spirotetra mat. A summary of the levels of concern for occupatio nal (worker) exposure is listed in Table 3.3.9.

Table 3.3.9. Summary of LOCs for Occupati onal (Worker) Exposure Risk Assessment.

Route Short-Term (1-30 Days) Intermediate- Term (1-6 Months) Long-Term (>6 Months)

Dermal 100 100 100

Inhalation 100 100 100

3.3.10 Recommendation for Aggregat e Exposure Risk Assessments

For oral exposure, dietary and drinking water exposures were combined. For occupational exposure dermal and inhalation exposures were combined since the toxi cological effects of
concern are the same and iden tified from the same study.

3.3.11 Classification of Carcinogenic Potential

Spirotetramat was determined to be non-mutageni c in bacteria and mammalian cells, as well as non-clastogenic in in vivo mammalian assays. No evidence of carcinogenicity was observed in carcinogenicity studies in the rat and mouse. Based on thes e results, RAB1 toxicologists classified spirotetramat as “Not Like ly to be Carcinogenic to Humans.”

3.3.12 Summary of Toxicological Doses and En dpoints for Spirotetramat for Use in
Human-Health Risk Assessments

Summaries of the toxicological doses and endpoi nts for spirotetramat for use in dietary/nonoccupational risk assessments and occupational risk assessment are listed below in Tables 3.3.12a and 3.3.12b, respectively.

Table 3.3.12a. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Dietary HumanHealth Risk Assessments.

Exposure Scenario Point of Departure 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

UF FQPA = 1X aRfD = aPAD = 1.0 mg/kg/day Acute neurotoxicity (rat; gavage) LOAEL = 200 mg/kg based on clinical signs (M&F) and decreased motor activity (M). Chronic Dietary (All Populations) NOAEL = 5 mg/kg/day UF A = 10X

UF H = 10X

UF F Q PA = 1X cRfD = cPAD = 0.05 mg/kg/day 1 Chronic toxicity (dog; dietary) LOAEL = 20 mg/kg/day (M) based on thymus involution. Cancer (Oral, Dermal, Inhalation) Classification: “Not Likely to be Carcinoge nic to Humans” based on lack of evidence of carcinogenicity in two oral ro dent carcinogenicity studies.
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), UF FQPA = FQPA Safety Factor, NOAEL = no-observe d adverse-effect level, LOAEL = lowestobserved adverse-effect level, RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, LOC = level of co ncern.

1 The cRfD has been harmonized across American (USEPA), Canadian (PMRA), and Austrian (AGES) regulatory agencies. However, it i s noted that USEPA considered a NOAEL = 6 mg/kg/da y in males and a NOAEL = 19 mg/kg/day in fe males to more accurately reflect the toxic ological data. The difference between 5 mg/kg/day (N OAEL in females for PMRA and AGES) and 6 mg /kg/day was considered negligible for ri sk

assessment.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 21 of 47 Table 3.3.12b. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Occupational
Human-Health Risk Assessments.
Exposure
Scenario Point of Departure Uncertainty Factors LOC for Risk Assessment Study and Toxicological
Effects

Dermal
Short- and
IntermediateTerm (1-30 days and 1-6 months) NOAEL = 10 mg/kg/day

Dermalabsorption
factor = 10% UF A = 10X

UF H = 10X Occupational LOC for MOE

<100 Prenatal developmental toxicity (rabbit) Maternal LOAEL = 40 mg/kg/day based on late abortion ( ≥ GD 22), clinical signs, impaired food and water consumption, and body weight loss.

Dermal Long-Term (>6 months) NOAEL = 5 mg/kg/day

Dermalabsorption
factor = 10% UF A = 10X

UF H = 10X Occupational LOC for MOE

<100 Chronic toxicity (dog; dietary) LOAEL = 20 mg/kg/day (M) based on thymus involution.

Inhalation
Short- and
IntermediateTerm (1-30 days and 1-6 months) NOAEL = 10 mg/kg/day

100%
inhalation
assumed UF A = 10X

UF H = 10X Occupational LOC for MOE

<100 Prenatal developmental toxicity (rabbit) Maternal LOAEL = 40 mg/kg/day based on late abortion ( ≥ GD 22), clinical signs, impaired food and water consumption and body weight loss.

Inhalation Long-Term (>6 months) NOAEL = 5 mg/kg/day

100%
inhalation
assumed UF A = 10X

UF H = 10X Occupational LOC for MOE

<100 Chronic toxicity (dog; dietary) LOAEL = 20 mg/kg/day (M) based on thymus involution.

Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans based on lack of evidence of carcinogenicity in two oral rodent carcinogenicity studies.

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), UF FQPA = FQPA Safety Factor, NOAEL = no-observe d adverse-effect level, LOAEL = lowestobserved adverse-effect level, RfD = reference dose (a = acute, c = chronic), MOE = margin of exposure, LOC = level of concern.

3.4 Endocrine Disruption

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered ap proach to making the statutorily required
determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients.
This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.
This list should not be construed as a lis t of known or likely e ndocrine disruptors.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 22 of 47 Spirotetramat is not among the group of 58 pesticid e active ingredients on th e initial list to be
screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/.

4.0 Public Health and Pesticide Epidemiology Data

Literature searches performed by the registra nt did not yield any epidemiology data for spirotetramat. Two cases of Type IV hypersen sitivity (facial) were reported and confirmed by patch testing in spirotetramat manu facturing plant personnel in 2004.

5.0 Dietary Exposure/Risk Characterization

The residue chemistry data submitted in support of the proposed uses were summarized in the pending HED memorandum by G. Kramer (D3 62952). The drinking water assessment was provided by EFED in a memo dated 22-JAN-2008 (J. Meléndez; D345275). New drinking water
numbers were not calculated for the new uses of spirotetramat because the new use rates are similar to or lower than the previously a ssessed use rates in the 22-JAN-2008 EFED memo. The acute and chronic dietary exposure assessments were completed in a HED memorandum by J. Van Alstine (22-DEC-2010; D368786).

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops

The submitted metabolism data for apple, lettuce, cotton, and potato are adequate to elucidate the nature of the residue in plants. Major metabolic reaction involved the hydrolytic cleavage of the carbonate ester parent bo nd of the parent compound to form BYI 08330-enol. Further reduction of the double bond in the tetramic acid moiety of BYI 08330-enol occurred to form the BYI 08330-mono-hydroxy metabolite. Hydroxylation in th e tetramic acid moiety resulted in BYI 08330-ketohydroxy. Demethylation of the methoxy group of the cyclohexyl ring resulted via a proposed intermediate (BYI 08330-desmethyl-e nol) in BYI 08330-desmethyl-ketohydroxy (after the corresponding hydroxylation). Oxidati on of the methoxy group resulted in BYI 08330- ketohydroxy-formiate. Partly, metabolites bearing a hydroxy group we re conjugated with glucose.

5.1.2 Metabolism in Rotational Crops

It appears that two major metabo lic routes in rotational crops st art with the soil metabolites BYI 08330-ketohydroxy and BYI 08330-enol. The first metabolic route proceeds by demethylation of the cyclohexyl ring or hydroxylation of one methyl group of the xylol ring. Another
metabolic route starts with the addition of wa ter to the tetramic ac id ring of BYI 08330-enol resulting in the formation of BYI 08330-di- hydroxy, followed by the demethylation of the metabolite. Additionally, hydroxylation of one methyl group of the xylol ring of BYI 08330- enol followed by demethylation of the cycl ohexyl ring results in BYI 08330-desmethyl-enol-Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 23 of 47 alcohol, which was detected in all matrices. Mo st of the metabolites were rapidly conjugated. Glucosides and/or glucosyl malonic acid conjugates were detected for BYI 08330-enol, BYI 08330-desmethyl-di-hydroxy, BYI 08330-desmet hyl-ketohydroxy and BYI 08330-ketohydroxyalcohol. The percentage of conjugates increased from the 30-day to the 260-day rotation.

5.1.3 Metabolism in Livestock

The submitted goat and poultry metabolism data are ad equate to satisfy data requirements. The degradation of spirotetramat in livestock can be characterized as cleavage of the carbonate ester group to the primary metabolite BYI 08330-enol followed by conjugation of the enol hydroxy group with glucuronic acid to BYI 08330-enol-GA. Oxidation of the azaspirodecenyl moiety to BYI 08330-ketohydroxy and demethylation of the methoxy group to BYI 08330-desmethyl-enol were minor metabolic reactions in ruminants as well as reduction of the azaspirodecenyl moiety to BYI 08330-monohydroxy.

5.1.4 Analytical Methodology

The petitioner has submitted several HPLC-MS/ MS residue analytical methods for the determination of residues of the parent and its metabolites in/on plant and livestock commodities. Analytical method 00857 was devel oped for the determination of residues of spirotetramat, the metabolites BYI 08330-enol, BYI 08330-ket ohydroxy, BYI 08330-mono-hydroxy, and BYI 08330-enol-Glc in plant matrices by HPLC-MS/ MS. Analytical method 00966 was developed
for the determination of residue s of spirotetramat and the me tabolites BYI 08330-enol and BYI08330-enol-GA in livestock matrices by HPLC-MS/MS. These methods were used as the datacollection methods in the analysis of samples fo r residues of concern from the various studies associated with the current petition. Each method has been adequately validated by the petitioner as well as by inde pendent laboratories. Met hods 00857 and 00966 were also adequately radiovalidated using weathered samples obtained from metabolism studies.

HED has determined that Methods 00857 and 00966 are suitable enforcement methods for plant and livestock commodities, respectively, since the methods passed a successful PMV by Agency chemists at ACL/BEAD (E-mail, C. Stafford to D. Vogel; 2/19/08).

Spirotetramat and five metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-monohydroxy, BYI 08330-enol-Glc, and BYI 08330-enol- GA were screened through multiresidue methods (MRMs) described in the U.S. F ood and Drug Administration (FDA) Pesticide Analytical Manual, Vol. I (PAM I). The MRMs are not suitable for the anal ysis of spirotetramat or its metabolites. The MRM testing data were forwarded to the FDA for further evaluation and
inclusion of results in PAM Vol. I.

5.1.5 Environmental Degradation

The hydrolysis of spirotetramat is pH and temperat ure dependent. The rate of reaction increased with increasing pH. At 25°C, the experimental half-lives for the chemical were 32.5, 8.6, and 0.32 days at pHs of 4, 7, and 9, respectively. In addition, hydrolysis rates increased with increasing temperature. The ma jor hydrolysate is BYI 08330-enol, wh ich appeared to be stable to hydrolysis. Spirotetramat photolyzes with hydrolysis-corrected DT50’s of 3.0 and 0.22 days, in sterile buffer (pH 5) solution and natural water (pH 7.9), respectively. These half-lives correspond to 14.4 and 0.74 days, respectively, under environmental conditions (summer light inSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 24 of 47 Phoenix, AZ). In sterilized natural water, the major products observed were BYI 08330-enol (81.9% at 1 day), methoxycyclohexanone (17.5% at 8 days) and me thoxy-cyclohexylamino carboxylic acid (11.3 % at 10 days). In sterile buffer solution (p H 5), four major photoproducts (at up to 42.9%) are the resu lt of rearrangement of the parent. Definite conclusions on the rate of soil photodegradation could not be derived fr om the available study. However, useful information on the identity of the degradates in the study may be obtained from it. The following degradates were identified only in th e irradiated samples: methoxycyclohexanone and dimethyl-benzoic acid.

Spirotetramat degraded quickly, with DT50s of <1 day in four aerobic soils. Furthermore, spirotetramat-enol also degraded relatively quick ly, with calculated DT50s of <1 day, in four aerobic soils. DT50s for BYI 08330-ketohydroxy (a t a maximum of 24.0% of the applied, range of DT50s 1.5-16.7 days) and spirotetramat-amid e (maximum 5.2% of the applied, range of DT50’s 0.03-5.4 days) were derived from th e study conducted on BYI 08330-enol. Carbon dioxide formation was 9.7-19.4% by 50 days in the study conducted with spirotetramat and 10.9- 34.9 by 60 days in the study conducted with BYI 08330- enol. Volatiles were insignificant while non-extractable residues were important (bot h cases). In an outdoor metabolism study, spirotetramat degraded with calculated DT50s of 1.2 and 2.9 days. BYI 08330-enol was a maximum of 7.8%. The degradates spirotetrama t-glyoxylic amide and dimethyl-benzoic acid
were observed besides the aerobic soil metabolite s observed in the laboratory. The latter two compounds were also observed in the marginal ly supplemental soil photodegradation studies.

In aquatic environments, under aerobic aquatic conditions, spirotetramat degraded with calculated half-lives (DT50s) of 0.7 and 0.9 days in the total system. Spirotetramat was initially mostly associated with the aqueous phase. The metabolite BYI 08330-enol reached a maximum at 14 days at 99.0%, and decrease d to less than the limit of quant itation (<LOQ) to 21.0% at 120 days. The degradate BYI 08330-ketohydroxy was a maximum of 50.8% at study termination. It appeared to be relatively stable in the aer obic aquatic system. Non-extractable residues increased throughout the study to a maximum of 33.9% at 120 days. Mineralization was a maximum of 13.5-24.0% at 120 days.

In the anaerobic soil metabolism study, the metabo lites observed were consistent with the ones for the aerobic soil metabolism studies for sp irotetramat and BYI 08330-enol. Under anaerobic soil conditions, spirotetramat di ssipated quickly with a calculated half-life of <<1 day. The major degradates were BYI 08330-enol, which increased throughout the study (maximum 54.6% at 180 days) and BYI 08330-ketohydroxy (maximum 19.3% at 1 day). Mineralization was very
low. Non-extractable residues were a maximum of 17.5% at 0.6 days. In an anaerobic aquatic metabolism system, spirotetramat completely degraded to BYI 08330-enol, which was found to be stable thereafter. The half-life (DT50) for the transformation of spir otetramat was calculated to be 2.8 days in the total anaerobic system.

5.1.6 Comparative Metabolic Profile

Spirotetramat was completely metabolized by the rat; no parent compound was detected in the
excreta. Identified metabolites accounted for 87-95% of the administered dose. Only very minor metabolites (<0.7% of the dose) were not identif ied. The main metabolic reaction was cleavage of the ester group which resulted in the form ation of the primary and most predominant metabolite BYI 08330-enol (53-87% of the administer ed dose). All other identified metabolites
could be derived from the enol intermediate. The second prominent metabolic transformationSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 25 of 47 was oxidative demethylation of the 8-met hoxy group to BYI 08330-desmethyl-enol (5-37% of the administered dose). Oxidation of the azaspiro moiety to BYI 08330-ketohydroxy and BYI 08330-desmethyl-ketohydroxy were detected as minor pathways. Other minor metabolic transformations were conjugation of the enol with glucuronic acid to BYI 08330-enol-GA and oxidation of the aromatic methyl group of the enol metabolit e to BYI 08330-enol-alcohol. A
sex-related difference was observed in metabolism with male rats showin g much higher rates of demethylation to BYI 08330-desmethyl-e nol compared to female rats.

The metabolism of spirotetramat in plants and liv estock appears to be similar to its metabolism in rats. The primary metabolic pa thway in animals (rats, goats, and hens) and plants involves the hydrolytic cleavage of the carbona te ester parent bond of the parent compound to form BYI
08330-enol. All other identified metabolites ar e derived from the enol intermediate. Hydroxylation in the tetramic acid moiety of BYI 08330-enol resulted in BYI 08330- ketohydroxy (animals and plants ) and oxidative demethylation of the 8-methoxy group to BYI 08330-desmethyl-enol (animals and plants). Furt her reduction of the double bond in the teramic acid moiety of BYI 08330-enol occurred to form the BYI 08330-mono-hydroxy metabolite (ruminants and plants). Conjugation of BYI 083 30-enol was also a significant pathway in both plants and animals. Minor pathways include hyd roxylation of one methyl group of the xylol ring of BYI 08330-enol followed by demethylation of the cyclohexyl ring resulting in BYI 08330- desmethyl-enol-alcohol (rotational crops), oxi dation of the methoxy group of BYI 08330- ketohydroxy resulted in BYI 08330- ketohydroxy-formiate (plants), co njugation with glucose of
various metabolites beari ng a hydroxy group (plants).

5.1.7 Toxicity Profile of Major Metabolites and Degradates

Limited information is available on the toxicity of the major spirotetramat metabolites (BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol -Glc/GA, and BYI 08330-mono-hydroxy). However, based on the structural similarity of the parent and these metabolites, and in the absence of toxicological evidence to the contrary, they are assumed to be of comparable toxicity to the parent.

5.1.8 Pesticide Metabolites and Degradates of Concern

Table 5.1.8. Summary of Metabolites and Degradates to be included in Risk Assessment and Tolerance Expression.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression for Compliance Monitoring

Plants Primary Crop Spirotetramat, BYI 08330-enol, BYI 08330- ketohydroxy, BYI08330-enol-Glc, and BYI 08330- mono-hydroxy Spirotetramat, BYI 08330-enol, BYI 08330- ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy

Rotational Crop Not Applicable 1 Not Applicable 1

Livestock (Ruminant and Poultry) Spirotetramat, BYI 08330-enol, and BYI 08330-enolGA 2 Spirotetramat and BYI 08330-enol 2

Drinking Water Spirotetramat, BYI 08330-enol, and BYI 08330- ketohydroxy Not ApplicableSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 26 of 47 1 The following potential residues of con cern were identified in the confined rotational crop study: Spirotetramat, BYI 08330- ketohydroxy and free and conjugated BYI 08330-desmethyl-ke tohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330- ketohydroxy-alcohol. None of these residues were found in the limited rotational crop field tria ls at a 30-day PBI. Provided a 30-day PBI is specified on the spirotetramat labels, residues in rotational crops are not currently of concern for the risk assessment or for tolerance setting.

2 If future proposed uses result in significant exposure of li vestock to the plant metabolites BYI 08330-ketohydroxy, BYI08330-e nol-Glc, and BYI 08330-mono-hydroxy, then these metabolites may need to be included as additional residues of concern for livestock
commodities.

Plants (Primary Crops): The residues of concern for bot h tolerance and ri sk assessment purposes are spirotetramat and its me tabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy (Memo, J. Tyler, et al. , 14-MAY-2008; D333437). This decision was based on the following:

• BYI 08330-enol was a major metabolite in appl e leaves, lettuce, cotton gin trash and seed, and in rat tissues and excr eta. Based on the structural similarity to the parent, BYI 08330-enol is assumed to be of comp arable toxicity to the parent.

• BYI 08330-ketohydroxy was a major metabolite in cotton gin trash and lint and potato tops. Also, in the cauliflower field tria ls, BYI 08330-ketohydroxy (0.32 ppm) accounted for >80% of the total spirotetramat residue in some samples. Based on the structural similarity to the parent, BY I 08330-ketohydroxy is assumed to be of comparable toxicity to the parent.

• BYI08330-enol-Glc was a major metabolite in lettuce. Also, in the hop field trials, BYI08330-enol-Glc (0.79 ppm) accounted for ~20% of the total spirotetramat residue in some samples. Based on the structural si milarity to the parent, BYI08330-enol-Glc is assumed to be of comparable toxicity to the parent.

• BYI 08330-mono-hydroxy was a major metabolite in apple fruit. Also, in the plum field trials, BYI 08330-mono-hydroxy (0.18 ppm) accounted for >50% of the total spirotetramat residue in some samples. Base d on the structural similarity to the parent, BYI 08330-mono-hydroxy is assumed to be of comparable toxicity to the parent.

• The data-collection method, Method 00857, is a HPLC-MS/MS method for residues of spirotetramat, BYI 08330-enol, BYI 08330- ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy in crop matrices. The anal ytes are all determined in a single chromatographic analysis. All samples in the cr op residue trials were analyzed with this
method.

Plants (Rotational Crops): The residues of concern are spir otetramat and its metabolites BYI 08330-ketohydroxy and free and conjugate d BYI 08330-desmethyl-ketohydroxy, BYI 08330- desmethyl-di-hydroxy, and BYI 08330-ket ohydroxy-alcohol (Memo, J. Tyler, et al. , 14-MAY2008; D333437). This decision wa s based on the following:

• BYI 08330-ketohydroxy was a major metabolite in wheat forage, chard, and turnip roots. Based on the structural similarity to the parent, BYI 08330-ketohydroxy is assumed to be of comparable toxicity to the parent.

• BYI 08330-desmethyl-ketohydroxy (conjugated) was a major metabolite in wheat forage, hay, and straw, and chard. Based on the stru ctural similarity to the parent, BYI 08330- desmethyl-ketohydroxy is assumed to be of comparable toxicity to the parent.

• BYI 08330-desmethyl-di-hydroxy (conjugated) was a major metabolite in wheat straw, forage, and hay. Based on the structural si milarity to the parent, BYI 08330-desmethyldi-hydroxy is assumed to be of comp arable toxicity to the parent.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 27 of 47 • BYI 08330-ketohydroxy-alcohol (conjugated) was a major metabolite in wheat straw, hay, and grain, chard, and turnip leaves. Based on the structural similarity to the parent, BYI 08330-ketohydroxy-alcohol is a ssumed to be of comparable toxicity to the parent.

• The data-collection method, Method 00929, is a HPLC-MS/MS method for residues of spirotetramat, BYI 08330-ketohydroxy and free and conjugated BYI 08330-desmethylketohydroxy, BYI 08330-desmethyl-di-hydroxy, and BYI 08330-ketohydroxy-alcohol in crop matrices. The analytes are all determined in a single chromatogr aphic analysis. All samples in the limited field rotational crop resi due trials were analy zed with this method.

Livestock: The residues of concern for the tolerance expression fo r livestock commodities are spirotetramat and its metabolite BYI 08330-enol and the residues of concern for the risk assessment for livestock commodities are spirot etramat and its metabolites BYI 08330-enol and BYI 08330-enol-GA (Memo, J. Tyler, et al. , 14-MAY-2008; D333437). This decision was based on the following:

• BYI 08330-enol was a major metabolite in all ruminant commodities and in rat tissues
and excreta. Based on the structural simila rity to the parent, BYI 08330-enol is assumed to be of comparable toxicity to the parent.

• BYI 08330-enol-GA was a major metabolite in ruminant fat, liver , kidney, milk, and poultry liver. Based on the structural sim ilarity to the parent, BYI 08330-enol-GA is assumed to be of comparable toxicity to th e parent. However, as the low dietary burden associated with the currently proposed uses is expected to resu lt in non-quantifiable
residues and BYI 08330-enol can serve as a marker for potential misuse, BYI 08330-
enol-GA does not need to be incl uded in the tolerance expression.

• If future proposed uses result in significant exposure of lives tock to the plant metabolites BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, then these metabolites may need to be included as additional residues of concern for livestock
commodities.

Drinking Water: The residues of concern in drinking wa ter for risk assessment purposes are spirotetramat, BYI 08330-enol, and BY I 08330-ketohydroxy (Memo, J. Tyler, et al. , 14-MAY2008; D333437). BYI 08330-enol and BYI 08330-ket ohydroxy were the major metabolites in
the aerobic soil outdoor metabolism studies. BYI 08330-MA-amide was excluded as a residue
of concern since it was never found at a level of >10% of the total residue.

5.1.9 Drinking Water Residue Profile

All the following appear to be important routes of degradation/transfor mation for spirotetramat: hydrolysis in basic media, photolysis in sterile natural water, and biodegr adation in aerobic and anaerobic environments (DT50s range <1-2.8 days). Hydrolysis in neutral and acidic environments and photolysis in sterile buffered solution (half-lives 8.6-32.5 days) appear to be
routes of transformation of rela tively low importance for spirotetramat. Spirotetramat degrades to BYI 08330-enol (product of cleavage of the este r link), which also degrades relatively rapidly in aerobic environments and under photolytic conditions, and subsequently forms numerous degradates most of which have th e basic backbone struct ure of spirotetramat. It appears that the
metabolites BYI 08330-enol and BYI 08330-ket ohydroxy are of high concern in soils, sediments, and water. The parent spirotetrama t appears to be labile in most environments (particularly in aerobic media). Total re sidues (spirotetramat + BYI 08330-enol + BYI 08330- ketohydroxy) have a potential to contaminate surface waters for a period of weeks to monthsSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 28 of 47 post-treatment, and a potential to move subsurfa ce and contaminate groundw ater. There is also the chance that spirotetramat woul d be deposited off-target by sp ray drift [the chemical may be applied by ground (groundboom and airblast) and aerial methods]. In addition, given the relatively high solubility of BYI 08330-enol and BYI 08330-ke tohydroxy and their relatively low level of binding, these partic ular transformation products coul d be released via plant washoff to soils in large rain events, especially if th ey occur shortly after app lication. It appears that the residues could reach adjacent bodies of wate r in runoff events both via dissolution or bound to the soils (high levels of bound residue were observed in most laboratory studies).

Drinking water monitoring data are not availabl e for spirotetramat. The effects of water treatment on the pesticide and de gradates is uncertain. Spirot etramat and its metabolites, BYI 08330-enol, BYI 08330-ketohydroxy, and BYI 08330- MA-amide, were highly mobile to moderately mobile, and low levels of binding ar e expected. It appear s that spirotetramat metabolites BYI 08330-ketohydroxy and BYI 08330-MA -amide are of higher concern because the parent degrades relatively fast in most environments.

EFED provided Tier 1 ground and surface wate r EDWCs for spirotetramat and its major transformation products spirotetramat-enol and spirotetramat-ketohydroxy (D345275, J. Meléndez, 22-JAN-2008). New drinking water number s were not calculated for the new uses of spirotetramat because the new use rates are simila r to or lower than the previously assessed use
rates in the 22-JAN-2008 EFED memo. The ground and surface water EDWCs were generated using SCI-GROW and FIRST, respectively, and were based on the highest application rates. The ground water EDWCs are based on the use of sp irotetramat on pome fru it (0.4 lb ai/A/year);
and the surface water EDWCs are based on the use of spirotetramat on Christmas trees (0.32 lb ai/A/year). The total surface water EDWCs (s pirotetramat and transformation products of concern) are 0.212 ppb (acute) and 1.37x10 -3 ppb (chronic). The acute and chronic groundwater
EDWC is 3.96x10 -4 ppb. Table 5.1.9 lists the summary of estimated ground and surface water EDWCs for spirotetramat.

Table 5.1.9. Summary of Surface Water and Groundwater EDWCs fo r Spirotetramat.

Drinking Water Source (Model) Type of
Risk EDWC (ppb)

Spirotetramat Spirotetramatenol Spirotetramat - ketohydroxy Maximum Total
Residues 3

Ground-water (SCI-GROW) 1 Acute and
Chronic 2.25x10 -5 1.64x10 -5 3.57x10 -4 3.96x10 -4

Surface Water (FIRST) 2 Acute 0.208 8.0x10 -5 3.60x10 -3 0.212

Chronic 1.1x10 -3 1.7x10 -5 2.50x10 -4 1.37x10 -3

1 From the SCI-GROW model. Input parameters are based on application to pome fruit at a rate of 0.4 lb ai/A/year.

2 From the Tier 1 FIRST model. Input parameters are based on application to Christmas trees at a rate of 0.32 lb ai/A/year.

3 Total residues = spirotetramat + spirotetramat-enol + spirotetramat-ketohydroxy.

5.1.10 Food Residue Profile

The submitted magnitude of the residue data fo r the raw agricultural commodities (RACs) of cotton and legume vegetables including soyb ean (crop groups 6 and 7a) will support the proposed use patterns. There are adequate st orage stability data to validate the storage conditions and intervals of samples collected from the field trials. The submitted residue data for tropical fruit will not support the proposed use pa ttern as the trials were conducted at a ~2X use rate. HED thus requests that the petitioner condu ct bridging studies with lychee and guava (1Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 29 of 47 trial each with four samples per treatment regimen) in orde r to determine the relationship between residues resulting from the labeled use pattern and that used in the submitted field trials.
Field trial data are also required for sugar apple (the repr esentative crop for atemoya, custard apple, cherimoya, ilama, soursop, and birida). As these data have not been submitted, the spirotetramat labels should be revised to dele te instructions for use on sugar apple, atemoya, custard apple, cherimoya, ilama, soursop, and birida.

Acceptable cotton and soybean proc essing studies are available. The processing studies show that following processing of RAC samples bear ing quantifiable residues, total residues of spirotetramat and its metabolites concentrated in cotton meal (1.2X) and hulls (1.1X) and soybean AGF (4.1X) and meal (1.4X).

An adequate dairy cow feeding study has been submitted; this study is acceptable for determining tolerance levels for livestock co mmodities. Based on the submitted data, HED has concluded that the tolerances, expressed as sp irotetramat and its metabolite BYI 08330-enol, are required for some livestock commodities. The required tolerances for residues in eggs and poultry meat byproducts are based on the hen metabolism study. A poultry feeding study will not be required to support the currently proposed new uses due to the do se level (1 ppm, 0.8X) and the duration (14 days) of the hen metabolism study. However, the petitioner is advised that any significant in7crease in the poultry dietary burden may trigger the requirement for a poultry feeding study.

The Agency’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized for determining appropriate toleranc e levels listed in Appendix B.

5.1.11 International Residue Limits

There are no Codex, Canadian, or Mexican MRLs established for residues of spirotetramat and its metabolites in cotton, legume vegetables in cluding soybean (crop groups 6 and 7a), and tropical fruit.

5.2 Dietary Exposure and Risk

Spirotetramat acute and chronic dietary expos ure assessments were conducted using DEEMFCID TM , Version 2.03, which incorporates consump tion data from USDA’s CSFII, 1994-1996
and 1998. The 1994-96 and 1998 data are based on th e reported consumption of more than 20,000 individuals over two non-consecutive survey days. Foods “as consumed” (e.g., apple pie) are linked to EPA-defined food commodities (e.g., a pples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) using p ublicly available recipe translation files developed jointly by USDA /ARS and EPA. For chronic exposure assessment, consumption data are averaged for the entire U.S. populati on and within population subgroups, but for acute exposure assessment are retained as individual co nsumption events. Based on analysis of the 1994-96 and 1998 CSFII consumption data, which took into account dietary patterns and survey respondents, HED concluded that it is most appropriate to re port risk for the following population subgroups: the general U.S. population, all infants (< 1 year old), children 1-2, children 3-5, children 6-12, yout h 13-19, adults 20-49, females 13-49, and adults 50+ years old.

For chronic dietary exposure assessment, an esti mate of the residue level in each food or foodform (e.g., orange or orange juice) on the f ood commodity residue list is multiplied by theSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 30 of 47 average daily consumption estimate for that food/f ood form to produce a residue intake estimate. The resulting residue intake estimate for each f ood/food form is summed w ith the residue intake
estimates for all other food/food forms on the comm odity residue list to arrive at the total average estimated exposure. Exposure is expres sed in mg/kg body weight/day and as a percent of the cPAD. This procedure is performed for each population subgroup.

For acute exposure assessments, individual one-d ay food consumption data are used on an individual-by-individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic exposure assessment, or “matched” in multiple random pairings with residue values and then summed in a probabilistic assessment. The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user (i.e., only those who reported eating relevant commodities/food forms) and a per-capita (i.e., those who reporte d eating the relevant commodities as well as those who did not) basi s. In accordance with HED policy, per capita exposure and risk are reported for all tiers of analysis. However, for Tiers 1 and 2, any significant differences in user vs. per capita exposure and risk are specifically identified and
noted in the risk assessment.

HED’s LOC is when the exposure is greater th an 100% of the PAD. That is, estimated exposures above this level are of concern, while estimated exposures at or below this level are
not of concern. The DEEM-FCID TM analysis estimates the di etary exposure of the U.S. population and 26 population subgroups. The results reported in Table 5.2 are for the U.S. population, all infants (<1 year old), childre n 1-2, children 3-5, children 6-12, youth 13-19, females 13-49, males 20-49, and adults 50+ years.

5.2.1 Acute Dietary Exposure/Risk

The acute analysis assumed 100% CT and toleran ce-level residues for all foods. Empirical and

DEEM TM (ver. 7.81) default processing factors were used for processed commodities. Drinking water was incorporated directly in the dietary assessment using the acute concentration for surface water generated by the FIRST model. The re sults of this assessment indicate that the acute dietary exposure estimates (95 th percentile) are not of co ncern to HED (<100% of the aPAD) for the general U.S. population (4.8% of the aPAD) and all othe r populations subgroups. The most highly exposed population subgroup is ch ildren 1-2 years old at 11% of the aPAD.

5.2.2 Chronic Dietary Exposure/Risk

A conservative chronic dietary assessment assumi ng average field-trial residues, empirical and

DEEM TM (ver. 7.81) default processing factors, and 100% CT was also conducted. Drinking water was incorporated directly into the dietar y assessment using the chronic concentration for surface water generated by the FIRST model. The results of the assessmen t conclude that the chronic dietary exposure estimates are below HE D’s LOC (<100% of the cPAD) for the general U.S. population (34% of the cPAD) and all popu lation subgroups. The most highly exposed population subgroup is children 1-2 year s old at 93% of the cPAD.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 31 of 47 Table 5.2. Summary of Dietary (Food and Drinking Water) Exposure Risk for Spirotetramat. 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 0.048149 4.8 0.017143 34 All Infants (<1 year old) 0.092334 9.2 0.028378 57 Children 1-2 years old 0.112462 11 0.046603 93 Children 3-5 years old 0.090437 9.0 0.036756 74 Children 6-12 years old 0.056308 5.6 0.022814 46 Youth 13-19 years old 0.039450 3.9 0.014810 30 Adults 20-49 years old 0.037239 3.7 0.013886 28 Adults 50+ years old 0.036246 3.6 0.013593 27 Females 13-49 years old 0.037049 3.7 0.013754 28

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

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

As there are currently no register ed or proposed residential uses for spirotetramat, a residential exposure assessment was not conducted.

6.1 Spray Drift

Spray drift is always a potential source of expos ure to residents nearby to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be a potential source of exposure from the ground ap plication method employed for spirotetramat. The Agency has been working with the Spray Dr ift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and ot her parties to develop the best spray drift management practices. The Agen cy is now requiring interim mitigation measures for aerial applications that must be placed on product la bels/labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is de veloping a policy on how to appr opriately apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides app lied by air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift and risks associated with aerial as well as other applic ation types where appropriate.

7.0 Aggregate Risk Assessment s and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, a nd 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 th e risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED consider s 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), and chro nic aggregate exposure (food and drinking water). Short- and intermediate-term assessments , which are used to evaluate aggregate dietary and residential exposures, were not performed because there are no registeredSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 32 of 47 or proposed residential non-food uses. Spirotetramat is classi fied as “Not Likely to be Carcinogenic to Humans;” therefore, cancer aggr egate risk assessments were not performed.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment takes in to 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 95 th exposure percentile for the general U.S. population and all other population subgroups (see Table 5.2). The dietary exposure assessment was a screening-level assessment, utilizing tole rance-level residues and 100% CT information for all proposed agricultural uses and a Tier 1 acute surface water EDWCs generated by FIRST. Therefore, the acute aggregate risk associated wi th the proposed uses of spirotetramat is not of concern to HED for the general U.S. population or any population subgroups.

7.2 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of spirotetramat (food and drinking water). The ch ronic dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups (see Table 5.2). The diet ary exposure assessment was a conservative assessment, utilizing average field-trial resi dues and 100% CT information for all proposed agricultural uses and a Tier 1 chronic surface wa ter EDWCs generated by FIRST. Therefore, the chronic aggregate risk associated with the proposed uses of spirotetramat is not of concern to HED for the general U.S. populat ion or any population subgroups.

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has fo llowed 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 sp irotetramat 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 th e cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and proc edures for cumulating effects from substances found to have
a common mechanism on EPA’s website at http://www.epa.gov/pestic ides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

An occupational exposure assessment was pr ovided in a HED memorandum dated 12-NOV2009 (K. Lowe; D368787). It is anticipated that there will be occupa tional handler and postapplication exposure from the proposed uses of spirotetramat. Based on label information, exposure is expected to occur for sh ort- and intermediate-term durations.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 33 of 47 9.1 Short- and Intermediate-Term Handler Risk

The scenarios assessed for occupational handler s include mixing/loadi ng liquids for aerial, chemigation, airblast and groundboom applications, applying spra ys via aerial, airblast and groundboom equipment, and flagging for aerial applications.

As no chemical-specific data were available with which to assess potential exposure of spirotetramat to pesticide handl ers, the estimates of exposure to pesticide handlers are based upon surrogate study data available in the PHED Surrogate Exposure Guide (August 1998). For pesticide handlers, HED presents estimates of dermal exposure for “baseline” (i.e., workers wearing a single layer of work clothing consisting of a long-sleeved shirt, long pants, shoes plus socks, and no protective gloves), as well as fo r “baseline” and the use of protective gloves or other PPE, as might be necessary. The spirotetra mat product labels direct applicators and other handlers to wear a long-sleeved shirt, long pants, protective ey ewear, chemical-resistant gloves, and shoes plus socks.

Handler exposure is expected to be short- or intermediate-ter m based on information provided on proposed labels. In addition, the short- and in termediate-term toxicological endpoints are the same; therefore, the estimates of risk for short- term duration exposures ar e protective of those for intermediate-term duration exposures. Long-term exposures are not expect ed, therefore, a longterm assessment was not conducted.

Table 9.1 presents the short- a nd intermediate-term estimated ri sks for occupational handlers.
HED has determined that risks are not of c oncern (i.e., MOEs >100), provided workers wear protective gloves as recomme nded on the label.Spirotetramat Human-Health Risk Assessment DP#: 368785___________________________________________________________________________________________________________________________________________________________________________________________Page 34 of 47Table 9.1. Short- and Intermediate-Term Occupational Handler Exposure and Risk for Spirotetramat.ExposureScenarioCropAppRatea(lb ai/A)AcresTreatedDailybUnit ExposurecDose (mg/kg/day)MOEsBaselineDermald(mg/lbai)PPE-GDermale(mg/lb ai)BaselineInhalationf(μg/lb ai)BaselineDermalgPPE-GDermalgBaselineInhalationhBaselineDermaliPPE-GDermaliBaselineInhalationjCombinedBaselineDermal +InhalationkCombinedPPE-G +BaselineInhalationlMixer/LoaderMixing/Loading Liquids forAerialApplicationsCotton,soybeans0.078 1200 2.9 0.023 1.2 0.45 0.0036 0.0019222,800 5,300221,800Legumevegetables0.078 350 2.9 0.023 1.2 0.13 0.001 0.00055769,600 18,000756,300Tropicalfruits0.16 350 2.9 0.023 1.2 0.27 0.0021 0.0011374,700 8,900373,100Mixing/Loading Liquids forChemigationApplicationsLegumevegetables0.078 350 2.9 0.023 1.2 0.13 0.001 0.00055769,600 18,000756,300Mixing/Loading Liquids forGroundboomApplicationsCotton,soybeans0.078 200 2.9 0.023 1.2 0.075 0.00060.00031 130 17,000 32,000 130 11,000Legumevegetables0.078 80 2.9 0.023 1.2 0.03 0.000240.00012 330 42,000 80,000 330 27,000Mixing/Loading Liquids forAirblastApplicationsTropicalfruits0.16 40 2.9 0.023 1.2 0.031 0.000250.00013 320 41,000 78,000 320 27,000ApplicatorApplyingSprays viaAerialEquipmentCotton,soybeans0.078 12000.005(eng.controlm)No Data0.068(eng.control)0.00078(eng.control)No Data0.00011(eng.control)13,000(eng.control)NoData94,000(eng.control)11,000(eng.control)No DataLegumevegetables0.078 3500.005(eng.control)No Data0.068(eng.control)0.00023(eng.control)No Data0.000031(eng.control)44,000(eng.control)NoData320,000(eng.control)39,000(eng.control)No DataTropicalfruits0.16 3500.005(eng.control)No Data0.068(eng.control)0.00047(eng.control)No Data0.000063(eng.control)21,000(eng.control)NoData160,000(eng.control)19,000(eng.control)No DataApplyingSprays viaGroundboomEquipmentCotton,soybeans0.078 200 0.014 0.014 0.74 0.00036 0.000360.00019 27,000 27,000 52,000 18,000 18,000Legumevegetables0.078 80 0.014 0.014 0.74 0.00015 0.000150.000077 69,000 69,000 130,000 45,000 45,000Spirotetramat Human-Health Risk Assessment DP#: D368785___________________________________________________________________________________________________________________________________________________________________________________________Page 35 of 47Table 9.1. Short- and Intermediate-Term Occupational Handler Exposure and Risk for Spirotetramat.ExposureScenarioCropAppRatea(lb ai/A)AcresTreatedDailybUnit ExposurecDose (mg/kg/day)MOEsBaselineDermald(mg/lbai)PPE-GDermale(mg/lb ai)BaselineInhalationf(μg/lb ai)BaselineDermalgPPE-GDermalgBaselineInhalationhBaselineDermaliPPE-GDermaliBaselineInhalationjCombinedBaselineDermal +InhalationkCombinedPPE-G +BaselineInhalationlApplyingSprays viaAirblastEquipmentTropicalfruits0.16 40 0.36 0.24 4.5 0.0038 0.00260.00048 2,600 3,900 21,000 2,300 3,300FlaggerFlagging forAerial SpraysApplicationsCotton,soybeans0.078 350 0.011 NAn0.35 0.0005 NA 0.00016 20,000 NA 63,000 15,000 NALegumevegetables0.078 350 0.011 NA 0.35 0.0005 NA0.00016 20,000 NA 63,000 15,000 NATropicalfruits0.16 350 0.011 NA 0.35 0.001 NA0.00033 9,700 NA 31,000 7,400 NAa. Application Rates based on proposeduses on labels for spirotetramat products BYI 8330 150 OD Insecticide, UltorTM, and MoventoTM.b. ExpoSAC Policy # 9.1.c. Unit Exposures based on PHED.d. Baseline Dermal: long-sleevedshirt, long pants, and no gloves.e. PPE-G Dermal: baseline dermal plus chemical-resistant gloves.f. Baseline Inhalation: no respirator.g. Dermal Dose (mg/kg/day) = unit exposure (mg/lb ai) * application rate (lb ai/acre) * acres treated * dermal-absorption factor (10%) / body weight (60 kg).h. Inhalation Dose (mg/kg/day) =unit exposure (ug/lb ai) * 1E-03 mg/ug * application rate (lb ai/acre)* acres treated * inhalation absorption (100%) / body weight (60 kg).i. Dermal MOE = NOAEL (10 mg/kg/day)/ dermal dose (mg/kg/day). LOC = 100.j. Inhalation MOE = NOAEL (10 mg/kg/day)/ inhalation dose (mg/kg/day). LOC = 100.k. Combined Baseline Dermal + Inhalation MOE = NOAEL (10 mg/kg/day) / (baseline dermal dose + baseline inhalation dose).l. Combined PPE-G + Baseline Inhalation MOE = NOAEL (10 mg/kg/day) / (PPE-G dermal dose+ baseline inhalation dose).m. Eng. control = engineering control; enclosed cockpit.n. Not applicable.Spirotetramat Human-Health Risk Assessment DP#: 368785

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Page 36 of 47 9.2 Short-Term Post-application Risk

HED expects that post-application exposure will o ccur since spirotetramat is applied as a foliar spray. Post-application exposure is expected to be short-term based on information provided on the proposed labels. However, the short- and intermediate-term toxicological endpoints are the same; therefore, the estimates of risk for short- term duration exposures ar e protective of those for intermediate-term duration exposures.

Since no post-application exposure data were su bmitted in support of this registration action, dermal exposures during post-application activitie s were estimated using dermal TCs from the ExpoSAC Policy Number 3.1: Agricultural TC s (August, 2000). Table 9.2.1 summarizes the scenarios assessed. In addition, the following assumptions were used in the calculations:

• Application Rate = 0.078 lb ai/A for foliar applications to cotton, soybean, and legume vegetables; 0.16 lb ai/A for foliar applications to tropical fruit crops;

• Exposure Duration = 8 hours per day;

• Body Weight = 60 kg;

• Dermal Absorption = 10%; and

• Fraction of ai retained on foliage is assumed to be 20% (0.2) on day zero (= % dislodgeable-foliar residue, DFR, after initial treatment) for agricultural crops . This fraction is assumed to further dissipate at th e rate of 10% (0.1) per day on following days.
These are default values es tablished by HED’s ExpoSAC.

Table 9.2.1. Anticipated Post-App lication Activities and Dermal TCs.

Proposed

Crops Policy Crop Group Category Application Rate (lb ai/acre) TCs (cm 2 /hr) Activities

Cotton, soybean, legume vegetables Field/row

crop, low/medium 0.0078 100 Irrigation, hand weeding and scouting (minimum foliage)

1,500 Irrigation, hand weeding and scouting (full foliage)

2,500 Hand harvesting

Tropical

fruit Tree, “fruit,”

evergreen 0.16 1,500 Harvesting

3,000 Thinning

The following equations were used to calculate risks for workers performing postapplication
activities:

DFR t (μg/cm 2 ) = AR (lb ai/acre) * F * (1-D) t * 4.54E8 μg/lb * 24.7E-9 acre/cm 2

Where:

DFR t = dislodgeable foliage residue on day "t" (μg/cm 2 ); AR = application rate (lb ai/acre); F = fraction of ai retained on foliage (unitless); andSpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 37 of 47 D = fraction of residue that dissipates daily (unitless).

and

Daily dermal dose t (mg/kg-day) = [DFR t (μg/cm 2 ) * 1E-3 mg/μg * TC (cm 2 /hr) * DA * ET (hrs)] / BW (kg)

Where:

DFR t = dislodgeable foliage residue on day "t" (μg/cm 2 ); t = number of days after application day (days); TC = transfer coefficient (cm 2 /hr); DA = dermal-absorption factor (unitless); ET = exposure time (hr/day); and BW = body weight (kg).

The post-application exposure asso ciated with the proposed new uses in agricultural crops is
summarized in Table 9.2.2. All s cenarios resulted in MOEs gr eater than 100 on day 0 (12 hours after application) and, therefore, are not of concern to HED.

Table 9.2.2. Postapplication Exposure and Risk for Spirotetramat.

Crop Grouping (Crop) TC (cm 2 /hr) Days after

Treatment DFR a (μg/cm 2 ) Daily Dermal

Dose b (mg/kg/day) MOE c

Field/row crop, low/medium

(cotton, soybean, legume vegetables) 100

0 (12 hours) 0.18 0.00023 43,000

1,500 0.0035 2,900

2,500 0.0058 1,700

Tree, “fruit,” evergreen (tropical fruit) 1,500 0 (12 hours) 0.36 0.0072 1,400

3,000 0.014 700

a. DFR = Dislodgeable Foliar Residue = Appl ication rate (lb ai/A) * Fr action of ai retained on foliage (20%) * (1- daily dissipation rate) t * 4.54E8 μg/lb * 24.7E-9 A/cm 2

. b. Daily Dermal Dose = [DFR (μg/cm 2 ) x*1E-03 mg/μg * TC (cm 2 /hr) * dermal absorption (10%) * 8 hrs/day] / body weight (60 kg). c. MOE = NOAEL (10 mg/kg/day) / Daily Dose (mg/kg/day).

Since the post-application assessment is not a concer n on Day 0 (12 hours following application), the REI is based on the acute toxi city of spirotetramat technical material. Spirotetramat is classified as Toxicity Categor y III for acute dermal; Toxicity Category II for primary eye irritation; and as Toxicity Category IV for primary dermal irritation. Therefore, the acute toxicity categories for th is chemical require a 24 hour REI under the WPS. The 24-hour REI, which appears on the proposed label, is adequate for these proposed use patterns.

10.0 Data Needs and Label Recommendations

10.1 Toxicology

• Immunotoxicity study (new require ment under 40 CFR Part 158).

• Subchronic neurotoxicity study (new requirement under 40 CFR Part 158).Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 38 of 47 10.2 Residue Chemistry

860.1200 Directions for Use

• Field trial data are required for sugar apple (the representa tive crop for atemoya, custard apple, cherimoya, ilama, soursop, and birida). As these data have not been submitted, the spirotetramat labels should be revised to delete instructions for use on sugar apple, atemoya, custard apple, cherimoya , ilama, soursop, and birida.

860.1500 Crop Field Trials

• The submitted residue data for tropical fruit will not support the proposed use pattern as
the trials were conducted at a ~2X use rate . HED thus requests that the petitioner conduct bridging studies with lychee and guava (1 trial each with four samples per treatment regimen) in order to determine the relationship between resi dues resulting from the labeled use pattern and that used in the submitted field trials (MRID# 47648205).

860.1550 Proposed Tolerances

• The petitioner is requested to submit a revise d Section F specifying the revised tolerance levels and commodity definitions summarized in Appendix B.

10.3 Occupational Exposure

• None.

cc: J. Van Alstine, G. Kramer, K. Lowe RDI: RAB1 Branch (10/28/09); D. Vogel (11/12/09) J. Van Alstine: S-10951: Potomac Yard 1 (PY1): (703)603-8866: 7509P: RAB1Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 39 of 47 Appendix A. Toxicology Assessment

A.1. Toxicity Profiles

Table A.1.1. Acute Toxicity Pr ofile – 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/ASpirotetramat Human-Health Risk Assessment DP#: D368785

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Page 40 of 47 Table A.1.2. Subchronic and Chronic Toxicity an d 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 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 body-weight gain and 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.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 41 of 47 870.3700a 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, impaired body-weight gain, 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.

870.3700b Prenatal developmental (rabbit) 46904544 (2004)

Acceptable/guideline

0, 10, 40, or 160 mg/kg bw/day Maternal NOAEL = 10 mg/kg/day. LOAEL = 40 mg/kg/day based on late abortion ( ≥ GD 22), clinical signs, impaired food and water consumption, and body weight loss. 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 body-weight gain (P females) and 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 and body-weight gain during lactation in F 1 pups.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 42 of 47 870.3800 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), weight gain (P males, 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 and body-weight gain 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 and body-weight gain, 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 DP#: D368785

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Page 43 of 47 870.5100 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 μ g/mL (- S9)

0, 20, 40, 60, 80, 92, 100, 108, 116, 120, 124, 132,

or 140 μ 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 cy totoxic 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.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 44 of 47 870.6200a 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).

870.7485 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 hrs (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 hrs 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 hrs.

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 h to 24 h post dose. Metabolism profile qualitatively similar to that of the low dose; 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 (OD150 formulation) Dermal absorption = 10%.

Special study Male reproductive toxicity 46904569 (2005)

Acceptable/non-guideline

1000 mg/kg bw/day (3, 10, 21, or 41 days) Primary testicular effect s 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.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 45 of 47 Table A.1.3. USEPA 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 Decreased BWG; histopathology not evaluated.

Special study 21-day gavage (enol metabolite) 47070901 (2006)

Acceptable/non-guideline

800 mg/kg bw/day Clinical signs of toxicity, decreased BWG, 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 hrs.

Distribution: highest concentrations detected in GI, liver, and kidney; <0.2% of administered dose detected in body 48 hrs 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 identifiedmetabolites could be derived from desmethylketohydroxy metabolite.

Excretion: 54% of administered dose
eliminated via urine an d 44% via feces within
48 hrs.

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.Spirotetramat Human-Health Risk Assessment DP#: D368785

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Page 46 of 47 Table A.1.3. USEPA Toxicity Profile – Metabolites.

Guideline

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

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 hrs.

Distribution: plasma concentrations peaked 4 hrs post dose; 1% of administered dose detected in body 48 hrs 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 an d 44% via feces within
48 hrs.

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 DP#: D368785

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Page 47 of 47 Appendix B. Tolerance Summary Table for Spirotetramat

Commodity Proposed Tolerance (ppm) HED-Recommended Tolerance (ppm) Comments; Correct Commodity Definition

Cotton – undelinted seed 0.4 0.30 Cotton, undelinted seed Cotton gin byproducts 7.0 10 Soybean seed 3 5.0 Soybean forage 9 8.0 Soybean hay 16 16 Aspirated Grain Fraction 10 10 Vegetables, legume, group 06 (except soybean) 4.0 2.5 Vegetables, legume, group 06, except soybean Vegetables, foliage of legume, except soybean, subgroup 07A 5.0 7.0

Okra 2.5 2.5 Translated from fruiting vegetables

Pistachio 0.25 0.25 Tr anslated from tree nuts Dried prunes 4.5 - Not required Tropical Fruit (except lychee) 1.5 - Not a recognized crop group

Lychee 12 13 Longan - 13 Translated from lychee Spanish lime - 13 Tr anslated from lychee Rambutan - 13 Translated from lychee Pulasan - 13 Translated from lychee

Avocado - 0.60 Black sapote - 0.60 Tr anslated from avocado

Canistel - 0.60 Translated from avocado Mamey sapote - 0.60 Translated from avocado Mango - 0.60 Translated from avocado Sapodilla - 0.60 Translated from avocado Star apple - 0.60 Translated from avocado Papaya - 0.35

Guava - 2.5 Feijoa - 2.5 Translated from guava Jaboticaba - 2.5 Translated from guava Wax jambu - 2.5 Translated from guava Starfruit - 2.5 Translated from guava Passionfruit - 2.5 Translated from guava Persimmon - 2.5 Translated from guava Acerola - 2.5 Translated from guava White sapote - 0.60 Translated from citrus fruit Eggs - 0.02 Hog meat byproducts - 0.02 Poultry meat byproducts - 0.02 Cattle, meat byproducts - 0.20 Goat, meat byproducts - 0.20 Horse, meat byproducts - 0.20 Sheep, meat byproducts - 0.20