Page 1 of 36 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION

MEMORANDUM

DATE: 5/2/13

SUBJECT: Dinotefuran ID#: 13MI04 Section 18 Emergency Exemption for Use on Pome Fruits and Stone Fruits in Michigan to Control Brown Marmorated Stink Bugs.

PC Code: 044312 DP Barcode: D 409855

MRID No.: None Registration No. : 59639

- 135, 10163

- 317
Petition No.: None Regulatory Action: Section 18 Assessment Type: Single Chemical/Aggregate Reregistration Case No.: NA

T XR No.: NA CAS No.: 165252

- 70

- 0

40 CFR: 180.603

FROM: Nancy Dodd, Chemist, Risk Assessor Barry O’Keefe, Senior Biologist Sheila Healy, Ph.D, Toxicologist

R isk Assessment Branch III (RAB3) Health Effects Division (HED) (7509P)

THROUGH: Christine Olinger, Branch Chief RAB3/HED (7509P)

TO: Tawanda Maignan/Andrea Conrath, RM #9 Minor Use, Inerts and Emergency Response Branch Registration Division (7505P)

A Section 18 Emergency Exemption request has been received for use of the insecticide

dinotefuran to control the brown ma r morated stink bug on pome and stone fruits in M ichigan (MI)

. This document and attachments provide an assessment of the human health risk resulting from the proposed and registered uses of dinotefuran. The toxicology evaluation was performed by Sheila Healy, the drinking water assessment was conducted by Jim Wolf and Jim Hetrick of

the Environmental Fate and Effects Division (EFED), the occupational and residential exposure

assessment was conducted by Barry O’Keefe

, and the review of the residue chemistry data

, dietary assessment , and the overall human health risk assessment were conducted by Nancy

Dodd

.Page 2 of 36 1.0 Executive Summary

................................ ................................ ................................ ................ 4

2.0 HED Recommendations

................................ ................................ ................................ ......... 7

2.1 T olerance Considerations

................................ ................................ ................................ .. 7 2.2.1 Enforcement Analytical Method

................................ ................................ ................ 7
2.2.2 Recommended Tolerances

................................ ................................ ........................... 7

3.0 Introduction

................................ ................................ ................................ ............................. 7 3.1 Chemical Identity

................................ ................................ ................................ ................ 8

3.2 Physical/Chemical Characteristics

................................ ................................ ................... 9

3.3 Pesticide Use Pattern

................................ ................................ ................................ .......... 9 3.4 Anticipated Exposure Pathways

................................ ................................ ..................... 10
3.5 Consideration of Environmental Justice

................................ ................................ ....... 10

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ............ 11 4.1 Toxicology Studies Available for Analysis

................................ ................................ .... 11 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

............................... 11

4.3 Toxicological Effects

................................ ................................ ................................ ......... 12

4.4 Sa fety Factor for Infants and Children (FQPA Safety Factor)

................................ . 13

4.4.1 Completeness of the Toxicology Database

................................ ............................. 14

4.4.2 Evidence of Neurotoxicity

................................ ................................ ......................... 14

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

..... 14

4.4.4 Residual Uncertainty in the Exposure Database

................................ .................. 14

4.5 Toxicity Endpoint and Point of Departure Selections

................................ ................. 15

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............ 16 5.1 Residues of Concern Summary and Rationale

................................ ............................ 16

5.2 Food Residue Profile

................................ ................................ ................................ ........ 16

5.3 Water Residue Profile

................................ ................................ ................................ ....... 17

5.4 Di etary Risk Assessment

................................ ................................ ................................ .. 1 8

5.4.1 Description of Residue Data & Percent Crop Treated

................................ ........ 18

5.4.2 Acute Dietary Risk Assessment

................................ ................................ ............... 18

5.4.3 Chronic Dietary Risk Assessment

................................ ................................ ........... 18

5.4.4 Summary Table

................................ ................................ ................................ .......... 18

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................... 19 6.1 Residential Handler Exposure

................................ ................................ ....................... 19

6.2 Post

- Application Exposure

................................ ................................ ............................. 19 6.3 Combined Exposure

................................ ................................ ................................ ........ 22 6.4 Residential Bystander Post

- Application Inhalation Exposure

................................ . 22 6.5 Spray Drift

................................ ................................ ................................ ....................... 22

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ..... 22 7.1 Acute Aggregate Risk

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

7.2 Short

- Term Aggregate Risk

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

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ............... 24 7.4 Chronic Aggregate Risk

................................ ................................ ................................ ... 24 7.5 Cancer Aggregate Risk

................................ ................................ ................................ ..... 24

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ... 24

9.0 Occupational Exposure/Risk Characterization

................................ ................................ 24

10.0 References

................................ ................................ ................................ ............................... 25 Appendix A. Tox icology Profile

................................ ................................ ................................ ..... 26Page 3 of 36 A.1 Toxicology Data Requirements

................................ ................................ ....................... 26

A.2 Toxicity Profiles

................................ ................................ ................................ ................. 27 Appendix B . Physical/Chemical Properties

................................ ................................ ................. 33 Appendix C. Dinotefuran and Metabolites

................................ ................................ .................. 34 Appendix D. Review of Human Research

................................ ................................ .................... 36Page 4 of 36 1.0 E xecutive Summary

Dinotefuran ( (RS)

- 1

- methyl

- 2

- nitro

- 3

- (tetrahydro

- 3

- furylmethyl)guanidine) is a broad

- spectrum insecticide belonging to the nitroguanidine sub

- class of the neonicotino i d class of insecticides. It is insecticidal by contact and ingestion, resulting in the cessation of insect feeding within hours

of contact with death shortly thereafte r

. The mode of action is interference with the acetylcholine receptor on the post

- synaptic side of the nerve cells.

Dinotefuran is currently registered for use on various agricultural commodities. It is also registered on many residential/ non

- agricult ural use site s, including : t urf, i ndoor (including

residential and food / non

- food areas of food service/handling establishments) and pet areas,

o utdoor ( lawns, ornamentals, flower gardens, vegetable gardens, surfaces of buildings, porches, patios, etc.), an t baits, fire ant baits, pet spot

- on, foggers, Christmas t rees, o rnamental t rees, n on

b earing f ruit and nut t rees, p lantations r eforestation n urseries, f orests, and w oodland a reas

. R egistered dinotefuran formulations include baits, gels, soluble concentrates, granulars, soluble granules, and ready

- to

- use (RTU) products.

Use Profile The Michigan Department of Agriculture and Rural Development requested a Section 18 emergency specific exemption to use dinotefuran to control the brown marmorated st ink bug on pome fruit and stone fruit in MI. D inotefuran will be used on apples, peaches and necta r ines on up to a total of approximately 40,200 acres in MI. The applications would be made from April through November, 2013. The dinotefuran products to b e used are Venom Insecticide (EPA Reg. No. 59639

- 135) or Scorpion 35SL (EPA Reg. No. 10163

- 317).

F oliar application s will be made with ground equipment at a maximum application rate of 0.304 lb ai/A with a maximum of two applications per season for a tota l of 0.608 lb ai/A/season. The

minimum retreatment interval (RTI) is 7 days. The preharvest interval (PHI) is 3 days. The restricted entry interval (REI) is 12 hours.

This is the first Section 18 for use of dinotefuran to control the marmorated stink bug on pome

and stone fruits i n MI . S ection 18s have been previously granted to other states for use of dinotefuran to control stink bugs on pome and stone fruits; the previous Section 18 tolerances were based on data extrapolated from an apple metabolism study. A Section 3 tolerance of 1.0 ppm has been established on peach reflecting a lower seasonal rate than that proposed for this

Section 18.

T

oxicity/Hazard The dinotefuran hazard profile was updated in a recent risk assessment (D391885, B. O’Keefe,

7 /20/12) , and nothing has changed since this update . The toxicology database is adequate for

hazard characterization. The nervous system is the main target of dinotefuran toxicity. After a single dose in rats and rabbits, n e u ro toxicity was manifested as clinical signs (hypoactivity, prone position, panting, tremors, and erythema) and decreased motor activity and changes in motor activity

. These acute effects are consistent with effects seen on the nicotinic cholinergic
nervous system a fter repeated dosing. Dinotefuran was well tolerated at high doses following dietary administration for 90 days to mice, rats and dogs. The principal toxicological findingsPage 5 of 36 were decreases in body weight and/or body weight gain at or near the l imit d ose ; but for acute dietary exposure the endpoint is neurotoxicity . No systemic or neurotoxicity was seen following repeated dermal applications at the limit d ose to rats for 28 days. No systemic or portal of entry effects were seen following repeated inhalati on exposure at the maximum obtainable concentrations to rats for 28 days. N o evidence of functional immunotoxicity was observed in guideline immunotoxicity or developmental immunotoxicity studies of dinotefuran. There are

also no indications of perturbed reproductive function. No adverse effects in fetuses were seen in the developmental toxicity studies in rats or rabbits, at maternally toxic doses, and offspring effects in the reproduction study occurred at the same doses causing parental effects. Ther e are no concerns of developmental neurotoxicity. There was no evidence of carcinogenicity in male and female mice and in male and female rats fed diets containing dinotefuran at the limit d ose. Dinotefuran was non

- mutagenic in both in vivo and in vitro assays.

Based on hazard and exposure data , HED has concluded that there are no residual uncertainties for pre

- and / or post

- natal toxicity , or in the exposure database, and the Food Quality Protection Act ( FQPA ) Safety Factor can be re duc ed to 1X

.

For acu te dietary risk to the general population, including infants and children, an acute population adjusted dose (aPAD) of 1.25 mg/kg/day was derived from a maternal no observed

adverse effect level ( NOAEL ) of 125 mg/kg/day in a developmental toxicity study in rabbits based on clinical signs indicative of neurotoxicity in does (hypoactivity, prone position, panting,

tremors , and erythema ) obse rved at 300 mg/kg/day ( lowest observed adverse effect level; LOAEL).

For chronic dietary risk to all populations, a chronic population adjusted dose ( cPA D ) of 1.0 mg/kg/day was derived from a NOAEL of 99.7 mg/kg/day from the chronic toxicity/carcinogenicity study in rats

, based on decreased body weight gain and food efficiency

in females and increased incidences of kid ney pelvic mineralization and ulceration in males at 991 mg/kg/day (LOAEL).

To assess short

- and intermediate

- term incidental oral exposures, an oral point of departure (POD) was selected. The POD (NOAEL = 99.7 mg/kg/day) was based on decreased body

we ight gain, and food efficiency in females and increased incidences of kidney pelvic

mineralization and ulceration in males seen at the lowest observed adverse effect level (LOAEL) of 991 mg/kg/day seen in the chronic toxicity/carcinogenicity study in rats.

Quantification of short

- or intermediate

- term dermal and inhalation risks are not required because no systemic or developmental toxicity was seen up to the limit dose in route

- specific toxicity studies.

Dietary Exposure (Food and Water)

The results of the unrefined acute dietary analysis for food and drinking water show that the acute dietary risk estimates are well below the Agency’s level of concern ( LOC; <100% of the

acute population adjusted dose ( a PAD ) ) for all population subgroups and were estimated at 3. 7 %

of the a PAD for the general U.S. population and 12 % of the a PAD for the most highly exposed population subgroup ( children 1

- 2 years old). The results of the unrefined chronic dietaryPage 6 of 36 analysis for food and drinking water indicate that the chronic dietary risk estimates are well below the Agency’s LOC (<100% of the chronic population adjusted dose ( c PAD)) for all population subgroups and were estimated at 1

. 7 % of the c PAD for the general U.S. population

and 5.7 % of the c PAD for the most hig hly exposed population subgroup (children 1

- 2 years old).

Dinotefuran is classified as “not likely to be carcinogenic to humans;” therefore, a cancer dietary

risk assessment was not performed.

Residential Exposure There is potential for exposure in residential settings during the application of currently registered products containing dinotefuran, and from entering areas previously treated with dinotefuran, such as lawns where children might play, pets children might play with, or golf

courses and ho me gardens that could lead to exposures for adults. As a result, risk assessments were previously completed for both residential handler and postapplication scenarios (DP398048, B. O’Keefe, 8/31/12; DP285650, J. Arthur, 4/27/2004; DP318728, B. O’Keefe,

8/ 2/04; and DP347177, S. Recore, 5/7/08). The proposed Section 18 uses of dinotefuran do not add any additional residential exposures or risks.

Aggregate Exposure Acute and chronic aggregate exposure is equal to acute and chronic dietary exposure. The acute

and chronic aggregate risk estimates for all populations, resulting from exposure to dinotefuran in food and drinking water

, are not of concern. A short

- term aggregate risk assessment was performed for children to assess the potential for co

- occ urring post

- application exposure resulting in the greatest exposure (i.e., from use of the total release fogger product and the existing cat spot

- on use) , resulting in a MOE of 6 9 0 , which is greater than 100, and therefore not
of concern. An aggregate risk assessment was not performed for adults

, since no toxicity endpoints were identified for th e dermal and inhalation routes.

Occupational Exposure Occupational short

- (1 to 30 days) and intermediate

- term (1 to 6 months) dermal and inhalation

exposures are expected from dinotefuran handler activities

. However, since no hazard was

identified for the short

- or intermediate

- term dermal or inhalation route s of exposure , dermal and

inhalation risks were not assessed.

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studi es (listed in Appendix D ) have been determined to require a review of their ethical conduct, and have rece ived that review.

Environmental Justice Potential areas of environmental justice concerns were considered in this human health risk

assessment. Refer to Section 3.5 for details.Page 7 of 36 2.0 HED Recommendations

HED has no concerns regarding human health expos ure and risk from the proposed Section 18 use of dinotefuran on stone fruit and pome fruit for control of the brown ma r morated stink bug in MI. The specific tolerance recommendations are discussed in Section 2.1

.

2 .1 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Plants Adequate analytical methods are available for enforcement of the proposed tolerances. The methods include a high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) method for determination of residues of dinotefuran, DN, and UF; an HPLC/ultraviolet (UV) detection method for the determination of residues of dinotefuran; and

HPLC/MS and HPLC/MS/MS methods for determination of residues of DN and UF. Anal y t ical Chemistry Branch/Biological and Eco nomic Analysis Division (ACB/BEAD) found the methods to be adequate (D288743, 10/22/2003, D. Swineford, ACB/BEAD). The lowest level of method validation (LLMV) was reported as 0.01 ppm for dinotefuran (m/z 203 →129) and metabolites DN (m/z 158 →102) and U F (m/z 159 →102).

Multiresidue Methods Dinotefuran was not adequately recovered using any of the multiresidue methods. HED does not expect any of the FDA Protocols to recover these metabolites due to the structural similarities of

the metabolites as com pared to the parent.

2.2.2 Recommended Tolerances

HED recommends Section 18 tolerances be established on the following crop groups, for residues of dinotefuran, (RS)

- 1

- methyl

- 2

- nitro

- 3

- ((tetrahydro

- 3

- furanyl)methyl)guanidine, including its metabolite s and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of dinotefuran and its metabolites DN, 1

- methyl

- 3

- (tetrahydro

- 3

- furylmethyl)guanidine, and UF, 1

-

me thyl

- 3

- (tetrahydro

- 3

- furylmethyl)urea, calculated as the stoichiometric equivalent of

dinotefuran:

Fruit, pome, group 11

- 10

................................ ................................ ............................... 2.0 ppm Fruit, stone, group 12

- 12

................................ ................................ ............................... 2.0 ppm

3.0 I ntroduction

Dinotefuran is a broad

- spectrum insecticide belonging to the nitroguan idine sub

- class of the neonicotinoid class of insecticides. It is insecticidal by contact and ingestion, resulting in the cessation of insect feeding within hours of contact with death shortly. The mode of action is interference with the acetylcholine re ceptor on the post

- synaptic side of the nerve cells.Page 8 of 36 Dinotefuran is currently registered for use on various agricultural commodities. It is also registered on many residential/non

- agricultural use sites, including: turf, indoor (including

residential and food and non

- food areas of food service/handling establishments) and pet areas, outdoor (lawns, ornamentals, flower gardens, vegetable gardens, surfaces of buildings, porches, patios, etc.), ant baits, fire ant baits, pet spot

- on, foggers, Christmas trees, ornamental trees, non

bearing fruit and nut trees, plantations reforestation nurseries, forests, and woodland areas. Registered dino tefuran formulations include baits, gels, soluble concentrates, granulars, soluble granules, and ready

- to

- use (RTU) products.

A Section 18 Emergency Exemption request has been received for use of the insecticide

dinotefuran to control the brown marmorated stink bug on pome and stone fruits in MI.

3.1 Chemical Identity

The chemical structure and nomenclature of dinotefuran and its metabolites DN and UF are presented in Table 3.1. Structures of additional metabolites are shown in Appendix C.

TABLE 3.1. Dinotefuran Nomenclature.

Compound Chemical Structure

Common name dinotefuran

Company experimental

name MTI

- 446

IUPAC name ( EZ )

- ( RS )

- 1

- methyl

- 2

- nitro

- 3

- (tetrahydro

- 3

- furylmethyl)guanidine

CAS name N

- methyl

- N ́

- nitro

- N ̋

- [ ( tetrahydro

- 3

- furanyl)methyl]guanidine

CAS # 165252

- 70

- 0

End

- Use Products Scorpion 35 SL (EPA Reg. No. 10163

- 317); Venom (EPA Reg. No. 59639

- 135)

Compound Chemical Structure

Common name DN

IUPAC name 1

- methyl

- 3

- (tetrahydro

- 3

- furylmethyl)guanidine N H

N H N H O

C H 3 N H

N N H O

C H 3

N

O 2Page 9 of 36 TABLE 3.1. Dinotefuran Nomenclature.

Compound Chemical Structure

Common name UF

IUPAC name 1

- methyl

- 3

- (tetrahydro

- 3

- furylmethyl)

- urea

3.2 Physical/Chemical Characteristics

The physicochemical properties of dinotefuran are summarized in Appendix B. Dinotefuran has

a molecular weight of 202.2 g/mole, a very high water solubility (39,830 ppm), and a low octanol/water partition coefficient (K OW = 0.283), suggesting the potential for runoff and low bioaccumulation. The low vapor pressure (1.28 x 10 - 8 mm Hg) and a low Hen ry’s Law Constant (8.63 x 10 - 14 Atm • M 3 /mol) suggest that this compound is not expected to volatilize substantially

from water or soils in the natural environment.

3 .3 Pesticide Use Pattern

The Michigan Department of Agriculture and Rural Developmen t requested a Section 18 emergency specific exemption to use dinotefuran to control the brown marmorated stink bug on pome fruit and stone fruit in MI. D inotefuran will be used on apples, peaches and necta r ines on up to a total of approximately 40,200 acr es in MI. The applications would be made from April through November, 2013. The dinotefuran products to be used are Venom Insecticide (EPA Reg. No. 59639

- 135) or Scorpion 35SL (EPA Reg. No. 10163

- 317).

As shown in Table 3.3 below, t he use pattern for th e proposed Section 18 on pome and stone fruits in MI to control the brown marmorated stink bug is foliar application with ground equipment at a maximum application rate of 0.304 lb ai/A with a maximum of two applications per season for a total of 0.608 lb ai/A/season. The minimum retreatment interval is 7 days. The preharvest interval (PHI) is 3 days. The restricted entry interval (REI) is 12 hours. N H

O N H O

C H 3Page 10 of 36 Table 3.3 . Summary of Proposed Directions for Use of Dinotefuran

. Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic.

Rate (lb ai/A) 1, 2 Max. No. Applic.

per Season Max. Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and

Limitations

Pome Fruit and Stone Fruit

Foliar; Broadcast;

Ground equipment Scorpion

35 SL 3

[10163

- 317] 0.203

- 0.304 2 0.608 3 Do not apply until after petal fall.

The minimum

retreatment interval is 7 days.

The REI is 12 hours. Venom

70 S G 4

[59639

- 135] 0.1 79

- 0.30 2 2 0.60 4 3

1 Scorpion 35SL: Apply 8

- 12 fl oz /A/ application . The formulation contains 3.24 lb ai/gallon.

2 Venom 70 SG : Apply 4

- 6.75 oz /A/a pplication. The formulation contains approx. 70% ai

. 3 SL = soluble liquid

. 4 S G /SDG = soluble g ranule /soluble dispersible granule

.

3.4 Anticipated Exposure Pathways

Humans may be exposed through their diet from applications to agricultural commodities and from applications in food handling establishments. Humans may also be exposed to dinotefuran in drinking water, since application may result in dinotefuran reaching surface and ground water sources of drinking water. There are residential uses of dinotefuran, so exposure to dinotefuran may occur in residential or non

- occupational settings during application and as a result of residues present after application. In an occupational setting, handlers may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post

- application exposure for workers re

- entering treated sites.

Risk assessments have been completed for the existing uses of dinotefuran. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of dinotefuran, but also considers existing uses of dinotefuran, particula rly in the dietary exposure

assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part o f every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of th at subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the National

Health and Nutrition Examination S urvey, What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and region of the country. Additionally,Page 11 of 36 OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate,

non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children 3 to < 6 years old, youths and adults entering or playing on treated
areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Dinotefuran is in the neonicoti noid class of pesticides and acts as an agonist on insect nicotinic acetylcholine receptors. Consistent with its neurotoxic pesticidal mode of action (MOA)

, dinotefuran ’ s toxicity profile shows that the mammalian nervous system is the target of

dinotefura n toxicity, as demonstrated in the acute and subchronic neurotoxicity studies in rats,

and pre

- natal developmental toxicity study in rabbits

. A summary of the toxicology profile of dinotefuran is presented in Appendix A.

4.1 Toxicology Studies Available for Analysis

The toxicology database for dinotefuran is adequate for hazard characterization. Available studies include subchronic and chronic oral toxicity studies in rats, mice and dogs, developmental toxicity studies in rats and rabbits, a r eproductive toxicity study in rats, acute and subchronic neurotoxicity studies in rats

, and immunotoxicity studies in mice and rats

. Additionally, developmental neurotoxic ity (DNT) and immunotoxicity studies are also available.

4.2 Absorption, Distr ibution, Metabolism, & Elimination (ADME)

The ADME properties of radiolabeled dinotefuran have been thoroughly investigated in non

pregnant adult rats (males and non

- pregnant females) following oral (single and repeated) and intravenous (IV) single dosing . Also performed have been single oral dose studies with pregnant rats at gestation day (GD18), lactating rats at 12 days postpartum, and growing rat pups at postnatal day (PND) 12. In all cases where dinotefuran was administered orally, there was rapid (time to peak plasma levels was < 1 hr) and extensive (> 90%) absorption from the gastrointestinal (GI) tract, wide body distribution with no specific tissue accumulation, little or no metabolism (predominant species was the parent chemical), and relativel y fast body

clearance.

The data collected in male rats and non

- pregnant female adult rats did not suggest saturation of clearance at the doses tested (50 and 1000 mg/kg bw); the area under the plasma concentration

time curve (not peak plasma levels) scal ed proportionally with increases in administered oral dose. The radiolabel was widely and comparably distributed throughout the body at 30 minutes
post

- dosing (approximate t
max ) and had declined substantially in all tissues by 4 hours post

dosing. There was no evidence of specific tissue accumulation; the highest content of radioactivity at 30 minutes was found in the kidneys, reflective of the high water solubility property of dinotefuran and subsequent predominant route of excretion via the urine ( **≥** 93%)

.Page 12 of 36 Elimination was rapid with plasma half

- life of about 3.6 hours for males and about 2

- fold longer for female rats at 7.9 hours following a single oral dose of dinotefuran. Upon repeated daily dosing, plasma elimination half

- life estimates increased slig htly to 5.6 hrs for males, but remained about the same for females at 6.9 hrs. The predominant species detected in excreta was the parent chemical (75

- 93% of the administered radiolabel) in both oral and IV administration

studies. Minor metabolites ident ified accounted for only 2

- 6% of the administered radiolabel.

The ADME data collected from the single oral dose study with pregnant rats at GD18 suggests that dinotefuran readily crosses the placenta as evidenced by parallel profiles exhibited by

maternal blood and fetal tissues. Peak levels of radioactivity in maternal blood and fetal tissues were comparable and both reported at the first time measurement of 0.5 hours. When lactating rats at 12 days postpartum were similarly dosed with a single dose of radiolabeled dinotefuran, there was also a comparable profile between maternal blood radioactivity content and maternal milk; both matrices achieved comparable peak levels at the same first time measurement of 0.5 hours. The clearance of radioactivity fro m fetal tissues and milk paralleled that of maternal plasma, decreasing by **≥** 80% by 4 hours post

- dosing. No measurement of radioactivity was made in nursing pups.

PND 12 rat pups exhibited a similar ADME profile following a single oral dose of 50 mg/kg bw radiolabeled dinotefuran. Absorption could not be accurately quantified but was noted to be high (~80%). The radio label was widely distributed in the body with no specific tissue accumulation noted. Urine was the primary elimination route as indirec tly evidenced by finding high radioactive areas by whole body autoradiography in the kidneys and bladder

. There were no metabolites reported ; t he parent chemical was the predominant species accounting for >97% of the radiolabel in the excreta, plasma, kid neys, and stomach, and nearly 61

- 83% in intestines (and contents), and liver. Approximately 32

- 36% of the administered dose was excreted within 4

hours of treatment. It was noted that rat pups exhibited slower rates of absorption and

elimination as compa red to adult animals. The age

- dependent differences in absorption and

elimination were attributed to immature gastrointes tinal tracts and kidney systems and /or the

absence of maternal stimulation to elicit excretion

.

4.3 Toxicological Effects

Dinotefuran has low acute toxicity by oral (Toxicity Category III) , dermal (Toxicity Category IV) , and inhalation (Toxicity Category IV) exposure routes. It is not a dermal sensitizer, does not irritate the eye (Toxicity Category IV), but causes a low lev el of skin irritation. The main target of toxicity is the nervous system , but effects on the nervous system were only observed at high doses . Nervous system toxicity was manifested as clinical signs and decreased motor activity seen after acute dosing (i n both rats and rabbits) and changes in motor activity which are consistent with effects on the nicotinic cholinergic nervous system seen after repeated dosing. Typically, low to moderate levels of neonicotinoids, such as dinotefuran, activat e the nicotin ic acetylcholine receptors caus ing stimulation of the peripheral nervous system (PNS). H igh levels of neonicotinoids (agonists) can over stimulate the PNS, maintaining cation channels in the open state which blocks the action pot ential and leads to paraly sis.Page 13 of 36 Dinotefuran was well tolerated at high doses following dietary administration for ninety days to mice, rats and dogs. The most sensitive effects were decreases in body weight and/or body weight gain , but even these effects occurred at or near the l i mit d ose. Changes in spleen and thymus weights were seen in mice, rats and dogs following subchronic and chronic dietary exposures. However, these weight changes were not corroborated with alterations in hematology parameters, histopathological lesions i n these organs, or toxicity to the hematopoietic system. Furthermore, the toxicology database contains immunotoxicity studies in mice and rats and a developmental immunotoxicity study in rats. In the immunotoxicity studies

, no effect s on T

- cell dependent antibody response (TDAR) were seen when tested up to the l imit d ose in male and

female mice and in male and female rats. There were also no changes in spleen and thymus weight and there were no histopathological lesions in these organ s. In the developmental immunotoxicity study, no effects on functionality of the immune system in rats were seen following exposure to dinotefuran at the l imit d ose during the prenatal, postnatal, and post

weaning periods . Because of the lack of immunoto xicity seen in the immunotoxicity studies in mice, rats, and developing rats, the thymus weight changes seen in dogs and the spleen weight changes seen in mice and rats in the subchronic and chronic oral studies were not considered to be toxicologically re levant.

No systemic or neurotoxic effects were seen following repea ted dermal applications at the l imit

d ose to rats for 28 days. No systemic or portal of entry effects were seen following repeated inhalation exposure at the maximum obtainable concentrat ions to rats for 28 days.

In the available pre

- natal studies, no maternal or developmental toxicity was seen at the l imit

d ose in rats. In rabbits, maternal toxicity manifested as clinical signs of neurotoxicity but no developmental toxicity was seen. In the rat reproduction study, parental, offspring, and reproductive toxicity was seen at the l imit d ose. Parental toxicity included decreased body weight gain, transient decrease in food consumption, and decreased thyroid weights. Offspring toxicity was characterized as decreased forelimb grip strength or hindlimb grip strength in the F1 pups. There was no adverse effect on reproductive performance at any dose. In the developmental neurotoxicity study, no maternal or offspring toxicity was seen at any d ose including the limit d ose.

There was no evidence of carcinogenicity in male and female mice and in male and female rats

fed diets containing dinotefuran at the limit d ose for 78 weeks to mice and 104 weeks to rats.

Dinotefuran was non

- mutagenic in bot h in vivo and in vitro assays.

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

Based on the hazard and exposure data, the dinotefuran risk assessment team has recommended that the FQPA Safety Factor be reduced to 1X . The rationale for this recommendation is provided in the following sections.Page 14 of 36 4.4

. 1 Completeness of the Toxicology Database

The toxicity database for dinotefuran is complete, comprehensive, of good quality and considered adequate to support toxicity endpoint selection for risk assessment and for FQPA

evaluation.

4.4.2 Evidence of N eurotoxicity

The neurotoxic potential of dinotefuran has been adequately considered. Dinotefuran is a neonicotinoid and has a neurotoxic mode of pesticidal action. Consistent with the mode of action, changes in motor activity w ere seen in repeat

- dose studies, including the subchronic neurotoxicity study (SCN). Additionally, decreased grip strength and brain weight was observed in the offspring of a multi

- generation reproduction study albei t at doses close to the limit dose. For these reasons, a developmental neurotoxicity (DNT) study was required. The DNT study did not show evidence of a unique sensitivity of the developing nervous system; no effects on neurobehavioral parameters were see n in the offspring at any dose, including the limit dose.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

There was no evidence (qualitative or quantitative) of increased susceptibility following in utero exposures to rats and rabbits and following pre

- and post

- natal exposure to rats for two generations. In rats, no maternal or developm ental toxicity was seen at the limit d ose. In rabbits, maternal toxicity manifested as clinical signs of neurotoxicity but no developmental toxicity was

seen. In the reproduction study, offspring toxicity characterized as decreased forelimb or hindlimb grip strength in the F1 p ups was seen at the same dose (limit d ose) that caused parental toxicity (decreased body weights ). The concern is low for the observed qualitative increase in sensitivity since the effects in the offspring were seen at the limit d ose in the presence of parental toxicity. There was no adverse effect on reproductive performance at any dose. In the

d evelopmental neurotoxicity study, no maternal or offspring toxicity was seen at any dose including the limit d ose. In the developmental immunotoxicity study

, there was no evidence of an effect on the functionality of the immune system in rats that were ex posed to dinotefuran at
the limit d ose during the prenatal, postnatal, and post

- weaning periods

.

4.4.4 Residual Uncertainty in the Exposure Datab ase

E xposure data are complete or are estimated based on data that reasonably account for potential

exposures . The acute and chronic dietary analys e s are unrefined analyses using tolerance

- l evel

residues and assuming 100% crop treated

. The dietary drinking water assessment utilized water concentration values generated by model and associated modeling parameters which are designed to provide conservative, health protective, high

- end estimates of water concentrations.

HED concludes that the acute and chronic exposure estimates in this analysis are unlikely to underestimate actual exposure. The residential exposur e assessment uses the 2012 Residential

SOPs and is considered health

- protective.Page 15 of 36 4.5 Toxicity Endpoint and Point of D eparture Selections

The dinotefuran hazard profile was updated in a recent risk assessment (DP391885, B. O’Keefe, 7/20/12), and nothing has changed since this update. Please refer to that assessment for extensive details. The toxicology database is adequate for characterization of hazard. In

accordance with the EPA’s F inal Guidelines for Carcinogen Risk Assessment (March, 2005),

d inotefuran is classified as “Not Likely to be Carcinogenic to Humans” based on the lack of evidence for carcinogenicity in mice and rats. Table 1 summarizes the toxicological doses and endpoints for dinotefuran for use in human health risk assessments . For further details refer to Appendix A.

Table 4.5

. Summary of Toxicological Doses and Endpoints for Dinotefuran for Use in Human Health Risk

Assessments

Expos ure/
Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD, Level
of Concern for
Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population

, including Infants and Children) NOAEL=125 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Acute RfD = 1.25 mg/kg/day

aPAD =1.25 mg/kg/day Developmental Toxicity Study in
Rabbits LOAEL = 300 mg/kg/day based on clinical signs indicative of neurotoxicity in does ( hypoactivity, prone position, panting, tremor and erythema) seen following the first dose on Gestation Day 6.

Chronic Dietary (All Populations) NOAEL=99.7 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Chronic RfD =

1.0 mg/kg/day

cPAD = 1.0 mg/kg/day Chronic Toxicity/Carcinogenicity Study in Rats LOAEL = 991 mg/kg/day based on decreased body weight gain and nephrotoxicity.

Incidental Oral

Short

- Term (1

- 30 days) and

Intermediate

- Term (1

- 6 months) NOAEL=99.7 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential LOC

for MOE = 100 Chronic Toxicity/Carcinogenicity Study in Rats LOAEL = 991 mg/kg/day based on decreased body weight gain and nephrotoxicity.

Dermal Short

- Term (1

- 30 days) and

Intermediate

- Term (1

- 6 months) No systemic toxicity was seen at the limit dose in a 28

- day rat dermal toxicity study in which neurotoxicity was evaluated and there are no developmental toxicity concerns. No hazard was identified for these exposure scenarios. A dermal penetration study for dinotefuran showed low absorption, < 2%.

Inhalation Short

Term (1

- 30 days)

and Intermediate

Term (1

- 6 months) No quantitation required. No systemic toxicity was seen in a 28

- day inhalation toxicity study at doses that were in ~ 10,000

- fold excess of the highest anticipated human exposure. There are no developmental toxicity concerns.

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rode nt carcinogenicity studies. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant hu man exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the huma n population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level

of concern.Page 16 of 36 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The nature of the residue in plants and livestock is adequately understood for the purposes of th is

Section 18. Metabolism studies in rape, potato, rice, apple, and lettuce were submitted in conjunction with an earlier dinotefuran petition, PP#2F06427 (DP285648, L. Cheng, 2/26/04).

The database is adequate for determining dinotefuran residues of concern

. A listing of the

dinotefuran metabolites /degradates is provided in Appendix C

.

Table 5.1

. S ummary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

.

Matrix Residues for Tolerance Expression Residues for Risk Assessment

Plants Dinotefuran, DN, UF Dinotefuran, DN, UF , and PHP

Ruminants Dinotefuran Dinotefuran, UF, FNG

Poultry Dinotefuran Dinotefuran, FNG

Rotational Crops Not Needed 1 Not Needed 1

Drinking Water Not applicable Dinotefuran, MNG, DN, UF, DN

- 2

- OH, and DN

- 3

- OH

Food Handling Establishments Dinotefuran Dinotefuran

1 If the plant

- back interval of 120 days is shortened in the future, additional rotational crop data will be required.

5.2 Food Residue Profile

Re sidue data previously submitted to support a Section 3 on peach and nectarine (D389492, L. Cheng, 4/12/12) were used to es timate the Section 18 tolerances on pome and stone fruits

. The residue data are summa rized in the following table:

TABLE 5. 2

. Summary of Residue Data from Peach Crop Field Trials with Dinotefuran.

Com

modity Analyte Total App.

Rate (lb ai/A) PHI (days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. L AFT 2 HAFT 2 Median Mean Std.

Dev.

Foliar Application

Peach Dinotefuran 0.352

- 0.365 2

- 3 12 0.08 0.54 0.09 0.50 0.21 0.25 0.13

UF 3 12 <0.01 0.07 0.01 0.07 0.01 0.02 0.02

DN 3 12 <0.01 0.05 0.01 0.04 0.01 0.02 0.01

Total Residues 12 <0.11 0.66 0.11 0.62 0.24 0.29 0.16

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.01 ppm for all analytes) was used for any results reported as < LOQ in Table C.3

2 LAFT = lowest average field trial; HAFT = highest average field trial

. 3 Residues of UF and DN are reported in parent equivalents as calculated by the study reviewer.

Assuming residues increase proportionally with incr e asing rate, total residues of 0.66 ppm from a seasonal rate of 0.365 lb ai/A would be 1.1 ppm from the proposed seasonal rate of 0.608 lb ai/A. A tolerance of 2.0 ppm is adequate.Page 17 of 36 HED has concluded that no changes are needed to the existing tolerances for livestock commodities as a result of the proposed Section 18 uses on pome and stone fruits.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in the follow ing memorandum: “ Tier I Drinking Water Concentrations for Dinotefuran for Section 3 New Use on Rice ” ( D397490, J.

Wolf & J. Hetrick , 8/7/12 ) and incorporated directly into this dietary assessment. Water residues were incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.”

There are no drinking water monitoring data available on the concentration of parent dinotefuran or any of its degradates. EFED provided a Tier 1 dinotefuran drinking water assessment with estimated drinking water concentrations (EDWCs) for dinotefuran and its metabolite/degradate

DN. The modified Tier 1 Ri ce Model was used to determine EDWCs for surface water

. Groundwater EDWCs were obtained with the Tier 1 SCI

- GROW model v.2.3 using the turf

scenario.

Table 5. 3 summarizes the surface water EDWCs for dinotefuran and DN degradate. The peak

concentration is 269 μg/L and the longer term concentration ( ≈average) would depend upon retention time (10 to 30 days).

Table 5. 3

. Tier 1 Surface Water EDWCs (μg/L) for Drinking Water Risk Assessment for the Use of Dinotefuran on Rice. Based upon total toxic residu es (Dinotefuran + DN).

Peak Retention Time

10 day 30 day 60 day 100 day 150 day

269 257 253 248 240 198

The ground water EDWC, obtained using the Tier 1 SCI

- GROW, is the same value for the turf use and the Section 18 rice use; 4.90 μg/L for both the acute and chronic exposures. Since the application rate for turf (1 application at 0.54 lb ai/A) is higher than for rice and since SCI

GROW is not site or crop dependent, the resulting water concentration is considered to be

conservative.

Because the sur face water estimates are higher than the groundwater estimates, the surface water values, expressed to two significant figures and converted to ppm, were directly incorporated in

the DEEM

- FCID into the food categories “water, direct, all sources” and “wate r, indirect, all sources.” The peak value of 269 u g/L (ppb) was used in the acute assessment and the 10 day

retention time value of 257 u g/L was used in the chronic assessment.Page 18 of 36 5.4 Dietary R isk Assessment

5.4.1 Description of Residue Data & Percent Crop Treated

The acute and chronic dietary exposure assessment s of dinotefuran a re unrefined since it is

assum ed that 100% of the crops are treated and that all treated crops contain residues which are

tolerance

- level re s idues , adjusted for additional res idues which are not included in the tolerance

but are included in t he risk assessment

. Default processing factors were used as appropriate

. According to current HED policy, o nly the chronic dietary assessment included the food handling establishment use with 0.01 ppm tolerances for all food commodities without other

tolerances

.

5.4.2 Acute Dietary Risk Assessment

Potential residues in drinking water were included in the analyses based on surface water results

from the Tier 1 Rice model v. 1.0 and the mo dified Tier 1 Rice model as these values were higher than the ground water estimates from the SCI

- GROW model ( D P397490, J. Wolf & J.

Hetrick

, 8/7/ 1 2 )

. The surface water EDWC of 269 μg/L was used in the DEEM

- FCID. Thus, the results obtained from the prese nt analyses may be considered highly conservative. At the

95 th percentile of exposure, no population subgroups were of concern : the general U.S. population accounted for just 3. 7 % of the acute population

- adjusted dose (aPAD), while the most highly exposed population subgroup, children 1

- 2 years old

, accounted for 12 % of the aPAD.

5.4.3 Chronic Dietary Risk Assessment

Potential residues in drinking water were included in the anal yses based on surface water results

from the Tier 1 Rice model v.1.0 and the modified Tier 1 Rice model as these values were higher than the ground water estimates from the SCI

- GROW model ( D P 39 7490

, J. Wolf & J. Hetrick

, 8 / 7 / 1 2 ). The surface water EDWC of 2 57 μg/L was used in the DEEM

- FCID. No population subgroups were of concern: the general U.S. population accounted for 1

. 7 % of the chronic population

- adjusted dose (cPAD), while the most highly exposed population subgroup, children

1

- 2 years old, accoun ted for 5.7 % of the cPAD.

5.4.4 Summary Table

Table 5.4.4

. Summary of Dietary (Food and Drinking Water) Exposure and Risk

for D inotefuran

.

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 0.046286 3.7 0.0166 33 1.7

All Infants (< 1 year old) 0.132460 11 0.0476 75 4.8Page 19 of 36 Table 5.4.4

. Summary of Dietary (Food and Drinking Water) Exposure and Risk

for D inotefuran

.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary

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

Children 1

- 2 years old* 0.152112 12 0.0566 50 5.7

Children 3

- 5 years old 0.099267 7.9 0.0370 44 3.7

Children 6

- 12 years old 0.051696 4.1 0.0189 91 1.9

Youth 13

- 19 years old 0.031125 2.5 0.0112 61 1.1

Adults 20

- 49 years old 0.034765 2.8 0.0139 44 1.4

Adults 50

- 99 years old 0.031484 2.5 0.013 404 1.3

Females 13

- 49 years old 0.033791 2.7 0.0134 32 1.3

* The subpopulation with the highest risk estimates is bolded.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

This document addresses agricultural uses on pome and stone fruits, which will not contribute to residential exposure. There are currently registered uses of dinotefuran on several residential use sites, including turf, ornamentals, vegetable gardens, pet spot

- ons, indoor aerosol sprays, foggers, crack and crevice sprays. Each of these existing residential use patterns we re reassessed in

recent HED human health risk assessment s using the updated 2012 Residential SOPs and body weights ( D398048, B. O’Keefe, 8/31/12; DP391885, B. O’Keefe, 7/20/12). The new exposure and risk estimates for all residential post

- application scen arios resulted in risk estimates that are

not of concern.

6.1 Residential Handler Exposure

As indicated in Section 4.0, there are no dermal or inhalation toxicity concerns. Therefore , no residential handler exposure s w ere assessed.

6.2 Post

- Application Exposure

R esidential post

- application exposures and risk estimates from the existing uses of dinotefuran are shown in the following tables.

Table 6.2.1 presents these anticipated exposures from the total release fogger and their associated risk estimates. Residential incidental oral risk estimates ranged from 1,200 to 13,000, and were

not of concern to HED.Page 20 of 36 Table 6.2.1. Residential Post

- A pplication Short

- Term Oral Exposure and Risk Estimates for Children to Dinotefuran from Total Release Fogger.

Scenario 1 Deposited

Residue (μg/cm 2 ) Children Ages (yrs) Activity Daily Dose (mg/kg/day) MOE 1

Indoor

Rooms 14.6 1

- 2 Hand

- to

- mouth on carpet 0.08605 1,200

Hand

- to

- mouth on hard surface 0.02868 3,500

Object

- to

- mouth on carpet 0.01145 8,700
Object

- to

- mouth on hard surface 0.00763 13,000

1 MOE = NOAEL (99.7 mg/kg/day) / Daily Dose (mg/kg/day); where daily doses are as follows:

Hand

- to

- Mouth Daily Dose (mg/kg/day) = hand residue loading (mg/cm 2 ) x fraction of hand mouthed (0.13) x surface area of 1 hand (150 cm 2 ) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x number of replenishment intervals per hour (4) x (1

- (1

- fraction saliva extraction (0.48) / (number of contact events per hour (20 events/hr) / number of replenishment intervals per hour (4 intervals/hr))) / 11 kg body weight; where Hand Residue Loading (mg/cm 2 ) = fraction ai on hands (0.15) compared to total surface residue from Jazzercise studies (gloves) x dermal exposure (mg) / 2 x surface area of 1 hand (150 cm 2 );

Object

- to

- Mouth Daily Dose (mg/kg/day) = deposited residue (14.6 μg/cm 2 ) x fraction of residue transferred to object (0.06 for carpets , or 0.08 for hard surfaces) x conversion factor (0.001 mg/μg) x object surface area mouthed per event (10 cm 2 /event) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x number of replenishment intervals per hour (4 intervals/hr) x (1

- (1

- fraction saliva extraction (0.48) / (number of object

- to

mouth contact events per hour (14 events/hr) / number of replenishment intervals per hour (4 intervals/hr))) / 11 kg body weight

Dermal Exposure (mg) = deposited residue (14.6 μg/cm 2 ) x fraction transferred (0.06 for carpets, or 0.08 for hard surfaces) x transfer coefficient (1,800 cm 2 /hr) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x conversion factor (0.001 mg/μg); where

Deposited Residue (14.6 μg/cm 2 ) = Active Ingred ient Applied (340,194 μg) / Area Treated (23,225 cm 2 ); where Active Ingredient Applied (340,194 μg) = 6 oz fogger x % ai (0.2%) x conversion factor (28,349,526 μg/oz), and Area Treated (23,225 cm 2 ) = volume treated (200 ft 3 ) / ceiling height (8 ft) x conversion factor (929 cm 2 /ft 2 );

Table 6.2.2 lists the residential post

- application exposures and risk estimates from the other existing residential uses of dinotefuran. Because no dermal or inhalation endpoints were chosen for dinotefuran post

- applica tion residential dermal and inhalation exposure scenarios were not assessed. As a result, risk assessments were only completed for post

- application scenarios in which incidental oral exposures are expected. The post

- application exposure and risk estimate s for all existing residential uses resulted in risk estimates that are not of concern (MOEs ranged from 1,100 to 5,900,000).

Table 6.2.2. Residential Post

- Application Short

- Term Oral Exposure and Risk Estimates
for Children to Dinotefuran.

Scenario Formu

lation Application

Rate Amount

Treated Activity Current Assessment Daily Dose (mg/kg/day) MOE 1

Turf Granular 0.52 lb ai/A 0.5 A Oral ingestion of granules 0.11 1100

Oral hand

- to

- mouth 0.00076 1.3E+5 Oral object

- to

- mouth 0.00027 4.3E+5 Oral ingestion of soil 1.7E

- 5 5.9E+6Page 21 of 36 Table 6.2.2. Residential Post

- Application Short

- Term Oral Exposure and Risk Estimates

for Children to Dinotefuran.

Scenario Formu

lation Application

Rate Amount

Treated Activity Current Assessment Daily Dose (mg/kg/day) MOE 1

Liquid 0.54 lb ai/A 0.5 A Oral hand

- to

- mouth 0.0079 1.3E+4 Oral object

- to

- mouth 0.00024 4.1E+5 Oral ingestion of soil 1.8E

- 5 5.7E+6

Ant Bait Granular 0.00005 Fraction of ai in granular Oral ingestion of granules 0.0011 1.1E+5

RTU Garden Trigger Sprayer Liquid 0.042 lb ai/gal 1 gal No post

- application

exposure NA 2 NA

Dog Spot

- On Liquid 80.7 mg
ai/treatment 1 tube

Oral hand

- to

- mouth 0.00066 1.5E+5

161.6 mg

ai/treatment 1 tube 0.00057 1.8E+5

193.8 mg

ai/treatment 1 tube 0.00043 2.3E+5

Cat Spot

- On Liquid 192 mg

ai/treatment 1 tube

Oral hand

- to

- mouth 0.0019 5.3E+4

320 mg

ai/treatment 1 tube 0.002 5.1E+4

Indoor

Broadcast 0.25%

Aerosol 0.0033 lb

ai/can or 0.61 μg ai/cm 2 or 1.24E

- 6 lb

ai/ft 2 1 20

- oz can/2646

ft 2 Oral hand

- to

- mouth on
carpet 0.0036 2.8E+4

Oral hand

- to

- mouth on

hard surface 0.0012 8.3E+4

Object

- to

- mouth on
carpet 0.00046 2.2E+5

Object

- to

- mouth on hard

surface 0.00034 3.2E+5

Indoor Crack

& Crevice 0.5%

Aerosol 0.00626 lb ai/can or 0.3 ug

ai/cm 2 NA Oral hand

- to

- mouth on
carpet 0.0018 5.6E+5

Oral hand

- to

- mouth on

hard surface 0.00059 1.7E+5

Object

- to

- mouth on
carpet 0.00024 4.2E+5

Object

- to

- mouth on hard

surface 0.00016 6.4E+5

Dust 0.25 μg ai/cm 2 NA Oral hand

- to

- mouth on
carpet 0.0015 6.8E+4

Oral hand

- to

- mouth on

hard surface 0.00049 2.0E+5

Object

- to

- mouth on
carpet 0.00020 5.1E+5

Object

- to

- mouth on hard

surface 0.00013 7.6E+5

1 Scenarios for the incidental oral ingestion of granules use the dietary acute oral point of departure of 125 mg/kg/day. All other scenarios use the short

- term incidental oral point of departure of 99.7 mg/kg/day.

2 NA = not applicablePage 22 of 36 6.3 Combined Exposure

FQPA requires that residential exposures that could reasonably be expected to occur on the same day be combined and compared to the appropriate toxicity endpoint. The exposure estimates from use of the total release fogger product are higher than those fr om other existing residential uses. Additionally, co

- occurrence with the existing cat spot

- on use is possible, since both uses

can be for the treatment of fleas. Co

- occurrence with the existing indoor broadcast use would not be probable, because if you w ere fogging an area you would not also apply a broadcast treatment. The combined exposure estimate from the cat spot

- on (0.002 mg/kg/day) and total release fogger (0.08605 mg/kg/day) use is 0.08805 mg/kg/day. T his combined exposure estimate provides the worst case residential exposure estimate and is recommended for use in the dinotefuran aggregate risk assessment.

6.4 Residential Bystander Post

- Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation bystander exposure assessment was not performed for dinotefuran at this time. Although volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applications, quantificati on of short

- or intermediate

- term inhalation risk is not required for dinotefuran because no systemic toxicity or portal of entry effects were seen following repeated inhalation exposure at the highest practical concentration obtainable in the respirable r ange.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application (a method proposed to be employed for dinotefuran), but, to a lesser exten t, could also be a potential source of exposure from the ground application method also employed for dinotefuran. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation

and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its ev aluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applie d 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 with specific products with significant

risks associated with d rift. Also, note that the residential uses of dinotefuran resulted in risk estimates of no concern, i.e., incidental oral MOEs range from of 1100 to 5,900,000.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider a nd aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitativePage 23 of 36 estimates of hazard (e.g. a N OAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For dinotefuran, potential exposures from food, drinking water and

residential scen arios were aggregated.

The most recent a ssessment s ha ve considered the changes in the new residential SOPs implemented in January of 2012. HED f ound no changes that would affect the aggregate safety finding and confirms that there are no risks of concern resulting from the existing occupat ional and residential uses nor from utilizing the new residential SOPs to estimate residential exposure

and risk.

7 .1 Acute Aggregate Risk

The aggregate acute risk estimates include exposure to residues of dinotefuran in food and drinking water , and does not include dermal, inhalation, or other incidental oral exposure. The acute risk estimate for the U.S. popu lation and all other population subgroups, resulting from aggregate exposure to dinotefuran in food and drinking water, is not of concern. The food and drinking water exposure estimates are 3. 7 % of the aPAD for the general U.S. population, and

12 % for the most highly exposed subgroup, children 1

- 2 years old

.

7.2 Short

- Term Aggregate Risk

There is potential short

- term exposure to dinotefuran via dietary (which is considered background exposure) and residential (which is considered primary exposure) pathways. For adults, these pathways lead to exposure via dietary oral (background) as well as dermal and inhalation routes. However, as explained previously, there were no dermal or inhalation toxicity endpoints identified. Therefore, no short

- term agg regate assessment is needed for adults. For children, the pathways that lead to exposure are dietary oral (background) as well as dermal and oral routes. The most conservative exposure estimate for child oral hand to

- mouth exposure is 0.08805 mg/kg/day. For a description of the residential exposure scenarios considered in the aggregate assessment, see Section 6.0.

The aggregate MOE for childr en 1

- 2 years old is 6 90, which indicates that exposure and risk are

not of concern.

Table 7.2. Shor t

- Term Aggregate Risk Calculations.

Population & Activity NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential Exposure mg/kg/day 3 Total Exposure mg/kg/day 4 Aggregate MOE (food,

water and residential) 5

Children 1

- 2 yrs,

hand

- to

- mouth

exposure 99.7 100 0.997 0.0 566 50 0.08805 0.1 44 70 6 90

1 LOC includes standard inter

- (10X) and intra

- (10X) species uncertainty factors totaling 100.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral Exposure]. Source of residential exposure values used in aggregate assessment (Tables 6.2.1 and 6.2.2).Page 24 of 36 4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)], NOAEL=99.7 mg/kg/day.

7.3 Intermediate

- Term Aggregate Risk

Intermediate

- term exposure is not expected for the adult residential exposure pathway. Therefore, the intermediate

- term aggregate risk would be equivalent to the c hronic dietary exposure estimate. For children, intermediate

- term incidental oral exposures could potentially occur from indoor uses. However, while it is possible for children to be exposed for longer durations, the magnitude of residues is expected to be lower due to dissipation or other activities.

Since incidental oral short

- and intermediate

- term toxicity endpoints and points of departure are the same, the short

- term aggregate risk estimate, which includes the highest residential exposure estimate, is protective of any intermediate

- term exposures.

7.4 Chronic Aggregate Risk

Chronic exposure is not expected for the adult residential (dermal and inhalation) exposure pathway. Therefore, the chronic aggregate risk would be equivalent to the chronic dietary exposure estimate. Refer to Section 5.4.3 for the chronic dietary (food and drinking water)
exposure assessment.

7.5 Cancer Aggregate Risk

Dinotefuran is considered “not likely to be carcinogenic to humans;” therefore, an aggregate

c ancer risk assessment has not been conducted.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxi city finding as

to dinotefuran and any other substances and dinotefuran 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 dinotefuran has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have

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

.

9.0 Occupational Exposure/Risk Characterization

Application methods, maximum application rates and use sites are summarized in Section 3.3. Based on the proposed use patterns of dinotefuran, t here is a potential for occupa tional short

- and

intermediate

- term dermal and inhalation exposure s during handling (mixing & loading) and post

application activities. Chronic exposure is not expected for the proposed use patterns

.Page 25 of 36 As previously discussed in Se ction 4.0

, dermal and inh alation exposures were not assessed

because no hazard was identified.

10. 0 References

B. O’Keefe, DP398048, 8/31/12. Dinotefuran: Human Health Risk Assessments for Proposed Section 3 Uses on Rice and Food/Feed Handling Establishments, and New Horse Spot

- On and Total Release Fogger Products.

B. O’Keefe, DP391885, 7/20/12. Dinotefuran : Human Health Risk Assessment for Proposed

Section 3 Uses on Tuberous and Corm Vegetables Subgroup 1C, Onion Subgroup 3

- 07A, Onion Subgroup 3

- 07B, Small Fruit Subgroup 1 3

- 07F, Berry Subgroup 13

- 07H, Peach, and Watercress, And a Tolerance on Imported Tea.

B. O’Keefe, DP388993, 5/31/11. Dinotefuran ID#: 11VA02 Section 18 Emergency Exemption for Use on Pome Fruits and Stone Fruits in Virginia, New Jersey, Pennsylvania, Maryland, Delaware, West Virginia, and North Carolina to Control Stink Bugs.

C. Walls, DP 398050 , 8/ 20 /12

. Dinotefuran: Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for a Section 3 Registration Action on Rice and

Uses in Food

- Handling Establishments

.

J. Wolf, J. Hetrick , DP39 7490, 8 / 7 /1 2 . Tier I Drinking Water Concentrations for Dinotefuran for

Section 3 N e w Use on R ice

.

L. Cheng, D389492, 4/12/12. D inotefuran. Petition for the Establishment of Permanent Tolerances on Tuberous and Corm Vegetables Subgroup 1C, Onion Subgroup 3

- 07A, Onion Subgroup 3

- 07B, Small Fruit Subgroup 13

- 07F, Berry Subgroup 13

- 07H, Peach, Watercress, and Tea (Import). Summary of Analytical Chemistry and Residue Data.Page 26 of 36 A ppendix A

. Toxicology Profile

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for Food Use for Dinotefuran are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

no

yes yes

yes

yes

-
Yes

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... n/a

no n/a

yes

yes - yes

- yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ .................. no

no

yes

yes

yes -

-

yes

yes

yes

870.7485 General Metabolism

................................ ....................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

yes

yes yes

yes

yesPage 27 of 36 A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile

- Test Substance

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

870.1100 Acute oral, rat 45639823 LD 50 = 2804/2000 [M/F] III

870.1100 Acute O ral, m ouse 45639824 LD 50 =2450/2275 [M/F] III

870.1200 Acute dermal, rat 45639901 LD 50 > 2000 mg/kg IV

870.1300 Acute inhalation, rat 45639902 LC 50 > 4.09 mg/L IV

870.2400 Acute eye irritation, rabbit 46301601 no positive effects IV

870.2500 Acute dermal irritation, rabbit 45639904 low level of irritation IV

870.2600 Skin sensitization, guinea pig 45639905 not a sensitizer n/a

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./

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

870.3100
90

- Day oral toxicity

in rats MRID: 45654205, 45654203 (range

finding) (1997)

Acceptable/Guideline

Dose Levels: 0, 500, 5000, 25,000, 50,000 ppm (dietary); M/F= 34/38, 336/384, 1623/1871, 3156/3616 mg/kg/day NOAEL: 3 36 /384 [M/F] mg/kg

LOAEL: 1623/ 1871 [ M/ F] mg/kg/day based on decreased body weight and body weight gain and histopathological lesions of the adrenal glands in female rats

870.3100

90

- Day oral toxicity

in mice MRID: 45654206, 45654204 (range

finding) (1997)

Acceptable/ Guideline

Dose Levels: 0, 500, 5000, 25,000, 50,000

ppm (dietary); M/F= 81/102, 884/1064, 4442/5414, 10,635/11,560 mg/kg/day NOAEL: 4442/5414 [M/F] mg/kg/day

LOAEL: 10,635/11,560 [M/F] mg/kg/day,

based on decreased body weight and body weight gain

870.3150

90

- Day oral toxicity in dogs MRID: 45639906 (main study), 45639915, 45639916 (range

- finding studies) (1999)

Acceptable/Guideline

Dose Levels: 0, 1600, 8000, 24,000 ppm (dietary); M/F= 0, 58/58, 307/323, 862/950 mg/kg/day NOAEL: 307 mg/kg/day

LOAEL: 862 mg/kg/day, based on decreased body weight gain in males and decreased body weight and body weight gain in

females

.

870.3200

28

- Day dermal toxicity (rats) MRID: 45639908, 456399 0 7 (range

finding) (2001)

Acceptable/Guideline Systemic : NOAEL: 1000 mg/kg/day

LOAEL : Not Established.Page 28 of 36 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./

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

Dose Levels: 0, 40, 200, 1000 mg/kg/day Dermal : NOAEL: 1000 [M], **≤** 200 [F] mg/kg/day

LOAEL: not determined/ **≤** 1000 [M/F] mg/kg/day based on lack of effects in males,

and acanthosis/ hyperkeratosis in high dose females (lower doses not evaluated histopathologically)

.

870.3465

28

- Day inhalation toxicity (rat) MRID: 45639909, 46072401 (2002)

Acceptable/Guideline

Dose Levels: 0, 0.22, 0.66, 2.08 mg/L (nose

- only); M/F= 0, 60, 179, 565 mg/kg/day NOAEL: 2.08 [ M/ F] mg/L or 565 mg/kg/day; HDT

LOAEL: not identified

Note: The concentration tested is the highest practical concentration obtainable in the respirable rang e.

870.3700a

Prenatal developmental toxicity study (rats) MRID: 45654207, 45639910 (range

finding) (1998)

Acceptable/Guideline

Dose Levels: [F] 0, 100, 300, 1000 mg/kg/day Maternal
NOAEL: 1000 mg/kg/day , HDT

LOAEL: Not Established

Developmental NOAEL: 1000 mg/kg/day

LOAEL: Not Established

870.3700b

Prenatal developmental toxicity study (rabbits) MRID: 45654208 (main study), 45639911, 45639912 (range

- finding studies) (1998)

Acceptable/Guideline

Dose Levels: 0, 52, 125, 300 mg/kg/day Maternal
NOAEL: 125 mg/kg/day

LOAEL: 300 mg/kg/day based on clinical signs indicative of neurotoxicity ( i.e., hypoactivity, prone position

, tremors )

Developmental NOAEL: 300 mg/kg/day
LOAEL: Not Established

870.3800 Reproduction and fertility effects (rats) MRID: 45639913, 45639914 (range

finding) (2002)

Acceptable/Guideline

Dose Levels: 0, 300, 1000, 3000, 10,000 ppm (dietary); M/F: 0, 24.1/26.8, 79.9/90.1, 241.0/267.9, 822.1/907.0 mg/kg/day Parental/systemic NOAEL: 241/268[M/F] mg/kg/day LOAEL: 822/907[M/F] mg/kg/day, based on a transient decrease in food consumption and decreased premating weight gain in F 0 males, observations of soft feces in F 0 females and decreased thyroid weights in F 1 females.

Offspring NOAEL: 241/268 [M/F] mg/kg/day

LOAEL: 822 / 907 [M/F] based on decreased body weights, body weight gains, and decreased forelimb grip strength (F 1 male s) or hindlimb grip strength (F 1 females).Page 29 of 36 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./

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

Reproductive NOAEL: 241/268 [M/F] mg/kg/day LOAEL: 822/907 [M/F] mg/kg/day, based on decreased uterine weights and microscopic alterations in the uterus and vagina of F 0 females, decreased numbers of primordial follicles in F 1 females, altered estrous cyclicity in F 0 and F 1 females, slight increases in abnormal sperm morphology in

F 0 and F 1 males, and slight decreases in testicular sperm count in F 0 males and sperm motility in F 1 males.

870.4100b

Chronic toxicity (dogs) MRID: 45654209 (1999)

Acceptable/Guideline

Dose Levels: 0, 640, 3200, 16,000 ppm (dietary); M/F= 0, 20/22, 111/108, 559/512 mg/kg/day NOAEL: 559/512 [M/F] mg/kg/day ; HDT

LOAEL: Not Established

870.4200b Carcinogenicity (mice) MRID: 45639917 (2000)

Acceptable/Guideline

Dose Levels: 0, 25, 250, 2500, 25,000 ppm (dietary); M/F: 0, 3/4, 34/45, 345/441, 3694/4728 mg/kg/day NOAEL: 3694/4728 [M/F] mg/kg/day

LOAEL: Not Established

870.4300
Combined chronic toxicity/ carcinogenicity (rats) MRID: 45640001 (2000)

Acceptable/Guideline

Dose Levels: 0, 60, 200, 2000, 20,000 ppm (dietary); M/F: 3.0/3.9, 9.9/12.5, 99.7/127.3, 991/1332 mg/kg/day NOAEL: 99.7/127.3 [M/F] mg/kg/day LOAEL: 991/1332 [M/F] mg/kg/day based on decreased body weight gain and nephrotoxicity.

870.5100

Bacterial reverse

mutation test MRID: 45640003 (1996)

Acceptable Negative. ± S9 up to 16,000 μ g/plate

870.5100

Bacterial reverse

mutation test MRID: 45654210 (1996)

Acceptable Negative. ± S9 up to limit dose of 5000

μ g/plate

870.5300

In vitro mammalian cell gene mutation MRID: 45640002 (2002)

Acceptable Negative, ± S9 up to 2002 μ g/mL

(Mouse lymphoma L5178Y cells)Page 30 of 36 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./

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

test

870.5375

In vitro mammalian

chromosome

aberration test MRID: 45654211 (1996)

Acceptable Negative for clastogenic/aneugenic activity up to 2000 μ g/mL

(CHL/IU cells)

870.5395

In vivo mammalian cytogenics

- micronucleus assay MRID: 45654212 (1995)

Acceptable Negative at oral doses up to 1080 mg/kg/day for 2 days

870.6200a Acute neurotoxicity screening battery MRID: 45640005 (2001)

Acceptable /Guideline

Dose Levels: 0, 325, 750, 1500 [M/F] mg/kg/day NOAEL: 750 [M], 325 [F] mg/kg/day LOAEL: 1500 [M], 750 [F] mg/kg/day based on decreases in motor activity in both sexes on Day 1

.

870.6200b

Subchronic neurotoxicity screening battery MRID: 45640004 (2001)

Acceptable/Guideline

Dose Levels: 0, 500, 5000, 50,000 ppm (dietary); M/F= 0, 33/40, 327/400, 3413/3806 mg/kg/day NOAEL: 33/40 [M/F] mg/kg/day LOAEL: 327/400 [M/F] mg/kg/day based on

decreased motor activity

.

870.6300 Developmental neurotoxicity study (rats) MRID 48291601 (2010)

Acceptable / Guideline

Dose: 0, 1000, 3000 or 10000

Gestation/Lactation = 0 , 79.4/158, 237.4/500.7 or 784.1/1642.9 mg/kg/day Maternal NOAEL: 784 mg/kg/day

Maternal LOAEL: Not Established

Offspring NOAEL = 784 mg/kg/day

. Offspring LOAEL: Not Established.

870.7485

Metabolism and pharmacokinetics (rats) MRID: 45640006

Acceptable/Guideline Dose: single 50 or 1000 mg/kg oral or 50 mg/kg IV treatments or multiple oral 50 mg/kg treatments with MTI

- 446 (dinotefuran, >98% a.i., batch numbers VB9304, VB9302 (radiolabeled in the guanidine and furan posit ions) and 22

- 00210 & OFU

- 1265 (unlabeled) Absorption was > 90% regardless of dose. The radiolabel was widely distributed through the body and was completely

excreted within 168 hours of treatment. Urine was the primary elimination route, accounting for 88

- 99.8%. Excretion into the urine was rapid, being 84

- 99% complete within 24 hours of treatment. Absorption of the radioactivity was linear within the dose range of 50 and 1000 mg/kg. Elimination of radioactivity was fast for all groups with a

T

1⁄2 rangi ng from 3.64 to 15.2 hours for the low and high doses, respectively. Radioactivity was rapidly transferred from maternal blood to milk and widely

distributed in the fetal tissues. The C

max forPage 31 of 36 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./

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

milk and fetal tissues was detected 0.5 hours

after maternal t reatment. The concentra tions of radioactivity in fetal tissue and maternal milk declined quickly and were below detection limits 24 hours post

- treatment. After IV or oral treatment, 75

- 93% of the administered radiolabeled test material, or nearly 93

- 97% of total urinary radiolabel, was excreted unchanged in the urine. The parent compound was also the primary component in the plasma, milk, bile, feces,

and most tissues collected 4

- 8 hours after

treatment and at both dose levels. Less than 10% of the par ent compound was

metabolized into numerous minor metabolites that were not well resolved by

HPLC or 2D

- TLC. For all parameters measured in this study, no sex

- or dose

related differences or label position effects

were found.

870.7600 Dermal penetration 47013401 A dermal absorption factor (DAF) of 1.71% represents the radioactivity absorbed and remaining on the skin after removal of the stratum corneum, following a 10 hour exposure to 3.2 **μ** g/cm 2

870.7800 Immunotoxicity in

Rats MRID 48442101 (2010)

Acceptable/Guideline

Dose: 0, 2240, 5600 or 14000 ppm
M/F= 0, 164/179, 425/430, 992/1018 mg/kg/day Systemic

NOAEL : 425/430 [M/F] mg/kg/day

. LOAEL : 992/1018 [M/F] mg/kg/day based on decreased body weight, body weight gain, and food consumption.

Immunot oxicity

NOAEL : 992/1018 [M/F] mg/kg/day

LOAEL : Not Established

870.7800 Immunotoxicity in

Mice MRID 48442102 (2010)

Acceptable/Guideline

Dose: 0, 1120, 2800 or 7000 ppm
M/F= 0, 153/223, 405/581, 1053/1438 mg/kg/day Systemic

NOAEL : 1053/1438 [M/F] mg/kg/day

. LOAEL : Not Established

Immunotoxicity

NOAEL : 1053/1438 [M/F] mg/kg/day

. LOAEL : Not Established

Special study:

Neonatal rat metabolism study (12

- day old rat pups) MRID: 45640007

Acceptable/Non

- guideline

Dose: 50 mg/kg radiolabeled MTI

- 446 (dinotefuran, Lot No. VB9304, labeled on the central guanidine portion of the mole

cule, purity and radio purity >99% After a single oral 50 mg/kg dose of [G

14 C]

MTI

- 446 to 12

- day

- old rats, absorption was high (absorption could not be adequately determined but may have approached 80%)

and the radio label was widely distributed within the body. Approximately 32

- 36% of

the administered dose was excreted within 4 hours of treatment. Urine was the primary elimination route as indirectly evidenced byPage 32 of 36 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./

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

finding high radioactive areas in the kidneys and bladder by whole body autoradiography. No areas of tissue seques tration were found and no gender

- related differences were identified. The test material was essentially not metabolized, the parent compou nd accounting for >97% of the radiolabel in the excreta, plasma, kidneys, and stomach, and nearly 61

- 83% in intestines (and contents),

and liver.

Special study: Developmental Immunotoxicity Study in Rats MRID: 47677501

Acceptable/Non

- guideline

Dose: 0, 1000, 3000 or 10000 ppm which

are equivalent to 0, 105.4, 317.8 or 1035.4 mg/kg/day, respectively. Maternal

NOAEL: 1035.4 mg/kg/day

. LOAEL: Not Established

Offspring NOAEL: 317.8 mg/kg/day. LOAEL: 1035.4 mg/kg/day based on decreased pup body weight.

Immunotoxicity
NOAEL: 1035.4 mg/kg/day

. LOAEL: Not EstablishedPage 33 of 36 Appendix B. Physical/Chemical Properties

TABLE B . Physicochemical Properties of the Test Compound: Dinotefuran.

Parameter Value Reference (MRID)

Melting point/range 107.5oC 45639702

pH 5.6 @ 25oC 45654201
Density 1.40 g/cm 3 @ 20oC 45639702

Water solubility ( 20°C) 39.83 x 10 3 mg/L (pH 6.98) 45639702

Solvent solubility (mg/L at 20°C) g/100 mL Solvent 45639702

Hexane 9 x 10 - 7

Heptane 1.05 x 10
- 6

Xylene 0.0072

Toluene 0.0149

Dichloromethane 6.45

Acetone 6.13

Methanol 6.00

Ethanol 2.01

Ethyl Acetate 0.52

Vapor pressure at 30°C < 1.7 x 10 - 6 Pa @ 25oC 45639702

Dissociation constant (pK

a ) 12.6 @ 20oC (estimated) 45639702

Octanol/water partition coefficient Log(K OW )

- 0.549 (K

ow = 0.283) @ 25oC 45639702
UV/visible absorption spectrum Media Absorbance

Maximum

268 nm €

max : Molar

Absorbance

Coefficient 45639702

Acidic 1.0469 12,600

1.0180 12,300

Neutral 1.3017 12,500

1.2668 12,300

Basic 0.8869 10,700

0.9662 11,700Page 34 of 36 Appendix C

. Dinotefuran and Metabolites

Common name/code Chemical name Chemical structure

Dinotefuran; MTI

- 446 N

- methyl

- N  ́

- nitro

- N  ̋

- [(tetrahydro

3

- furanyl) methyl] guanidine

UF 1

- m ethyl

- 3

- (tetrahydro

- 3

- furylmethyl)

- urea

DN 1

- m eth yl

- 3

- (tetrahydro

- 3

- furylmethyl) guanidine

N H

N H N H O

C H 3 N H

O N H O

C H 3 N H

N N H O

C H 3

N

O 2Page 35 of 36 Common name/code Chemical name Chemical structure

PHP 6

- h ydroxy

- 5

- (2

- hydroxyethyl)

- 1

- methyl

- 1,3

- diazinane

- 2

- ylidene

- N

nitroamine

FNG 2

- nitro

- 1

- (tetrahydro

- 3

- furylmethyl)guanidine

MNG 2

- nitro

- 1

- methylguanidinePage 36 of 36 Appendix D

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, including studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agr icultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; and the Agricultural Re

- entry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, a nd are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can

be found at http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- da ta.html

.

The following studies were reviewed for ethical conduct:

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database , Version 1.1. Electronic Database. Task Force members Health Canada, U. S. Environmental Protection Agency, and the Nati onal Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011.

Data from the Outdoor Residential Exposure Task Force (ORETF).