Page 3 of 69

5.1.2 Summary of Environmental Degradation

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

5.1.3 Comparison of Metabolic Pathways

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

5.1.4 Residues of Concern Summary

................................ ................................ ............ 25

5.2 Food Residue Profile

................................ ................................ ................................ .... 25

5.3 Water Residue Profile

................................ ................................ ................................ .. 29

5.4 Di etary Risk Assessment

................................ ................................ .............................. 31

5.4.1 Description of Residue Data & Percent Crop Treated Used in Dietary

Assessment

................................ ................................ ................................ ........................... 31

5.4.2 Acute Dietary Risk Assessment

................................ ................................ ........... 31

5.4.3 Chronic Dietary Risk Assessment

................................ ................................ ....... 31

5.4.4 Summary Table

................................ ................................ ................................ ..... 31

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 32

6.1 Residential Handler Exposure

................................ ................................ .................... 32

6.2 Post

- Application Exposure

................................ ................................ .......................... 33

6.3 Combined Exposure

................................ ................................ ................................ ..... 34

6.4 Residential Bystander Post

- Application Inhalation Exposure

................................ 34

6.5 Spray Drif

t

................................ ................................ ................................ .................... 34

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 34

7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 35

7.2 Short

- Term Aggregate Risk

................................ ................................ ........................ 35

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ........... 36

7.4 Chronic Aggregate Risk

................................ ................................ .............................. 36

7.5 Cancer Aggregate Risk

................................ ................................ ................................ 36

8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 36

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 36

9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ... 37

9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................... 37

10.0 References

................................ ................................ ................................ ......................... 37 Appendix A. Toxicology Profile

................................ ................................ ................................ 38

A.1 Toxicology Data Requirements

................................ ................................ ................... 38

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 39

A.3 Hazard Identification and Endpoint Selection

................................ .......................... 44

A.4 Executive Summaries

................................ ................................ ................................ ... 47 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 66 Appendix C. International Residue Limit Status Sheet.

................................ ........................ 67 Appendix D. Dinotefuran and Metabolites

................................ ................................ .............. 68 Appendix E. Review of Human Research

................................ ................................ ................ 69Page 4 of 69

1.0 Executive 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 neonicotiniod class of insecticides. It is insecticidal by contact and ingestion, resulting in the cessation of insect feeding within hours of contact and death shortly thereafter by i nterfering with the acetylcholine receptor on the post

synaptic side of the nerve cells.

The Interregional Research Project No. 4 (IR

- 4) submitted a petition (#1E7863) proposing new

uses and requesting the establishment of tolerances for the residues of dinotefuran on the following crops and crop groups: berry, low growing, except strawberry, subgroup 13

- 07H; fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; onion, bulb, su bgroup 3

- 07A; onion, green, subgroup 3

- 07B; vegetable, tuberous and corm, subgroup 1C; peach; and

watercress. Additionally, the IR

- 4 petition requested the establishment of a tolerance on imported tea.

The most recent human health risk assessment was con ducted for a S ection 18 use on pome fruits and stone fruits to control stink bugs ( B. O’Keefe, D P388993, 5/31/11)

. Since the last risk

assessment, HED has re

- evaluated the dinotefuran toxicological database and updated the hazard

characterization and dose respo nse assessment. This toxicology database reevaluation has resulted in changes to the toxicity endpoints, points of departure, and safety factors for several routes of exposure from those presented in previous HED risk assessments.

Use Profile

IR

- 4 has submitted an application for a Section 3 registration of three water

- dispersible granule (WDG) formulations (D INOTEFURAN 20SG, EPA Reg. No. 86203

- 12; STARKLE 70SG, EPA Reg. No. 86203

- 23; D INOTEFURAN 70SG, EPA Reg. No. 59639

- 135) to control sucking and chewing insects infesting the following crops and crop groups: low growing berry subgroup, except strawberry; small fruit vine climbing, except fuzzy kiwifruit; bulb and green onions; peach and nectarine; tuberous and corm vegetables; and watercress. The proposed maximum rates are 0.338 lb ai/A per application and per season when applied to the soil using ground equipment or 0.18 lb ai/A per application and 0.36 lb ai/A per season when applied to the foliage using aerial or ground equipment. The proposed labels also state that “Regardless of application method, the maximum application rate is 0.54 lb ai/A/season.” Pre

- harvest intervals (PHIs) range from 1 to 21 days. Retreatment intervals (RTIs) range from ≥7 to ≥14 days. For handlers, personal protecti ve equipment (PPE) includes long

- sleeved shirt and long pants, shoes plus socks, and chemical resistant gloves. The full use profile for dinotefuran is

shown in Section 3.3.

Toxicity/Hazard The toxicology database is adequate for characterization of haza rd. The main target of toxicity is the nervous system. Nervous system toxicity was manifested as clinical signs and decreased motor activity seen after acute dosing (in both rats and rabbits) and changes in motor activity

which are consistent with effect s on the nicotinic cholinergic nervous system seen after repeatedPage 5 of 69

dosing. Dinotefuran was well tolerated at high doses following dietary administration for ninety days to mice, rats and dogs. The principal toxicological findings were decreases in body we ight and/or body weight gain at or near the Limit Dose. No systemic or neurotoxicity was seen following repeated dermal applications at the Limit Dose to rats for 28 days. No systemic or portal of entry effects were seen following repeated inhalation exp osure 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 repro ductive 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.

There 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 Dose. 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 FQPA Safety Factor can

be re duc ed to 1X

.

For acute 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 NOAEL of 125 mg/kg/day in a developmental toxicity study in rabbits based on clinical signs indicative of neurotoxicity (hypo activity, prone position, panting, tremors) obse rved at 300 mg/kg/day (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 (chronic toxicity/carcinogeni city study in rats) based on decreased body weight gain, and food efficiency in females and increased incidences of kidney pelvic mineralization and ulceration in males at 991 mg/kg/day (LOAEL).

For incidental oral exposure scenarios, the NOAEL of 99.7 mg/kg/day established in the combined chronic toxicity/carcinogenicity study was selected to assess risk from both short

- and intermediate term exposures.

Quantification of short

- or intermediate

- term dermal risk is not required. No systemic toxicity

wa s seen at the Limit Dose in an acceptable dermal toxicity study in rats and there are no developmental or reproductive toxicity concerns. Additionally, the potential for neurotoxicity was evaluated in the dermal study and no treatment

- related effects were seen in any of the neurological parameters. Further, no increase in toxicity with duration was observed throughout the toxicology database for dinotefuran. Therefore, it is reasonable to attribute no hazard to

intermediate

- term exposure based on a 28

- da y dermal toxicity study.

Quantification of short

- or intermediate

- term inhalation risk is not required. No systemic toxicity or portal of entry effects were seen following repeated inhalation exposure at the highestPage 6 of 69

practical concentration obtainable in the respirable range. No effects were seen at doses approximately 100,000 times greater than the greatest expected human exposure. Although neurotoxicity was not specifically evaluated in this study, effects of increased/decreased motor activity, pantin g, tremor and prone position would be evident with clinical observation if present. Since no increase in toxicity with duration was observed throughout the toxicology database for dinotefuran this study is also appropriate for intermediate

- term inhalation exposure.

Dietary Exposure (Food and Water)

The results of the acute dietary analysis for food and drinking water show that the acute dietary

risk estimates are well below the Agency’s level of concern (<100% of the acute population adjusted dose ( a PAD ) ) for all population subgroups and were estimated at 2.2 % of the a PAD for

the U.S. general population and 5 .8 % of the a PAD for the most highly exposed population subgroup (children 1

- 2 years old). The results of the chronic dietary analysis for food and

dr inking water indicate that the chronic dietary risk estimates are well below the Agency’s level of concern (<100% of the chronic population adjusted dose ( c PAD)) for all population subgroups

and w ere estimated at <1 % of the c PAD for the U.S. general popula tion and 2

. 6 % of the c PAD for the most highly 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

A ll of the existing residential use patterns have been reassessed for residential handler and post

application exposures using the new residential standard operating procedures (SOPs) and body weights used in all human health risk assessments. There are currently registered uses of dinotefuran on several residential use sites, including turf, ornamentals, vegetable gardens, pets, indoor aerosol sprays, crack and crevice sprays, etc. Short

- t erm incidental oral exposures were assessed using the s hort

- term point of departure of 99.7 mg/kg/day. The new exposure and risk estimates for all residential post

- application scenarios are not of concern to HED (MOEs ranged

from 1100 to 5,900,000 ).

Aggregate Exposure The aggregate acute and chronic dietary risk estimates for all populations, resulting from aggregate exposure to dinotefuran in food and drinking water are not of concern. For children, a

short

- term aggregate risk assessment was performed for the post

- application scenario resulting in the great est exposure, resulting in a MOE of 3,000

, which is greater than 100, and therefore not
of concern. For adults, no aggregate risk assessment was performed

, 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 inhal ation route s of exposure , dermal and

inhalation risks were not assessed.Page 7 of 69

Occupational post

- application dermal exposures are possible following applications to the proposed crops. However, since no hazard was identified for the dermal route of exposure

de rmal post

- application exposures were not estimated. Since no hazard was identified for the inhalation route of exposure, and dinotefuran has low acute inhalation toxicity (Toxicity Category I V ) and a low vapor pressure ( 1 .2 8 x10 - 8 mm Hg), post

- application inhalation exposures

and risks we re not quantitatively assessed.

Technical dinotefuran has a Toxicity Category IV for acute dermal, primary skin irritation, and primary eye irritation. Per the Worker Protection Standard (WPS), a 12 hour restricted entry interval (REI) is required for chemicals classified under Toxicity Category IV. Therefore, the REI of 12 hours appearing on the proposed dinotefuran label is adequate.

2.0 HED Recommendations

HED recommends the registration request be granted for dinotefuran use on berry, low growing, except strawberry, subgroup 13

- 07H; fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; onion, bulb, subgroup 3

- 07A; onion, green, subgroup 3

- 07B; vegetable, tuberous and corm, subgroup 1C; peach; an d watercress

. Additionally, HED recommends the establishment of an import tolerance for tea. HED also recommends that the use profile of

dinotefuran be updated to incorporate the recent revisions to various crop groups , along with the

tolerance revisions requested in Section 2.2.3.

2.1 Data Deficiencies/ Prior Conditions of Registration

There are no data deficiencies at this time.

2. 2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Parent dinotefuran and the metabolites DN and UF are the residues of concern in plant commodities for tolerance setting purpose. There are analytical methods available for enforcement: a high performance liquid chromatography/tandem mass spectrometry (HPL C/MS/MS) method for the 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 the determination of DN and UF. These methods have been deemed acceptable for tolerance enforcement by the EPA for residues in plant

commodities.

Dinotefuran is the residue of concern in livestock commodities for tolerance setting. A liquid chromatograp h y/mass spectrometry/ mass spectrometry ( LC/MS/MS ) method is adequate for the determination of residues of dinotefuran, DN, and UF in livestock commodities. Method validation data demonstrated acceptable recoveries of dinotefuran and its metabolites DN and UFPage 8 of 69

in milk, cream, cattle liver, kidney , muscle, and fat, and poultry eggs. The LC/MS/MS method is adequate for tolerance enforcement.

Dinotefuran is not adequately recovered using any of FDA’s multi

- residue methods. Although

no multi

- residue method data have been submitted for the DN and U F metabolites, HED do es not expect any of the FDA Protocols to recover these metabolites due to the structural similarities of the metabolites with the parent.

2.2.2 International Harmonization

There are currently no established Codex, Canadian, or Mexic an maximum residue limits (MRLs) for dinotefuran. An International Residue Limits (IRL) Status sheet is attached to this review as Appendix C.

2.2.3 Recommended Tolerances

Pending submission of a revised Section F , there are no residue chemistry issues that will preclude establish ment of permanent tolerance s for dinotefuran in/ on the following crops or crop groups/subgroups:

Table 2.2.3. Tolerance Summary for Dinotefuran.

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments ( correct commodity definition )

Berry, low growing, except strawberry, subgroup 13

- 07H 0.2 0.2

Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 0.9 0.9 A revised Section F must be submitted to delete the grape tolerance at 0.9 ppm. Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F

Onion, bulb, subgroup

3

- 07A 0.07 0.15 A revised Section F must be submitted to propose a tolerance at 0.15 ppm.

Onion, green, subgroup

3

- 07B 6.0 5.0 A revised Section F must be submitted to propose a tolerance at 5.0 ppm.

Peach 0.9 1.0 A revised Section F must be submitted to propose a tolerance at 1.0 ppm.

Tea, plucked leaves 25 50 Tea, dried

Vegetable, tuberous and corm, subgroup 1C 0.05 0.05 A revised Section F must be submitted to delete the potato tolerance at 0.05 ppm.

Watercress 5.0 8.0 A revised Section F must be submitted to propose a tolerance at 8.0 ppm.

Note to RD: Concomitant w ith the establishment of crop group tolerances for the small fruit subgroup 13

- 07F and tubero us and corm vegetable subgroup 1C, the individual tolerances already established in/on grape and potato should be deleted.Page 9 of 69

2.2.4 Revisions to Petitioned

- For Tolerances

Adequate field trial data are available to support this petition. HED concurs with the tolerance level of 0.2 ppm for the low growing berry (except strawberry) subgroup 13

- 07H as proposed by the registrant. HED concurs with the registrant’s proposal for the establishment of tolerances for the tuberous and corm vegetable subgroup 1C at 0.05 ppm and for the small fruit except fuzzy kiwifruit subgroup 13

- 07F at 0.9 ppm, and concomitant removal of the tolerances for potato and

grape. Use of the O rganization for E conomic C ooperation and D evelopment tolerance

calculat ion procedures indicates that the tolerances for residues in/on the onion subgroup 3

- 07A, onion subgroup 3

- 07B, peach, and watercress should be established at 0.15 ppm, 5.0 ppm, 1.0 ppm, and 8.0 pp m, respectively, instead of those values proposed by the registrant.

For imported tea, the ChemSAC (ChemSAC Meeting Minutes, 3/7/12) noted that residue decline studies were conducted. The ChemSAC decided that two tea trials were sufficient for setting a tolerance on import tea, and the level should be based on dried tea leaves. From the study report it was unclear whether the tea samples analyzed for residues had been dried beforehand. An answer was provided through a contact with a JMPR colleague in J apan. According to a string of email correspondence, the tea leaves in Japan are routinely dried before residue analysis. This information agrees well with a phrase of “covered with the sunshade for 10 days before gather”

stated in the table of results o f the “Dinotefuran: Pesticide Residue Analysis in Tea”, IR

- 4 PR No. 10838. Application of the OECD tolerance calculation procedure to the four residue values available (duplicate sample analysis from two trials) results in a recommended tolerance level of 50 ppm. The ChemSAC concurs with the calculator result. The ChemSAC also concluded that since dried tea is the commodity in commerce, the proper commodity definition should be tea, dried. Additionally, HED notes that the use pattern must stipulate a se asonal maximum rate of 0.356 lb ai/A (0.4 kg/ha) with a 7

- day PHI.

2.3 Petition Recommendations

860.1550 Proposed Tolerances The petitioner must submit a revised Section F to propose the tolerances recommended in

Table 2.2.3.

2. 4 Label Recommendatio ns

2. 4 .1 Recommendations from Residue Reviews

OPPTS 860.1200 Directions for Use The petitioner must submit proposed labels (with English translations) for dinotefuran use on tea in any country from which the treated tea may be imported into the U.S. The available data support application of an SG formulation at a seasonal rate of 0.356 lb ai/A (0.4 kg/ha) with a 7

- day retreatment interval (RTI) and a 7

- day pre

- harvest interval (PHI).Page 10 of 69

With the exception of the cranberry and watercress trials, crop field trials were conducted without an adjuvant added in the spray mixtures. Thus, a statement is needed on the label that prohi bits use of adjuvants when applications are made to the propose d crops except cranberry and watercress. For cranberry and watercress, the label needs to specify that a

non

- ionic surfactant may be added at no higher than 0.25% and 0.125% (v/v), respectively.

For the EPA Reg. No. 59639

- 135, the 70SG label, the p etitio ner needs to revise the PHI for soil application to peach and nectarine from 3 day s to 21 day s , since there are only

soil residue data for the 21

- day PHI.

3.0 In troduction

Dinotefuran is a broad

- spectrum insecticide belonging to the nitroguanidine sub

- cl ass of the neonicotiniod class of insecticides. It is insecticidal by contact and ingestion, resulting in the cessation of insect feeding within hours of contact and death shortly thereafter by interfering with the acetylcholine receptor on the post

- synap tic side of the nerve cells.

Dinotefuran is currently registered for use on numerous agricultural use sites, including:

Brassica l eafy greens, s ubgroup 5 B; c otton ; c ucurbits ; f ruiting v egetables ; g rapes ; h ead & s tem

Brassica v egetables, subgroup 5A; l eafy v egetables, except Brassica , group 4; p otatoes; turnip

g reens ; and g reenhouse g rown t omatoes

. It is also registered on many residential/ non

agricultural use site s, including : t urf, i ndoor (including residential and food and 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.), ant baits, fire ant baits,

pet s pot

- 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

. Dinotefuran formulations include baits, gels, soluble concentrates, granulars, soluble granules, and rea dy

- to

- use (RTU) products, including total

- release foggers and RTU sprays.

IR

- 4

, on behalf of the Agricultural Stations of HI, FL, OR, MA, UT, GA, NJ, MI, SC, ID, TX, OK, and NM

, submitted a petition (#1E7863) proposing new uses and requesting the

establ ishment of tolerances for the residues of dinotefuran on the following crops and crop groups: berry, low growing, except strawberry, subgroup 13

- 07H; fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; onion, bulb, subgroup 3

- 07A; onion, green, subgroup

3

- 07B; vegetable, tuberous and corm, subgroup 1C; peach; and watercress. Additionally, the IR

4 petition requested the establishment of a tolerance on imported tea.

The propose d uses of dinotefuran are expected to result in occupational exposure only; no residential exposure is expected from the proposed uses of dinotefuran

. Only s hort

- and

intermediate

- term occupational exposure s w ere assessed for the proposed uses of dinotefuran

.Page 11 of 69

3.1 Chemica l Identity

The chemical structure and nomenclature of dinotefuran are presented in Table 3.1.

T ABLE 3. 1. Dinotefuran Nomenclature.

Compound Chemical Structure

Common name d inotefuran

Company experimental

name MTI

- 446

IUPAC name ( EZ )

- ( RS )

- 1

- m ethyl

- 2

- nitro

- 3

- (tetrahydro

- 3

- furylmethyl)guanidine

CAS name N

- m ethyl

- N  ́

- nitro

- N  ̋

- [tetrahydro

- 3

- furanyl)methyl] g uanidine

CAS # 165252

- 70

- 0

End

- Use Product DINOTEFURAN 20SG (EPA Reg. No. 86203

- 12), STARKLE 70SG (EPA Reg. No. 86203

- 23), DINOTEFURAN 70 SG (EPA Reg. No. 59639

- 135)

Compound Chemical Structure

Common name DN

IUPAC name 1

- m ethyl

- 3

- (tetrahydro

- 3

- furylmethyl)guanidine

Compound Chemical Structure

Common name UF

IUPAC name 1

- m ethyl

- 3

- (tetrahydro

- 3

- furylmethyl

- urea N H

O N H O

C H 3 N H

N H N H O

C H 3 N H

N N H O

C H 3

N O 2Page 12 of 69

3.2 Physical/Chemical Characteristics

The physi c ochemical properties of dinotefuran are summarized in Appendix B

.

3.3 Pesticide Use Pattern

The IR

- 4, on behalf of the Agricultural Stations of HI, FL, OR, MA, UT, GA, NJ, MI, SC, ID, TX, OK, and NM

, submitted a petition (#1E7863) requesting the establishment of tolerances for the residues of dinotefuran on berry, low growing, except strawberry, subgroup 13

- 07H ; fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F ; onion, bulb, subgroup 3

- 07A ; onion, green, subgroup 3

- 07B ; peach ; watercress ; and vegetable, tuberous and corm, subgroup 1C.

IR

- 4 has submitted an application for a S ection 3 registration of three water

- dispersible granule (WDG) formulations (D INOTEFURAN 20SG, EPA Reg. No. 86203

- 12; STARKLE 70SG, EPA Reg. No. 86203

- 23; D INOTEFURAN 70SG, EPA Reg. No. 59639

- 135) to control sucking and chewing insects infesting low growin g berry subgroup, except strawberry; small fruit vine climbing, except fuzzy kiwifruit; bulb and green onions; peach and nectarine; tuberous and corm vegetables; and watercress. Dinotefuran is proposed for foliar application by ground or aerial

methods. Additionally it is proposed for application to soil for onions and peaches. For handlers, PPE includes long

- sleeved shirt and long pants, shoes plus socks, and chemical resistant gloves. There is a rotational crop restriction that imposes a 120

- day plant

- back interval for crops that are not currently allowed on the label. Table 3.3.1 summarizes the proposed

directions for use.Page 13 of 69

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

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max.

Seasonal Applic.

Rate (lb ai/A) PHI

(days) Use Directions and Limitations

Onion, bulb and green: (bulb)

– Daylily, Fritillaria, Garlic, Garlic (Great

- headed, serpent), Lily, Onion, Onion (Chinese, pearl, potato), Shallot, and Cultivars of these; (green)

– Chive (fresh leaves), Chive (Chinese, fresh leaves), Elegans hosta, Fritillaria leaves, Kurrat, Leady’s leek, Leek, Leek (wild), Onion (Beltsville bunching), Onion (fresh), Onion (green), Onion (macrostem), Onion (tree, tops), Onion (Welsh, tops), Shallot (fresh leaves), Cultivars of these

Foliar,

Broadcast

Ground and

Aerial

Soil, Ground 20% SG

[86203

- 12]

70% SG [86203

- 23]

70% SG [59639

- 135] 0.09

- 0.18

(foliar)

0.225

- 0.27 (soil) Not

specified (NS) 0.27

(foliar)

0.27 (soil) 1

(foliar)

NS (soil) Begin applications when first pest activity is

noticed or when insects reach threshold levels. Apply at 7

- day retreatment intervals. Applications may be made in a minimum of 5 gal/A by air and 20 gal/A by ground.

Apply at planting or immediately after

t ransplanting in a minimum of 10 gal/A.

Regardless of application method, the

combined (soil & foliar) maximum seasonal

rate is 0.383 lb ai/A/season.

Small Fruit Vine Climbing, Except Fuzzy Kiwifruit ; also known as Berry and Small Fruit (Subgroup 13

- 07F): Amur river grape, Gooseberry, Grape, Kiwifruit hardy, Maypop, Schisandra berry, Cultivars, Varieties and/or hybrids of these

Foliar,

Broadcast Ground, Aerial, and

Airblast 20% SG

[86203

- 12]

70% SG [86203

- 23]

70% SG [59639

- 135] 0.045

-

0.135 (foliar)

0.225

– 0.338 (soil) NS (foliar)

1 (soil) 0.27

(foliar)

0.338 (soil) 1

(foliar)

28 (soil) Begin applications when first pest activity is

noticed or when insects reach threshold levels. Apply at 14

- day retreatment intervals. Applications may be made in a minimum of 5 gal/A by air and 50 gal/A by ground.

Regardless of application method, the combined (soil & foliar) maximum application

rate is 0.54 lb ai/A/season

. Low Growing Berry Subgroup, Except Strawberry ; also known as Berry and Small Fruit (Subgroup 13

- 07H): Bearberry, Bilberry, Blueberry lowbush, Cloudberry, Cranberry, Lingonberry, Muntries, Partridgeberry, Cultivars of these

Foliar,

Broadcast Ground, Aerial, and

Airblast 20% SG

[86203

- 12]

70% SG [86203

- 23]

70% SG [59639

- 135] 0.09

- 0.18

(foliar) NS 0.36 7 Begin applications when first pest activity is

noticed or when insects reach threshold levels. Apply at 14

- day retreatment intervals. Applications may be made in a minimum of 5 gal/A by air and 30 gal/A by ground.

Peach and Nectarine

Foliar,

Broadcast Ground, Aerial, and

Airblast

Soil, Ground 20% SG

[86203

- 12]

70% SG [86203

- 23]

70% SG [59639

- 135]* 0.090

-

0.18 (foliar)

0.27 (soil) NS 0.27 (foliar)

0.27 (soil) 3

(foliar)

21 (soil) Begin applications when first pest activity is

noticed or when insects reach threshold levels. Apply at 7

- day retreatment intervals. Applications may be made in a minimum of 5 gal/A by air and 50 gal/A by ground.

For soil treatment, apply in a minimum of 100 gal/A. Regardless of application method, the

maximum seasonal rate is 0.36 lb ai/A/season.

Regardless of application method, the combined (soil & foliar) maximum application

rate is 0.36 lb ai/A/season

.Page 14 of 69

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

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max.

Seasonal Applic.

Rate (lb ai/A) PHI

(days) Use Directions and Limitations

Tuberous and Corm Vegetables (Subgroup 1C) : Arracacha, Arrowroot, Artichoke, Chinese, Artichoke, Jerusalem, Cana, edible, Cassava, bitter and sweet, Chayote (root), Chufs, Dasheen (taro), Ginger, Leren, Potato, Sweet Potato, Tanier, Turmeric, Yam bean, Yam, true

Foliar,

Broadcast Ground, Aerial, and

Airblast 20% SG

[86203

- 12]

70% SG [86203

- 23]

70% SG [59639

- 135] 0.045

-

0.068 (foliar)

0.293

– 0.338 (soil) NS (foliar)

NS (soil) 0.203

(foliar)

0.338 (soil) 7

(foliar)

NS (soil) Do not combine foliar applications with soil applications, or vice versa. Only use one application method. Begin applications when first pest activity is noticed or when insects reach threshold levels. Apply at 14

- day retreatment intervals. Application s may be made in a minimum of 3 gal/A by air and 10 gal/A by ground.

Watercress

Foliar,

Broadcast

Ground and

Aerial 20% SG

[86203

- 12]

70% SG [86203

- 23]

70% SG [59639

- 135] 0.09

- 0.18 NS 0.36 1 Begin applications when first pest activity is

noticed or when insects reach threshold levels. Apply at 7

- day retreatment intervals. Applications may be made in 5

- 10 gal/A by air

and 50

- 300 gal/A by ground.

* Label indicates a 3

- day PHI for soil application.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use s of dinotefuran on the low growing berry subgroup, except strawberry; small fruit vine climbing, exc ept fuzzy kiwifruit; bulb and green onions; peach and nectarine; tuberous and corm vegetables; and watercress ; and the import tolerance for tea

. Humans may be exposed through their diet from applications to agricultural commodities

. Humans may also be ex posed

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

- occupati onal settings. 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 complete d for the existing uses of dinotefuran . This risk assessment considers all of the aforementioned exposure pathways bas ed on the proposed new uses of

dinotefuran , but also considers existing uses of dinotefuran , particula rly in the dietary exposure

assessment.Page 15 of 69

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 Continuing Survey of Food Intake by Individ uals (CSFII) 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, season of the year, ethnic group and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adul t 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 o f 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 neonico tinoid 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 also affected as

demo nstrated in the acute neurotoxicity (ACN), subchronic neurotoxicity (SCN) studies in rats, and developmental toxicity study in rabbits

.

4 .1 Toxicology Studies Available for Analysis

The toxicology database for dinotefuran is adequate for the characterization of its hazard. Available studies include subchronic and chronic oral toxicity studies in rats, mice and dogs, developmental toxicity studies in rats and rabbits, a reproductive toxicity study in rats, acute and subchronic neurotoxicity st udies in rats and immunotoxicity studies in mice and rats

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

4.2 Absorption, Distribution, 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) andPage 16 of 69

intravenous (IV) single dosing. Also performed have been single oral dose studies with pregnant
rats at ges tation 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 relatively fast body

clearance.

The data collected in male and non

- pregnant female ad ult 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) scaled proportionally with increases in administered oral

dose. The radiolabel was wid ely and comparably distributed throughout the body at 30 minutes
post

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

dosing. There was no evidence of specific tissue accumulation; the highest content of

radioactivi ty at 30 minutes was found in the kidneys, probably reflective of the predominant route of excretion being via the urine ( 93%). 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 slightly to 5.6 hrs for males, but remained about the same for females at 6.9 hrs. The predominant species detected in excreta was t he parent chemical (75

- 93% of the administered radiolabel) in both oral and IV administration studies. Minor metabolites identified accounted for only 2

- 6% of the administered radiolabel.

The ADME data collected from the single oral dose study with pregn ant 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; bot h matrices achieved comparable peak levels and at the same first time measurement of 0.5 hours. The clearance of radioactivity from fetal tissues and milk paralleled that of maternal plasma, decreasing by 80% by 4 hours post

- dosing. No measurement of r adioactivity 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 indirectly evidenced by finding high radioactive areas by whole body autoradiography in the kidneys and bladder

. There were no

metab olites reported ; t he parent chemical was the predominant species accounting for >97% of the radiolabel in the excreta, plasma, kidneys, and stomach, and nearly 61

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

- 36% of the administered dose w as excreted within 4

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

elimination as compared to adult animals. The age

- dependent differences in absorption andPage 17 of 69

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

absence of maternal stimulation to elicit excretion

.

4.2.1 Dermal Absorption

A dermal absorption factor (DAF) of 1.71% was determined from a guideline dermal penetration study and represents the radioactivity absorbed and remaining on the skin after removal of the stratum corneum, following a 10 hour exposure to 3.2 g/cm 2 (technical grade active ingredient, TGAI)).

4.3 Toxicological Effects

The main target of toxicity is the nervous system. Nervous system toxicity was manifested as clinical signs and decreased motor activity seen after acute dosing (in both rats and rabb its) and changes in motor activity which are consistent with effects on the nicotinic cholinergic nervous system seen after repeated dosing. In the subchronic neurotoxicity study (SCN), increased motor activity and habituation was observed at the mid

- dose while decreased activity was observed at the high

- dose. Typically, low to moderate activation of nicotinic acetylcholine receptors (nAChR) causes stimulation of the peripheral nervous system (PNS). Whereas high levels of neonicotinoids (agonists) can ov er stimulate the PNS, maintaining cation channels in the open state which blocks the action potential and leads to paralysis. It is pertinent to note that the developing nervous system is not more sensitive to the effects of dinotefuran than the adult

ner vous system; no neurotoxic effects were observed in offspring exposed to dinotefuran perinatally (maternal doses: 748 mg/kg/day, gestation; 1643 mg/kg/day, lactation).

Dinotefuran was well tolerated at high doses following dietary administration for ninet y days to mice, rats and dogs. The principal toxicological findings were decreases in body weight and/or body weight gain at or near the Limit Dose. Changes in spleen and thymus weights were seen in mice, rats and dogs following subchronic and chronic di etary exposures. However, these weight changes were not corroborated with alterations in hematology parameters, histopathological lesions in these organs, or toxicity to the hematopoietic system. Furthermore, the toxicology

data base contains immunotoxic ity studies in mice and rats and a developmental immunotoxicity study in rats. In the immunotoxicity studies there were no effect on T

- cell dependent antibody response (TDAR) when tested up to the Limit Dose in male and female mice and in male and

female rats. There were no changes in spleen and thymus weight and there were no histopathological lesions in these organs in those studies. In the developmental immunotoxicity study, there was no evidence of an effect on the functionality of the immune system in rats that were exposed to dinotefuran at the Limit Dose during the prenatal, postnatal, and post

- weaning periods . Consequently, the thymus weight changes seen in dogs and the spleen weight changes

seen in mice and rats were not considered to be toxicol ogically relevant.

No systemic or neurotoxicity was seen following repeated dermal applications at the Limit Dose to rats for 28 days. No systemic or portal of entry effects were seen following repeated inhalation exposure at the maximum obtainable conce ntrations to rats for 28 days.Page 18 of 69

In the pre

- natal studies, no maternal or developmental toxicity was seen at the Limit Dose in rats. In rabbits, maternal toxicity manifested as clinical signs of neurotoxicity but no developmental toxicity was seen. In the reproduction study, parental, offspring, and reproductive toxicity was seen at the Limit Dose. Parental toxicity included decreased body weight gain, transient decrease in food consumption, and decreased thyroid weights. Offspring toxicity was charact erized 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 dose inc luding the Limit Dose.

There was no evidence of carcinogenicity in male and female mice and in male and female rats fed diets containing dinotefuran at the Limit Dose for 78 weeks to mice and 104 weeks to rats.

Dinotefuran was non

- mutagenic in both in vi vo 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 rec ommendation is provided in the following sections.

4.4.1 Completeness o f the Toxicology Database

The toxicity database for dinotefuran is complete, comprehensive, of good quality and considered adequate to support toxicity endpoint selection for risk ass essment 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 was 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 albeit at doses close to the limit dose. For these reasons, a developmental neurotoxicity (DNT) study was required. Upon submission of the DNT, it was concluded that there is no evid ence of a unique sensitivity to the developing nervous system since no effects on neurobehavioral parameters were seen in the offspring at doses that approached or exceeded 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 developmental toxicity was seen at the Limit Dose. In rabbits, maternal toxicity manifested as clinical signs of neurotoxicity but no developmentalPage 19 of 69

toxicity was seen. In the reproduction study, offspring toxicity characterized as decreased forelimb grip strength or hindlimb grip strength in the F1 pups was seen at the same dose (Limit Dose) that caused parental toxicity (decreased body weights). The concern is low for the observed qualitative increase in sensitivity since the effe cts in the offspring were seen at the Limit Dose in the presence of parental toxicity. 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 dose i ncluding the Limit Dose. In the developmental immunotoxicity study there was no evidence of an effect on the functionality of the immune system in rats that were exposed to dinotefuran at the Limit Dose during the prenatal, postnatal, and post

- weaning

per iods

.

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 dietary analysis was based on tolerance level residues and 100% crop

treated a ssumptions for all commodities. The chronic dieta ry analysis included tolerance level

residues and 100% crop treated. T he field trials represent maximum application rates and

minimum pre

- harvest intervals ( PHIs )

. 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 estimate s in this analysis are unlikely to underestimate actual exposure.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

The details for selecting toxicity endpoints and points of departure for various exposure

scenario s are presented in the A ppendix A. Briefly, neurotoxic effects are the most sensitive endpoint (seen in rabbits and rats). Beyond neurotoxicity, the only other consistently observed effect (in all species) is decreased body weight gain (≤ 10%) which in t he absence of body weight decrements per se was not regarded as biologically significant or adverse even at near

Limit Doses. The toxicological database indicates that dinotefuran toxicity does not progress with duration of exposure ( i.e., NOAELs/LOAELs a re not lower with longer exposure durations nor are the effects seen progressed in severity).

The Agency has selected Points of Departures (P O Ds) based on the most sensitive toxicological endpoint of concern observed in the most sensitive species for asse ssing risks via dietary and

non

- dietary exposure scenarios.

For the general population, an acute Reference Dose (aRfD) of 1.25 mg/kg/day was derived from a maternal NOAEL of 125 mg/kg/day and the application of an Uncertainty Factor of 100 which

includes 10X for inter

- species extrapolation and intra

- species variation. The NOAEL was established in a developmental toxicity study in rabbits based on clinical signs indicative ofPage 20 of 69

neurotoxicity (hypoactivity, prone position, panting, tremors) observed at 300 m g/kg/day (LOAEL). This study/endpoint is appropriate for assessing acute dietary risk since the signs were seen following administration of the first dose on Gestation Day 6. This PoD would address the concern for the decreased motor activity seen on Day 1 in females at 750 mg/kg/day and in males at 1500 mg/kg/day in the acute neurotoxicity study.

In previous risk assessments, decreased thymus weight seen in the chronic toxicity study in dogs was selected as the toxicity endpoint for chronic exposure. S ince then, immunotoxicity studies in mice and rats as well as a developmental immun otoxicity study were submitted and reviewed by the Agency. In the immunotoxicity studies there were no effects on T

- cell dependent antibody response (TDAR) at the Limit Dos e in male and female mice and in male and female rats. There were no changes in spleen and thymus weight and there were no histopathological lesions in these studies. In the developmental immunotoxicity study, there was no evidence of

an effect on the fu nctionality of the immune system in rats that were exposed to dinotefuran at
the Limit Dose during the prenatal, postnatal, and post

- weaning periods in a developmental immunotoxicity study. Consequently, the thymus weight changes seen in the dog study wer e not considered to be toxicologically relevant and appropriate for endpoint selection/risk assessment.

A chronic RfD of 1.0 mg/kg/day was derived from a NOAEL of 99.7 mg/kg/day (chronic toxicity/carcinogenicity study in rats) and the application of an Un certainty Factor of 100

, which

includes 10X for inter

- species extrapolation and 10X for intra

- species variation. The NOAEL

was established based on decreased body weight gain, and food efficiency in females and increased incidences of kidney pelvic minera lization and ulceration in males at 991 mg/kg/day (LOAEL). This study/endpoint is appropriate for this exposure scenario since the effects of concern were seen following chronic exposure in the most sensitive species. This NOAEL would also address the concern for the decreased motor activity seen in rats at 327 mg/kg/day in the subchronic neurotoxicity study as well as the clinical signs of neurotoxicity (prone position, panting, tremors) seen at 300 mg/kg/day in the does in the pre

- natal developmental toxicity study

with rabbits

.

For incidental oral exposure scenarios, the NOAEL of 99.7 mg/kg/day established in the combined chronic toxicity/carcinogenicity was selected to assess risk from both short

- and intermediate term exposures. In a subchronic neurotoxicity, a NOAEL of 33 mg/kg/day was

established based d ecreased motor activity seen in two weeks at 327 mg/kg/day in the subchronic neurotoxicity (SCN) study. This study with a lower NOAEL was not selected for these exposure

scenarios because the lower NOAEL in the SCN is an artifact of dose selection. The h igher NOAEL would still be protective of the neurotoxicity seen not only in the SCN but also the clinical signs of neurotoxicity (prone position, panting, tremors) seen at 300 mg/kg/day in does in the developmental toxicity study and the decreased motor ac tivity seen in female rats at 750 mg/kg/day in the acute neurotoxicity study. The pattern of motor activity seen with single and repeated exposure is consistent with the neonicotinic mode of action. Thus, the selected PoD would protect for neurotoxicity, the principal toxicological effect of dinotefuran. This endpoint is appropriate for the population (infants and children) and durations (short to intermediate term) of concern since the decrease in motor activity was seen two weeks after initiation of tr eatmentPage 21 of 69

and there is no increased toxicity observed with increased exposure duration throughout the

database

. The Level of Concern is a Margin of Exposure of 100 which includes 10X for inter

species extrapolation and 10X for intra

- species variation.

Quantification of dermal and inhalation risks were not required since no systemic toxicity or neurotoxicity was seen following repeated dermal applications at the Limit Dose in a 28

- day dermal toxicity study in rats and no systemic or portal of entry effec ts following repeated inhalation exposures at the highest practical concentration obtainable in a 28

- day inhalation toxicity study in rats. Furthermore, the inhalation NOAEL (2.08 mg/L or 565 mg/kg/day) represents an exposure approximately 10 5 times great er than the maximum human exposure via inhalation for registered and currently proposed uses (5.85 x10 - 3 mg/kg/day for belly grinder application of granular formulations) . Additionally, there are no concerns for developmental or reproductive toxicity.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inh alation exposures. In the case of dinotefuran, dermal and inhalation risk assessments are not performed as there is no identifiable hazard via these routes of exposure at excessive dose.

4.5.3 Cancer Classification and Increased Tumor Incidence Risk Asse ssment
Recommendation

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

Dinotefuran is classified as “ Not Likely to be Carcinogenic to Humans” based on the lack of evidence for carcinogenicity in mice and rats.

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

Assessment

The most recent human health risk assessment was conducted for a Section 18 use on pome fruits and stone fruits to control stink bugs (B. O’Keefe, DP388993, 5/31/11 ). Since the last risk assessment, HED has re

- evaluated the dinotefuran toxicological database and updated the hazard characterization and dose response assessment. This toxicology database re

- evaluation has resulted in changes to the toxicity endpoints, points of departure, and safety factors for several routes of exposure from those presented in previous HED risk assessments. Table 4.5.4.1 summarizes these changes. For further details refer to Appendix A.Page 22 of 69

Table 4 .5. 4.1

. Summary of Toxicological Do ses and Endpoints for Dinotefuran for Use in Dietary Human

Health Risk Assessments

Exposure/

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 in does (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/Carcinogenic ity

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 d ermal 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.

Ther e 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 rodent 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 human exposures. NOAEL = no observed adverse effe ct 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 human population (intraspecies). FQPA SF = FQPA Saf ety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level

of concern.

5.0 Dietary Exposure and Risk Assessment

References:

- Dinotefuran: Acute and Chronic Aggregate (Food and Dri nking Water) Dietary Exposure and Risk Assessments for a Section 3 Registration Action 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). C. Walls, DP391889, 7 / 17 /12.

- Tier I Human Health Drinking Water Assessment of Dinotefuran and its Transformation Products of Concern (MNG, DN, UF and DN

- 2

- OH + DN

- 3

- OH) in Support of Proposed IR

- 4 New Uses (Onion, BulbPage 23 of 69 and Green; Berry and Small Fruit; Tuberous and Corm Vegetables; Peach; and Watercress). R. Parker, DP394848, 12/12/11.

- Dinotefuran. Petition for the Establishment of Permanent Tolerances on Tuberous and Corm Vegetables Subgroup 1C, Onion Subgroup 3

- 07A, Onion Subgroup 3

- 07 B, Small Fruit Subgroup 13

- 07F, Berry Subgroup 13

- 07H, Peach, Watercress, and Tea (Import). Summary of Analytical Chemistry and Residue

Data. L. Cheng, DP389492, 4 / 12 /12.

5.1 Metabolite/Degradate Residue Profile

5.1.1. Summary of Plant and Animal Metabolism Studies

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

th e IR

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

The database is adequate for determining dinotefuran residues of concern

. A listing of the

dinotefuran metabolites is provided in Appendix D.

Primary Crops The nature of the residue in plants is adequat ely understood. Metabolism was found to be similar in the crops studied (rape, potato, rice, apple, and lettuce) and proceed s through hydrolysis of the nitroimino moiety of dinotefuran, loss of the nitro group, intra

- molecular ring formation, and tetrahyd rofuran ring hydroxylation and ring opening. Parent dinotefuran and the metabolites DN and UF are the residues of concern in plant commodities for tolerance setting purpose, and dinotefuran, DN, UF and PHP are the residues of concern for risk assessment

p urpose (MARC report, TXR #52304, DP293759, L. Cheng, 1/20/2004).

Rotational Crops In a previously submitted petition, PP#2F06427 (DP285648, L. Cheng, 2/26/04), the petitioner did not propose a metabolic profile for rotational crops; however, metabolites t hat were identified in rotational crop commodities were consistent with those identified in primary crops. Based on the results of the study, the petitioner concluded that no dinotefuran residues of concern would accumulate at levels >0.01 ppm in rotation al crops planted 120 days after

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

Livestock Adequate metabolism studies with dinotefuran on ruminants and laying hens were submitted in PP#2F06427. The metabolism of dinotefuran was observed to be similar in the goat and hen studies. The primary metabolic pathways of dinotefuran in plants were also found similar to those described for livestock, with certain extensions of th e pathway in plants. Dinotefuran is the residue of concern in livestock commodities for tolerance setting. For risk assessment, parent and metabolites UF and FNG are the residues of concern in ruminants, and parent and metabolite

FNG are the residues of concern in poultry (MARC report, TXR # 00 52304, DP293759, L. Cheng, 1/20/04).Page 24 of 69

5.1.2 Summary of Environmental Degradation

Dinotefuran has a molecular weight of 202.2 g/mole, a very high water solubility (39,830 ppm), and a low octanol/water partition coeff icient (K OW = 0.283), suggesting the potential for runoff and low bioaccumulation. The low vapor pressure (1.2 8 x 10 - 8 mm Hg) and a low Henrys’s Law Constant (8.63 x 10 - 14 Atm • M 3 /mol) suggest that this compound is not expected to volatilize

substantiall y from water or soils in the natural environment.

The major route of dissipation for dinotefuran appears to be aqueous photolysis (half

- life 1.8 days) and leaching. Since there is no valid soil photolysis data, it is unknown if dinotefuran
parent residues break down quickly in soil via photolysis. Dinotefuran appears to be relatively persistent to metabolism, both in aerobic (half

- life = 17

- 89 days) and anaerobic (half

- life = 51

- 62 days) conditions. It appears that under metabolic conditions, din otefuran degrades to MNG and subsequently to NG. Dinotefuran is stable to hydrolysis in a range of pH values of 4 to 9. It is considered to be very highly mobile (K

oc = 6

– 45 L/kg

- OC ) in various soil types. It is also very highly soluble (39,830 ppm). Since dinotefuran may persist in soils, it may have a high potential to leach to subsurfaces. Furthermore, it can migrate to adjacent bodies of water through spray drift and in runoff events, probably dissolved in the water column. Once in the rivers, p onds, or other bodies of water, the fate of dinotefuran is somewhat uncertain. Aqueous photolysis should be important in clear and shallow bodies of water; however, in deep ponds or rivers or flowing bodies of water, it is more likely to dissipate via dis solution, and subsequently via metabolism.

5.1.3 Comparison of Metabolic Pathways

I n rats a fter intravenous ( IV ) or oral treatment, 75

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

- 97% of total urinary radiolabel dinotefuran , 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 parent compound was metabolized into numerous minor metabolites that were not we ll resolved by HPLC or 2D

- thin layer chromatography ( TLC )

.

In plants, dinotefuran is metabolized through hydrolysis of the nitroimino moiety of dinotefuran, loss of the nitro group, intra

- molecular ring formation , and tetrahydrofuran ring hydroxylation and ring opening. Parent dinotefuran and the metabolites DN

, UF

, and PHP are the major

metabolites identified in plant commodities.

In livestock, dinotefuran is metabolized in a manner similar to that in plants wi th certain extensions of the pathway in plants. Parent d inotefuran and metabolites UF and FNG are the major metabolites identified in ruminants, and parent dinotefuran and metabolite FNG are the major metabolites identified in poultry.Page 25 of 69

5.1.4 Residues o f Concern Summary

Table 5.1.4

. Residues of Concern in Crops, Livestock, Rotational Crops, and Water

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

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

Adequate residue data are available to support dietary risk assessment as well as the proposed tolerances/expan sions of crop groups/subgroups of the insect icide dinotefuran in/on berry, low growing, except strawberry, subgroup 13

- 07H; fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F; onion, bulb, subgroup 3

- 07A; onion, green, subgroup 3

- 07B; vegetable, tuberous and corm, subgroup 1C; peach; watercress; and imported tea.

The submitted residue data for bulb onion, green onion, cranberry, peach, watercress, and tea are adequate to fulfill data requirements. The number and locations of the field trials are in

accordance with O CSPP Guideline 860.1500 for bulb onion

, green onion, cranberry, peach, watercress, and tea . Field trials were conducted at ~1x the proposed maximum seasonal rate and samples were harvested at the proposed PHI for all crops

.

Residue chemistry studies are supported by adequate storage stability data which demonstrate

that dinotefuran and its metabolites UF and DN in/on onions, cranberry, peach, and watercress

are stable for 7 to 25 months (at

- 40 to

- 2oC). Previously submitt ed storage stability data also indicate these compounds are stable in tomato, melon, broccoli, grape, potato, lettuce, apple and cotton for up to 12 months.

Proposed Uses

Onion, bulb, subgroup 3

- 07A

IR

- 4 has submitted residue data for bulb onion, the r epresentative crop for subgroup 3

- 07A. The

results from the bulb onion field trials are summarized in Table 5.2

. 1.Page 26 of 69

TABLE 5.2

. 1. Summary of Residue Data from Dry Bulb Onion Crop Field Trials with Dinotefuran.

Commodity 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.

Drench/In

- furrow Application

Dry onion bulbs Dinotefuran 0.258

- 0.346 71

- 156 8 <0.01 0.01 0.01 0.01 0.01 0.01 N/A

UF 3 8 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

DN 3 8 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

Total Residues 8 <0.03 <0.03 0.03 0.03 0.03 0.03 N/A

Foliar Application

Dry onion bulbs Dinotefuran 0.352

- 0.370 1

- 2 8 <0.01 0.06 0.01 0.05 0.02 0.02 0.02

UF 3 8 <0.01 0.02 0.01 0.01 0.01 0.01 <0.01

DN 3 8 <0.01 0.02 0.01 0.01 0.01 0.01 <0.01

Total Residues 8 <0.03 0.09 0.03 0.08 0.04 0.04 0.02

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; N/A = Not applicab le.

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.

Onion, green, subgroup 3

- 07B

IR

- 4 has submitted residue data for green onion, the representative crop for subgroup 3

- 07B.

The results from the green onion field trials are summarized in Table 5 .2.2

.

TABLE 5

. 2.2. Summary of Residue Data from Green Onion Crop Field Trials with Dinotefuran.

Commodity 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

Green onion Dinotefuran 0.36 1 5 0.084 2.24 0.086 1.93 0.523 0.811 0.780

UF 3 5 <0.01 0.162 0.01 0.149 0.060 0.072 0.060

DN 3 5 0.017 0.352 0.022 0.343 0.266 0.204 0.136

Total Residues 5 <0.115 2.63 0.118 2.37 0.906 1.09 0.864

Post

- plant Application to Soil

Green onion Dinotefuran 0.27 93 1 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

UF 3 1 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

DN 3 1 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

Total Residues 1 <0.03 <0.03 0.03 0.03 0.03 0.03 N/A

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. N/A = Not applica ble.

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.Page 27 of 69

Berry

, low growing, except strawberry , subgroup 1 3

- 07 H

IR

- 4 has submitted residue data for cranberry, the representative crop for subgroup 13

- 07H. The results from the cranberry field trials are summarized in Table 5.2.3

.

TABLE 5.2.3

. Summary of Residue Data from Cranberry Crop Field Trials with Dinotefura n.
Commodity 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.

Cranberry Dinotefuran 0.348

- 0.362 6

- 8 4 0.01 0.06 0.01 0.05 0.04 0.04 0.02

UF 3 4 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

DN 3 4 <0.01 0.02 0.01 0.02 0.01 0.01 <0.01

Total Residues 4 < 0.03 <0.09 0.03 0.08 0.06 0.06 0.02

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. N/A = Not applica ble.

2 LAFT = lowest average field trial; HAFT = highest a verage f ield t rial.

3 Residues of UF and DN are reported in parent equivalents using a molecular weight conversion factor of 1.3 for each analyte as calculated by the study reviewer.

Peach

IR

- 4 has submitted residue data for peach. The results from the peach field trials are

summarized in Table 5.2.4

.

TABLE 5.2.4

. 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

Soil Drench Application

Peach Dinotefuran 0.268

- 0.269 21 2 <0.01 0.01 0.01 0.01 0.01 0.01 N/A

UF 3 2 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

DN 3 2 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

Total Residues 2 <0.03 <0.03 0.03 0.03 0.03 0.03 N/A

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. N/A = Not applicable.

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.Page 28 of 69

Watercress

IR

- 4 has submitted residue data for watercress. The results from the watercress field trials are

summarized in Table 5.2.5

.

TABLE 5.2.5

. Summary of Residue Data from Watercress Field Trials with Dinotefuran.

Commodity 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.

Without Adjuvant

Watercress Dinotefuran 0.355

- 0.363 1 3 1.23 3.47 1.25 3.38 1.88 2.17 1.09

UF 3 3 0.042 0.119 0.044 0.118 0.069 0.077 0.038

DN 3 3 0.273 0.397 0.287 0.385 0.301 0.324 0.053

Total

Residues 3 1.55 3.85 1.58 3.74 2.38 2.57 1.10

With Adjuvant

Watercress Dinotefuran 0.363 1 2 1.44 2.13 1.61 2.12 1.86 1.86 0.357

UF 3 2 0.044 0.170 0.049 0.161 0.105 0.105 0.079

DN 3 2 0.314 0.687 0.338 0.650 0.494 0.494 0.220

Total

Residues 2 1.80 2.99 2.00 2.93 2.46 2.46 0.656

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials.

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.

Vegetable, tuberous and corm, subgroup 1C & Berry, low growing, except strawberry, subgroup

13

- 07H

Potato is the representative crop for the tuberous and corm vegetable subgroup 1C. Therefore, the previously submitte d potato residue data (DP290191, L. Cheng, 11/23/04) are adequate to support the establishment of a subgroup 1C tolerance at the level set for potato (0.05 ppm). Also, grape is the representative crop for the small vine climbing fruit except fuzzy kiwifru it subgroup 13

- 07F. Therefore, the previously submitted grape residue data (DP290191, L. Cheng, 11/23/04) are adequate to support the establishment of a subgroup 13

- 07F tolerance at the level set for grape (0.9 ppm).

Tea (import)

IR

- 4 has submitted resi due data for tea. The results from the tea field trials are summarized in

Table 5.2.6 . The available data would support application of an SG formulation at a 0.356 lb

ai/A seasonal rate

, with a 7

- day RTI and a 7

- day PHI. The submitted residue data for t ea support
a tolerance of 5 0 ppm in tea , dried

.Page 29 of 69

TABLE 5.2.6

. Summary of Residue Data from Tea 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.

Tea Dinotefuran 0.356 7 2 8.16 19.5 8.56 19.1 13.8 13.8 7.45

14 2 4.34 5.10 4.55 4.89 4.72 4.72 0.24

21 2 0.68 1.64 0.68 1.62 1.15 1.15 0.66

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials.

2 LAFT = lowest average field trial; HAFT = highest a verage f ield t rial.

Processed Food and Feed

There are no processed commodities associated with the proposed crops.

Livestock

The new uses proposed in this action do not result in any commodities that are new livestock

feed items. The existing dinotefuran tolerances for milk and the fat, meat, and meat byproducts of cattle, goat, hog, horse, and sheep are adequate; no revision to the existing tolerances is needed to support the proposed uses of dinotefuran . The proposed uses of dinotefuran addressed in this document do not alter the Agency’s pr evious conclusion that there is no reasonable expectation of finite residues in poultry commodities [Category 3 of §180.6(a)]. No tolerances are needed for poultry tissues or eggs.

Rotational Crops Adequate confined field rotational crop data are avail able. Dinotefuran residues of concern would be <0.01 ppm in rotational crops planted 120 days after treatment. There are no field rotational crop data. However, none are needed as long as a 120

- day plantback interval is specified on the label.

5. 3 Wa ter Residue Profile

There are no drinking water monitoring data available on the concentrations of parent dinotefuran or any of its ’ degradates. EFED provided a T ier 1 dinotefuran drinking water assessment with estimated drinking water concentrations (EDWCs) for dinotefuran and its metabolites/degradates (MNG, DN, UF, DN

- 2

- OH, and DN

- 3

- OH) ( D P 394848, R

. Parker

, 12 /1 2 / 11 ). The EDWCs for the metabolites/degradates were reported in parent dinotefuran equivalents. The degradates UF and DN

- 2

- OH are photol ysates and are not likely to be formed in the fields of most crops. The formation of these degradates would be a result of direct exposure of parent dinotefuran to surface waters through spray drift, or through direct application to water, followed by pho tolysis. The estimated values for DN, UF, and DN

- 2

- OH+DN

- 3

- OH photolysates are considered to be the upper bound estimates, since these degradates are likely to form only in puddles or small water pockets in the field through photolysis, and therefore, the se EDWCs should be considered an unrefined assessment. The surface water EDWCs were derivedPage 30 of 69

using the FQPA Index Reservoir Screening Tool (FIRST) simulation model. The Screening Concentration in Ground Water (SCIGROW) model was used to derive the ground water
EDWCs.

For the proposed crops, r esulting EDWCs for parent dinotefuran for the two terrestrial crop groups with the highest annual application amount are 33.4 μg/L for surface water acute risk, 5.5 μg/L for surface water chronic risk

, and 1.07 μg/L f or ground water. These values are all less than the previous EDWC values calculated by EFED for pome and stone fruits (DP389034, R.

Parker

, 5/26/11). Therefore, the pome and stone fruit EDWCs are still recommended for assessing dinotefuran residues in dr inking water. The drinking water assessment was conducted for total dinotefuran residues including parent, MNG, DN, UF

, DN

- 2

- OH

, DN

- 3

- OH as recommended by HED. Total EDWCs for dinotefuran residues in surface source drinking water are not expected to exce ed 91.31 μg/L for the 1 in 10 year daily peak concentration and 25.16 for the 1 in 10 year annual average concentration. In ground water, the EDWC for dinotefuran

residues is not expected to exceed 3.5 μg/L

. Because the surface water estimates are higher than the ground water 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 “water, indirect, all sources.” ED WCs recommended for use in the human health risk assessment for all proposed/registered crops are listed in Table 5. 3

.

EFED noted that a qualitative assessment was performed for the proposed use on watercress which is typically cultivated in shallow, flowing water. The Agency does not currently have a methodology for exposure assessment for crops cultivated in flowing water. The EFED T ier 1

rice model w as therefore used as the basis of the exposure assessment and the results were characterized to reflect differences between the conditions represented in th e rice model and the

actual methods of watercress cultivation. The three main differences are (1) simulation of application efficiency (fraction of amount applied which is intercepted by the crop), (2) simulation of degradation of the pesticide in water after application

, and (3) simulation of flow through and downstream from the area of cultivation. Consideration of these three differences

from t he rice model plus extensive runoff dilution from areas of the watershed which are not used for watercress cultivation would be expected to produce concentration values substantially less than those of other labeled crops.

Table 5. 3 Summary of Estimated Surface Water Concentrations for Dinotefuran

.

Scenario Surface Water Conc entration ( ppb )

Acute 91.31

Chronic (non

- cancer) 25.16Page 31 of 69

5. 4 Dietary Risk Assessment

5. 4 .1 Description of Residue Data & Percent Crop Treated Used in Dietary Assessment

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

assum ed that 100% of crops with the requested uses and currently registered uses of dinotefuran are treated and that all treated crops contain residues at tolerance level s

. Default processing factors were assumed for both registered and requested crop uses.

5. 4

. 2 Acute Dietary Risk Assessment

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

from the screening

- level FIRST model as these values were higher than the ground water estimates from the SCIGROW model ( D P394848, R. Parker

, 12/12/ 1 1 ). Thus, the results obtained from the present analyses may be considered highly conservative. At the 95 th percentile of exposure, no population subgroups were of concern : the U.S. population accounted for just

2 .2 % of the acute population

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

- 2 years old, accounted for 5.8 % of the aPAD.

5. 4

. 3 Chronic Dietary Risk Assessment

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

from the screening

- level FIRST model as these values were higher than the ground water estimates from the SCIGROW model ( D P 394848, R. Parker

, 12/1 2 / 1 1 ). No population subgroups were of concern: the U.S. population acc ounted for <1 % of the chronic population

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

- 2 years old, accounted for 2

. 6 % of the cPAD.

5. 4

. 4 Summary Table

Table 5.4. 4. Result of Acute and Chronic Dietary Exposure and Risk Estimates for Dinotefuran using DEEM

- FCID (food and water).

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 0.027173 2.2 0.008041 <1

All Infants (< 1 year old) 0.061791 4.9 0.017327 1.7

Children 1

- 2 years old 0.072092 5.8 0.025775 2.6

Children 3

- 5 years old 0.052397 4.2 0.018474 1.8Page 32 of 69

Table 5.4. 4. Result of Acute and Chronic Dietary Exposure and Risk Estimates for Dinotefuran using DEEM

- FCID (food and water).

Population Subgroup* Acute Dietary (95 th Percentile) Chronic Dietary

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

Children 6

- 12 years old 0.028815 2.3 0.009781 1.0

Youth 13

- 19 years old 0.019797 1.6 0.006209 <1

Adults 20

- 49 years old 0.019742 1.6 0.006311 <1

Adults 50+ years old 0.020109 1.6 0.006453 <1

Females 13

- 49 years old 0.019914 1.6 0.006307 <1

*The values for the highest exposed population for each type of risk assessment are bolded. ** Report %PADs to 2 significant figures.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Reference s :

- Dinotefuran: Occupational and Residential Exposure Assessment for Proposed Section 3 Use 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, and Watercress. B

. O’Keefe , DP39 1888

, 7 / 20 /201 2.

This document addresses t he proposed new domestic agricultural uses of dinotefuran. These proposed uses do not involve applications by homeowners or commercia l applicators in

resi dential settings. T herefore, no new residential exposure is expected. There are currently registered uses of dinotefuran on several residential use sites, including turf, ornamentals, vegetable gardens, pets, indoor aerosol sprays, c rack and crevice sprays, etc. Each of these existing residential use patterns has previously been assessed and the resulting exposures and

risk estimates that were not of concern . However, HED has recently updated the residential standard operating proce dures (SOPs) and body weights used in all human health risk assessments. Therefore, all of the existing residential use patterns have been reassessed for residential handler and post application exposures using the new procedures and data.

All existing r esidential use patterns were reassessed using the new residential SOPs and new body weight designations. The new exposure and risk estimates for all residential post

application scenarios result in risk estimates that are also not of concern

.

6.1 Residential Handler Exposure

As previously discussed in Se ction 4.0

, dermal and inhalation risks were not assessed because no

hazard was identified. Therefore, no residential handler exposures were assessed.Page 33 of 69

6.2 Post

- Application Exposure

When determining the potential for residential exposure, the Agency considers residues, leaf to skin/hand residue transfer, children’s hand

- to

- mouth residue transfer and exposure time.

Because no dermal or inhalation endpoint s w ere chosen for dinotefuran post

- application

residential dermal and inhalation exposure scenarios are not assessed

. As a result, risk

assessments have only been completed for post

- application scenarios in which incidental oral exposures are expected. S hort

- term incidental oral expo sures were assessed using the short

- term point of departure of 99.7 mg/kg/day. Additionally, the acute dietary point of departure of 125 mg/kg/day was used to assess the incidental oral ingestion of granules.

Table 6 .2 lists the residential post

- applicat ion exposures and risk estimates. The post

- application exposure and risk estimates for all residential uses result in risk estimates that are not of concern (MOEs ranged from 1, 1 00 to 5,9 00,000)

.

Table 6.2. Residential Post

- Application Short

- Term Oral E xposure and Risk Estimates for Children to Dinotefuran.

Scenario Formulation 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+6

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 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

N A = not applicable

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.Page 34 of 69

6. 3 Combined Exposure

FQPA requires residential exposures that could reasonably be expected to occur on the same day be combined and compared to the appropriate toxicity endpoint. While it is possible for children to be exposed to indoor broadcast sprays on hard surfaces/ carpets and to spot

- on treatment to cats or dogs on the same day, these exposures have not been combined in this assessment

because incidental oral hand

- to

- mouth ex posure from treatment turf is higher and still results in
an MOE that does not exceed HED’s LOC.

6. 4 Residential Bystander Post

- A pplication Inhalation Exposure

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

- application inhalation bystande r 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 , for dinotefuran quantification o f short

- or intermediate

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

range.

6. 5 Spray Dr ift

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 extent, 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 pestici de 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 Age ncy has completed its evaluation 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 assessmen ts for pesticides applied 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 drift. Also, note that the residential uses of dinotefuran resulted in risk estimates of no concern, i. e. incidental oral MOEs rang e from of 1100 to 5 ,900,000.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative

estim ates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. WhenPage 35 of 69

aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For dinotefuran , potential exposures from food, drinking wa ter and residential scenarios were aggregated.

This assessment has considered the changes in the new r esidential SOPs implemented in January of 2012. HED finds no changes that would affect the aggregate safety finding and confirms that

there are no ris ks of concern resulting from the proposed occupational uses, the existing residential uses, nor from utilizing the new r esidential 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 incidental oral exposure. The acute risk estimate for the U.S. population and all other population subgroups, resulting from aggregate
exposure to dinotefuran in food and drinking water

, is not of concer n

. The food and drinking water exposure estimates are 2

. 2 % of the aPAD for the U.S. general population, and 5

. 8 % for the most highly exposed sub group, 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 explaine d previously there were no dermal or inhalation toxicity endpoints identified. Therefore, no short

- term aggregate assessment is needed for adults. For children, the pathways that lead to exposure are dietary oral (background) as well as dermal and

oral r outes

. The most conservative scenario was chosen ; i.e.

, oral hand to

- mouth exposure from

turf following application of a liquid formulation

. For a description of the residential exposure scenario considered in the aggregate assessment

, see Section 6.0.

The aggregate MOE for children 1

- 2 years old is 3, 0 00 , which indicates that exposure and risk

are not of concern.

Table 7.2

. Short

- 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 from

treated turf 99.7 100 0. 997 0.02 5 7 75 0. 0079 0. 033675 3 ,00 0

1 LOC includes standard inter

- (10 X ) and intra

- (10 X ) species uncertainty factors totaling 100

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

3 Residential Exposure = [Oral Exposure]. S ource of residential exposure values used in aggregate assessment (Ta ble 6.2 ).Page 36 of 69 4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5 Aggregate MOE = [NOAE L , 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 chronic dietary exposure estimate

. For children, intermediate

- term incidental oral exposures could potentially

occur from indoor uses. However, w hile 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.

S ince incidental oral short

- and intermedi ate

- term toxicity endpoints and points of departure are

the same

, the short

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

- term exposures.

7.4 Chronic Aggregate Risk

C hronic 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 a nd drinking water)
exposure assessment.

7.5 Cancer Aggregate Risk

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

cancer risk ass essment has not been conducted.

8.0 Cumulative Exposure/Risk Characterization

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

to 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 pro cedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Reference s :

- Dinotefuran: Occupational and Residential Exposure Assessment for Proposed Section 3 Use 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, and Watercress. B

. O’Keefe , D P 39 1888

, 7 / 2 0 / 20 1 2

.Page 37 of 69

Application methods, maximum application rates and use sites are summarized in Table 3.3.1

. Based on the proposed use patterns of dinotefuran, t here is a potential for occupational short

- and

intermediate

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

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

.

As previously discussed in Se ction 4.0

, dermal and inhalation exposures were not assessed

because no hazard was identified.

9 .1 Short

- /Intermediate

- Term Handler Risk

For handlers, PPE on the proposed labels include long

- sleeved shirt and long pants, shoes plus socks, and chemical resistant gloves.

R isk estimate s for occupational handlers were not assessed because no hazard was identified for

either the dermal or inhalation route of exposure.

9 .2 Short

- /Intermediate

- Te rm Post

- Application Risk

Occupational workers performing typical post

- application activities such as scouting, irrigation, harvesting , etc. may rece ive dermal e xposure to dinotefuran residues. However, since no hazard

was identified for the short

- or intermediate

- term dermal route of exposure , dermal risks were

not assessed.

Technical dinotefuran has a Toxicity Category IV for acute dermal, primary skin irritation, and primary eye irritation. Per the WPS, a 12 hour REI is required for chemicals classified under Toxicity Category IV. Therefore, the REI of 12 hours appearing on the proposed dinotefuran labels is adequate.

10 .0 References

C. Walls, DP391889, 7 / 17 /12. Dinotefuran: Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for a Section 3 Registration Action on Tuberous and Corm Vegetables Subgroup 1C, Onion Subgroup 3

- 07A, Onion Subgroup 3

- 07 B, Small Fruit Subgroup 13

- 07F, Berry Subgroup 13

- 07H, Peach, W atercress, and Tea (Import).

R. Parker, DP394848, 12/12/11. Tier I Human Health Drinking Water Assessment of

Dinotefuran and its Transformation Products of Concern (MNG, DN, UF and DN

- 2

- OH + D N

- 3

- OH) in Support of Proposed IR

- 4 New Uses (Onion, Bulb and Green; Berry and Small Fruit;

Tuberous and Corm Vegetables; Peach; and Watercress).

L. Cheng, DP389492, 4 / 12 /12. Dinotefuran. Petition for the Establishment of Permanent

Tolerances on Tubero us 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 38 of 69

B. O’Keefe, DP388993, 5/31/11. Din otefuran 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.

B . O’Keefe, DP391888, 7 /2 0 /2012

. Dinotefuran: Occupational and Residential Exposure Assessment for Proposed Section 3 Use 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, and Watercress.

A ppendix A . T oxicology 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

yesPage 39 of 69 Study Technical

Required Satisfied

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

yes

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 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 gainPage 40 of 69

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

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

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

Dose Levels: 0, 40, 200, 1000 mg/kg/day Systemic : NOAEL: 1000 mg/kg/day

LOAEL : Not Established.

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 )Page 41 of 69

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

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).

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 MRID: 45640001 (2000) NOAEL: 99.7/127.3 [M/F] mg/kg/dayPage 42 of 69

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Combined chronic toxicity/ carcinogenicity (rats) 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 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

test MRID: 45640002 (2002)

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

(Mouse lymphoma L5178Y cells)

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 MRID 48291601 (2010) Maternal NOAEL: 784 mg/kg/dayPage 43 of 69

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

neurotoxicity study

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 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 for

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 hourPage 44 of 69

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

exposure to 3.2 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 by 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.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

Not established. An endpoint attributable to a single dose was not available in the data base, including the pre

- natal toxicity studies in rats and rabbit.Page 45 of 69

A.3.2 Acute Reference Dose (aRfD)

- General Population

Selected Study: Developmental Toxicity Study in Rabbits

MRID No.: 45654208

Executive Summary: See Appendix A, Guideline 870.3700b

Dose and Endpoint for Establishing aRfD: NOAEL = 125 mg/kg based on clinical signs (prone position, panting, tremors) seen in does at 300 mg/kg/day (LOAEL). This end point is appropriate because the clinical signs were seen following the first day of dosing (Gestation Day 6). This NOAEL would also address the concern for the decreased motor activity seen in female rats at 750 mg/kg/day and in male rats at 1500 mg/kg o n Day 1 of dosing in the acute neurotoxicity study.

Uncertainty Factor (UF) : 100 (10x intraspecies, 10x interspecies)

A.3.3 Chronic Reference Dose (cRfD ) `

Study Selected : Combined Chronic Toxicity/Carcinogenicity Study in Rats

MRID No.: 456 40001

Executive Summary: See Appendix A, Guideline 870.4300

Dose and Endpoint for Establishing cRfD: NOAEL=99.7 mg/kg/day based on decreased body weight gain, and food efficiency in females and increased incidences of kidney pelvic

mineralization and ulcerat ion in males at 991 mg/kg/day (LOAEL).

Uncertainty Factor (UF) : 100 (10x intraspecies, 10x interspecies)

Comments about Study/Endpoint/Uncertainty Factor : This study and endpoint is appropriate for this exposure scenario since the endpoint of concern was seen following chronic exposure to the most sensitive species. This NOAEL would also address the concern for the decreased motor activity seen in rats a t 327 mg/kg/day in the subchronic neurotoxicity study as well as the clinical signs of neurotoxicity (prone position, panting, tremors) seen at 300 mg/kg/day in the does in the

pre

- natal developmental toxicity study with rabbits. In previous risk assessme nts, decreased thymus weight seen in the chronic toxicity study in dogs was selected as the toxicity endpoint for chronic exposure. Since then, immunotoxicity studies in mice and rats as well as a developmental immun otoxicity study were submitted and revi ewed by the Agency. There was no evidence of adverse effects on functional immunotoxicity when tested up to the Limit Dose in these studies. Additionally, there were no changes in spleen and thymus weight and there were no histopathological lesions in th ese studies. Consequently, the thymus weight changes seen inPage 46 of 69

the dog study were not considered to be toxicologically relevant and appropriate for endpoint

selection/risk assessment.

A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

Selected Study: Combined Chronic Toxicity/Carcinogenicity Study in Rats

MRID No.: 45640001

Executive Summary: See Appendix A, Guideline 870.4300b

Dose and Endpoint for Risk Assessment: NOAEL=99.7 mg/kg/day. See discussion below for endpoints of concern.

Uncertainty Factor (UF) : 100 (10x intraspecies, 10x interspecies)

Comments about Study/Endpoint/Margins of Exposure: For incidental oral exposure scenarios,

the NOAEL of 99 .7 mg/kg/day established in the combined chronic toxicity/carcinogenicity study wa s selected to assess risk from both short

- and intermediate term exposures. In a subchronic neurotoxicity study, a NOAEL of 33 mg/kg/day was established based on decreased motor activity seen in two weeks at 327 mg/kg/day in the subchronic neurotoxicity (S CN) study. This study with a lower NOAEL was not selected for these exposure scenarios because the lower NOAEL in the SCN is an artifact of dose selection. The higher NOAEL would still be protective of the neurotoxicity seen not only in the SCN but also the clinical signs of neurotoxicity (prone position, panting, tremors) seen at 300 mg/kg/day in does in the developmental toxicity study and the decreased motor activity seen in female rats at 750 mg/kg/day in the acute neurotoxicity study. The pattern of motor activity seen with single and repeated exposure is consistent with the neonicotinic mode of action. Thus, the selected POD would protect for neurotoxicity, the principal toxicological effect of dinotefuran. This endpoint is appropriate for the pop ulation (infants and children) and durations (short to intermediate term) of concern since the decrease in motor activity was seen two weeks after initiation of treatment and there is no increased toxicity observed with increased duration throughout the da tabase

. The Level of Concern is a Margin of Exposure of 100 which includes 10X for inter

- species extrapolation and 10X for intra

- species

variation.

A.3.5 Dermal Exposure (Short

- , Intermediate

- and Long

- Term )

Quantification of short

- or intermediate

- te rm dermal risk is not required. No systemic toxicity was seen at the Limit Dose in an acceptable dermal toxicity study in rats (MRID 45639908) and there are no developmental or reproductive toxicity concerns. Additionally, the potential for neurotoxicity was evaluated in the dermal study and no treatment

- related effects were seen in any of the neurological parameters. Further, no increase in toxicity with duration was observed throughout the toxicology database for dinotefuran. Therefore, it is reasonab le to attribute no

hazard to intermediate

- term exposure based on a 28

- day dermal toxicity study.Page 47 of 69

A.3.6 Inhalation Exposure (Short

- and Intermediate

- Term)

Quantification of short

- or intermediate

- term inhalation risk is not required. No systemic toxicity or portal of entry effects were seen following repeated inhalation exposure at the highest practical concentration obtainable in the respirable range (MRID 45639909)

. No effects were seen at doses approximately 100,000 times greater than the greatest expected human exposure. Although neurotoxicity was not specifically evaluated in this study, effects of increased/decreased motor activity, panting, tremor a nd prone position would be evident with clinical observation if present. Since no increase in toxicity with duration was observed throughout the toxicology database for dinotefuran this study is also appropriate for

intermediate

- term inhalation exposure.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

– Rat

In a 90

- day oral toxicity study (MRID 45654205), Dinotefuran (96.5% a.i., lot number 22

- 00110) was administered to 10 Crl:CD (SD) BR VAF/Plus rats/sex/dose in the diet at concentrations of 0, 500, 5000, 25,000, or 50,000 ppm (equivalent to 0, 34, 336, 1623 , and 3156 mg/kg bw/day for males and 0, 38, 384, 1871, and 3616 mg/kg bw/day for females). All animals survived until scheduled sacrifice, and no treatment

- related clinical signs were noted. Body weights of both sexes in the 25,000 and 50,000 ppm groups were significantly lower than those

of controls from week 2 until termination. Overall body weight gain was 84% of control values in the 5000 ppm females, 68% of the control values in the 25,000 ppm females and 60% and 48% of the control values in the 50, 000 ppm males and females, respectively. Food consumption was significantly lower for the 25,000 and 50,000 ppm groups throughout the study. Food efficiency was negative for the 50,000 ppm group during week 1, but generally similar for all groups afterwa rd.

No treatment

- related effects were seen on survival, clinical signs, hematology, clinical chemistry, and urinalysis, parameters and gross pathology. Decreased body weight gain was seen in females at the 25,000 ppm group (68% of the control value) and in males (60%) and females (48%) at the 50,000 ppm group. Additionally, although not significant, decreases (12

- 16%) in absolute body weight were also se en in females at the 25,000 ppm dose group. Based on these observations, the decreases in body weight/body weight gain were attributed to

treatment. Histopathology revealed a dose

- dependent increase in the incidence and/or severity of

vacuolization in th e adrenal zona glomerulosa and zona fasciculata at 25,000 ppm

.

Under the conditions of this study, the LOAEL was 25,000 ppm (1623/1871 [M/F] mg/kg/day) based on decreased body weight and body weight gain and histopathologicalPage 48 of 69

lesions of the adrenal glands in female rats. The NOAEL is 5000 ppm ((336/384 [M/F] mg/kg/day) for males and females.

This 90

- day oral toxicity study in the rat is Acceptable/Guideline and satisfies the guideline requirement for a 90

- day oral toxicity s tudy (OPPTS 870.3100; OECD 408) in rats.

870.3100 90

- Day Oral Toxicity

– Mouse

In a 90

- day oral toxicity study (MRID 45654206), Dinotefuran (96.5% a.i., lot number 22

- 00110) was administered to 10 Crl:CD

- 1(ICR)BR VAF/Plus mice/sex/dose in the diet at concentrations of 0, 500, 5000, 25,000 or 50,000 ppm (equivalent to 0, 81, 844, 4442 , and 10,635 mg/kg bw/day for males and 0, 102, 1064, 5414, and 11,560 mg/kg bw/day for females). All animals survived until the scheduled sacrifice, and there were no treatment

- related clinical signs of toxicity. Body weights of the 50,000 ppm animals w ere significantly lower (11

- 16% for males, 14

- 22% for females) than those of controls beginning at week 3 until termination, except

for males at week 6. Overall body weight gain of the 50,000 ppm group was reduced by 61% in

males and 72% in females. Ther e were no adverse treatment

- related effects on hematology, clinical chemistry, urinalysis, organ weight, or gross or macroscopic pathology.

Under the conditions of this study, the LOAEL for Dinotefuran in mice was 50,000 ppm (10,635 mg/kg/day for males, and 11,560 mg/kg/day for females), based on decreased body weight and body weight gain. The corresponding NOAEL was 25,000 ppm (4442 mg/kg/day for males, and 5414 mg/kg/day for females).

This 90

- day oral toxicity study in the mouse is Acceptable/Guidel ine and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in mice.

870.3150 90

- Day Oral Toxicity

– Dog

In a 90

- day oral toxicity study (MRID 45639906), Dinotefuran (MTI

- 446) (99.1% a.i., lot # 2200210)] wa s administered to 4 beagle dogs/sex/dose in diet at dose levels of 0, 1600, 8000, or 24,000 ppm [mean equivalents: 0, 58, 307, or 862 mg/kg bw/day (males), and 0, 58, 323, or 950 mg/kg bw/day (females)]. An initial high

- dose of 40,000 ppm MTI

- 446 was offe red to the high

dose group from days 1

- 4, but the concentration was reduced on day 5 to 30,000 ppm, and again on day 12 to 24,000 ppm, due to in appetence and general deteriorating condition of at least 2 of the animals (vomiting, diarrhea, red feces, subd ued behavior, and/or pale gums).

The initial high doses of the test compound (40,000 ppm and 30,000 ppm) adversely affected food efficiencies and body weight gains in the high

- dose animals for the first 2 weeks. At study termination, body weight gain was reduced for high dose males (71% of control values), and body weight and body weight gain were reduced for females at all doses (88

- 92% and 66

- 71% of control values, respectively), though not in a dose

- dependent manner.Page 49 of 69

No treatment

- related changes were seen in: survival, hematology, clinical chemistry or urinalyses parameters; absolute and/or relative organ weights; gross pathology; and histopathology in either sex at any dose level. The areas of hemorrhage seen in the mesenteric and mandibular lymph nodes were not considered to be of toxicological significance since no

effect on T

- cell dependent antibody response (TDAR) was seen at the Limit Dose in adult male

and female mice and adult male and female rats. There were no changes or histopathological lesions of the spleen and thymus in either species in these studies. Additionally, there was no evidence of an effect on the functionality of the immune system in rats that were exposed to dinotefuran during the prenatal, p ostnatal, and post

- weaning periods in a deve lopmental immunotoxicity study.

Under the conditions of this study, the LOAEL for dinotefuran is 24,000 ppm (equivalent to 862 mg/kg bw/day), based on decreased body weight gain in males and decreased body weigh t and body weight gain in females. The NOAEL is 8000 ppm (equivalent to 307 mg/kg/day).

This 90

- day oral toxicity study in the dog is classified as Acceptable/Guideline and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3 150; OECD 409) in dogs.

870.3200 21/28

- Day Dermal Toxicity

– Rat

In a 28

- day dermal toxicity study (MRID 45639908; range

- finding study MRID 45639907),

MTI

- 446 (93.0% a.i., Lot #2200210) was applied to the shaved skin of 10 Crl:CD(SD)IGS BR

rats/sex/dose at dose levels of 0 (5% CMC in reverse osmosis water), 40, 200, or 1000 mg/kg bw/day, 6 to 7 hours/day, 7 days/week for 29 days.

One male treated with 40 mg/kg/day died during week 4; however, in the absence of clinical observations and macroscopic or m icroscopic compound

- related pathology and no deaths at other doses, this death is not considered treatment

- related. All other animals survived until scheduled sacrifice, and there were no compound

- related dermal observations, clinical signs, or

adverse ef

fects on motor activity, opthalmoscopic observations, body weights or body weight gain, food consumption, organ weights, or gross or histopathology.

Under the conditions of this study, the NOAEL for systemic toxicity for Dinotefuran is 1000 mg/kg/day, t he highest dose tested; a LOAEL is not established.

Under the conditions of this study, for NOAEL dermal toxicity for Dinotefuran is 1000 mg/kg/day; a LOAEL was not established.

870.3465 90

- Day Inhalation

– Rat

In a 28

- day inhalation toxicity study (MRID 45639909) [MTI 446 (Batch 5400610, 99.1 % purity)] four groups of rats consisting of 10 males and 10 females per group were administered the test material by nose

- only exposure at concentrations of 0, 0.22, 0.66, and 2.08 mg/LPage 50 of 69

(approximately 60, 179, and 565 mg/kg/day). The exposures were for six hours per day for a total of 29 days for males and 30 days for females. There were no compound

- related effects on survival, clinical signs, body weight/body weight gain , hematology, clinical chemistry, gross pathology, or histologic pathology. The NOAEL is 2.08 mg/L (approximately 565 mg/kg/day), the highest concentration obtainable. A LOAEL was not established.

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

– Rat

In a developmental toxicity study (MRID 45654207), MTI

- 446 (92.9% a.i., Lot #2200210) was administered to 24 pregnant Sprague

- Dawley rats/dose in aqueous 0.5% Carmellose

- sodium by gavage at dose levels of 0, 100 , 300, 1000 mg/kg bw/day on gestation days (GD) 6

- 15, inclusive. Doses were based on the results of a range

- finding study (MRID 45639910). On GD 20, dams were sacrificed, subjected to gross necropsy, and all fetuses examined externally. One

- half of

the f etuses were examined viscerally, and the other one

- half of the fetuses were examined for skeletal malformations/variations. The total numbers of fetuses (number of litters) examined was 298 (22), 309 (22), 272 (20), and 236 (20) for the 0, 100, 300, and 1 000 mg/kg bw/day groups, respectively.

No effects of treatment were observed in survival, clinical signs, body weight/body weight gain, water intake, or gross necropsy at doses up to and including the Limit Dose.

Under the conditions of this study, the m aternal toxicity NOAEL for Dinotefuran in rats is 1000 mg/kg bw/day. A maternal toxicity LOAEL was not established.

No treatment

- related, statistically significant effects on pregnancy rates, number of corpora lutea,

pre

- or post

- implantation losses, res orptions/dam, fetuses/litter, fetal body weights, or fetal sex ratios were observed in the treated groups as compared with the controls. No treatment related external, visceral, or skeletal malformations/variations were observed in any fetus.

Under the conditions of this study, the developmental toxicity NOAEL for Dinotefuran in rats is 1000 mg/kg bw/day. A developmental LOAEL was not established.

This developmental toxicity study in the rat is classified Acceptable/Guideline and satisfies th e guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rats.

870.3700b Prenatal Developmental Toxicity Study

– Rabbit

In a developmental toxicity study (MRID 45654208), MTI

- 446 (92.9% a.i., Lot #2200210) was

administer ed to 22 presumed pregnant female New Zealand White rabbits/dose in aqueous 0.5%

Carmellose

- sodium by gavage at dose levels of 0, 52, 125, 300 mg/kg bw/day on gestation days (GD) 6

- 18, inclusive. Doses were based on the results of range

- finding studies (M RID 45639911, 45633912). On GD 28, does were sacrificed and subjected to gross necropsy. AllPage 51 of 69

fetuses were examined for external, visceral, and skeletal malformations/variations. The total numbers of fetuses (litters) examined was 151(20), 153(19), 170(2 1), and 147(19) for the 0, 30, 60, and 120 mg/kg bw/day groups, respectively, except the number of fetuses (litters) examined for visceral alterations in the high

- dose group was 138(19). No maternal toxicity adverse effects

were observed in the low

- dose g roup (52 mg/kg/day).

Does in the mid dose (125 mg/kg/day) group had transiently decreased body weight gain over the dosing interval (GD 6

- 18; 80% of controls) and a transient decrease in food consumption during the first few daily intervals following init iation of dosing (84

- 90% of controls during daily intervals of GD 6

- 10). Gross necropsy findings in the mid

- dose group included a dose

related increase in the incidence of pale brown discoloration of the liver (8/22 affected) and gray white plaques in the fundic region of the stomach (14/22 affected). However, in the absence of corroborating histopathology the toxicological significance of these findings is unclear. Moreover, these effects are not consistent with dinotefuran’s mode of action.

Maternal t oxicity was evident at the high doses of 300 mg/kg/day. Does in the high

- dose group had a number of transient clinical signs indicative of neurotoxicity including hypoactivity (number of animals affected/number of observations: 21/91), prone position (20/ 74), panting (20/63), tremor (9/16), and erythema of nose/auricle (10/14). The signs were noted following administration of the first dose on GD 6 and were not observed by GD 14. High

- dose does had decreased body weight gain over the treatment interval o f GD 6

- 18 (41% of controls), accompanied by decreases in daily food consumption (50

- 84% of controls), and daily water consumption (generally 90% or less than the controls). Gross necropsy revealed almost all animals had pale brown discoloration of the liv er (19/21 affected) and gray white plaques in the fundic region of the stomach (20/21 affected). The doe not affected with white plaques in the fundic region of the stomach instead had gray white discoloration of the mucosa in the fundic, pyloric region o f the stomach. Additionally, one doe had enlargement of the liver.

Under the conditions of this study, the maternal toxicity LOAEL for Dinotefuran in rabbits is 300 mg/kg bw/day based on clinical signs indicative of neurotoxicity (hypoactivity, prone

pos ition, and tremors). The maternal toxicity NOAEL is 125 mg/kg bw/day.

No treatment related, statistically significant effects on pregnancy rates, number of corpora lutea,

pre

- or post

- implantation losses, resorptions/doe, fetuses/litter, fetal body weig hts, or fetal sex ratios were observed in the treated groups as compared with the controls. No treatment

- related external, visceral, or skeletal malformations/variations were observed in any fetus.

Under the conditions of this study, the developmental toxicity NOAEL for Dinotefuran in

rabbits is 300 mg/kg bw/day, the highest dose tested; a developmental LOAEL was not

established.

The developmental toxicity study in the rabbit is classified Accepta ble/Guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in

rabbits.Page 52 of 69

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat

In a 2

- generation reproduction study (MRID 45639913) MTI

- 446 (Dinotefuran; 98.9% a.i., batch # 5400810) was administered to 25 Han Wistar [Hanlbm:WIST (SPF)] rats/sex/dose in feed at dietary concentrations of 0, 300, 1000, 3000, or 10,000 ppm. Premating doses were respectively 0, 24.1, 79.9, 241.0 , or 822.1 mg/kg bw/day for F 0 males, 0, 26.8, 90.1, 267.9, or 907.0 mg/kg bw/day for F 0 females, 0, 27.2, 90.5, 269.0, or 934.7 mg/kg bw/day for F 1 males, and 0, 29.6, 96.5, 292.6, or 1004.8 mg/kg bw/day for F 1 females. F 0 and F 1 parental animals were

ad ministered the treated or control diets for at least 70 days prior to mating, throughout mating, gestation, and lactation, and until necropsy

, and one litter was produced by each generation. Additional groups of 20 F 1 pups/sex/dose were selected for post

- weaning functional evaluations, including a functional observational battery, and quantitative grip strength and motor activity measurement, at approximately 6 weeks of age. Dose selection was based on a range

- finding 1

- generation reproduction study in ra ts (MRID 45639914).

Death of one high

- dose F 0 female on LD 21 may have been related to gross and microscopic renal abnormalities (bilateral dilatation of the pelves, tubular mineralization, and pyelitis), and

not a treatment

- related effect. Treatment

- rel ated clinical signs were limited to observations of soft feces from all high

- dose F 0 females and one high

- dose F 1 female beginning on LD 11

- 16 and continuing through the end of lactation. Body weight gains of high

- dose F 0 males were margin

ally decreased during the first three weeks of premating and for the cumulative premating interval (90 and 91% of controls, respectively), and this group also had a transient reduction in food consumption during the first week of premating (90% of controls). Biologicall y significant decreases in absolute body weight were seen in high

- dose F 1 males during the first 5 weeks of premating and in F 1 females during the first 2 weeks of premating (85

- 90% and 88

- 90% of controls, respectively), and both groups also had decreased body weight gains during the first week of premating (83

- 84% of controls) and decreased food consumption during the first 2

wee ks of premating (84

- 88% and 88

- 92% of controls, for males and females respectively). However, the effects on body weight and food consumption in the F 1 animals represented a continuation of an offspring effect rather than a parental effect. High

- dose F 0 males and females had decreased absolute spleen weights (90% and 84% of controls, respectively; p<0.05) and decreased spleen/brain weight ratios (90% and 86% of controls; p<0.05).

Under the conditions of this study, the Parental/ Systemic Toxicity NOAEL is 3000 ppm (241.0 mg/kg bw/day in males and 267.9 mg/kg bw/day in females) and the Parental Systemic Toxicity LOAEL is 10,000 ppm (822.1

- 934.7 mg/kg bw/day in males and 907.0

- 1004.8 mg/kg bw/day in females), based on a transient decrease in food consumpti on 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.Page 53 of 69

There were no treatment

- related effects on mean litter size, numbers of live and dead pups, sex ratio at birth, or th e birth, viability, and weaning indices, and no treatment

- related clinical signs were observed in offspring during lactation of either generation. In both generations, mean pup weights of the treated groups were similar to those of controls on LD 1. F 1 h igh

- dose male and female pups had decreased body weight gains during LD 4

- 21 (80

- 88% and 84

- 87% for males and females, respectively), which resulted in significantly decreased absolute body weights on LD 14 and 21 for males (86

- 89%; p<0.01) and on LD 21 fo r females (88%; p<0.05). In high

dose F 2 pups, the decreased body weight gains occurred during LD 7

- 21 (77

- 85% of controls), and significantly decreased absolute body weights were noted on LD 14 and 21 for both sexes (85

- 87% of controls; p<0.01).

High

- dose F 1 and F 2 pups of both sexes had decreased mean absolute spleen weights and spleen/brain weight ratios (72

- 77% and 75

- 81% of controls, respectively). Significant decreases in absolute and relative thyroid weight were observed at 300, 1000 and 10,000 ppm but not at an intermediate dose of 3,000 ppm. Though not dose

- dependent at lower doses, a 25% decrease in absolute organ weight at 10,000 ppm (822 mg/kg/day) is considered adverse. High

- dose F 2 male and female pups had decreased mean absolute thymus weights (76% and 82% of controls for males and females, respectively) and decreased thymus/brain weight ratios (83% and 85% of controls). There was also a slight decrease in brain weight (96

- 98% of controls). There were no

treatment

- related FOB observati ons, and the motor activity results from the treated F 1 groups were similar to those of controls. High

- dose F 1 males had significantly decreased forelimb grip strength (82% of controls), and high

- dose F 1 females had significantly decreased rearlimb grip

s trength (79%).

Under the conditions of this study, the Offspring Toxicity NOAEL is 3000 ppm (241.0

- 269.0 mg/kg bw/day for males and 267.9

- 292.6 mg/kg bw/day for females and the Offspring Toxicity LOAEL is 10,000 ppm (822.1

- 934.7 mg/kg bw/day for males and 907.0

- 1004.8 mg/kg bw/day for females), based on decreased body weights, body weight gains, and decreased forelimb grip strength (F 1 males) or hindlimb grip strength (F 1 females).

Ovaries from high

- dose F 1 females had decreased numbers of primordial fol licles (37.2 vs. 62.0 for controls). There were no treatment

- related effects on estrous cyclicity during premating. However, estrous staging from vaginal smears collected at necropsy indicated a trend towards increased numbers of high

- dose females in die strus (F 0 : 15/25 vs. 9/25 controls; F 1 : 16/25 vs. 12/25 controls) and an absence of high

- dose F 0 or F 1 females in metestrous (vs. 3 controls for both generations). High

- dose F 0 females had increased incidences of atrophy of the uterus (19/25 vs. 11/25 con trols) and atrophy of the vaginal mucosa (18/25 vs. 8/25 controls). Uterine atrophy may be related to decreased absolute uterine weights and uterus/brain weight ratios noted in high

- dose F 0 females (79% and 80% of controls). Microscopic lesions were not

observed in F 1 females.

High

- dose F 0 males had an increased percentage of intact sperm with an abnormally curved hook (2.0% vs. 1.1% in controls), and high

- dose F 1 males had increased percentages of intact sperm with a misshapen hook (1.0% vs. 0.5% in con trols) and sperm with a normal head and a detachedPage 54 of 69

tail (1.8 vs. 1.3% in controls). A marginally decreased testicular sperm count was noted in high

dose F 0 males (91% of controls), and high

- dose F 1 males had decreased percentages of progres

sive sperm and increased percentages of stationary sperm (86% and 125% of controls, respec

tively). There were no treatment

- related effects on mating performance, fertility, gestation length, or precoital intervals. There were also no treatment

- related effects on the mean ages and weights at which preputial separation or vaginal perforation was observed in F 1 offspring or the mean anogenital distances in F 2 offspring.

Under the conditions of this study, the Reproductive Toxicity NOAEL is 3000 ppm (241.0

- 269.0 mg/kg bw /day in males and 267.9

- 292.6 mg/kg bw/day in females) and the Reproductive Toxicity LOAEL is 10,000 ppm (822.1

- 934.7 mg/kg bw/day in males and

907.0

- 1004.8 mg/kg bw/day in females), based on decreased uterine weights and microscopic alterations in the ute rus 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.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 2

- generation reproductive study in rats [OPPTS 870.3800; OPP §83

- 4; OECD 416].

A.4.4 Chronic Toxicity

870.4100b Chronic Toxicity

– Dog

In a chronic toxicity study (MRID 45654209), Dinotefuran (98.9% a.i., lot # 2200210) was administered to 4 beagle dogs/sex/dose in the diet at concentrations of 0, 640, 3200, or 16,000 ppm (equivalent to 0, 20, 111, or 559 mg/kg bw/ day (males) and 0, 22, 108, or 512 mg/kg bw/day (females) for 52 weeks. Treatment had no adverse effect on survival or clinical signs of toxicity. The reduced overall body weight gains, final body weights, and reduced food efficiencies in the high

- dose m ales and mid

- and high

- dose females were marginal and did not follow a pattern of dose

- response nor showed statistical significance when compared to controls.

There were no treatment

- related changes in hematology, clinical chemistry and urinalysis
paramet ers, organ weights, gross or histopathology. The decrease in thymus weight observed at the mid and high dose groups were not considered to be treatment related due to lack of histopathological changes of the thymus in this study, in other studies in the d ata base, and in the immunotoxicity studies in mice and rats. Additionally, there was no evidence of impairment of functional immunotoxicity at the Limit Dose in adult mice and rats and during the prenatal, postnatal, and post

- weaning periods in a develop mental immunotoxicity study.

Under the conditions of this study, the NOAEL for Dinotefuran in dogs is 16000 ppm (512 mg/kg bw/day), the highest dose tested. A LOAEL was not established.

This chronic study in the dog is classified as Acceptable/Guideline and satisfies the guideline requirement for a chronic oral study [OPPTS 870.4100, OECD 452] in dogs.Page 55 of 69

A.4.5 Carcinogenicity

870.4300 Combined Chronic Toxicity/Carcinogenicity Study

– rat

In a combined chronic toxicity/carcinogenicity study (MRID 45640001), MTI

- 446 (Dinotefuran, 98.9% a.i., Lot/Batch # 2200210) was administered to groups of 60 male and 60 female rats per group at dietary concentrations of 0, 60, 200, 2000, or 20,000 ppm (2. 98, 9.89, 99.7, and 991 mg/kg bw/day, respectively, for males and 3.91, 12.5, 127.3, and 1332 mg/kg bw/day, respectively, for females) for 104 weeks. Additional groups of ten rats/sex/group were administered the same dietary concentrations of test materia l for 26, 52, and 78 weeks for interim evaluations. Groups of ten rats/sex also were administered basal or 20,000

- ppm diets for 26 weeks followed by 6 weeks on basal diet to assess the reversibility of any treatment

- related effects (recovery study).

No treatment

- related or adverse effects occurred on survival, clinical signs, hematology parameters, clinical chemistry parameters, urinalysis parameters, organ weights; or the eyes in male or female rats administered any dose of the test material at any time during the study. Male
rats in the 20,000

- ppm group weighed 4

- 9% (p 0.05) less than controls from weeks 2

- 90 and 4% (not significant) less at study termination; they also gained 20% less weight than controls between weeks 26 and 54, but only 5% less over the entire study. Females in the 20,000

- ppm group weighed up to 17% (p 0.05) less than controls during the first year of the study and up to 32% (p 0.05) less during the second year. Females in the 20,000

- ppm group gained 52

- 58% less weight than control s between weeks 26

- 52 and 52

- 78 and 36% (p 0.05) less weight than controls over the entire study. Food consumption was 7

- 12% (p<0.05) less than that of controls for 20,000

- ppm group male and female rats. Food efficiency values were 2.09% and 1.82% for males in the control and 20,000

- ppm group, respectively, for weeks 26

- 52, 1.84% and 0.95% for females in the control and 20,000

- ppm groups, respectively, for weeks 26

- 52 and 1.49% and 0.70%, respectively, for females in the control and 20,000

- ppm groups fo r weeks 52

- 78. Therefore, reduced food consumption likely contributed to the decreased weight gain in the males, but is not sufficient to explain the decreased weight gain in females. No treatment

- related decreases in body weight, weight gain, food consu mption, or food efficiency were observed in

either sex at 60 or 2000 ppm dose groups.

The only treatment

- related gross finding was increased incidence of thinness (49% vs 28% for controls, p 0.05) in 20,000

- ppm group females that died or were killed morib und before study termination. Microscopic findings considered treatment related included pelvic mineralization (22/60 rats vs. 5/60 for controls) and ulceration (5/60 rats vs 0/60 for controls) in 20,000

- ppm group males.

The incidence of C

- cell adenomas of the thyroid gland was increased (p=0.053) in male rats at the high dose (15/60; 25%) when compared to controls (7/59; 12%). This increase was not

considered to be toxicologically relevant based on the following factors: 1) the increase was only

in beni gn tumors ( i.e

. , adenomas); 2) absence of corroborative pre

- non

- neoplastic lesions in thePage 56 of 69

thyroids (e.g., hypertrophy or hyperplasia); 3) lack of progression to malignancy ( i.e.

, no carcinomas were seen); 4) no reduction in the latency period ( i.e. , not a fatal tumor); and 5) the incidence (25%) was numerically comparable to the high end (24%) of the historical control range (1.7

– 24%). The incidences of C

- cell adenomas at the other dose levels were within the historical controls range.

Under the condi tions of this study, the lowest

- observed

- adverse

- effect level (LOAEL) for Dinotefuran in rats is 20,000 ppm (991 and 1332 mg/kg bw/day, respectively) based on decreased body weight gain and increased incidences of kidney pelvic mineralization

, tubular baso philia, lymphocytic infiltration and ulceration in males. The no

- observed

adverse

- effect level (NOAEL) is 2000 ppm (99.7 and 127.3 mg/kg bw/day, for males and females, respectively).

This chronic/carcinogenicity study in the rats is classified as Acceptable/Guideline and satisfies the guideline requirement for a chronic toxicity/carcinogenicity study in rats (OPPTS 870.4300; OECD 453].

870.4200b Carcinogenicity (feeding)

– Mouse

In a carcinogenicity study (MRID 45639917) MTI

- 446 (93% a.i., lot # 2200210) was

administered to 70 Crl:CD

- 1® (ICR)BR VAF/Plus® mice/sex/dose in the diet at concentrations of 0, 25, 250, 2500, or 25,000 ppm (equivalent to 0, 3, 34, 345, or 3694 mg/kg bw/day for males and 0, 4, 45, 441, or 4728 mg/kg bw/day for females) f or 78 weeks. Ten mice/sex/dose were

sacrificed at week 53.

Treatment had no adverse effects on survival, clinical sings, body weight, body weight gain, food consumption, organ weights, gross pathology or histopathology. The high dose of 25,000 ppm in

th e diet affected body weights and body weight gains of both male and female mice. Final mean body weights of male and female mice administered 25,000 ppm in the diet were 95 and 91% of the respective control group body weights. Respective overall weight g ains were 82 and 75% of the control weight gains. There was no evidence of carcinogenicity in either sex at any dose including the highest dose tested which was three

- fold the Limit Dose.

Under the conditions of this study there was no evidence of carcin ogenicity in either sex.

T he NOAEL for dinotefuran in mice is 25,000 ppm in the diet (3,694/4,728 [M/F] mg/kg/day), the highest dose tested. A LOAEL was not established

.

This carcinogenicity study is classified as Acceptable/Guideline and satisfies guideline requirements for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice.Page 57 of 69

A.4.6 Mutagenicity

Gene Mutation

870.5100 and 870.5300

MRID 45640003, 45654210, 45640002 Negative ±S9 up to 16,000 μ g/plate

Negative ±S9 up to 5000 μ g/plate

Negative ±up to 2002 μ g/mL (Mouse lymphoma L5178Y cells)

Cytogenetics

870.5395

MRID 45654212 Negative at oral doses up to 1080 mg/kg/day for 2 days

Other Genotoxicity

870.5375

MRID 45654211 Negative for clastogenic/aneugenic activity up to 2000 μ g/mL.

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity

In an acute neurotoxicity study (MRID 45640005), groups of fasted, 48

- 54 day old Crl:CD (SD) IGS BR rats (10 animals/sex/group) were given a single oral dose of MTI

- 446 (93% [98.9% purity of dried matter]; lot # 2200210) in 0.5% carboxymethylcellulose in r everse osmosis water at doses of 0, 325, 750, or 1500 mg/kg bw and observed for 15 days. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in 10 animals/sex/group one week prior to treatment, approximat ely 3 hours post

- dosing (time of peak effect) on Day 1, and on Days 8 and 15. At study termination, all animals were euthanized and perfused in situ for gross pathology examination. Of the perfused animals, 6 animals/sex in the control and high

- dose groups were subjected to neuropathologic evaluation of brain and peripheral nervous system tissues.

There were no treatment

- related effects on mortality , clinical observations, body weight, functional observational battery parameters, gross pathology or neuropathology. Motor activity was decreased on day 1 at the high dose in both males and females. This decrease was statistically significant for males i n the first subsession (0

- 10 min, 68% of control values) and for females in the first and last subsession (33

- 56% of control values), as well as for total activity (53% of control values). Total activity for males was also reduced on day 1 (70% of control values, n.s.). For females only, motor activity was also reduced at the mid

- dose (28

- 80% of controls for subsessions, 68% of controls for total activity). Although the decreases at the mid

dose was not statistically significantly different when compared to the controls, it was considered to be biologically significant due to the magnitude of the effect, presence of dose

- response, and consistency across all subsessions. The decreases in motor activity observed were observed on Day 1 in both sexes at the high dose and in female at the mid dose were attributable to treatment. On days 8 and 15, motor activity in all treated groups was comparable to control values.Page 58 of 69

Under the conditions of this study, the LOAEL for Dinotefuran in rats is 1500 mg/kg in males and 750 mg/kg/day in females based on decreases in motor activity on Day 1. The NOAEL is 750 mg/kg/day in males and 325 mg/kg/day in females.

870.6200 Subchroni c Neurotoxicity

In a subchronic neurotoxicity study (MRID 45640004), groups of 10 Crl:CD®(SD)IGS BR rats/sex/dose were administered Dinotefuran [93.0% a.i., Lot No. 2200210 (dried matter 98.9% a.i.)] at dietary dose levels of 0, 500, 5,000, or 50,000 ppm (equivalent to 0, 33, 327, or 3,413 mg/kg/day for males and 0, 40, 400, or 3,806 mg/kg/day for females) for 13 weeks. All animals were observed twice daily. Individual body weights and food consumption were determined weekly. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in all animals/sex/group prior to treatment and once during weeks 2, 4, 8, and 13. At study termination, all animals/sex/group were euthanized and perfused in situ for neuropathol ogical examination. Of the perfused animals, six rats/sex in the control and high

dose groups were subjected to microscopic examination of brain and peripheral nervous system

tissues.

No deaths occurred and there were no clinical signs attributable to t reatment. Body weights were significantly (p 0.05) reduced in high

- dose males and females throughout the 13

- week treatment period. The final body weights for males and females in the high

- dose group were 79% and 81% of the respective controls. Total bo dy weight gains over the entire study period were 62% and 46% of controls for high

- dose males and females, respectively (p 0.05). Food consumption was significantly (p 0.05) reduced during most treatment weeks in high

- dose animals, with average daily fo od consumption 87% and 82% of control males and females, respectively. Overall food efficiency was 70% and 58% of controls for high

- dose males and females, respectively. Relative to controls, there were no treatment

- related effects on body weight, body w eight gain, food consumption, or food efficiency in the lower dose groups.

At 50,000 ppm, FOB assessments revealed significantly decreased body temperature (0.5 o C below controls) and decreased rearing (35% of control values) in high dose females during we ek 2. In addition, motor activity was decreased in high dose females; the decrease was statistically significant during week 2 (55% of control levels), and remained below control levels (72

- 84% of control values) throughout the treatment period (during as sessments at weeks 4, 8, and 13).

At 5000 ppm, there were significant increases in subsession motor activity in both males and females during week 2 (220

- 429% of control levels). This inverted U pattern of activity

– increased activity at mid dose and de creased activity at high

- dose, compared to control

- is consistent with the mode of action of neonicotinoids. Typically, low to moderate activation of nicotinic acetylcholine receptors (nAChR) causes stimulation of the peripheral nervous system (PNS). Wh ereas high levels of neonicotinoids (agonists) can over stimulate the PNS, maintaining the voltage

- gated sodium channels in the open state which blocks the action potential and leads to paralysis.Page 59 of 69

Under the conditions of this study, the LOAEL for Dinote furan in rats is 5000 ppm (327 mg/kg/day for males and 400 mg/kg/day for females) based on changes in motor activity during week 2. The corresponding NOAEL is 500 ppm (33 mg/kg /day and 40 mg/kg /day

, respectively, for males and females).

870.6300 Developmental Neurotoxicity Study

One hundred presumed pregnant Cr1:CD(SD) rats were randomly assigned to four exposure groups, 25 rats per group (MRID 48291601) . The test substance in the diet, MTI

- 446 (Dinotefuran), or vehicle were offered continuously on days 6 of gestation (GD 6) through day 21 of lactation (PND 21) until sacrifice at exposures of 0 , 1000, 3000 or 10000 ppm. Dietary exposures were equivalent to 0, 79.4, 237.4 or 784.1 mg/kg/day during gestation and 0, 158.0, 500.7 or 1642.9 mg/kg/day during lactation. All maternal rats were sacrificed after completion

of the 21

- day postpartum period and a gross necropsy was performed. The following parameters were evaluated: viability, clinical observations, detailed clinical observations, maternal body weight and body weight changes, maternal behavior, feed consumption values, necropsy observations, the number and distribution of corpo ra lutea, implantation sites, uterine contents, litter size and pup viability.

On day 4 (PND 4) all litters were reduced to ten pups each by random selection; 25 appropriately sized litters per group were selected for examination on study. Ten pups of e ach sex and dosage group were randomly selected for brain weight/dimensions determination and neurohistopathology (Subsets 1 and 4). Litters with fewer than nine pups were not assigned to study, but retained until not needed. One male and one female pup/ litter (up to 25/sex/subset) were assigned to each evaluation as follows: PND 21 brain weight/gross dimensions (all dose groups) and neurohistopathology and microscopic brain measurements (0 and 10000 ppm dose groups only); water maze and passive avoidanc e; motor activity and acoustic startle habituation; brain weight/gross dimensions (all dose groups) and neurohistopathology and microscopic brain measurements (0 and 10000 ppm dose groups); o ne pup per sex used for replacement of rats

found dead or sacrifi ced prior to scheduled termination during PND 4 through 21.

Rats were observed for viability at least twice daily during the postweaning period and clinical observations and general appearance once weekly during the postweaning period. Additionally,

rats assigned to Subsets 2 and 3 were examined for gross signs of toxicity and clinical observations; and rats assigned to Subset 4 were examined by an individual unaware of each rat's dosage group for detailed clinical observations. Body weights for male and female rats were recorded weekly during the postweaning period and prior to sacrifice. Pup body weights were recorded on PNDs 0, 4, 7, 11, 13, 17 and 21. Food consumption values for male and female rats were recorded weekly during the postweaning period and on the day of preputial separation or vaginal patency for subsets 2 through 4.

Subset I pups selected for brain weight/dimension determination and neurohistopathological evaluations were sacrificed and processed on PND 21. All pups in Subset I were examined for gross lesions. Subsets 2 and 3 rats were sacrificed after completion of the postweaningPage 60 of 69

behavioral evaluations. Subset 4 rats randomly selected for neurohistopathological evaluations

were sacrificed on PND 69 and those not selected for these procedures were sacrificed and examined for gross lesions. Subset 5 pups were sacrificed on PND 21 and examined for gross

lesions.

All F0 generation female rats survived to scheduled sacrifice. No adverse clinical observations related to exposure to MTl

- 446 occurred. Body weight gains for intervals GD 6 to 9and GD 6 to 20 were significantly reduced, 45% and 11%, respectively, in the 10000 ppm exposure group compared to the control group value; however, this body weight decrement was not sustained

and bo dy weights on GD 20 in all treatment groups were essentially equivalent to control values. Body weight gains during the lactation period did not differ significantly among the treatment groups. While maternal body weights were significantly reduced in th e 10000 ppm exposure group on days 11 and 16 of lactation (LD 11 and 16), this ~4% decrement is not considered toxicologically significant. Exposure to MTI

- 446 at up to 3000 ppm during gestation and lactation did not affect body weight gains or body weigh ts. Absolute and relative food consumption values were generally comparable among the exposure groups. No maternal gross lesions related to exposure to MTI

- 446 occurred.

The maternal NOAEL for dinotefuran in rats was 10,000 ppm (784 mg/kg/day gestation; 1643 mg/kg/day, lactation), the highest dose tested.

No clinical and no necropsy observations in the Fl generation pups were attributed to maternal exposure to the test substance at doses as high as 10

, 000 ppm. No mortality related to maternal

exposure to MTI

- 446 occurred in the male or female rats postweaning. All male offspring rats

survived to scheduled sacrifice. One female rat in the 10

, 000 ppm maternal exposure group was found dead on postnatal day PND23, another was found dead on PND 26 and two female rats in the 0 ppm exposure group were missing on PND 21 or 22 and another was sacrificed due to

adverse clinical observations on PND 58. These single events were not considered related to

MTl

- 446. All other rats survived to scheduled sacrifice.

A ll clinical and necropsy observations for the F1 generation male and female rats were

considered to be unrelated to the test substance. Average body weights, body weight gains and absolute and relative feed consumption values in the male and female offspr ing were unaffected by maternal exposure to MTI

- 446 at exposures up to 10

, 000 ppm. There were no microscopic changes in the tissues evaluated histologically that were considered to have been the result of test substance administration. No statistically s ignificant inter

- group differences were noted for brain weights or for gross brain dimensions on days 21 and 69 postpartum. No treatment

- related microscopic lesions were present in any of the tissues examined in the central and peripheral

nervous systems at 10

, 000 ppm. Maternal exposure to MTI

- 446 at concentrations as high as

10

, 000 ppm did not affect the day of vaginal patency or preputial separation. Motor activity was not affected by maternal exposures to MTI

- 446 as high as 10

, 000 ppm. Maternal expos ure to

MTI

- 446 as high as 10

, 000 ppm did not affect learning and memory in offspring as evaluated in a passive avoidance paradigm.Page 61 of 69

The offspring NOAEL for dinotefuran in rats was 10,000 ppm (784 mg/kg/day gestation; 1643 mg/kg/day, lactation), the highest dose tested.

This study is classified acceptable/guideline and satisfies the guideline requirement for a developmental neurotoxicity in rats

A.4.8 Metabolism

870.7485 Metabolism

– Rat

In a metabolism study (MRID 45640006), MTI

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

- 00210 & OFU

1265 (unlabeled) was administered to multiple groups of 5 or more male and female rats. The rats received single 50 or 1000 mg/kg oral or 50 mg/kg IV treatments or multiple oral 50 mg/kg

treatments and were killed 0.5 to 168 hours after treatment.

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% with <5% of the radiolabel recovered in the feces, cage wash, expired air, carcass, and tissues of treated animals. Excretion into the urine was rapid, being 84

- 99% complete within 24 hours of treatment. Less than 0.1% of the radiolabel was retained by the tissues and carcass 168 hours after treatment.

The pharmacokinetic parameters confirmed rapid absorption with a C

max of 40.8

- 47.4 ppm

reached in 0.25

- 0.625 hours in low

- dose rats. In high

- dose rats, a C

max of 471

- 566 ppm was

reached ~2 hours after treatment. The AUC 0

- ranged from 69.0

- 110 ppm hr for low

- dose rats

and 2370

- 2660 ppm hr for high dose rats. 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 ranging 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 for milk and fetal tissues was detected 0.5 hours after maternal treatment. 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 trea tment, 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 collect ed 4

- 8 hours after treatment and at both dose levels. Less than 10% of the parent compound was metabolized into numerous minor metabolites that were not well resolved by HPLC or 2D

- TLC. Of the limited metabolism that occurred, MTI

- 446 initially underwent enzymatic hydroxylation of the furan ring to form 6

- hydroxy

- 5

- (2

- hydroxyethyl)

- 1

- methyl

- 1,3

- diazinane

- 2

- ylidene

- N

nitroamine (PHP) isomers. Further oxidation, reduction and acetylation of PHP occurred to form

1

- methyl

- 2

- nitro

- 3

- (2

- oxotetrahydro

- 3

- furylme thyl)guanidine (446

- CO), 1

- [4

- hydroxy

- 2

- (hydroxymethyl)butyl]

- 3

- methyl

- 2

- nitroguanidine (446

- DO) and its acetyl conjugate, and 3

-Page 62 of 69

hydroxymethyl

- 4

- (

- 3

- methyl

- 2

- nitroguanidino)butyric acid (446

- OH + COOH). A minor pathway involves the C

- N bond cleavage to yi eld the furan and guanidine moieties; the free guanidine is represented by trace amounts of MNG, MG, and MG

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

- or dose

- related differences or label position effects were found.

A.4.9 Immunotoxicity

87 0.7800 Immunotoxicity

- Rat

In an immunotoxicity study (MRID 48442101) Dinotefuran (MTI

- 446, 97.9% a.i., batch# K09C3718) was administered to 10 Crl:CD (SD) rats/dose/sex via diet at dose levels of 0, 2240, 5600, or 14000 ppm (0/0, 164/179, 425/430, or 99 2/1018; males/females respectively) for 4

- weeks. The positive control group consisting of 8 Crl:CD (SD) rats/sex were administered 50 mg/kg cyclophosphamide via intraperitoneal injection on Day 27. On Day 25, all test animals

were immunized with a 1.0 mL intravenous injection of sheep red blood cells (SRBCs) at a

concentration of 2x10 8 cells/mL. On Day 29, T

- cell dependent antibody response (TDAR) was determined with a plaque forming cell (PFC) assay. Parameters evaluated include mortality, clinical sig ns of toxicity, body weight, body weight gain, food consumption, water consumption, organ weights (i.e. spleen and thymus), macroscopic pathology, and assay

- specific parameters.

There were no unscheduled mortalities in any treatment group. In the treated animals there were

no treatment

- related effects on water consumption or organ weights (i.e. spleen and thymus); and

there were no treatment

- related findings for clinical signs of toxicity or macroscopic pathology.

At the 14000 ppm dose (M: 992 mg/kg/day ), the treatment

- related effects observed were decreased body weight, body weight gain, and food consumption.

The systemic toxicity NOAEL is 5600 ppm (425/430 mg/kg/day for males and females respectively) and the LOAEL is the HDT, 14000 ppm (992/1018 mg/k g/day for males and females respectively), based on decreased body weight, body weight gain, and food consumption.

The plaque forming cell (PFC) assay results showed that there were no statistical differences in quantity of cells/spleen, PFC/10 6 viable ce lls, or PFC/spleen in any treatment group when compared with the vehicle controls. A high inter

- individual variability was noted in all the treatment groups as well as in the control group. Evaluation of individual animal data did not show any trend or d istribution that would demonstrate significant suppression of SRBC antibody

response.

The Natural Killer (NK) cells activity assay was not performed in this study. In a previous developmental immunotoxicity study in rats (MRID 47677501), it was concluded that dinotefuran showed no evidence of an effect on the functionality of the immune system in rats that were exposed to dinotefuran during the prenatal, postnatal, and post

- weaning period (TXR# 0055238). The overall weight of evidence suggests that this chemical does not directly target thePage 63 of 69

immune system. Under HED guidance, NK cells activity assay is not required at this time.

The immunotoxicity NOAEL is the HDT, 14000 ppm (992/1018 mg/kg/day for males and females respectively), based on results of a P FC assay and the LOAEL was not established

.

870.7800 Immunotoxicity

– Mouse

In an immunotoxicity study (MRID 48442102) Dinotefuran (MTI

- 446, 97.9% a.i., batch# K09C3718) was administered to 10 Crl:CD1 (ICR) mice/dose/sex via diet at dose levels of 0, 1120, 2800, or 7000 ppm (0/0, 153/223, 405/581, or 1053/1438; males/females respectively) for

4

- weeks. The positive control group consisting of 8 Crl:CD1 (ICR) mice/sex were administered 20 mg/kg/day cyclophosphamide via gavage (oral) on Days 22

- 26. On D ay 25 of the study, all animals were immunized with a 0.2 mL intravenous injection of sheep red blood cells (SRBCs)

at a concentration of 2x10 9 cells/mL. On Day 29, T

- cell dependent antibody response (TDAR) was determined with a plaque forming cell (PFC) assay. Parameters evaluated include mortality, clinical signs of toxicity, body weight, body weight gain, food consumption, water consumption, organ weights (i.e. spleen and thymus), macroscopic pathology, and assay

- specific parameters.

There were no uns cheduled mortalities in any treatment group. In the treated animals there were

no treatment

- related effects on body weight, body weight gain, food consumption, water consumption, or organ weights (i.e. spleen and thymus); and there were no treatment

- relat ed findings for clinical signs of toxicity or macroscopic pathology.

The systemic toxicity NOAEL is the HDT, 7000 ppm (1053/1438 mg/kg/day for males and females respectively), and the LOAEL was not established.

The plaque forming cell (PFC) assay results showed that there were no statistical differences in quantity of cells/spleen, PFC/10 6 viable cells, or PFC/spleen in any treatment group when compared with the vehicle controls. A high inter

- individual variability was noted in all the
treatment groups a s well as in the control group. Evaluation of individual animal data did not show any trend or distribution that would demonstrate significant suppression of SRBC antibody

response.

The Natural Killer (NK) cells activity assay was not performed in this s tudy. In a previous developmental immunotoxicity study in rats (MRID 47677501), it was concluded that dinotefuran showed no evidence of an effect on the functionality of the immune system in rats that were exposed to dinotefuran during the prenatal, postn atal, and post

- weaning period (TXR# 0055238). The overall weight of evidence suggests that this chemical does not directly target the immune system. Under HED guidance, NK cells activity assay is not required at this time.

The immunotoxicity NOAEL is the HDT, 7000 ppm (1053/1438 mg/kg/day for males and females respectively) , based on results of a PFC assay and the LOAEL was not established

.Page 64 of 69

A.4. 10 Special/Other Studies

Non

- guideline

In a developmental immunotoxicity study and a dose

- range finding for a developmental neurotoxicity study (DNT) (MRID 47677501), MTI

- 446 (dinotefuran; 94.7%; Lot # 2200210) was administered in the diet to presumed pregnant Sprague Dawley (Crl:CD[SD]) rats (10/dose) at dietary levels of 0, 1000, 3000, or 10,000 ppm (equivalent to 0, 105.4, 317.8, or 1035.4 mg/kg/day, respectively) beginning on gestation day (GD) 6, and continuing through lactation day (LD) 21. The F1 generation was potentially exposed through the maternal milk and the
dam’s dose formulation through weaning. On PND 21, the F1 generation were selected (up to three pups/sex/litter) randomly for immunotoxicity assays. F1 pups (20/sex/dose) were fed the same dietary concentrations as their dams beginning on PND 21 until terminati on (PND 42). Systemic toxicity parameters were evaluated in the P and F1 generations, and immunotoxicity was evaluated in the F1 generation. Ten F1 pups/sex/dose group were examined for humoral immune response by measuring IgM antibody forming cell respo nses following immunization with sheep red blood cell (SRBC); the remaining ten F1 pups/sex/dose group were examined for innate immune response by performing a natural killer (NK) cell assay. The splenocytes of the pups used for the NK cell assay were als o phenotyped by flow cytometry.

For maternal toxicity, no treatment

- related adverse effects were observed on mortality, clinical signs, body weights, body weight gains, food consumption, reproductive performance, or gross pathology.

The maternal toxicity LOAEL was not observed. The NOAEL for maternal toxicity is 10,000 ppm (equivalent to 1035.4 mg/kg bw/day ).

For offspring toxicity, no treatment

- related effects were observed on the birth, live birth, viability, or lactation indices or on sex ratio on PN D 21. There were no clinical signs of toxicity, and all pups sacrificed on PND 4 and PND 21 appeared normal at necropsy. At 10,000 ppm, pup body weights were decreased (p≤0.01) by 13

- 18% during PND 13

- 21. After weaning, no

treatment

- related adverse effe cts were observed on mortality, clinical signs, food consumption, or gross pathology in the post

- weaning F1 generation. At 10,000 ppm, post

- weaning body weights were decreased (p≤0.05) by 7

- 22% during PND 22

- 57 in the males, and by 7

- 11% during PND 22

- 36 and PND 57

- 64 in the females.

The offspring toxicity LOAEL was 10,000 ppm (equivalent to 1035.4 mg/kg bw/day ), based on decreased body weights in both sexes. The NOAEL for offspring toxicity is 3000 ppm (equivalent to 317.8 mg/kg bw/day ).

For dose

- ran ge finding of a developmental neurotoxicity study, this diet concentration (10000 ppm) is considered suitable as a high dose level for the DNT study.Page 65 of 69

For developmental immunotoxicity, there were no treatment

- related effects on antibody forming cell respon se (humoral immunity) and Natural Killer Cell activity (innate immunity). No differences that attributable to treatment were noted in the distribution of splenocyte subpopulations. Increased spleen weights were observed in the 1000 and 3000 ppm males, bu t this finding was not dose

- dependent and was considered incidental.

Under conditions of this study, there were no immunologically adverse effects on antibody forming cell response or Natural Killer cell activity in male and female rats that exposed to

di notefuran during the prenatal, postnatal and post

- weaning period. The LOAEL for developmental immunotoxicity was not observed. The NOAEL is 10,000 ppm (equivalent to

1035.4 mg/kg bw/day ).

Non

- Guideline

In a neonatal metabolism study (MRID 45640007), radiolabeled MTI

- 446 (dinotefuran, Lot No. VB9304, labeled on the central guanidine portion of the molecule, purity and radiopurity >99%)

was administered to 12

- day old male and female Sprague Dawley pups. The pups were divided

int o two groups. Group 1, consisting of 25 male and 25 female pups, received a single oral dose of 50 mg/kg labeled test material. Five pups of each sex were sacrificed 0.5 and 1.5 after treatment and 15 pups of each sex were sacrificed 4 hours after treatm ent. At sacrifice, blood, plasma, intestinal tract with contents, kidney, liver, stomach and contents, the residual carcass, and pooled excreta were collected. Three male and 3 female pups in Group 2 received a single oral dose of 50 mg/kg labeled test m aterial and one pup of each sex was sacrificed 0.5, 1.5, and 4 hours after treatment and subjected to whole body autoradiography (WBA).

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

e videnced by finding high radioactive areas in the kidneys and bladder by WBA. No areas of tissue sequestration were found and no gender

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

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

This neonatal metabolism study is classified Acceptable/Non

- guideline , and satisfies the intent of the study to investigat e the absorption, distribution, metabolism and excretion of radiolabeled

MTI

- 446 in the neonatal rat. The study was not considered Guideline for the following reasons:

12

- day

- old neonatal rats were used; a single dose was used (50 mg/kg); urine and feces were not collected separately, excreta were not collected individually for the determination of the percent of dose contained in each; the study duration was 4 hours; no expired air was collected; and no biliary studies were done

.Page 66 of 69

Appendix B

. Physical/ Chemical Properties

1 DP# 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 67 of 69

Appendix C

. International Residue Limit Status Sheet

.



### Dinotefuran ( 044312; 11/03/ 2011)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180.603

Plant (a) General (1) dinotefuran, sum of dinotefuran and its metabolites DN, 1

- methyl

- 3

- (tetrahydro

- 3

- furylmethyl)guanidine, and UF, 1

- methyl

- 3

- (tetrahydro

- 3

- furylmethyl)urea None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3
Berry, low growing, except strawberry, subgroup 13

- 07H 0.2

Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 0.9

Onion, bulb, subgroup 3

- 07A 0.15 Onion, green, subgroup 3

- 07B 5 .0

Peach 1.0 Tea, plucked leaves 25 Vegetable, tuberous and corm, subgroup 1C 0.05

Watercress 8 .0

Completed: M. Negussie; 11/03/11

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated store d wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.Page 68 of 69

Appendix D. 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 ethyl

- 3

- (tetrahydro

- 3

-

furylmethyl)

- guanidine

PHP 6

- h ydroxy

- 5

- (2

-

hydroxyethyl)

- 1

- methyl

- 1,3

- diazinane

- 2

- ylidene

- N

nitroamine 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 69 of 69

Common name/code Chemical name Chemical structure

FNG 2

- nitro

- 1

- (tetrahydro

- 3

-

furylmethyl)guanidine

Appendix E

. Review of Human Research

Studies 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 National Agricultural Chemicals Associati on, 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).