Page **1** of **49** UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **:** 8 / 31 /12 **SUBJECT:** Dinotefuran : Human Health Risk Assessment for Proposed Section 3 Use s on

Rice and Food/Feed Handling Establishments, and New Horse Spot - On and Total Release Fogger Products . **PC Code:** 044312 **DP Barcode:** D 398048, D398481, D 397013, D398247 **Decision No s**  **.:** 458508, 459304, 447391, 449845 **Registration No s**  **. :**  86203 - 2 5 , 499 - LAN, 83399 - RR , 499 - 526, 499 - 527, 499 - 531 **Petition No .:**  1 F 7 9 53, 1F7967 **Regulatory Action :**  Section 3 Registration **Risk A**  **ss essment Typ**  **e :**  Single Chemical/Aggregate **Case No.:** NA **T XR No.:**  NA **CAS No.:** 165252 - 70 - 0 **MRID No.:** NA **40 CFR:** §180.6 0 3 **FROM:** Barry O’Keefe , Senior Biologist

Sheila Heal y , Ph.D., Toxicologist Leung Cheng , Ph.D., Senior Chemist Cassi Walls, Ph.D., Senior Biologist Risk Assessment Branch III Health Effects Division (7509P) **THROUGH:** Jeff Dawson, Acting Branch Chief

Risk Assessment Branch III Health Effects Division (7509P) **TO:** Rita Kumar, Senior Regulatory Specialist In secti cide/Rodenticide Branch Registration Division (7505P) This document and attachments provide an assessment of the human health risk resulting from the proposed and registered uses of dinotefuran . The proposed uses of dinotefuran include agricultural use on rice, use in food/feed handling establishments, a hor se spot - on product, and a new total release fogger product. The toxicology evaluation was performed by Sheila Heal y , the drinking water assessment was conducted b y Jim Wolf and Jim Hetrick of the Environmental Fate and Effects Division (EFED) , the review of the residue chemistry data was conducted by Leung Cheng, the dietary assessment was conducted by Cassi Walls , and the occupational and residential exposure assessment and the overall human health risk assessment were conducted by Barry O’Ke efe .Page **2** of **49**

**1.0 Executive Summary**  ................................ ................................ ................................ ........... 4 **2.0 HED Recommendations**  ................................ ................................ ................................ .... 7 **2.1 Data Deficiencies**  ................................ ................................ ................................ ............ 8 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 9 **2.2. 1**  **Enforcement Analytical Method** ................................ ................................ ........... 9 **2.2.2 International Harmonization**  ................................ ................................ ................. 9 **2.2.3 Recommended Tolerances**  ................................ ................................ .................... 10 **2.2.4 Revisions to Petitioned**  **- For Tolerances**  ................................ .............................. 11 **2.3 Label Recommendations**  ................................ ................................ .............................. 12 **2.3.1 Recommendations from Residue Reviews**  ................................ .......................... 12 **2.3.2 Recommendations from Occupational Assessment**  ................................ ........... 13 **3.0 Introduction**  ................................ ................................ ................................ ...................... 13 **3.1 Chemical Identity**  ................................ ................................ ................................ ......... 13 **3.2 Physical/Chemical Characteristics**  ................................ ................................ ............. 14 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ .... 15 **3.4 Anticipated Exposure Pathways**  ................................ ................................ ................. 18 **3.5 Consideration of Environmental Justice**  ................................ ................................ .... 18 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  ................................ .......... 19 **4.1 Toxicology Studies Available for Analysis**  ................................ ................................ . 19 **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  ............................. 19 **4.2.1 Dermal Absorption**  ................................ ................................ ............................... 20 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 2 0 **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  ............................... 21 **4.4.1 Completeness of the Toxicology Database**  ................................ .......................... 22 **4.4.2 Evidence of**  **Neurotoxicity** ................................ ................................ .................... 22 **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  .... 22 **4.4.4 Residual Uncertainty in the Exposure Database**  ................................ ................ 22 **4.5 Toxicity Endpoint and Point of Departure Selections**  ................................ .............. 23 **5.0 Dietary Exposure and Risk Assessment**  ................................ ................................ ......... 24 **5.1 Residues of Concern Summary and Rationale**  ................................ .......................... 24 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 24 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 28 **5.4 Dietary Risk Assessment**  ................................ ................................ .............................. 30 **5.4.1 Description of Residue Data & Percent Crop Treated Used in Dietary**  **Assessment** ................................ ................................ ................................ ........................... 30 **5.4.2 Acute Dietary Risk Assessment**  ................................ ................................ ........... 30 **5.4.3 Chronic Dietary Risk Assessment**  ................................ ................................ ....... 30 **5.4.4 Summary Table**  ................................ ................................ ................................ ..... 31 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  ............................. 31Page **3** of **49**

**6.1 Residential Handler Exposure**  ................................ ................................ .................... 32 **6.2 Post**  **- Application Exposure**  ................................ ................................ .......................... 32 **6.3 Combined Exposure**  ................................ ................................ ................................ ..... 34 **6.4 Residential Bystander Post**  **- Application Inhalation Exposure**  ................................ 34 **6.5 Spray Drift**  ................................ ................................ ................................ .................... 34 **7.0 Aggregate Exposure/Risk Characterization**  ................................ ................................ .. 35 **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 35 **7.2 Shor** **t -**  **Term Aggregate Risk** ................................ ................................ ........................ 35 **7.3 Intermediate**  **- Term Aggregate Risk**  ................................ ................................ ........... 36 **7.4 Chronic Aggregate Risk**  ................................ ................................ .............................. 36 **7.5 Ca**  **ncer Aggregate Risk** ................................ ................................ ................................ 36 **8.0 Cumulative Exposure/Risk Characterization**  ................................ ............................... 37 **9.0 Occupational Exposure/Risk Characterization**  ................................ ............................ 37 **9.1 Short**  **- /Intermediate**  **- Term Handler Risk**  ................................ ................................ ... 37 **9.2 Short**  **- /Intermediate**  **- Term Post** **- Application Risk**  ................................ .................... 37 **10.0 References**  ................................ ................................ ................................ ......................... 38 **Appendix A. Toxicology Profile** ................................ ................................ ................................ 39 **A.1 Toxicology Data Requirements**  ................................ ................................ ................... 39 **A.2 Toxicity Profiles**  ................................ ................................ ................................ ............ 40 **Appendix B. Physical/Chemical Properties** ................................ ................................ ............. 46 **Appendix C. International Residue Limit Status Sheet.** ................................ ........................ 47 **Appendix D. Dinotefuran and Metabolites** ................................ ................................ .............. 48 **Appendix E. Review of Human Research** ................................ ................................ ................ 49Page **4** of **49**

**1.0 Executive Summary**  The HED risk assessment team has evaluated the following four new submissions for new uses of dinotefuran: 1) On behalf of the registrant , Mitsui Chemicals Agro, Inc, Landis International, In c. has submitted a petition (#1F7953) to add a new food use, rice, to the LX434 Dinotefuran 20SG label (EPA Reg. No. 86203 - 25); 2) On behalf of the registrant s, Mitsui Chemicals Agro, In c., BASF Corporation, and Whitmire Micro - Gen Research Laboratories Inc., Landis International, Inc. has submitted a petition (#1F7967) to add a new use in food/feed handling establishments for control of numerous insects; 3) Whitmire Micro - Gen Research Laboratories, In c. requested registration of a new total release fogger for indoor use (TRF; EPA Reg. No. 499 - LAN; TC - 320); and 4) Ceva Animal Health, LL C, has submitted an application for a new horse spot - on product SVP 11 (Vectra EQ) (EPA Reg No. 83399 - RR) . Dinotefuran ((RS) - 1 - methyl - 2 - nitro - 3 - (tetrahydro - 3 - furylmethyl)guanidine) is a broad spectrum insecticide belonging to the nitroguanidine sub - class of the neonicotino i d class of insecticides. It is insecticidal by contact and ingestion, resulting in the cessation of insect feeding within hours of contact with death shortl y . The mode of action is interference with the acetyl choline receptor on the post - sy naptic side of the nerve cells. Dinotefuran is currently registered for use on numerous agricultural crops. Dinotefuran is also regist ered for occupational use for professional turf management and ornamental production. There are residential and commercial indoor uses of dinotefuran, including ready- to - use (RTU) products, crack and crevice products , and spot application product s. Resid ential handlers may also appl y dinotefuran to pets (spot - on), and on lawns and gardens. Use Profile The proposed uses of dinotefuran include agricultural use on rice, use in food/feed handling establishments (liquid, foam, and dust products) , a horse spot - on product, and a new total release fogger (TRF) product. The horse spot - on product is restricted to use on horses, ponies, donkey s, and mules and is not allowed to be used on cats and dog. The TRF product is proposed for use in apartments, attics, buse s, nonfood areas of food handling establishments (including restaurants, food service, storage and processing areas, and USDA inspected facilities), garages, homes, hospitals, nursing homes, office buildings, railroad cars, schools, ships, supermarkets, empty truck trailers, warehouses, zoos, dairy barns, dairy

parlors, enclosed calf structures, horse stables, riding arenas, and swine facilities. The full proposed use profile for dinotefuran is detailed in Section 3.3. Toxicity/Hazard The dinotefuran hazard profile was updated in the most recent risk assessment (DP391885, B. O’Keefe, 7/20/12) , and nothing has changed since this update . The toxicology database is adequate for hazard characterization. The nervous sy stem is the main target of dinotefuran toxicity . After a single dose in rats and rabbits, n euro toxicity was manifested as clinical signs (hy poactivity , prone position, panting, tremors, and ery thema) and decreased motor activity and changes in motor activity . These acute effects are consist ent with effects seen on the nicotinic cholinergic nervous sy stem a fter repeated dosing. Dinotefuran was well tolerated at high dosesPage **5** of **49**

following dietary

administration for 90 day s 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 ; but for acute dietary

exposure the endpoint is neurotoxicity . No s ys temic 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 concentrations to rats for 28 day s. N o evidence of functional immunotoxicity was observed in guideline immunotoxicity or developmental immunotoxicity studies of dinotefuran. There are also no indications of perturbed reproductive function. No adverse effects in fetuses were seen in the developmental toxicity studies in rats or rabbits, at maternally toxic doses, and offspring effects in the reproducti on 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 assay s. Based on hazard and exposure data , HED has concluded that there are no residual uncertainties for pre - and

/ or post - natal toxicity, or in the exposure database, and the Food Quality Protection Act ( FQPA ) Safety Factor can be re duc ed to 1X . For 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 no observed adverse effect level (NOAEL ) of 125 mg/kg/day in a developmental toxicity study in rabbits based on clinical signs indicative of neurotoxicity in does (hy poactivity , prone position, panting, tremors , and ery

thema) observed at 300 mg/kg/day ( lowest observed adverse effect level; LOAEL). For chronic dietary

risk to all populations, a chronic population adjusted dose ( cPAD ) of 1.0 mg/kg/day

was derived from a NOAEL of 99.7 mg/kg/day from the chronic toxicity /carcinogenicity s tudy

in rats , based on decreased b ody weight gain and food efficiency in females and increased incidences of kidney pelvic mineralization and ulceration in males at 991 mg/kg/day

(LOAEL). To assess short - and intermediate - term incidental oral exposures, an oral point of departure (POD) was selected. The POD (NOAEL = 99.7 mg/kg/day) was based on decreased body weight gain, and food efficiency in females and increased incidences of kidney pelvic mineralization and ulceration in males seen at the lowest observed adverse effect level (LOAEL) of 991 mg/kg/day

seen in the chronic toxicity /carcinogenicity study in rats. Quantification of short - or intermediate - term dermal and inhalation risks are not required because no s ys temic or developmental toxicity was seen up to the limit dose in route - specific toxicity studies.Page **6** of **49**

Dietary Exposure (Food and W ater) The results of the acute dietary anal ys is for food and drinking water show that the acute dietary risk estimates are well below the Agency ’s level of concern ( LOC; <100% of the acute population adjusted dose ( aPAD ) ) for all population subgroups and were estimated at 3.0 % of the aPAD for the general U.S. population and 7.6 % of the aPAD for the most highly exposed population subgroup ( all infants <1 yr old). The results of the chronic dietary anal ys is for food and drinking water indicate that the chronic dietary risk esti mates are well below the Agency ’s LOC (<100% of the chronic population adjusted dose ( c PAD)) for all population subgroups and were estimated at 1 .4 % of the c PAD for the general U.S. population and 3 . 9 % 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 Of the new proposed uses, only the total release fogger results in new residential exposures. Based on the proposed use pattern, HED does not expect residential handler exposure. T otal release fogger products are activated and then handlers leave the area being treated. Th ere is the potential for post - application exposure for individuals exposed entering a treated environment . Quantification of short - or intermediate - term dermal and inhalation risks are not required because no s ys temic or developmental toxicity was seen up to the limit dose in route - specific toxicity studies. The only

potential post - application exposure pathway quantitatively assessed is incidental oral exposure (e.g., hand to mouth) for children. HED’s assessment for the incidental oral exposure pathway for children results in margins of exposure ( MOEs ; range 1,200 to 13,000) that do not exceed HED’s LOC ( LOC = 100) . Aggregate Exposure Acute and chronic aggregate exposure is equal to acute and chronic dietary exposure. The acute and chronic aggregate risk estimates for all populations, resulting from exposure to dinotefuran in food and drinking water , are not of concern. For children, a short - term aggregate risk assessment was performed to assess the potential for co - occurring post - application exposure resulting in the greatest exposure (i.e., from use of the total release fogger product and the existing cat spot - on use) , resulting in a MOE of 79 0 , which is greater than 100, and therefore not of concern. An aggregate risk assessment was not performed for adults , since no toxicity endpoints were identified for th e dermal and inhalation routes. Occupational Exposure Occupational short - (1 to 30 day s) and intermediate - term (1 to 6 months) dermal and inhalation exposures are expected from dinotefuran handler activities . However, since no hazard was identified for the short - or intermediate - term dermal or inhalation route s of exposure , dermal and inhalation risks were not assessed. For handlers, personal protective equipment ( PPE ) appearing on the din otefuran label (EPA Reg. No. 86203 - 25) for the proposed use on rice includes coveralls, chemical resistant gloves made of any waterproof material such as polyethylene or poly vinyl chloride, and shoes plus socks. RiskPage **7** of **49**

estimate s for occupational handlers were not assessed because no hazard was identified for either the dermal or inhalation route of exposure. Therefore, the PPE of coveralls and chemical resistant gloves are not needed. 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 , dermal 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 IV ) and a low vapor pressure ( 1 .2 8 x10 - 8 mm Hg), post - application inhalation exposures and risks were not quantitativel y assessed. Technical dinotefuran is classified as 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 und er Toxicity Category IV. Therefore, the REI of 12 hours appearing on the dinotefuran label (EPA Reg. No. 86203 - 25) for the proposed use on rice is adequate. Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data , including studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Resi dential Exposure Task Force (ORETF) database; and the Agricultural Re - entry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studi es that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler- exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html . Environmental Justice Potential areas of environmental justice concerns were considered in this human health risk assessment. Refer to Section 3.5 for details. **2.0 HED**  **Recommendations** HED recommends that the registration and tolerance request s be granted for the following: 1) dinotefuran use on rice ; 2) the liquid, foam and dust formulations in food/feed handling establishments ; 3) the total release fogger (except in food handling establishments) ; 4) an d the horse spot - on product . Additional data are needed as outlined in Section 2.1 below. The specific tol erance recommendations are discussed in Section 2.2 and label modifications are discussed in Section 2.3.Page **8** of **49**

**2.1 Data Deficiencies**  See also Section 2.3.1 for required label changes for residue chemistry issues. **Data that needs to be submitted prior to a tolerance being established or registration**  **allowed. For the**  **P roposed**  **U se on**  **R ice**  **:** 860.1550 Proposed Tolerances

 The petitioner should submit a revised Section F reflecting the revision to the proposed tolerance on rice grain and the addition of poultry tolerances. **For the Proposed Food/Feed Handling Establishment Use by BASF Corp.:** 860.1550 Proposed Tolerances

 The petitioner should submit a revised Section F reflecting the revision s to the proposed tolerance language that are listed below in Section 2 .2.3. **B oth registrants**  **(i.e., Mitsui Chemicals Agro Inc.**  **and BASF Corp.) mu**  **st maintain a sufficient amount of the**  **r eference standard at the EPA Repository as stated below:**  OPPTS 860.1650 Submittal of Anal ytical Reference Standards

 The standard for dinotefuran will expire i n 2012. An updated certificate of anal ys is or a new anal ytical reference standard (5 grams) must be provided to the EPA National Pesticide Standards Repository . **Data that should be submitted with future uses or if there will be h igher li** **vestock dietary burdens.**  860. 148 0 Li vestock Feeding Study - Poultry

 A poultry

feeding study

may be required if the poultry dietary burden is significantly raised in a future petition.Page **9** of **49**

**2. 2**  **Tolerance Considerations 2.2.1**  **Enforcement Analytical Method**  For tolerance setting in plant commodities, p arent dinotefuran and the metabolites DN (1 - methyl - 3 - (tetrahydro - 3 - furylmethyl) guanidine) and UF (1 - methyl - 3 - (tetrahydro - 3 - furylmethyl) urea) are the residues of concern. There are analytical methods available for tolerance 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 HPL C/ultraviolet (UV) detection method for the determination of resi dues of dinotefuran; and HPL C/MS and HPL C/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. Samples from the submitted rice crop field trial and processing studies and the food - handling establishment study

were anal yz ed for residues of dinotefuran, DN, and UF using acceptable LC/MS/MS methods similar to the established enforcement method. The method s w ere adequatel y validated prior to and/or in conjunction with the anal ys is of the field trial , processing , storage stability

and food - handling establishment study samples. The validated limits of quantitation (L OQs; determined as the lowest levels of method validation, LLMV) for rice commodities were 0.01 ppm for all anal yt es in rice grain and processed commodities and 0.10 ppm for all anal yt es in rice straw. For the food - handling establishment study , the LOQs (determined as the LLMV) were 0.01 ppm for dinotefuran in perishable and non - perishable food items and 10 μg for dinotefuran in inert food surface items. For tolerance setting in livestock commodities, dinotefuran is the residue of concern in livestock commodities for tolerance setting. A liquid chromatograp h y/tandem 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 UF 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 UF m etabolites, 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 Mexican maximum residue limits (MRL s) for dinotefuran in/on rice, egg, poultry , or food/feed handling establishments . An International Residue Limits (IRL ) Status sheet is attached to this review as Appendix C.Page **10** of **49**

**2.2.3 Recommended Tolerances**  Tolerances are estab lished under 40 CFR §180.603 for residues of dinotefuran, including its metabolites and degradates. For plant commodities [under 40 CFR §180.603(a)(1)] , compliance with the tolerance levels is to be determined b y m easuring onl y the sum of dinotefuran and its metabolites DN and UF. For livestock commodities (under 40 CFR §180.603(a)(2)], compliance with the tolerance levels is to be determined b y m easuring onl y dinotefuran. Pending submission of a revised Section s F and B , and revised label s, there are no residue chemistry issues that will preclude establishment of permanent tolerances for dinotefuran as specified in Table 2.2.3 . **For the Proposed Rice Use by Mitsui Chemicals Agro Inc.**  **:** Pending submission of a revised Section s B and F, and updated certificate(s) of anal ys is or new anal ytical reference standard(s) as specified in Sections 2.1 and 2.3.1 , there are no residue chemistry issues that would preclude granting registration for the requested use of dinotefuran on rice f or establishment of the following tolerance for combined residues of dinotefuran, UF, and DN : Rice, grain ................................ ................................ ........ 9 ppm and, for establishment of poultry tolerances for residues of dinotefuran: Egg ................................ ................................ .............. 0.01 ppm Poultry , meat b yproducts ................................ ............ 0.01 ppm **For the Proposed Food/Feed Handling Establishment Use by BASF Corp**  **. :**  Pending submission of revised Section s B and F, and updated certificate(s) of anal ys is or new anal ytical reference standard(s) as specified in Sections 2.1 and 2.3.1 , there are no residue chemistry issues that would preclude granting registration for the requested use of dinotefuran in food/feed - handling establishments or establishment of the proposed tolerance under 40 CFR §180.603(a)(3) as follows: A tolerance of 0.01 ppm is established for residues of the insecticide dinotefuran, ( R,S ) - 1 - methyl - 2 - nitro - 3 - ((tetrahydro - 3 - furanyl)meth yl )guanidine, including its metabolites and degradates, in or on the commodities identified below. Compliance with the tolerance level is to be to be determined by measuring only

dinotefuran as follows: (i) F ood/feed items (other than those covered by a higher tolerance as a result of use on growing crops) in food/feed handling establishments.Page **11** of **49**

(ii) The insecticide may

be present as a resid

ue from application of dinotefuran in food/feed handling establishments, including places other than private residences in which food is held, processed, prepared, or served, including those operating under the Federal meat, poultry, shell egg grading and egg products inspection programs, in accordance with the following prescribed conditions. (A) Application shall be limited to general surface and spot and/or crack and crevice treatment in food/feed handling establishments where food/feed products, are he ld, processed, prepared, and served. General surface application may be used only

when the facility is not in operation, provided exposed food/feed has been covered or removed from the area prior to application . Reapplications may be made at 6 - day

interv als. Crack and crevice and/or spot application may be used while the facility is in operation, provided exposed food/feed has been covered or removed from the area prior to application. Reapplications may be made at 3 - day

intervals. Spray

concentration shall be limited to a maximum of 0.5% active ingredient. D ishes, utensils , food processing equipment, and food preparation surfaces in the treatment area should be removed, covered, or washed before use . Applications should be made to selective surfaces such as baseboards, under elements of construction, stainless steel equipment, shelving, machinery , storage areas, pallets, tables, chairs, and other areas where listed pests may

be harboring, traveling, breeding, or entering the structure. Contamination of food/feed or food/feed contact surfaces shall be avoided. (B) To assure safe use of the insecticide, its label and labeling shall conform to that registered with the U.S. Environmental Protection Agency and shall be used in accordance with such label and labeling. **Table 2.2.3**  **. Tolerance Summary for Dinotefuran**  **Comm odity**  **Proposed Tolerance**  **(ppm) Recommended** 

**Tolerance (ppm)**  **Comments (correct**

**comm odity definition)**  Rice, grain 10 9 Egg - 0.01 Poultry, meat byproducts - 0.01 All food/feed items (other than those covered by a higher tolerance as a result of use on growing crops) in food/feed handling establishments. 0.01 0.01 **2.2.4 Revisions to Petitioned**  **- For Tolerances**  For the proposed use on rice, Mitsui proposed a tolerance for the combined residues of dinotefuran, UF, and DN in/on “Rice grain” at 10 ppm. T he submitted field trial data for rice are sufficient for establishing a tolerance for rice grain. The Organization of Economic Cooperation and Development ( OECD ) tolerance calculation procedures were utilized in determining an appropriate tolerance level. Using the OECD tolerance calculation procedures, the recommended tolerance is 9 ppm. The appropriate residue definition is “Rice, grain”.Page **12** of **49**

Also for the proposed use on rice (Mitsui), HED has concluded that n o changes are needed to the existing tolerances for milk , ruminant or swine tissues as a result of the addition of rice grain or bran to the diet. For poultry , with the increased dietary burden resulting from the proposed use on rice, and in consideration of the results from the available poultry metabolism study, HED concludes that poultry tolerances in egg and liver (as poultry meat by products) at the LOQ of 0.01 ppm are now needed. A poultry feedin g study

may be required if the poultry dietary burden is significantly

raised in a future petition. The submitted rice processing study is adequate and indicates that separate tolerances are not needed for polished rice or bran. **2. 3**  **Label Recommendations 2.**  **3 .1**  **Recommendations from Residue Reviews For the**  **P roposed**  **U se on**  **R ice**  **:** 860.1200 Directions for U se
 In the absence of data pertaining to residues of dinotefuran in water, fish, and irrigated crops, the petitioner must include label restrictions against use of flood water from treated fields for irrigation purposes for any food/feed crops, and against app lication to rice fields if fields are used for fish production, especially catfish or crayfish farming.

 For handlers, personal protective equipment ( PPE ) appearing on the proposed dinotefuran label (EPA Reg. No. 86203 - 25) includes coveralls, chemical resistant gloves made of any waterproof material such as polyeth yl ene or pol yv inyl chloride, and shoes plus socks. Since the risk estimate s for occupational handlers were not assessed because no hazard was identified for the dermal route of exposure, the PPE of coveralls and chemical resistant gloves are not needed. **For the Proposed Food/Feed Handling Establishment Use:** 860.1200 Directions for U se
 Revise “ Remove or cover dishes, utensils, food processing equipment, and food preparation surfaces in the treatment area, or wash them before use .” to “ Remove or cover food

/feed , dishes, utensils, food processing equipment, and food preparation surfaces in the treatment area, or wash them before use .”

 To ensure that applications of products will be made at rates similar to or less than those used in the study , the use directions must be revised to spec ify a maximum rate in g ai/linear f oo t and a minimum 6 - day re - treatment interval ( RTI ) for general treatment, and a 3 - day RTI for crack and crevice and spot treatments. The submitted data support aPage **13** of **49**

maximum use rate of 0.05 g ai/linear foot. **2.3. 2**  **Recommendations from Occupational Assessment For the Proposed**  **Total R** **elease Fogger Product** The label language for using the proposed fogger in non - food areas of food handling establishments should be removed from the label. The registrant did not submit any residue data to support this use site. Use of a fogger in the non - food areas of a food handling e stablishment may result in residues in the food areas. **3.0 In**  **troduction** Dinotefuran is a broad - spectrum insecticide belonging to the nitroguanidine sub - class of the neonicotino i d class of insecticides. It is insecticidal by contact and ingestion, resulting in the cessation of insect feeding within hours of contact with death shortly . The mode of action is interference with the acetylcholine receptor on the post - sy naptic side of the nerve cells. Dinotefuran is currentl y registered for use on numerous agricultural use sites, including: Brassica l eaf

y greens, s ubgroup 5 B; c otton ; cucurbits ; f ruiting v egetables ; grapes ; h ead & s tem Brassica v egetables, subgroup 5A; l eaf y v egetables, except Brassica , group 4; p otatoes; turnip greens ; and greenhouse grown t omatoes . It is also registered on many residential/non agricultural use site s, including : turf, 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 spot - on, foggers, Christmas trees, o rnamental trees, n on - b earing f ruit and nut trees, p lantations reforestation nurseries, f orests, and w oodland areas . Registered dinotefuran formulations include baits, gels, soluble concentrates, granulars, soluble granules, and ready- to use (RTU) products . The HED risk assessment team has evaluated four new submissions for new uses of dinotefuran; they are as follows: 1 ) On behalf of the registrant , Mitsui Chemicals Agro, Inc, Landis International, Inc. has submitted a petition (#1F7953) to add a new food use, rice, to the LX434 Dinotefuran 20SG label (EPA Reg. No. 86203 - 25); 2) On behalf of the registrant s, Mitsui Chemi cals Agro, Inc., BASF Corporation, and Whitmire Micro - Gen Research Laboratories Inc., Landis International, Inc. has submitted a petition (#1F7967) to add a new use in food/feed handling establishments for control of numerous insects; 3) Whitmire Micro - Gen Research Laboratories, Inc. requested registration of a new total release fogger (TRF; EPA Reg. No. 499 - LAN; TC - 320); and 4) Ceva Animal Health, LL C, has submitted an application for a new horse spot - on product SVP 11 (Vectra EQ) (EPA Reg No. 83399 - RR) . **3.1 Chemical Identity**  The chemical structure and nomenclature of dinotefuran and its metabolites DN and UF) arePage **14** of **49**

presented in Table 3.1. **T ABLE**  **3. 1. Dinotefuran**  **No me**  **nclature.** Compound Chemical Structure

Common name d inotefuran Company experimental name MTI - 446 IUPAC name (EZ ) - (RS ) - 1 - methyl - 2 - nitro - 3 - (tetrahydro - 3 - furylmethyl)guanidine CAS name N - m ethyl -N  ́- nitro -N  ̋

- [tetrahydro - 3 - furanyl)methyl] guanidine CAS # 165252 - 70 - 0 End - Use Product s LX434 Dinotefuran 20SG label (EPA Reg. No. 86203 - 25) , TC 267 (EPA Reg. No. 499 - 531), TC 259 (EPA Reg. No. 499 - 526), TC 249 (EPA Reg. No. 499 - 527) , TC - 320 (EP A Reg. No. 499 - LAN); and SVP 11 (Vectra EQ) (EPA Reg No. 83399 - RR) Compound Chemical Structure

Common name DN IUPAC name 1 - methyl - 3 - (tetrahydro - 3 - furylmethyl)guanidine Compound Chemical Structure

Common name UF IUPAC name 1 - methyl - 3 - (tetrahydro - 3 - furylmethyl ) - urea **3.2 Physical/Chemical Characteristics**  The phy si c ochemical properties of dinotefuran are summarized in Appendix B . Dinotefuran has a molecular weight of 202.2 g/mole, a very high water solubility

(39,830 ppm), and a low octanol/water partition coefficient (KOW = 0.283), suggesting the potential for runoff and low 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 **15** of **49**

bioaccumulation. The low vapor pressure (1.28 x 10 - 8 mm Hg) and a low Henry s’s Law Constant (8.63 x 10 - 14 Atm • M 3 /mol) suggest that this compound is not expected to volatilize substantially

from water or soils in the natural environment. The major route of dissipation for dinotefuran appears to be aqueous photolysis (half - life 1.8 day s ) and leaching. Since there is no valid soil photoly sis data, it is unknown if dinotefuran parent residues break down quickly in soil via photoly sis. Dinotefuran appears to be relativel y persistent to metabolism, both in aerobic (half - life = 17 - 89 day s) and anaerobic (half - life = 51 - 62 day s) conditions. It appears that under metabolic conditions, dinotefuran 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 (Koc = 6

– 45 L/kg

- OC ) in various soil ty pes. It is also very highl y 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 throu gh spray drift and in runoff events, probabl y dissolved in the water column. Once in the rivers, ponds, 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 dissolution, and subsequently via metabolism. **3.3 Pesticide Use Pattern**  **Proposed Use on Rice**  On behalf of the registrant , Mitsui Chemicals Agro, Inc, Landis International, Inc. has submitted a petition (#1F7953) to add a new food use, rice, to the LX434 Dinotefuran 20SG label (EPA Reg. No. 86203 - 25). The proposed new use is for the control of sucking and chewing insects on rice. For handlers, PPE appe aring on the LX434 Dinotefuran 20SG label includes coveralls, chemical resistant gloves made of any waterproof material such as pol yeth ylene or pol yvinyl chloride, and shoes plus socks. The proposed use directions are presented in Table 3.3.1. **Table 3.3.**  **1. Summary of Directions for Use of**  **Dinotefuran on Rice .**  Applic. Timing, Ty pe, and Equip. Form

ulation [EPA Reg. No.] Applic.

Rate Max. No. Applic. per Season Max.

Seasonal Applic. Rate PHI 1

(days) Use Directions and

Limitations Broadcast, Foliar, Aerial (min. 3 gal/A) 20% SG

(soluble granule) [86203 - 25] 0.09375 -

0.131 lb ai/A 2 0.262 lb ai/A 7 Applications are to begin

when insects reach threshold levels and repeat as needed on a 7 - day

retreatment interval (RTI). 1 PHI = Pre - harvest interval. **Proposed Use in Food/Feed Handling Establishments**  On behalf of the registrant s ( Mitsui Chemicals Agro, Inc., BASF Corporation, and Whitmire Micro - Gen Research Laboratories Inc. ) Landis International, Inc. has submitted a petition (#1F7967) to add a new use in food/feed handling establishments for control of numerous insects. This new use is proposed to be added to three existing dinotefuran end use productPage **16** of **49**

labels [ i.e., TC 267 (EPA Reg. No. 499 - 531), TC 259 (EPA Reg. No. 499 - 526), and TC 249 (EPA Reg. No. 499 - 527) ] . TC 267 is a 0.5% pressurized liquid injection product. TC 259 is 0.025% foam product. TC 249 is a 0.25% dust product. All three products are proposed for crack and crevice and spot treatments, and the TC 267 product is also proposed for general broadcast treatments. The proposed use directions are presented in Table 3.3.2. **Table 3.3.2**  **Summary of Directions for Use of Dinotefuran in Food/Feed Handling Establishments**  **.** Applic. Timing, T ype, and Equip. Form

ulation [EPA Reg. No.] Applic.

Rate Max.

No. Applic. per Season Max.

Seasonal Applic. Rate PHI

(days) Use Directions and Limitations

Crack and crevice treatment 0.5% PrL

[499 - 531] (with supplied actuator and injection tubes) 3 ft/sec

(crack & crevice) 1 - 5 sec/3 ft 3 (void) Not

specified (NS) NS Not

applicable (NA) Place injection tip into cracks, crevices, holes, and other small openings. Reapply as necessary. Spot treatment NS NS NS NA Direct nozzle ~12 inches from surface to be treated. Apply directly on pests in these locations when possible. Reapply as necessary. General treatment NS NS NS NA Direct applications 6 - 12 inches away from the surface to walls, ceilings, around and in cupboards, underside of shelving, around windows, door frames, between, beneath, and under equipment. For floors, do not treat entire area, concentrate around drains, under equipment, cupboards, and shelving, and areas of suspected insect activity. Crack and crevice treatment 0.025%

Foam [499 - 526] (with supplied injector and injection tips) 1 NS NS NS NA Fill the crack and crevice at or near point of infestation. Spot treatment NS NS NS NA Wet the surface area: ≤20% of total surface area or ≤2 ft2 for each spot of application. Allow foam to dissipate or wipe surface dry before leaving site. Crack and crevice treatment, Hand/bulbous or powder duster 0.25% DP

Dust [499 - 527] 0.15 - 0.3

oz. product /yd2 (0.16 - 0.32 oz. product/ 10 ft2 ) NS NS NA Apply lightly and uniformly to infested areas. Repeat treatments as necessary.Page **17** of **49**

**Table 3.3.2**  **Summary of Directions for Use of Dinotefuran in Food/Feed Handling Establishments**  **.** Applic. Timing, T ype, and Equip. Form

ulation [EPA Reg. No.] Applic.

Rate Max.

No. Applic. per Season Max.

Seasonal Applic. Rate PHI

(days) Use Directions and Limitations
Spot treatment, Hand/bulbous or powder duster NS NS NS NA Apply lightly and uniformly to infested areas. Limit individual treatments to ≤20% of total surface area or ≤2 ft2 for individual spot treatments. Repeat treatments as necessary. 1 For application of the 0.025% foam, the injector tip is to be held in place for ~8 seconds to allow the product within the injector tube to dispense into the treatment area: expansion ratio of 30:1, with 1 oz. (~5 sec) of product producing ~1 qt. foam. **Proposed Horse Spot**  **- On Use**  The registrant , Ceva Animal Health, LL C, has submitted an application for a new horse spot - on product, SVP 11 (Vectra EQ) (EPA Reg No. 83399 - RR) , containing permethrin (36.08 %) ; dinotefuran (4.95%); and py riprox yf en (0.445). Th e proposed new use is for the control of stable flies for use on horses, ponies, donkeys, and mules. The SVP 11 (Vectra EQ) product can be applied by

occupational and residential handlers. The product is restricted to use on horses, ponies, donkeys, and mules and is not allowed for use on cats and dog. The spot - on treatment should not exceed the application rate as defined by the label. The application rate for the active ingredient dinotefuran as a spot - on product is 0.0027 lbs ai per animal. One 24 m l applicator is applied to the animal. One third (8 ml) is applied as a continuous strip from the base of the ear to the base of the tail approximately 6 - 8 inches off the midline and a second third ( 8 ml ) is applied on the other side of the midline from the base of the ear to the base of the tail, and the remaining third (8 ml) is applied in a small stripe below forelock and then a s a uniform stripe from the caudal aspect of the hock to the pastern and caudal aspect of knee to pastern. This treatment is t o be repeated every

month or as recommended by a veterinarian. **Proposed Total Release Fogger Product**  A Section 3 registration was requested b y Whitmire Micro - Gen Research Laboratories, Inc. for use of a new total release fogger (TRF; EPA Reg. No. 499 - LAN) for use in apartments, attics, buses, nonfood areas of food handling establishments (including restaurants, food service, storage and processing areas, and USDA inspected facilities), garages, homes, hospitals, nursing homes, office buildings, railroad cars, schools, ships, supermarkets, empty truck trailers, warehouses, zoos, dairy

barns, dairy

parlors, enclosed calf structures, horse stables, riding arenas, and swine facilities. The TRF is co - formulated with dinotefuran (0.2%), p yrethrins (0.5%), and piperonylbutoxide (4.0%) and is packaged in a 6 oz fogger is designed to treat up to 5,000 cu ft (i.e. , a 25 ft x 25 ft x 8 ft room). The label restricts use in a room smaller than 5 ft x 5 ft x 8 ft, equivalent to 200 cu ft. No more than one fogger may be used per room and may only be applied once per day . PPE listed on the proposed label for applicator s and other handlers to wear include long - sleeve shirt, long pants, socks and shoes.Page **18** of **49**

**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 rice, i n food/feed handling establishments, as a horse spot on product, and as a total release fogger. Humans may be exposed through their diet from applications to agricultural commodities and from applications in food handling establishments . Humans may

also be exposed to dinotefuran in drinking water, since application may result in dinotefuran reaching surface and ground water sources of drinking water. There are residential uses of dinotefuran , so exposure to dinotefuran may occur in residential or non - occupational settings during application and as a result of residues present after application . In an occupational setting, handlers may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential f or 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 pathway s bas ed on the proposed new uses of dinotefuran , but also considers existing uses of dinotefuran , particularl y in the dietary exposure assessment. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http ://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Examination Survey , What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups base d on age, season of the year, ethnic group and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children 3 to < 6 years old , youths and adults entering or playing on treated areas post - application are evaluated. Further consideratio ns are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.Page **19** of **49**

**4.0 Hazard Characterization and Dose**  **- Response Assessment**  Dinotefuran is in the neonicotinoid class of pesticides and acts as an agonist on insect nicotinic acetyl choline receptors. Consistent with its neurotoxic pesticidal mode of action (MOA) , dinotefuran ’ s toxicity

profile shows that the mammalian nervous s ys tem is the target of dinotefuran toxicity , as demonstrated in the acute and subchronic neurotoxicity studies in rats, and pre - natal developmental toxicity study in rabbits . **4 .1**  **Toxi cology Studies Available for Analysis**  The toxicology

database for dinotefuran is adequate for hazard characterization. Available studies include subchronic and chronic oral toxicity studies in rats, mice and dogs, developmental toxicity

studies in rats and rabbits, a reproductive toxicity study in rats, acute and subchronic neurotoxicity

studies in rats and immunotoxicity studies in mice and rats . Additionally , developmental neurotoxic ity (DNT) and immunotoxicity studies are also available. **4.2 Absorpt** **ion, 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) and intravenous (IV) sin gl e dosing. Also performed have been single oral dose studies with pregnant rats at gestation day

(GD18), lactating rats at 12 day s 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 rats and non - pregnant female adult rats did not suggest saturation of clearance at the doses tested (50 and 1000 mg/kg bw); the area under the plasma concentration time curve (not peak plasma levels) scaled proportionally with increases in administered oral dose. The radiolabel was widely and comparabl y distributed throughout the body at 30 minutes post - dosing (approximate tmax) and had declined substantially in all tissues by

4 hours post dosin g. There was no evidence of specific tissue accumulation; the highest content of radioactivity

at 30 minutes was found in the kidney s, reflective of the high water solubility property of dinotefuran and subsequent predominant route of excretion 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 dail y 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 the parent chemical (75 - 93% of the administered radiolabel) in both oral and IV administration studies. Minor metabol ites identified accounted for only 2 - 6% of the administered radiolabel.Page **20** of **49**

The ADME data collected from the single oral dose study with pregnant rats at GD18 suggests that dinotefuran readil y crosses the placenta as evidenced b y parallel profiles exhibited b y 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 day s postpartum were similarl y dosed with a singl e dose of radiolabeled dinotefuran, there was also a comparable profile between maternal blood radioactivity content and maternal milk; both matrices achieved comparable peak levels at the same first time measurement of 0.5 hours. The clearance of radioac tivity from fetal tissues and milk paralleled that of maternal plasma, decreasing b y  80% by 4 hours post - dosing. No measurement of radioactivity was made in nursing pups. PND 12 rat pups exhibited a similar ADME profile following a single oral dose of 50 mg/kg bw radiolabeled dinotefuran. Absorption could not be accuratel y quantified but was noted to be high (~80%). The radio label was widel y distributed in the body with no specific tissue accumulation noted. Urine was the primary elimination route a s indirectly evidenced by finding high radioactive areas b y whole body autoradiography in the kidney s and bladder . There were no metabolites reported ; the parent chemical was the predominant species accounting for >97% of the radiolabel in the excreta, pl asma, kidney s, and stomach, and nearl y 61 - 83% in intestines (and contents), and liver. Approximately 32 - 36% of the administered dose was excreted within 4 hours of treatment. It was noted that rat pups exhibited slower rates of absorption and elimination as compared to adult animals. The age - dependent differences in absorption and elimination were attributed to immature gastrointes tinal tracts and kidney sy stems and

/or the absence of maternal stimulation to elicit excretion . **4.2.1 Dermal Absorption**  A d ermal 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/cm2 (technical grade active ingredient, TGAI)). **4.3 Toxicological Effects**  Dinotefuran has low acute toxicity by oral (Toxicity

Category I II) , dermal (Toxicity

Category IV ) , and inhalation (Toxicity Category IV) exposure routes. It is not a dermal sensitizer, does not irritate the eye (Toxicity Category IV), but causes a low level of skin irritation. The main target of toxicity

is the nervous s ys tem , but effects on the nervous s ys tem were onl y observed at high doses . Nervous s ys tem 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 effects on the nicotinic cholinergic nervous s ys tem seen after repeated dosing. Ty pically , low to moderate levels of neonicotinoids, such as dinotefuran, activat e the nicotinic acetyl choline receptors caus ing stimulation of the peripheral nervous s ys tem (PNS). H igh levels of neonicotinoids (agonists) can over stimulate the PNS, maintaining cation channels in the open state which blocks the action pot ential and leads to paral ys is.Page **21** of **49**

Dinotefuran was well tolerated at high doses following dietary administration for ninety days to mice, rats and dogs. The most sensitive effects were decreases in body weight and /or body weight gain , but even these effects occurred at or near the Limit Dose. Changes in spleen and thy mus weights were seen in mice, rats and dogs following subchronic and chronic dietary exposures. However, these weight changes were not corroborated with alterations in hematology parameters, histopathological lesions in these organs, or toxicity to the hematopoietic sy stem. Furthermore, the toxicology database contains immunotoxicity studies in mice and rats and a developmental immunotoxicity study in rats. In the immunotoxicity studies , no effect s on T - cell dependent antibody response (TDAR) were seen when tested up to the Limit Dose in male and female mice and in male and female rats. There were also no changes in spleen and thy mus weight and there were no histopathological lesions in these organs. In the developmental immunotoxicity

study , no effects on functionality of the immune system in rats were seen following exposure to dinotefuran at the Limit Dose during the prenatal, postnatal, and pos t weaning periods . Because of the lack of immunotoxicity seen in the immunotoxicity studies in mice, rats, and developing rats, the thy mus weight changes seen in dogs and the spleen weight changes seen in mice and rats in the subchronic and chronic oral s tudies were not considered to be toxicologically

relevant. No sy stemic or neurotoxic were seen following repeated dermal applications at the Limit Dose to rats for 28 day s. No sy stemic or portal of entry effects were seen following repeated inhalation exposure at the maximum obtainable concentrations to rats for 28 day s. In the available 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 rat 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 decrease d thy roid weights. Offspring toxicity was characterized as decreased forelimb grip strength or hindlimb grip strength in the F1 pups. There was no adverse effect on reproductive performance at any dose. In the developmental neurotoxicity study , no mater

nal or offspring toxicity

was seen at any

dose including 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 vivo and in vitro assay s. **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

Fa ctor be reduced to 1X . The rationale for this recommendation is provided in the following sections.Page **22** of **49**

**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 assessment and for FQPA evaluation. **4.4.2 Evidence of N**  **eurotoxicity** The neurotoxic potential of dinotefuran has been adequatel y considered. Dinotefuran is a neonicotinoid and has a neurotoxic mode of pesticidal action. Consistent with the mode of action, changes in motor activity w ere seen in repeat - dose studies, including the subchronic neurotoxicity

study (SCN). Additionally , decreased grip strength and brain weight was observed in the offspring of a multi - generation reproduction study albeit at doses close to the limit dose. For these reasons, a developmental neurotoxicity (DNT) study

was required. The DNT study did not show evidence of a unique sensitivity of the developing nervous s ys tem; no effect s on neurobehavioral parameters were seen in the offspring at any dose, including the limit dose. **4.4.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There was no evidence (qualitative or quantitative) of increased susceptibili ty 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 si gns of neurotoxicity but no developmental toxicity was seen. In the reproduction study, offspring toxicity characterized as decreased forelimb or hindlimb grip strength in the F1 pups was seen at the same dose (Limit Dose) that caused parental toxicity

(d ecreased body weights). The concern is low for the observed qualitative increase in sensitivity since the effects 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 including the Limit Dose. In the developmental immunotoxicity study , there was no evidence of an effect on the functionality of the immune sy stem in rats that were exposed to dinotefuran at the Limit Dose during the prenatal, postnatal, and post - weaning periods . **4.4.4 Residual**  **Uncertainty in the Exposure Datab ase**  E xposure data are complete or are estimated based on data that reasonabl y account fo r potential exposures . The acute dietary anal ys is was based on tolerance level residues derived from field trials and 100% crop treated assumptions for all commodities. The chronic dietary anal ys is included tolerance level residues and 100% crop treated. The tolerance level for rice, derived from field trial data, represent s maximum application rates and minimum pre - harvest intervals ( PHI s ) . The dietary

drinking water assessment utilized water concentration values generated b y model and associated model ing parameters which are designed to provide conservative, health protective, high - end estimates of water concentrations. HED concludes that the acute andPage **23** of **49**

chronic exposure estimates in this analy sis are unlikely to underestimate actual exposure. The resi dential exposure assessment uses the 2012 Residential SOPs and is considered health protective. **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  The dinotefuran hazard profile was updated in the most recent risk assessment (DP391885, B. O’Keefe, 7 /20/12), and nothing has changed since this update. Please refer to that assessment for extensive details. The toxicology database is adequate for characterization of hazard. In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment ( March, 2005), dinotefuran is classified as “Not Likel y to be Carcinogenic to Humans” based on the lack of evidence for carcinogenicity in mice and rats. Table 4.5.4 summarizes the toxicological doses and endpoints for dinotefuran for use in human health risk assessments . For further details refer to Appendix A. **Table 4 .5.**  **Summ ary of Toxicological Doses and Endpoints for**  **Dinotefuran for Use in Hum**  **an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/** 

**FQPA Safety Factors**  **RfD, PAD, Level**

**of Concern for Risk Assessment**  **Study and Toxicological Effects**
Ac ute Dietary (General Population , including Infants and Children) NOAEL=125

mg/kg/day UF A= 10x

UF H = 10x FQPA SF= 1x Ac ute RfD = 1.25

mg/kg/day aPAD =1.25 mg/kg/day Developmental Toxicity Study in

Rabbits LOAEL = 300 mg/kg/day based on clinical signs indicative of neurotoxicity in does ( hypoactivity, prone position, panting, tremor and erythema) seen followi ng the first dose on Gestation Day 6. Chronic Dietary (All Populations) NOAEL=99.

7 mg/kg/day UF A= 10x

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

1.0 mg/kg/day cPAD = 1.0 mg/kg/day Chronic Toxicity/Carcinogenicity

Study in Rats LOAEL = 991 mg/kg/day based on decreased body weight gain and nephrotoxicity. Incidental Oral Short - Term

(1 - 30 days) and Intermediate - Term (1 - 6 months) NOAEL=99.

7 mg/kg/day UF A= 10x

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

for MOE = 100 Chronic Toxicity/Carcinogenicity

Study in Rats LOAEL = 991 mg/kg/day based on decreased body weight gain and nephrotoxicity. Dermal Short - Term (1 - 30 days) and Intermediate - Term (1 - 6 months) No systemic toxicity was seen at the limit dose in a 28 - day rat dermal toxicity study in which neurotoxicity was evaluated and there are no developmental toxicity concerns. No hazard was identified for these exposure scenarios. A dermal penetration study for dinotefuran showed low

absorption, < 2%. Inhalation Short Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) No quantitation required. No systemic toxicity was seen in a 28 - day inhalation toxicity

study at doses that were in ~ 10,000 - fold excess of the highest anticipated human exposure. There are no developmental toxicity concerns. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of

significant tumor increases in two adequate rodent carcinogenicity studies.Page **24** of **49**

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 effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chro nic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Residues**  **of Concern Summary and Rationale** The nature of the residue in plants and livestock are adequatel y understood for the purposes of th is petition. Metabolism studies in rape, potato, rice, apple, and lettuce were submitted in conjunction with an earlier dinotefuran petition, PP#2F06427 (DP285648, L. Cheng, 2/26/04). The database is adequate for determining dinotefuran res idues of concern . A listing of the dinotefuran metabolites /degradates is provided in Appendix D. **Table 5.1. S**  **umm ary of Metabolites and Degradates**  **to be included in the Risk Assessment and Tolerance Expression**  **. Matrix**  **Residues for Tolerance Expression**  **Residues for Risk Assessment** Plants Dinotefuran, DN, UF Dinotefuran, DN, UF , and PHP Ruminants Dinotefuran Dinotefuran, UF, FNG Poultry Dinotefuran Dinotefuran, FNG Rotational Crops Not Needed 1 Not Needed 1 Drinking Water Not applicable Dinotefuran, MNG, DN, UF, DN - 2 - OH, and DN - 3 - OH Food Handling Establishments Dinotefuran Dinotefuran 1 If the plant -back interval of 120 days is shortened in the future, additional rotational crop data will be required. **5.2 Food Residue Profile**  Proposed Use on Rice Mitsui has submitted three field trial study reports reflecting two late - season applications in support of the proposed use of dinotefuran on rice ( i.e. , MRID Nos. 48680303 , 4 8680304 , and 48680305. The results of the studies are summarized in Table 5.2. 1. These data are acceptable. The studies reflect the maximum proposed use pattern for the 20% SG formulation, except as noted below, and the geographic locations of the field trials are in accordance with OCSPP 860.1500. An acceptable method was used f or residue quantitation, and the data are supported by adequate storage stability data. The field trial application rates for the studies submitted in MRIDs 48680303 and 48680305, as well as the rate for the TX trial in MRID 48680304, exceeded the maximum proposed seasonal application rate of 0.262 lb ai/A by 53 - 66%. Using the proportionality principle, HED hasPage **25** of **49**

adjusted the residue values from these five trials before inputting into the OECD calculation procedures for deriving a tolerance for rice grain. The available data support a tolerance of 9 ppm for rice grain with the requested registration of the 20% SG formulation on rice . Rice straw is no longer considered to be a significant livestock feedstuff; therefore, no tolerance is needed. **T able 5.2**  **. 1.**  **Summary of Residue Data from Rice Field Trials with**  **Dinotefuran .**  Commodity Adjuvant Total Rate (lb ai/A) PHI

(days) Residue Levels (ppm) 1 n Sam ple Min. Sam

ple Max. LAFT 2 HAFT 2 Median Mean Std. Dev. **RICE (proposed use = 0.262 lb ai/A total application rate; 7 -**  **day PHI) MRID 48680303**  Rice Grain Dinotefuran 0.408 8 1 3.23 3.52 3.38 3.38 3.38 3.38 N/A

UF 3 0.458 0.519 0.488 0.488 0.488 0.488 N/A DN 3 0.397 0.490 0.444 0.444 0.444 0.444 N/A Combined4 4.09 4.53 4.31 4.31 4.31 4.31 N/A **MRID 48680304** Rice Grain Dinotefuran 0.264 - 0.275 7 - 8 11 1.13 2.97 1.34 2.90 2.02 2.13 0.54

UF 3 0.19 0.95 0.23 0.89 0.49 0.51 0.22 DN 3 0.21 1.20 0.24 1.07 0.45 0.56 0.30 Combined4 1.53 4.56 1.81 4.41 3.29 3.20 0.94 Dinotefuran 0.435 7 1 3.65 3.76 3.71 3.71 3.71 3.71 NA UF 3 0.75 0.75 0.75 0.75 0.75 0.75 NA DN 3 0.63 0.65 0.64 0.64 0.64 0.64 NA Combined4 5.06 5.14 5.10 5.10 5.10 5.10 NA **MRID 48680305** Rice Grain Dinotefuran 0.400 - 0.415 6 - 8 3 1.7 3.3 1.8 3.3 2.8 2.6 0.76

UF 3 0.22 0.38 0.22 0.36 0.33 0.30 0.07 DN 3 0.30 0.44 0.32 0.43 0.37 0.37 0.06 Combined4 2.21 4.07 2.29 3.97 3.56 3.27 0.88 **Combined results -**  **All MRIDs** Rice Grain4 Combined 0.264 - 0.435 6 - 8 16 1.53 5.14 1.81 5.10 3.56 3.41 0.99 Rice Grain 5 Combined 0.26 - 0.28 6 - 8 16 1.44 4.56 1.51 4.41 2.83 2.96 0.90 1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. N/A = Not applicable. 2 LAF T = lowest average field trial; HAFT = highest average field trial. 3 Residues of UF and DN are reported in parent equivalents. 4 Combined residues of dinotefuran, UF, and DN **before** adjusting the residue levels of 5 trials conducted at > 25% proposed rate . 5 Combined residues of dinotefuran, UF, and DN **after** adjusting the residue levels of 5 trials conducted at >25% proposed rate . Food Handling Establishments In the food - handling establishment study (MRID 48707102) , from BASF C orporation, multiple crack and crevice treatment (CC), spot treatment (ST), and general treatment (GT) applications of the 0.5% pressurized liquid formulation were made to two rooms: one containing perishablePage **26** of **49**

food items and one containing non - perishable fo od items and inert food surface items. For most matrices, both covered and uncovered samples were collected. One set of covered and uncovered samples from both rooms were collected after a single combination treatment consisting of both crack and crevice treatment s and spot treatments (CC+ST), for a total of 1.259 to 2.199 g ai. Additional non - perishable food items and inert food surface items were collected at various intervals during the 15 - day study duration in which three CC+ST combination treatments at 3 - day

retreatment intervals as well as two general treatments at 6 - day RTI s were made. Finall y, sets of covered and un covered samples from both rooms received GT - onl y treatments at 2.186 to 2.369 g ai . These samples were placed in the room immediatel y prior to each general treatment event and were removed ~4 hours after the treatment event. The results of the food - handling establishment study indicated that residues of dinotefuran were generall y below the LOQ in/on all covered and/or wrapped food i tems and covered inert food surface items, regardless of treatment type and number of applications. The submitted food - handling establishment study is acceptable . The available data are sufficient for establishing a tolerance of 0.01 ppm for residues of dinotefuran in/on all food/feed items (other than those already covered b y a higher tolerance as a result of use on growing crops) in food/feed handling establishments where food products are held, processed or prepared . As ChemSAC indicated in a mee ting (minutes, 8/30/06), the final label should specify either a maximum weight of active ingredient per linear foot or flow rate or nozzle size for each application ty

pe. For specifying the amount of dinotefuran applied with the 0.5% pressurized liquid f ormulation TC267, HED has completed the following calculations: 1) 2.2 g ai was used in combined CC + ST treatments over a total treatment length of 157 feet (53 + 98 for CC + 6 for ST), which resulted in 0.01 g ai/linear foot; 2) 2.4 g ai was used in GT only treatment over a total treatment length of 48 feet (4 pieces of pl yw ood of 4 ft x 8 ft), which resulted in 0.05 g ai/linear foot. Therefore, the label should state a maximum use rate of 0.05 g ai per linear foot. Processed Food and Feed Mitsui subm itted a processing study for dinotefuran on rice ( i.e. , MRID 48680307 . The submitted processing study is adequate to satisfy

data requirements. The results of the study are shown in Table 5.2.2. The data indicate that combined residues of dinotefuran, U F, and DN may concentrate in rice hulls ( 4.6 x) but do not concentrate in bran or polished rice f ollowing processing of rice grain bearing quantifiable residues resulting from application of dinotefuran at 5 - 7.5x the maximum proposed seasonal application rate . The available data indicate that tolerances are not needed for the regulated commodities of rice bran and polished rice. Rice hulls are no longer considered to be a significant livestock feedstuff; therefore, no tolerance is needed.Page **27** of **49**

**Table 5.2.2. Summary of Processing Factors for Dinotefuran**  **RAC Processed** 

**Comm odity**  **Average Processing Factor**

**Dinotefuran UF**  **DN Combined**  Rice Hulls 4.6x 4.6x 4.7x 4.6x

Bran 0.66x 0.59x 0.40x 0.62x Polished Rice 0.03x 0.05x <0.01x <0.03x Meat, Milk, Poultry, and Eggs The livestock feedstuffs associated with the proposed use on rice are rice grain and bran. Rice straw is not considered a livesto ck feed item. Maximum theoretical dietary burdens (MTDBs) were originall y calculated for dinotefuran under PP#3F6566 reflecting proposed uses on cotton and potato commodities, the only other uses with associated livestock feedstuffs. The calculated dietary burdens were 2.07 and 1.98 ppm for beef and dairy cattle, respectively , and 0.08 and 0.09 ppm for poultry and swine, respectivel y. Since the original dietary burden calculation, HED has revised its approach to reflect a maximum reasonable dietary

burden (MRDB) calculation (refer to OCSPP 860.1000 Table 1 Feedstuffs ; June 2008) , and more recently to replace the use of tolerance values in the calculation with highest average field trial (HAFT) residues for most feedstuffs, median residues for blended feeds, and median residues x processing factors for most processed commodities. The updated livestock dietary burden calculations, reflecting current Agency policy , result in estimated MRDBs of dinotefuran at 1.41 and 1.16 ppm for beef and dairy cattle, respectively , and 0.879 and 0.872 ppm for poultry and swine, respectively . The current MRDBs for beef and dairy cattle are lower than those previously calculated; therefore, the addition of the proposed use on rice will have no effect on the established tolerances for ruminant commodities. Although the MRDB for swine is considerabl y higher than previously

calculated, tolerances for swine commodities were originall y established at the same levels as ruminant commodities; therefore, no changes are needed. No poultry

feeding study has been submitted for dinotefuran . In the poultry metabolism study , hens were dosed at 10 ppm. This corresponds to ~11x the current MRDB for poultry . In general, when evaluating the need for poultry tolerances, HED typicall y considers whether residues identified in the metabolism study would be quantifiable or exceed the L OQ (0.01 ppm) when extrapolated to a 10x - dosing level. When adjusted to the 10x - dosing level, residue s of parent dinotefuran would be <0.0049 ppm in muscle , <0.0012 ppm in fat, 0.010 ppm in liver, and 0.011 ppm in egg white. Thus, setting tolerances at the LOQ of 0.01 ppm in poultry egg and liver (as poultry

meat b yproducts) is appropriate. The available ruminant feeding study is acceptable to support the proposed use of dinotefuran on rice . HED has concluded that the addition of rice grain or bran to the diet of beef or dairy cattlePage **28** of **49**

would not be expected to increase the dietary burden. N o changes are needed to the existing tolerances for milk or ruminant tissues. Desp ite an increase in the dietary burden for swine, no changes are needed to the existing tolerances for swine commodities because tolerances for swine commodities were originally established at the same levels as those for ruminant commodities. With the in creased dietary burden resulting from the proposed use on rice, and in consideration of the results from the available poultry metabolism study , HED now concludes that poultry tolerances in egg and liver (as poultry meat b yproducts) are nee ded at the 0.01 ppm to support use on rice . Storage Stability The submitted storage stability data for dinotefuran and metabolites in/on rice commodities are adequate to support the storage durations and conditions of samples from the submitted crop field trial and processing studies. T he submitted storage stability data for perishable and nonperishable food items and dinner plates are considered adequate to support the storage durations and conditions of samples from the submitted food - handling establishment study . Water, Fish, and Irrigated Crops The proposed use of dinotefuran on rice may lead to residues in water, fish, shellfish, and irrigated crops. No data have been submitted pertaining to residues of dinotefuran in water, fish, shellfish, and irrigated c rops. In the absence of such data, the petitioner must include label restrictions against use of flood water from treated fields for irrigation purposes for any food/feed crops, and against application to rice fields if fields are used for fish production , especiall y catfish or crayfish farming. If the petitioner wishes to remove these label restrictions, additional data may be required, including metabolism and feeding studies on crayfish and/or catfish, and data depicting magnitude of the residue in irrigated crops. Rotational Crops Adequate confined field rotational crop data are available. Dinotefuran residues of concern would be <0.01 ppm in rotational crops planted 120 day s after treatment. There are no field rotational crop data. However, none are needed as long as a 120 - day plant - back interval is specified on the label. **5. 3**  **Water 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 waterPage **29** of **49**

assessment with estimated drinking water concentrations (EDWCs) for dinotefuran and its metabolite/degradate DN ( D P 39 7490 , J. Wolf & J. Hetrick , 8 / 7 / 1 2 ). In addition to its registered Section 3 uses , there is an active dinotefuran Section 18 for use on rice in Texas . For the Section 18, a drinking water assessment was previously prepared for dinotefuran and its transformation products MNG, DN, UF, and DN - 2 - OH + DN - 3 - OH, in support of the use on rice in Texas (surface water) and turf (ground water) . Based upon the results of an additional aerobic and anaerobic aquatic metabolism study , EFED has determined that in an aquatic environment such as a rice paddy the major transformation product is only the degradate DN. At the termination of the study , 77% to 86% of the applied radioactivity was identified as dinotefuran or DN; no other degradation products were identified (except CO 2 ). The environmental fate data have s hown that aqueous photolysis could also be important in the field depending upon the depth of the water and the degree of light penetration. Also, rice paddies are not used as sources of drinking water. For this assessment and the previous assessment for the Section 18 use on rice, the EDWCs for dinotefuran and relevant degradates for surface water were obtained using the Tier 1 Rice model v. 1.0 and the modified Tier 1 Rice Model (after DP354339, Meléndez, 2009 ). The modified Tier 1 Rice Model v. 1.0 assumes that only aerobic and anaerobic aquatic metabolism processes occur in the rice paddy , during the holding period. Ground water EDWCs were obtained with the Tier 1 SCI - GROW model v. 2.3 for the use of the chemical on turf (a higher use rate). SCI GROW is used for the rice assessment because the PRZM - GW is not applicable for paddy (flooded) conditions ( i.e. , water column over l yi ng soil) and saturated conditions. Additionally , the registrant has submitted additional data from an Aerobic and Anaerobic Aquatic Metabolism study (OCSPP Guideline # 835.4300 and 835.4400) per Data Call - In ( ID #GDCI - 044312 - 1147). In the previous assessment, a degradation period was considered to represent a water holding time of 10 day s. Also, the regional percent cropped area (PCA) factor was considere d. This assessment does not include the PCA factor because EFED guidance states that a PCA should only be used with a model that accounts for hydrology . The Tier 1 rice model does not consider the addition ( i.e ., runoff, precipitation) or loss ( i.e ., eva poration, outflow) of water into or out of the paddy ; therefore it is inappropriate to incorporate PCA into the model. The Tier 1 rice model conservativel y predicts concentrations that may be found in a rice paddy, as opposed to a drinking water reservoir . In the practical sense, no person drinks water from a rice paddy. There are onl y a few watersheds (e.g., Mermentau River in LA) that are mainly composed of fields of rice. Therefore, it is a conservative estimate of exposure through drinking water. The maximum application rate for dinotefuran for rice is 0.131 lbs ai/A (7.5 oz. to 10.5 oz. product per acre) as an aerial spray . Two applications are allowed per season. Application rates should not exceed more than a total of 0.262 lbs ai/A per season for aerial applications. The rates for this assessment and the previous Section 18 (DP354339; Meléndez , 2009 ) are the same. Table 5.3 summarizes the surface water EDWCs for dinotefuran and its relevant degradate , DN . The surface water EDWCs were obtain ed using the provisionally modified Tier 1 Rice Model v.Page **30** of **49**

1.0 for the use of dinotefuran on rice . The peak concentration is 269 μg/L and the longer term concentration ( ≈average) would depend upon retention time (10 to 30 day s). **Table 5.3**  **. Tier 1 Surface Water EDWCs (μg/L) for Drinking Water Risk Assessment for the Use of**  **Dinotefuran on Rice. Based upon total toxic residues (**  **D inotefuran + DN).** 

**Peak Retention Time**  **10 day 30 day**  **60 day 100 day**  **150 day** 269 257 253 248 240 198 The ground water EDWCs were obtained using the Tier 1 SCI - GROW v. 2.3 Model . The EDWC for ground water is the same value (turf use) as recommended in the Section 18; 4.90 μg/L for both the acute and chronic exposures. Since the application rate for turf (1 application at 0.54 lb ai/A) is higher than for rice , and since SCI - GROW is not site or crop dependent , the concentration would be conservative and was not included in the dietary risk assessment . **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 are unrefined since it is assum ed that 100% of crops with the requested uses and currentl y 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. Only the chronic dietary assessment was conducted for the food handling establishment use with 0.01 ppm tolerances for all food commodities. **5. 4**  **. 2**  **Acute Dietary Risk Assessment** Potential residues in drinking water were included in the anal ys es based on surface water results from the Tier 1 Rice model v. 1.0 and the modified Tier 1 Rice model as these values were higher than the ground water estimates from the SCI - GROW model ( D P39 7490, J. Wolf & J. Hetrick , 8/7/ 1 2 ) . The surface water EDWC of 269 μg/L was used in the DEEM - FCID. Thus, the results obtained from the present anal ys es may be considered highl y conservative. At the 95 th percentile of exposure, no population subgroups were of concern : the general U.S. population accounted for just 3.0 % of the acute population - adjusted dose (aPAD), while the most highl y exposed population subgroup, all infants (<1 y r old) , accounted for 7.6 % of the aPAD. **5. 4**  **. 3**  **Chronic Dietary Risk Assessment**  Potential residues in drinking water were included in the anal ys es based on surface water results from the Tier 1 Rice model v.1.0 and the modified Tier 1 Rice model as these values were higher than the ground water estimates from the SCI - GROW model ( D P 39 7490 , J. Wolf & J. Hetrick , 8 / 7 / 1 2 ). The surface water EDWC of 2 57 μg/L was used in the DEEM - FCID. No populationPage **31** of **49**

subgroups were of concern: the general U.S. population accounted for 1 .4 % of the chronic population - adjusted dose (cPAD), while the most highl y exposed population subgroup, children 1 - 2 years old, accounted for 3.9 % 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 (m**  **g/kg/day) % aPAD** ** **Dietary Exposure**  **(m g/kg/day)**  **% cPAD  General U.S. Population 0.037384 3.0 0.014212 1.4 ** All** **Infants (< 1 year old) 0.095276**  **7.6** 0.035606 3.6 **Children 1 -**  **2 years old** 0.094678 7.6 **0.038570 3.9**  Children 3 - 5 years old 0.069524 5.6 0.027569 2.8 Children 6 - 12 years old 0.040299 3.2 0.015393 1.6 Youth 13 - 19 years old 0.026648 2.4 0.009989 1.0 Adults 20 - 49 years old 0.031301 2.5 0.012827 1.3 Adults 50 - 99 years old 0.027932 2.2 0.012054 1.2 Females 13 - 49 years old 0.030602 2.5 0.012242 1.2 *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** This document addresses the proposed new uses of dinotefuran on rice, in food/feed handling establishments, from the horse spot - on product , and from the total release fogger product . Of these newl y proposed uses, only the total release fogger product is expected to result in residential exposure ( i.e., post - application exposure only) . The proposed uses on rice and in food/feed handling establishments do not involve applications by residential or commercial applicators in resi dential settings. The horse spot - on product can be used by a residential handler , but handler and post - application exposure s are expected to be negligible; therefore, no assessment is need ed . There are currently

registered uses of dinotefuran on several residential use sites, including turf, ornamentals, vegetable gardens, pet s pot - ons , indoor aerosol spray s, crack and crevice spray s, etc. Each of these existing residential use patterns were reassessed in the latest HED human health risk assessment using the updated 2012 Residential SOPs and body weights (DP391885, B. O’Keefe, 7/20/12). The new exposure and risk estimates for all residential post - application scenarios result ed in risk e stimates that are not of concern .Page **32** of **49**

**6.1 Residential Handler Exposure**  Exposure for adult residential handlers activating the total release fogger is not expected because the label instructs handlers to exit the area immediately after initiating application. Also, the horse spot - on product can be used by a residential handler, but exposure is expected to be negligible. Therefore no residential handler exposures were assessed. **6.2 Post**  **- Application Exposure**  There is potential for both short - and intermediate - term adult and child post - application exposure from the total rel ease fogger product; however , no dermal hazard was identified in the route specific dermal toxicity

study . The proposed product label has a 2 hour time entry restriction on the product label. As indicated in Section 7.2.1.1 of HED’s 2012 Residential SOP revision, “...as long as fogger product labels include a statement restricting entry for at least 2 hours, post application inhalation exposure to pesticide aerosols should be negligible .” Therefore, onl y incidental oral exposure to children who re - enter tr eated areas, such as homes, schools, barns, etc ., was quantitativel y assessed. Long - term exposure ( > 6 months) is not anticipated for this proposed product . Residential indoor post - application incidental oral risks from use of the total release fogger wer e estimated using HED’s recentl y updated SOPs (http://www.epa.gov/pesticides/science/residential - exposure - sop.html ) . The smallest room size of 5 ft x 5 ft was used as the worst case assessment based on label recommendations of “do not treat a room smaller than 5x5 ft ” . Exposure and risk estimates for the use in outdoor animal barns were not calculated because the estimates from the indoor rooms should be protective of thes e exposures . The area treated in barns will usually be much larger than a 5 ft by 5 ft room and the children exposed would 3 to 6 years olds, wh o have less hand - to - mouth replenishments per hour th an 1 to 2 year olds. Table 6.2.1 presents these anticipate d exposures from the total release fogger and their associated risk estimates. Residential incidental oral risk estimates ranged from 1,200 to 13,000, and were not of concern to HED. **Table 6.2**  **. 1.**  **Residential Post -**  **Application Short -**  **Term Oral Exposure a nd Risk Estimates for Children**  **to Dinotefuran from** **Total Release Fogger .**  **Scenario 1**  **Deposited**

**Residue (μg/cm** **2 )**  **Children**

**Ages (yrs)**  **Activity Daily Dose**  **(m g/kg/day)**  **MOE 1**  Indoor Room s 14.6 1 - 2 Hand - to - mo uth on carpet 0.08605 1,200 Hand - to - mo uth on hard surface 0.02868 3,500 Object - to - mo uth on carpet 0.01145 8,700 Object - to - mo uth on hard surface 0.00763 13,000 1 MOE = NOAEL (99.7 mg/kg/day) / Daily Dose (mg/kg/day); where daily doses are as follows:Page **33** of **49**

Hand - to - Mouth Daily Dose (mg/kg/day) = hand residue loading (mg/cm2 ) x fraction of hand mouthed (0.13) x surface area of 1 hand (150 cm2 ) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x number of replenishment intervals per hour (4) x (1 - (1 - fraction saliva extraction (0.48) / (number of contact events per hour (20 events/hr) / number of replenishment intervals per hour (4 intervals/hr))) / 11 kg body weight; where Hand Residue Loading (mg/cm2 ) = fraction ai on hands (0.15) compared to total surface residue from Jazzercise stu dies (gloves) x dermal exposure (mg) / 2 x surface area of 1 hand (150 cm2 ); Object - to - Mouth Daily Dose (mg/kg/day) = deposited residue (14.6 μg/cm 2 ) x fraction of residue transferred to object (0.06 for carpets, or 0.08 for hard surfaces) x conversion fa ctor (0.001 mg/μg) x object surface area mouthed per event (10 cm2/event) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x number of replenishment intervals per hour (4 intervals /hr) x (1 - (1 - fraction saliva extraction (0.48) / (numb er of object - to - mouth contact events per hour (14 events/hr) / number of replenishment intervals per hour (4 intervals/hr))) / 11 kg body weight Dermal Exposure (mg) = deposited residue (14.6 μg/cm 2 ) x fraction transferred (0.06 for carpets, or 0.08 for h ard surfaces) x transfer coefficient (1,800 cm2/hr) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x conversion factor (0.001 mg/μg); where Deposited Residue (14.6 μg/cm 2 ) = Active Ingredient Applied (340,194 μg) / Area Treated (23,225 cm2 ); where Active Ingredient Applied (340,194 μg) = 6 oz fogger x % ai (0.2%) x conversion factor (28,349,526 μg/oz), and Area Treated (23,225 cm2 ) = volume treated (200 ft 3 ) / ceiling height (8 ft) x conversion factor (929 cm2/ft2 ); Table 6 .2 .2 lists the residential post - application exposures and risk estimates from the existing residential uses of dinotefuran . Because no dermal or inhalation endpoints were chosen for dinotefuran post - application residential dermal and inhalation exposure s cenarios were not assessed. As a result, risk assessments were only completed for post - application scenarios in which incidental oral exposures are expected. The post - application exposure and risk estimates for all existing residential uses result ed in risk estimates that are not of concern (MOEs ranged from 1, 1 00 to 5,9 00,000) . **Table 6.2.**  **2. Residential**  **Post -**  **Application Short**  **- Term Oral**  **Exposure and Risk Estimates for Children to**  **Dinotefuran. Scenario**  **Formulation Application Rate**  **Am ount**  **Treated Activity**  **Current Assessment**  **Daily Dose (m**  **g/k g/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 NA2 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/cm2 or 1.24E - 6 lb ai/ft2 1 20 - oz

can/2646 ft2 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 0.5% Aerosol 0.00626 lb ai/can or NA Oral hand - to - mouth on carpet 0.0018 5.6E+5Page **34** of **49**

**Table 6.2.**  **2. Residential**  **Post -**  **Application Short**  **- Term Oral**  **Exposure and Risk Estimates for Children to**  **Dinotefuran. Scenario**  **Formulation Application Rate**  **Am ount**  **Treated Activity**  **Current Assessment**  **Daily Dose (m**  **g/k g/day)**  **MOE 1**  & Crevice 0.3 ug ai/cm2 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/cm2 NA Oral hand - to - mouth on carpet 0.0015 6.8E+4 Oral hand - to - mouth on hard surface 0.00049 2.0E+5 Object - to - mouth on carpet 0.00020 5.1E+5 Object - to - mouth on hard surface 0.00013 7.6E+5 1 Scenarios for the incidental oral ingestion of granules use the dietary acute oral point of departure of 125 mg/kg/day. All other scenarios use the short - term incidental oral point of departure of 99.7 mg/kg/day. 2 NA = not applicable **6. 3**  **Combined Exposure**  FQPA requires that residential exposures that could reasonabl y be expected to occur on the same day be combined and compared to the appropriate toxicity endpoint. The exposure estimates from use of the total release fogger product are higher tha n those from existing residential uses. Additionally , co - occurrence with the existing cat spot - on use is possible, since both uses can be for the treatment of fleas. Co - occurrence with the existing indoor broadcast use would not be probable, because if you were fogging an area you would not also apply a broadcast treatment. The combined exposure estimate from the cat spot - on (0.002 mg/kg/day) and total release fogger (0.08605 mg/kg/day) use is 0.08805 mg/kg/day . This exposure estimate is greater than th e exposure estimate from use on turf (i.e. , 0.0079 mg/kg/day), which was previously the highest residential exposure. Therefore, this combined exposure estimate provides the worst case residential exposure estimate and is recommended for use in the dinote furan aggregate risk assessment. **6. 4**  **Residential Bystander Post -** **A pplication Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation by stander exposure assessment was not performed for dinotefuran at this ti me. Although volatilization of pesticides may

be a potential source of post - application inhalation exposure to individuals nearby to pesticide applications , quantification of short - or intermediate - term inhalation risk is not required for dinotefuran beca use no s ys temic 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 Drift** Spray drift is alway s a potential source of exposure to residents nearb y 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 als o employed for dinotefuran . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State L ead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical byPage **35** of **49**

chemic al basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its 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 appropriatel y appl y the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y 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 pesticide exposures and risks from three major sources: food, drinking water , and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For dinotefuran , potential exposures from food, drinking water and residential scenarios were aggregated. This assessment has considered the changes in the new residential SOPs implemented in January of 2012. HED finds no changes that would affect the aggregate safety finding and confirms that there are no risks of concern resulting from the proposed occupational and residential uses, the existing residential uses, nor from utilizing the new residential SOPs to estimate residential exposure and risk. **7.1 Acute Aggregate Risk**  The aggregate acute risk estimates include exposure to residues of dinotefuran in food and drinking water, and does not include dermal, inhalation , or 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 expos ure estimates are 3.0 % of the aPAD for the U.S. general population, and 7.6 % for the most highly

exposed sub group, all infants (<1 yr 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 ) pathway s. For adults, these pathway s lead to exposure via dietary oral (background) as well as dermal and inhalation routes. However, as explain ed previously , there were no dermal or inhalation toxicity endpoints identified. Therefore, no short - term aggregate assessment is needed for adults. For children, the pathway s that lead to exposure are dietary oral (background) as well as dermal and oral routes . The most conservative exposure estimate for child oral hand to - mouth exposure isPage **36** of **49**

0.08805 mg/kg/day . For a description of the residential exposure scenario s considered in the aggregate assessment , see Section 6.0. The aggregate MOE for children 1 - 2 years old is 790 , 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 99.7 100 0. 997 0.0 38 57 0. 0 8805 0. 126 62 79 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 (Table s 6.2 .1 and 6.2.2 ). 4 Total Exposure = Avg Food & Water Exposure + Residential Exposure) 5 Aggregate MOE = [NOAE L / (Avg Food & Water Exposure + Residential Exposure)] , NOAEL= 99.7 mg/kg/day. **7.3 Intermediate**  **- Term Aggregate Risk**  Intermediate - term exposure is not expected for the adult residential exposure pathway . Therefore, the intermediate - term aggregate risk would be equivalent to the chronic dietary exposure estimate . For children, intermediate - term incidental oral exposures could potentially occur from indoor uses. However, while it is possible for children to be exposed for longer durations, the magnitude of residues is expected to be lower due to dissipation or other activities. S ince incidental oral short - and intermediate - term toxicity endpoints and points of departure are the same , the short - term aggregate risk estimate , which includes the highest residential exposure estimate, is protective of any intermediate - term exposures. **7.4 Chronic Aggregate Risk**  Chronic exposure is not expected for the adult residential (dermal and inhalation) exposure pathway . Therefore, the chronic aggregate risk would be equivalent to the chronic dietary exposure estimate. Refer to Section 5.4. 3 for the chronic dietary (food and drinking water) exposure assessment. **7.5 Cancer Aggregate Risk**  Dinotefuran is considered “not likely to be carcinogenic to humans;” therefore, an aggregate cancer risk ass essment has not been conducted.Page **37** of **49**

**8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to dinotefuran and any

other substances and dinotefuran does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that dinotefuran has a common mechanism of toxicity with other substances. For information regarding EPA ’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk Characterization**  Application methods, maximum application rates and use sites are s ummarized in Section 3.3. Based on the proposed use patterns of dinotefuran, there is a potential for occupational short - and intermediate - term dermal and inhalation exposure s during handling (mixing & loading) and post application activities. Chronic exposure is not expected for the proposed use patterns . 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 appearing on the dinotefuran label (EPA Reg. No. 86203 - 25) for the proposed use on rice includes coveralls, chemical resistant gloves made of any waterproof material such as polyeth yl ene or pol yvinyl chloride, and shoes plus socks. Risk estimate s for occu pational handlers were not assessed because no hazard was identified for the dermal route of exposure. Therefore, the PPE of coveralls and chemical resistant gloves are not needed. **9 .2**  **Short -** **/Intermediate -**  **Te rm**  **Post -**  **Application Risk** Occupational workers performing typical post - application activities such as scouting, irrigation, harvesting , etc. may

receive 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 REIis required for chemicals classified under Toxicity Category IV. Therefore, the REI of 12 hours appearing on the dinotefuran label (EPA Reg. No. 86203 - 25) for the proposed use on rice is adequate.Page **38** of **49**

**10 .0**  **References** C. Walls, DP 398050.drs , 8 / 31 /12 . Dinotefuran: Acute and Chronic Aggregate (Food and Drinking Water) Dietary

Exposure and Risk Assessments for a Section 3 Registration Action on Rice and Uses in Food - Handling Establishments . J. Wolf, J. Hetrick , DP39 7490, 8 / 7 /1 2 . Tier IDrinking Water Concentrations for Dinotefuran for Section 3 new use on rice . L. Cheng, DP3 97469 , 8 / 15 /12. Dinotefuran: Petition for the Establishment of Permanent Tolerances for Use on Rice (Mitsui Chemicals Agro, Inc.) and Uses in Food - Handling Establishments (BASF Corporation). Summary of Analy tical Chemistry

and Residue Data. B. O’Keefe, DP39 1885 , 7 /20 /1 2 . Dinotefuran : Human Health Risk Assessment for Proposed Section 3 Uses on Tuberous and Corm Vegetables Subgroup 1C, Onion Subgroup 3 - 07A, Onion Subgroup 3 - 07B, Small Fruit Subgroup 13 - 07F, Berry Subgroup 13 - 07H, Peach, and Watercress, And a Tolerance on Imported Tea. B . O’Keefe, DP391888, 7/20/2012. 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 - 07 F, Berry Subgroup 13 - 07H, Peach, and Watercress. B . O’Keefe, DP398049, 8/31/2012. Dinotefuran: Occupational and Residential Exposure Assessment for Proposed New Use on Rice. B . O’Keefe, DP398482, 8/31/2012. Dinotefuran: Occupational and Residential Exposure Assessment for Proposed New Use in Food/Feed Handling Establishments. B . O’Keefe, DP397013, 8/31/2012. Dinotefuran: Occupational and Residential Exposure Assessment for Proposed New Horse Spot - On Product. B . O’Keef

e, DP398247, 8/31/2012. Dinotefuran: Occupational and Residential Exposure Assessment for Proposed New Total Release Fogger Use.Page **39** of **49**

**A ppendix**  **A . Toxicology Profile**  **A.1 Toxicology Data Requirements**  The requirements (40 CFR 158.500) for Food Use for Dino tefuran are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 90 - Day

Inhalation ................................ .......................... yes yes yes no yes yes

yes yes

- Yes 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... n/a no n/a yes yes -

yes

- yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

—Gene Mutation - mammalian ................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ... 870.5xxx Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen) ............................... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90 - Day

Neurotoxicity Screening Battery (rat) ............... 870.6300 Develop. Neurotoxicity ................................ ................. no no yes yes yes -

- yes yes yes 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes yes yes yes

yes yesPage **40** of **49**

**A.2 Toxicity Profiles**  **Table A.2.1 Acute Toxicity Profile**  **- Test Substance**  **Guideline No. Study Type**  **MRID(s) Results**  **Toxicity Category**  870.1100 Ac ute oral, rat 45639823 LD 50 = 2804/2000 [M/F] III 870.1100 Ac ute O ral, mouse 45639824 LD 50 =2450/2275 [M/F] III 870.1200 Ac ute dermal, rat 45639901 LD 50 > 2000 mg/kg IV 870.1300 Ac ute inhalation, rat 45639902 LC 50 > 4.09 mg/L IV 870.2400 Ac ute eye irritation, rabbit 46301601 no positive effects IV 870.2500 Ac ute dermal irritation, rabbit 45639904 low level of irritation IV 870.2600 Skin sensitization, guinea pig 45639905 not a sensitizer n/a **Table A.2.2 Subchronic, Chronic and Other Toxicity**  **Profile Guideline No./**  **Study Type MRID No. (year)/ Classification /Doses**  **Results** 870.3100 90 - Day oral toxicity in rats MRID: 45654205, 45654203 (range finding) (1997) Acceptable/Guideline Dose Levels: 0, 500, 5000, 25,000, 50,000 ppm (dietary); M/F= 34/38, 336/384, 1623/1871, 3156/3616 mg/kg/day NOAEL: 3 36 /384 [M/F] mg/kg LOAEL: 1623/ 1871 [ M/F] mg/kg/day based on decreased body weight and body weight gain and histopathological lesions of the adrenal glands in female rats 870.3100 90 - Day oral toxicity in mice MRID: 45654206, 45654204 (range finding) (1997) Acceptable/ Guideline Dose Levels: 0, 500, 5000, 25,000, 50,000 ppm (dietary); M/F= 81/102, 884/1064, 4442/5414, 10,635/11,560 mg/kg/day NOAEL: 4442/5414 [M/F] mg/kg/day LOAEL: 10,635/11,560 [M/F] mg/kg/day, based on decreased body weight and body weight gain

870.3150 90 - Day oral toxicity in dogs MRID: 45639906 (main study), 45639915,

45639916 (range - finding studies) (1999) Acceptable/Guideline Dose Levels: 0, 1600, 8000, 24,000 ppm (dietary); M/F= 0, 58/58, 307/323, 862/950 mg/kg/day NOAEL: 307 mg/kg/day LOAEL: 862 mg/kg/day, based on decreased body weight gain in males and decreased body weight and body weight gain in females . 870.3200 MRID: 45639908, 456399 0 7 (range - **Systemic** :Page **41** of **49**

**Table A.2.2 Subchronic, Chronic and Other Toxicity**  **Profile Guideline No./**  **Study Type MRID No. (year)/ Classification /Doses**  **Results** 28 - Day dermal toxicity (rats) finding) (2001)

Acceptable/Guideline Dose Levels: 0, 40, 200, 1000 mg/kg/day NOAEL: 1000 mg/kg/day LOAEL : Not Established. **Derm al**  : 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 **Developm ental**  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 ) **Developm ental**  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/system ic**  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.Page **42** of **49**

**Table A.2.2 Subchronic, Chronic and Other Toxicity**  **Profile Guideline No./**  **Study Type MRID No. (year)/ Classification /Doses**  **Results 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 ma les) or hindlimb grip strength (F 1 females). **Reproductive** NOAEL: 241/268 [M/F] mg/kg/day LOAEL: 822/907 [M/F] mg/kg/day, ba sed 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 mo tility 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 Com bined chronic toxicity/ carcinogenicity (rats) MRID: 45640001 (2000)

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

870.5100 Bacterial reverse mutation test MRID: 45640003 (1996)

Acceptable **Negative.** ± S9 up to 16,000 μ g/platePage **43** of **49**

**Table A.2.2 Subchronic, Chronic and Other Toxicity**  **Profile Guideline No./**  **Study Type MRID No. (year)/ Classification /Doses**  **Results** 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 cy togenics - micronucleus assay MRID: 45654212 (1995)

Acceptable **Negative** at oral doses up to 1080 mg/kg/day for 2 days 870.6200a Ac ute 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 mo tor activity .

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

Acceptable/ Guideline Dose: 0, 1000, 3000 or 10000 Gestation/Lactation = 0 , 79.4/158, 237.4/500.7 or 784.1/1642.9 mg/kg/day Maternal NOAEL: 784 mg/kg/day Maternal LOAEL: Not Established Offspring NOAEL = 784 mg/kg/day . Offspring LOAEL : Not Established.

870.7485 Metabolism and pharmacokinetics (rats) MRID: 45640006

Acceptable/Guideline Dose: single 50 or 1000 mg/kg oral or 50 mg/kg IV treatments or multiple oral 50 mg/kg treatments with MTI - 446 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 thePage **44** of **49**

**Table A.2.2 Subchronic, Chronic and Other Toxicity**  **Profile Guideline No./**  **Study Type MRID No. (year)/ Classification /Doses**  **Results**

(dinotefuran, >98% a.i., batch numbers VB9304, VB9302 (radiolabeled in the guanidine and furan positions) and 22 - 00210 & OFU - 1265 (unlabeled) urine was rapid, being 84 - 99% com plete 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 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 concentrations 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, wa s 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 well resolved by HPLC or 2D - TLC. For all parameters measured in this study, no sex - or dose related differences or label position effects were found. 870.7600 Dermal penetration 47013401 A dermal absorption factor (DAF) of 1.71% represents the radioactivity absorbed and remaining on the skin after removal of the stratum corneum, following a 10 hour exposure to 3.2  g/cm2 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 **Systemic** NOAEL : 1053/1438 [M/F] mg/kg/day . LOAEL : Not EstablishedPage **45** of **49**

**Table A.2.2 Subchronic, Chronic and Other Toxicity**  **Profile Guideline No./**  **Study Type MRID No. (year)/ Classification /Doses**  **Results**

Dose: 0, 1120, 2800 or 7000 ppm M/F= 0, 153/223, 405/581, 1053/1438 mg/kg/day **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 compound accounting for >97% of the radiolabel in the excreta, plasma, kidneys, and stomach, and nearly 61 - 83% in intestines (and contents), and liver. Special study: Developmental Immunotoxicity Study in Rats MRID: 47677501

Acceptable/Non - guideline Dose: 0, 1000, 3000 or 10000 ppm which are equivalent to 0, 105.4, 317.8 or 1035.4 mg/kg/day, respectively. **Maternal** NOAEL: 1035.4 mg/kg/day . LOAEL: Not Established **Offspring** NOAEL: 317.8 mg/kg/day. LOAEL: 1035.4 mg/kg/day based on decreased pup body weight. **Immunotoxicity** NOAEL: 1035.4 mg/kg/day . LOAEL: Not EstablishedPage **46** of **49**

**Appendix B**  **. Physical/Chemical Properties**  **TABLE B**  **. Physicochemical Properties of the Test Compound: Dinotefuran.** Parameter Value Reference (MRID) Melting point/range 107.5oC 45639702 pH 5.6 @ 25oC 45654201 Density 1.40 g/cm3 @ 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 (pKa) 12.6 @ 20oC (estimated) 45639702 Octanol/water partition coefficient Log(KOW) - 0.549 (Kow = 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 **47** of **49**

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



### Dinotefuran ( 0 44312 , Requested 25April , 201 2 ) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3 40 CFR 180. 603 : Plant : Combined residues of dinotefuran, ( RS ) - 1 - methyl 2 -nitro - 3 - ((tetrahydro - 3 - furanyl)methyl)guanidine, and its metabolites DN, 1 -methyl - 3 - (tetrahydro - 3 - furylmethyl)guanidine, and UF, 1 - methyl - 3 - (tetrahydro - 3 - furylmethyl)urea Livestock: Residues of dinotefuran None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3 Rice, grain 9 Egg 0.01 Poultry , meat b yproducts 0.01 Food/ Feed Handling Establishments 0.01

Completed: M. Negussie; 04/27/2012 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 stored 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 **48** of **49**

**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 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 **49** of **49**

Common name/code Chemical name Chemical structure PHP 6 - hydrox y- 5 - (2 -

hydrox ye thyl) - 1 - methyl - 1,3 - diazinane - 2 - yl idene -N

nitroamine

FNG 2 - nitro - 1 - (tetrahydro - 3 -

furylmethyl)guanidine

MNG 2 - nitro - 1 - methylguanidine H N H 2 N N CH 3

N + O O – **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 Association, released February , 1995. The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. Environment al Protection Agency . Released June 21, 2011. Data from the Outdoor Residential Exposure Task Force (ORETF).