
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM

Date: 		8/31/12

SUBJECT:	Dinotefuran: Human Health Risk Assessment for Proposed Section 3 Uses on Rice and Food/Feed Handling Establishments, and New Horse Spot-On and Total Release Fogger Products.

PC Code:  044312
DP Barcode:  D398048, D398481, D397013, D398247
Decision Nos.:  458508, 459304, 447391, 449845
Registration Nos.:  86203-25, 499-LAN, 83399-RR, 499-526, 499-527, 499-531
Petition No.:  1F7953, 1F7967
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical/Aggregate
Case No.: NA
TXR No.:  NA
CAS No.: 165252-70-0
MRID No.:  NA
40 CFR: §180.603

FROM:	Barry O'Keefe, Senior Biologist
      Sheila Healy, 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
		Insecticide/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 horse spot-on product, and a new total release fogger product.  The toxicology evaluation was performed by Sheila Healy, the drinking water assessment was conducted by Jim Wolf and Jim Hetrick of the Environmental Fate and Effects Division (EFED), the 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'Keefe.  
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	20
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	31
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	Short-Term Aggregate Risk	35
7.3	Intermediate-Term Aggregate Risk	36
7.4	Chronic Aggregate Risk	36
7.5	Cancer Aggregate Risk	36
8.0	Cumulative Exposure/Risk Characterization	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	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, 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 registrants, 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; 3) Whitmire Micro-Gen Research Laboratories, Inc. requested registration of a new total release fogger for indoor use (TRF; EPA Reg. No. 499-LAN; TC-320); and 4) Ceva Animal Health, LLC, 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 neonicotinoid class of insecticides.  It is insecticidal by contact and ingestion, resulting in the cessation of insect feeding within hours of contact with death shortly.  The mode of action is interference with the acetylcholine receptor on the post-synaptic side of the nerve cells.  Dinotefuran is currently registered for use on numerous agricultural crops.  Dinotefuran is also registered 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 products.  Residential handlers may also apply 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, donkeys, and mules and is not allowed to be used on cats and dog.  The TRF product is proposed 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 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 system is the main target of dinotefuran toxicity.  After a single dose in rats and rabbits, neurotoxicity was manifested as clinical signs (hypoactivity, prone position, panting, tremors, and erythema) and decreased motor activity and changes in motor activity.  These acute effects are consistent with effects seen on the nicotinic cholinergic nervous system after repeated dosing.  Dinotefuran was well tolerated at high doses following dietary administration for 90 days to mice, rats and dogs.  The principal toxicological findings were decreases in body weight and/or body weight gain at or near the Limit Dose; but for acute dietary exposure the endpoint is neurotoxicity.  No systemic or neurotoxicity was seen following repeated dermal applications at the Limit Dose to rats for 28 days.  No systemic or portal of entry effects were seen following repeated inhalation exposure at the maximum obtainable concentrations to rats for 28 days.  No evidence of functional immunotoxicity was observed in guideline immunotoxicity or developmental immunotoxicity studies of dinotefuran.  There are also no indications of perturbed reproductive function.  No adverse effects in fetuses were seen in the developmental toxicity studies in rats or rabbits, at maternally toxic doses, and offspring effects in the reproduction study occurred at the same doses causing parental effects.  There are no concerns of developmental neurotoxicity.  There was no evidence of carcinogenicity in male and female mice and in male and female rats fed diets containing dinotefuran at the Limit Dose.  Dinotefuran was non-mutagenic in both in vivo and in vitro assays.

Based on hazard and exposure data, HED has concluded that there are no residual uncertainties for pre- and/or post-natal toxicity, or in the exposure database, and the Food Quality Protection Act (FQPA) Safety Factor can be reduced 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 (hypoactivity, prone position, panting, tremors, and erythema) 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 study in rats, based on decreased body weight gain and food efficiency in females and increased incidences of kidney pelvic mineralization and ulceration in males at 991 mg/kg/day (LOAEL).  

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 systemic or developmental toxicity was seen up to the limit dose in route-specific toxicity studies.  


Dietary Exposure (Food and Water)
The results of the acute dietary analysis for food and drinking water show that the acute dietary risk estimates are well below the Agency's level of concern (LOC; <100% of the acute population adjusted dose (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 analysis for food and drinking water indicate that the chronic dietary risk estimates are well below the Agency's LOC (<100% of the chronic population adjusted dose (cPAD)) for all population subgroups and were estimated at 1.4% of the cPAD for the general U.S. population and 3.9% of the cPAD 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.  Total release fogger products are activated and then handlers leave the area being treated.  There 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 systemic 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 790, 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 the dermal and inhalation routes.

Occupational Exposure
Occupational short- (1 to 30 days) and intermediate-term (1 to 6 months) dermal and inhalation exposures are expected from dinotefuran handler activities.  However, since no hazard was identified for the short- or intermediate-term dermal or inhalation routes of exposure, dermal and inhalation risks were not assessed.

For handlers, personal protective equipment (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 polyethylene or polyvinyl chloride, and shoes plus socks.  Risk estimates 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 (1.28x10[-8] mm Hg), post-application inhalation exposures and risks were not quantitatively 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 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.

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 Residential Exposure Task Force (ORETF) database; and the Agricultural Re-entry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-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 requests 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) and the horse spot-on product.  Additional data are needed as outlined in Section 2.1 below.  The specific tolerance recommendations are discussed in Section 2.2 and label modifications are discussed in Section 2.3.


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 Proposed Use on Rice:

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 revisions to the proposed tolerance language that are listed below in Section 2.2.3.

Both registrants (i.e., Mitsui Chemicals Agro Inc. and BASF Corp.) must maintain a sufficient amount of the reference standard at the EPA Repository as stated below:

OPPTS 860.1650 Submittal of Analytical Reference Standards

   * The standard for dinotefuran will expire in 2012.  An updated certificate of analysis or a new analytical 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 higher livestock dietary burdens.

860.1480 Livestock Feeding Study - Poultry

   * A poultry feeding study may be required if the poultry dietary burden is significantly raised in a future petition.


2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method 

For tolerance setting in plant commodities, parent 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 (HPLC/MS/MS) method for the determination of residues of dinotefuran, DN, and UF; an HPLC/ultraviolet (UV) detection method for the determination of residues of dinotefuran; and HPLC/MS and HPLC/MS/MS methods for the determination of DN and UF.  These methods have been deemed acceptable for tolerance enforcement by the EPA for residues in plant commodities.

Samples from the submitted rice crop field trial and processing studies and the food-handling establishment study were analyzed for residues of dinotefuran, DN, and UF using acceptable LC/MS/MS methods similar to the established enforcement method.  The methods were adequately validated prior to and/or in conjunction with the analysis of the field trial, processing, storage stability and food-handling establishment study samples.  The validated limits of quantitation (LOQs; determined as the lowest levels of method validation, LLMV) for rice commodities were 0.01 ppm for all analytes in rice grain and processed commodities and 0.10 ppm for all analytes 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 ug 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 chromatography/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 metabolites, HED does 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 (MRLs) 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.

2.2.3	Recommended Tolerances 

Tolerances are established 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 by measuring only 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 by measuring only dinotefuran.

Pending submission of a revised Sections F and B, and revised labels, 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 Sections B and F, and updated certificate(s) of analysis or new analytical 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 for 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 byproducts	0.01 ppm

For the Proposed Food/Feed Handling Establishment Use by BASF Corp.:

Pending submission of revised Sections B and F, and updated certificate(s) of analysis or new analytical 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)methyl)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) Food/feed items (other than those covered by a higher tolerance as a result of use on growing crops) in food/feed handling establishments.
   
   (ii) The insecticide may be present as a residue 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 held, 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 intervals.  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.  Dishes, 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
Commodity
                              Proposed Tolerance
                                     (ppm)
                          Recommended Tolerance (ppm)
Comments (correct commodity 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.  The 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".

Also for the proposed use on rice (Mitsui), HED has concluded that no 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 byproducts) at the LOQ of 0.01 ppm are now needed.  A poultry feeding 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 Proposed Use on Rice:

860.1200 Directions for Use

   * 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 application 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 polyethylene or polyvinyl chloride, and shoes plus socks.  Since the risk estimates 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 Use

   * 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 specify a maximum rate in g ai/linear foot 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 a maximum use rate of 0.05 g ai/linear foot.

2.3.2	Recommendations from Occupational Assessment

For the Proposed Total Release 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 establishment may result in residues in the food areas.

3.0	Introduction

Dinotefuran is a broad-spectrum insecticide belonging to the nitroguanidine sub-class of the neonicotinoid class of insecticides.  It is insecticidal by contact and ingestion, resulting in the cessation of insect feeding within hours of contact with death shortly.  The mode of action is interference with the acetylcholine receptor on the post-synaptic side of the nerve cells.

Dinotefuran is currently registered for use on numerous agricultural use sites, including: Brassica leafy greens, subgroup 5B; cotton; cucurbits; fruiting vegetables; grapes; head & stem Brassica vegetables, subgroup 5A; leafy vegetables, except Brassica, group 4; potatoes; turnip greens; and greenhouse grown tomatoes.  It is also registered on many residential/non-agricultural use sites, including: turf, indoor (including residential and food and non-food areas of food service/handling establishments) and pet areas, outdoor (lawns, ornamentals, flower gardens, vegetable gardens, surfaces of buildings, porches, patios, etc.), ant baits, fire ant baits, pet spot-on, foggers, Christmas trees, ornamental trees, non-bearing fruit and nut trees, plantations reforestation nurseries, forests, and woodland areas.  Registered 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 registrants, 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; 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, LLC, 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) are presented in Table 3.1.

TABLE 3.1.  Dinotefuran Nomenclature.
Compound
                              Chemical Structure
                                       N
H
N
N
H
O
C
H
3
N
O
2
Common name
dinotefuran
Company experimental name
MTI-446
IUPAC name
(EZ)-(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine
CAS name
N-methyl-N'-nitro-N˝-[tetrahydro-3-furanyl)methyl]guanidine
CAS #
165252-70-0
End-Use Products
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 (EPA Reg. No. 499-LAN); and SVP 11 (Vectra EQ) (EPA Reg No. 83399-RR) 
Compound
                              Chemical Structure
                                       N
H
N H
N
H
O
C
H
3

                                       

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

N
H
O
C
H
3



Common name
UF
IUPAC name
1-methyl-3-(tetrahydro-3-furylmethyl)-urea

3.2	Physical/Chemical Characteristics

The physicochemical properties of dinotefuran are summarized in Appendix B.  Dinotefuran has a molecular weight of 202.2 g/mole, a very high water solubility (39,830 ppm), and a low octanol/water partition coefficient (KOW = 0.283), suggesting the potential for runoff and low bioaccumulation.  The low vapor pressure (1.28 x 10[-8] mm Hg) and a low Henrys's Law Constant (8.63 x 10[-14] Atm :: M[3]/mol) suggest that this compound is not expected to volatilize 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 days) and leaching.  Since there is no valid soil photolysis data, it is unknown if dinotefuran parent residues break down quickly in soil via photolysis.  Dinotefuran appears to be relatively persistent to metabolism, both in aerobic (half-life = 17-89 days) and anaerobic (half-life = 51-62 days) conditions.  It appears that under metabolic conditions, 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 types.  It is also very highly soluble (39,830 ppm).  Since dinotefuran may persist in soils, it may have a high potential to leach to subsurfaces.  Furthermore, it can migrate to adjacent bodies of water through spray drift and in runoff events, probably dissolved in the water column.  Once in the rivers, 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 appearing on the LX434 Dinotefuran 20SG label includes coveralls, chemical resistant gloves made of any waterproof material such as polyethylene or polyvinyl 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, Type, and Equip.
                                  Formulation
                                [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 registrants (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 product 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.  TC249 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, Type, and Equip.
                                  Formulation
                                [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 ft[2] 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
                                    /yd[2]
                            (0.16-0.32 oz. product/
                                   10 ft[2])
                                      NS
                                      NS
                                      NA
Apply lightly and uniformly to infested areas.   Repeat treatments as necessary.   
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 ft[2] 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, LLC, 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 pyriproxyfen (0.445).  The 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 ml 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 as a uniform stripe from the caudal aspect of the hock to the pastern and caudal aspect of knee to pastern.  This treatment is to be repeated every month or as recommended by a veterinarian.    

Proposed Total Release Fogger Product
A Section 3 registration was requested by 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%), pyrethrins (0.5%), and piperonyl butoxide (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 applicators and other handlers to wear include long-sleeve shirt, long pants, socks and shoes.  

3.4	Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new uses of dinotefuran on rice, in 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 for post-application exposure for workers re-entering treated sites.  

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

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part 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 analyzed and categorized by subgroups based on age, season of the year, ethnic group and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children 3 to < 6 years old, youths and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.


4.0	Hazard Characterization and Dose-Response Assessment

Dinotefuran is in the neonicotinoid class of pesticides and acts as an agonist on insect nicotinic acetylcholine receptors.  Consistent with its neurotoxic pesticidal mode of action (MOA), dinotefuran's toxicity profile shows that the mammalian nervous system is the target of dinotefuran toxicity, as demonstrated in the acute and subchronic neurotoxicity studies in rats, and pre-natal developmental toxicity study in rabbits.

4.1	Toxicology Studies Available for Analysis

The toxicology database for dinotefuran is adequate for hazard characterization.  Available studies include subchronic and chronic oral toxicity studies in rats, mice and dogs, developmental toxicity studies in rats and rabbits, a reproductive toxicity study in rats, acute and subchronic neurotoxicity studies in rats and immunotoxicity studies in mice and rats.  Additionally, developmental neurotoxicity (DNT) and immunotoxicity studies are also available. 

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

The ADME properties of radiolabeled dinotefuran have been thoroughly investigated in non-pregnant adult rats (males and non-pregnant females) following oral (single and repeated) and intravenous (IV) single dosing.  Also performed have been single oral dose studies with pregnant rats at gestation day (GD18), lactating rats at 12 days postpartum, and growing rat pups at postnatal day (PND) 12.  In all cases where dinotefuran was administered orally, there was rapid (time to peak plasma levels was < 1 hr) and extensive (> 90%) absorption from the gastrointestinal (GI) tract, wide body distribution with no specific tissue accumulation, little or no metabolism (predominant species was the parent chemical), and 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 comparably distributed throughout the body at 30 minutes post-dosing (approximate tmax) and had declined substantially in all tissues by 4 hours post-dosing.  There was no evidence of specific tissue accumulation; the highest content of radioactivity at 30 minutes was found in the kidneys, reflective of the high water solubility property of dinotefuran and subsequent predominant route of excretion via the urine (93%).  Elimination was rapid with plasma half-life of about 3.6 hours for males and about 2-fold longer for female rats at 7.9 hours following a single oral dose of dinotefuran.  Upon repeated daily dosing, plasma elimination half-life estimates increased slightly to 5.6 hrs for males, but remained about the same for females at 6.9 hrs.  The predominant species detected in excreta was the parent chemical (75-93% of the administered radiolabel) in both oral and IV administration studies.  Minor metabolites identified accounted for only 2-6% of the administered radiolabel.

The ADME data collected from the single oral dose study with pregnant rats at GD18 suggests that dinotefuran readily crosses the placenta as evidenced by parallel profiles exhibited by maternal blood and fetal tissues.  Peak levels of radioactivity in maternal blood and fetal tissues were comparable and both reported at the first time measurement of 0.5 hours.  When lactating rats at 12 days postpartum were similarly dosed with a single dose of radiolabeled dinotefuran, there was also a comparable profile between maternal blood radioactivity content and maternal milk; both matrices achieved comparable peak levels at the same first time measurement of 0.5 hours.  The clearance of radioactivity from fetal tissues and milk paralleled that of maternal plasma, decreasing by  80% by 4 hours post-dosing.  No measurement of radioactivity was made in nursing pups.

PND 12 rat pups exhibited a similar ADME profile following a single oral dose of 50 mg/kg bw radiolabeled dinotefuran.  Absorption could not be accurately quantified but was noted to be high (~80%).  The radio - label was widely distributed in the body with no specific tissue accumulation noted.  Urine was the primary elimination route as indirectly evidenced by finding high radioactive areas by whole body autoradiography in the kidneys and bladder.  There were no metabolites reported; the parent chemical was the predominant species accounting for >97% of the radiolabel in the excreta, plasma, kidneys, and stomach, and nearly 61-83% in intestines (and contents), and liver.  Approximately 32-36% of the administered dose 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 gastrointestinal tracts and kidney systems and/or the absence of maternal stimulation to elicit excretion.

4.2.1	Dermal Absorption

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

4.3	Toxicological Effects

Dinotefuran has low acute toxicity by oral (Toxicity Category III), dermal (Toxicity Category IV), and inhalation (Toxicity Category IV) exposure routes.  It is not a dermal sensitizer, does not irritate the eye (Toxicity Category IV), but causes a low level of skin irritation.  The main target of toxicity is the nervous system, but effects on the nervous system were only observed at high doses.  Nervous system toxicity was manifested as clinical signs and decreased motor activity seen after acute dosing (in both rats and rabbits) and changes in motor activity which are consistent with effects on the nicotinic cholinergic nervous system seen after repeated dosing.  Typically, low to moderate levels of neonicotinoids, such as dinotefuran, activate the nicotinic acetylcholine receptors causing stimulation of the peripheral nervous system (PNS).  High levels of neonicotinoids (agonists) can over stimulate the PNS, maintaining cation channels in the open state which blocks the action potential and leads to paralysis.

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 thymus weights were seen in mice, rats and dogs following subchronic and chronic dietary exposures.  However, these weight changes were not corroborated with alterations in hematology parameters, histopathological lesions in these organs, or toxicity to the hematopoietic system.  Furthermore, the toxicology database contains immunotoxicity studies in mice and rats and a developmental immunotoxicity study in rats.  In the immunotoxicity studies, no effects 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 thymus 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 post-weaning periods.  Because of the lack of immunotoxicity seen in the immunotoxicity studies in mice, rats, and developing rats, the thymus weight changes seen in dogs and the spleen weight changes seen in mice and rats in the subchronic and chronic oral studies were not considered to be toxicologically relevant.

No systemic or neurotoxic were 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 days. 

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 decreased thyroid weights.  Offspring toxicity was characterized as decreased forelimb grip strength or hindlimb grip strength in the F1 pups.  There was no adverse effect on reproductive performance at any dose.  In the developmental neurotoxicity study, no maternal or offspring toxicity was seen at any 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 assays. 

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

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


4.4.1	Completeness of the Toxicology Database

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

4.4.2	Evidence of Neurotoxicity

The neurotoxic potential of dinotefuran has been adequately considered.  Dinotefuran is a neonicotinoid and has a neurotoxic mode of pesticidal action.  Consistent with the mode of action, changes in motor activity were 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 system; no effects on neurobehavioral parameters were seen in the offspring at any dose, including the limit dose.

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

There was no evidence (qualitative or quantitative) of increased susceptibility following in utero exposures to rats and rabbits and following pre- and post-natal exposure to rats for two generations.  In rats, no maternal or developmental toxicity was seen at the Limit Dose.  In rabbits, maternal toxicity manifested as clinical signs of neurotoxicity but no 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 (decreased body weights).  The concern is low for the observed qualitative increase in sensitivity since the effects in the offspring were seen at the Limit 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 system 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 Database

Exposure data are complete or are estimated based on data that reasonably account for potential exposures.  The acute dietary analysis was based on tolerance level residues derived from field trials and 100% crop treated assumptions for all commodities.  The chronic dietary analysis included tolerance level residues and 100% crop treated.  The tolerance level for rice, derived from field trial data, represents maximum application rates and minimum pre-harvest intervals (PHIs).  The dietary drinking water assessment utilized water concentration values generated by model and associated modeling parameters which are designed to provide conservative, health protective, high-end estimates of water concentrations.  HED concludes that the acute and chronic exposure estimates in this analysis are unlikely to underestimate actual exposure.  The residential exposure assessment uses the 2012 Residential SOPs and is considered health-protective.

4.5	Toxicity Endpoint and Point of Departure 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 Likely 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.  Summary of Toxicological Doses and Endpoints for Dinotefuran for Use in Human Health Risk Assessments
Exposure/
Scenario
Point of Departure
Uncertainty/
FQPA Safety Factors
RfD, PAD, Level of Concern for Risk Assessment
Study and Toxicological Effects
Acute Dietary (General Population, including Infants and Children)
NOAEL=125 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x
Acute RfD = 1.25 mg/kg/day

aPAD =1.25 mg/kg/day
Developmental Toxicity Study in Rabbits
LOAEL = 300 mg/kg/day based on clinical signs indicative of neurotoxicity in does (hypoactivity, prone position, panting, tremor and erythema) seen following the first dose on Gestation Day 6.
Chronic Dietary (All Populations)
NOAEL=99.7 mg/kg/day
UFA= 10x
UFH= 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
UFA= 10x
UFH= 10x
FQPA SF= 1x 
Residential LOC for MOE = 100
Chronic Toxicity/Carcinogenicity Study in Rats
LOAEL = 991 mg/kg/day based on decreased body weight gain and nephrotoxicity.
Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 months)
No systemic toxicity was seen at the limit dose in a 28-day rat dermal toxicity study in which neurotoxicity was evaluated and there are no developmental toxicity concerns.  No hazard was identified for these exposure scenarios.  A dermal penetration study for dinotefuran showed low absorption, < 2%. 
Inhalation Short- Term (1-30 days) and Intermediate-Term (1-6 months)
No quantitation required.  No systemic toxicity was seen in a 28-day inhalation toxicity study at doses that were in ~ 10,000-fold excess of the highest anticipated human exposure.  There are no developmental toxicity concerns.
Cancer (oral, dermal, inhalation)
Classification:  "Not likely to be Carcinogenic to Humans" based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.

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 adequately understood for the purposes of this 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 residues of concern.  A listing of the dinotefuran metabolites/degradates is provided in Appendix D.

Table 5.1.  Summary 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, 48680304, 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 for 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 has 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.

Table 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
                                  Sample Min.
                                  Sample 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
                                       
                                  Combined[4]
                                       
                                       
                                       
                                     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

                                  Combined[4]
                                       
                                       
                                       
                                     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

                                  Combined[4]
                                       
                                       
                                       
                                     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
                                       
                                  Combined[4]
                                       
                                       
                                       
                                     2.21
                                     4.07
                                     2.29
                                     3.97
                                     3.56
                                     3.27
                                     0.88
Combined results - All MRIDs
                                 Rice Grain[4]
                                   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]  LAFT = 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 Corporation, 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 perishable food items and one containing non-perishable food 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 treatments 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 RTIs were made.  Finally, sets of covered and uncovered samples from both rooms received GT-only treatments at 2.186 to 2.369 g ai.  These samples were placed in the room immediately 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 generally below the LOQ in/on all covered and/or wrapped food items 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 by 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 meeting (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 type.  For specifying the amount of dinotefuran applied with the 0.5% pressurized liquid formulation 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 plywood 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 submitted 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, UF, and DN may concentrate in rice hulls (4.6x) but do not concentrate in bran or polished rice following 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.

Table 5.2.2.  Summary of Processing Factors for Dinotefuran
RAC
                              Processed Commodity
                           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 livestock feed item.

Maximum theoretical dietary burdens (MTDBs) were originally 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, respectively.

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 considerably higher than previously calculated, tolerances for swine commodities were originally 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 typically considers whether residues identified in the metabolism study would be quantifiable or exceed the LOQ (0.01 ppm) when extrapolated to a 10x-dosing level.  When adjusted to the 10x-dosing level, residues 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 byproducts) 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 cattle would not be expected to increase the dietary burden.  No changes are needed to the existing tolerances for milk or ruminant tissues.

Despite 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 increased 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 byproducts) are needed 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.  The 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 crops.  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, especially 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 days 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 Tier 1 dinotefuran drinking water assessment with estimated drinking water concentrations (EDWCs) for dinotefuran and its metabolite/degradate DN (DP397490, J. Wolf & J. Hetrick, 8/7/12).  

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 CO2).  The environmental fate data have shown 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 lying 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 days.  Also, the regional percent cropped area (PCA) factor was considered.  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., evaporation, outflow) of water into or out of the paddy; therefore it is inappropriate to incorporate PCA into the model.  The Tier 1 rice model conservatively 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 only 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 obtained using the provisionally modified Tier 1 Rice Model v. 1.0 for the use of dinotefuran on rice.  The peak concentration is 269 ug/L and the longer term concentration (≈average) would depend upon retention time (10 to 30 days).

Table 5.3.  Tier 1 Surface Water EDWCs (ug/L) for Drinking Water Risk Assessment for the Use of Dinotefuran on Rice.  Based upon total toxic residues (Dinotefuran + 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 ug/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 assessments of dinotefuran are unrefined since it is assumed that 100% of crops with the requested uses and currently registered uses of dinotefuran are treated and that all treated crops contain residues at tolerance levels.  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 analyses 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 (DP397490, J. Wolf & J. Hetrick, 8/7/12).  The surface water EDWC of 269 ug/L was used in the DEEM-FCID.  Thus, the results obtained from the present analyses may be considered highly conservative.  At the 95[th] percentile of exposure, no population subgroups were of concern: the general U.S. population accounted for just 3.0% of the acute population-adjusted dose (aPAD), while the most highly exposed population subgroup, all infants (<1 yr old), accounted for 7.6% of the aPAD.

5.4.3	Chronic Dietary Risk Assessment

Potential residues in drinking water were included in the analyses based on surface water results from the Tier 1 Rice model v.1.0 and the modified Tier 1 Rice model as these values were higher than the ground water estimates from the SCI-GROW model (DP397490, J. Wolf & J. Hetrick, 8/7/12).  The surface water EDWC of 257 ug/L was used in the DEEM-FCID.  No population subgroups were of concern:  the general U.S. population accounted for 1.4% of the chronic population-adjusted dose (cPAD), while the most highly 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 (mg/kg/day)
                                   % aPAD**
                               Dietary Exposure
                                  (mg/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 newly 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 residential settings.  The horse spot-on product can be used by a residential handler, but handler and post-application exposures are expected to be negligible; therefore, no assessment is needed.  

There are currently registered uses of dinotefuran on several residential use sites, including turf, ornamentals, vegetable gardens, pet spot-ons, indoor aerosol sprays, crack and crevice sprays, 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 resulted in risk estimates that are not of concern.


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 release 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, only incidental oral exposure to children who re-enter treated areas, such as homes, schools, barns, etc., was quantitatively 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 were estimated using HED's recently 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 these 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, who have less hand-to-mouth replenishments per hour than 1 to 2 year olds.

Table 6.2.1 presents these anticipated exposures from the total release fogger and their associated risk estimates.  Residential incidental oral risk estimates ranged from 1,200 to 13,000, and were not of concern to HED.  

Table 6.2.1.  Residential Post-Application Short-Term Oral Exposure and Risk Estimates for Children to Dinotefuran from Total Release Fogger.
                                  Scenario[1]
                         Deposited Residue (ug/cm[2])
                                 Children Ages
                                     (yrs)
                                   Activity
                            Daily Dose (mg/kg/day)
                                    MOE[1]
                                 Indoor Rooms
                                     14.6
                                      1-2
                            Hand-to-mouth on carpet
                                    0.08605
                                     1,200
                                       
                                       
                                       
                         Hand-to-mouth on hard surface
                                    0.02868
                                     3,500
                                       
                                       
                                       
                           Object-to-mouth on carpet
                                    0.01145
                                     8,700
                                       
                                       
                                       
                        Object-to-mouth on hard surface
                                    0.00763
                                    13,000
[1] MOE = NOAEL (99.7 mg/kg/day) / Daily Dose (mg/kg/day); where daily doses are as follows: 

Hand-to-Mouth Daily Dose (mg/kg/day) = hand residue loading (mg/cm[2]) x fraction of hand mouthed (0.13) x surface area of 1 hand (150 cm[2]) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x number of replenishment intervals per hour (4) x (1- (1-fraction saliva extraction (0.48) / (number of contact events per hour (20 events/hr) / number of replenishment intervals per hour (4 intervals/hr))) / 11 kg body weight; where
Hand Residue Loading (mg/cm[2]) = fraction ai on hands (0.15) compared to total surface residue from Jazzercise studies (gloves) x dermal exposure (mg) / 2 x surface area of 1 hand (150 cm[2]);

Object-to-Mouth Daily Dose (mg/kg/day) = deposited residue (14.6 ug/cm[2]) x fraction of residue transferred to object (0.06 for carpets, or 0.08 for hard surfaces) x conversion factor (0.001 mg/ug) x object surface area mouthed per event (10 cm[2]/event) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x number of replenishment intervals per hour (4 intervals/hr) x (1- (1-fraction saliva extraction (0.48) / (number of object-to-mouth contact events per hour (14 events/hr) / number of replenishment intervals per hour (4 intervals/hr))) / 11 kg body weight

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

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

Table 6.2.2 lists the residential post-application exposures and risk estimates from the existing residential uses of dinotefuran.  Because no dermal or inhalation endpoints were chosen for dinotefuran post-application residential dermal and inhalation exposure scenarios were not assessed.  As a result, risk assessments were only completed for post-application scenarios in which incidental oral exposures are expected.  The post-application exposure and risk estimates for all existing residential uses resulted in risk estimates that are not of concern (MOEs ranged from 1,100 to 5,900,000).

Table 6.2.2.  Residential Post-Application Short-Term Oral Exposure and Risk Estimates for Children to Dinotefuran.
                                   Scenario
                                  Formulation
                               Application Rate
                                Amount Treated
                                   Activity
                              Current Assessment
                                       
                                       
                                       
                                       
                                       
                            Daily Dose (mg/kg/day)
                                    MOE[1]
                                     Turf
                                   Granular
                                 0.52 lb ai/A
                                     0.5 A
                          Oral ingestion of granules
                                     0.11
                                     1100
                                       
                                       
                                       
                                       
                              Oral hand-to-mouth
                                    0.00076
                                    1.3E+5
                                       
                                       
                                       
                                       
                             Oral object-to-mouth
                                    0.00027
                                    4.3E+5
                                       
                                       
                                       
                                       
                            Oral ingestion of soil
                                    1.7E-5
                                    5.9E+6
                                       
                                    Liquid
                                 0.54 lb ai/A
                                     0.5 A
                              Oral hand-to-mouth
                                    0.0079
                                    1.3E+4
                                       
                                       
                                       
                                       
                             Oral object-to-mouth
                                    0.00024
                                    4.1E+5
                                       
                                       
                                       
                                       
                            Oral ingestion of soil
                                    1.8E-5
                                    5.7E+6
                                   Ant Bait
                                   Granular
                      0.00005 Fraction of ai in granular
                          Oral ingestion of granules
                                    0.0011
                                    1.1E+5
                          RTU Garden Trigger Sprayer
                                    Liquid
                                0.042 lb ai/gal
                                     1 gal
                         No post-application exposure
                                     NA[2]
                                      NA
                                  Dog Spot-On
                                    Liquid
                             80.7 mg ai/treatment
                                    1 tube
                              Oral hand-to-mouth
                                    0.00066
                                    1.5E+5
                                       
                                       
                             161.6 mg ai/treatment
                                    1 tube
                                       
                                    0.00057
                                    1.8E+5
                                       
                                       
                             193.8 mg ai/treatment
                                    1 tube
                                       
                                    0.00043
                                    2.3E+5
                                  Cat Spot-On
                                    Liquid
                              192 mg ai/treatment
                                    1 tube
                              Oral hand-to-mouth
                                    0.0019
                                    5.3E+4
                                       
                                       
                              320 mg ai/treatment
                                    1 tube
                                       
                                     0.002
                                    5.1E+4
                               Indoor Broadcast
                                 0.25% Aerosol
         0.0033 lb ai/can or 0.61 ug ai/cm[2] or 1.24E-6 lb ai/ft[2]
                            1 20-oz can/2646 ft[2]
                         Oral hand-to-mouth on carpet
                                    0.0036
                                    2.8E+4
                                       
                                       
                                       
                                       
                      Oral hand-to-mouth on hard surface
                                    0.0012
                                    8.3E+4
                                       
                                       
                                       
                                       
                           Object-to-mouth on carpet
                                    0.00046
                                    2.2E+5
                                       
                                       
                                       
                                       
                        Object-to-mouth on hard surface
                                    0.00034
                                    3.2E+5
                          Indoor Crack & Crevice
                                 0.5% Aerosol
                     0.00626 lb ai/can or 0.3 ug ai/cm[2]
                                      NA
                         Oral hand-to-mouth on carpet
                                    0.0018
                                    5.6E+5
                                       
                                       
                                       
                                       
                      Oral hand-to-mouth on hard surface
                                    0.00059
                                    1.7E+5
                                       
                                       
                                       
                                       
                           Object-to-mouth on carpet
                                    0.00024
                                    4.2E+5
                                       
                                       
                                       
                                       
                        Object-to-mouth on hard surface
                                    0.00016
                                    6.4E+5
                                       
                                     Dust
                               0.25 ug ai/cm[2]
                                      NA
                         Oral hand-to-mouth on carpet
                                    0.0015
                                    6.8E+4
                                       
                                       
                                       
                                       
                      Oral hand-to-mouth on hard surface
                                    0.00049
                                    2.0E+5
                                       
                                       
                                       
                                       
                           Object-to-mouth on carpet
                                    0.00020
                                    5.1E+5
                                       
                                       
                                       
                                       
                        Object-to-mouth on hard surface
                                    0.00013
                                    7.6E+5
[1] Scenarios for the incidental oral ingestion of granules use the dietary acute oral point of departure of 125 mg/kg/day.  All other scenarios use the short-term incidental oral point of departure of 99.7 mg/kg/day.
[2] NA = not applicable

6.3	Combined Exposure

FQPA requires that residential exposures that could reasonably be expected to occur on the same day be combined and compared to the appropriate toxicity endpoint.  The exposure estimates from use of the total release fogger product are higher than those 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 the 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 dinotefuran aggregate risk assessment.

6.4	Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation bystander exposure assessment was not performed for dinotefuran at this time.  Although volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby to pesticide applications, quantification of short- or intermediate-term inhalation risk is not required for dinotefuran because no systemic toxicity or portal of entry effects were seen following repeated inhalation exposure at the highest practical concentration obtainable in the respirable range.

6.5	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application (a method proposed to be employed for dinotefuran), but, to a lesser extent, could also be a potential source of exposure from the ground application method also employed for dinotefuran.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices.  On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.  Also, note that the residential uses of dinotefuran resulted in risk estimates of no concern, i.e., incidental oral MOEs range 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 concern.  The food and drinking water exposure estimates are 3.0% of the aPAD for the U.S. general population, and 7.6% for the most highly exposed subgroup, all infants (<1 yr old).

0.2 Short-Term Aggregate Risk

There is potential short-term exposure to dinotefuran via dietary (which is considered background exposure) and residential (which is considered primary exposure) pathways.  For adults, these pathways lead to exposure via dietary oral (background) as well as dermal and inhalation routes.  However, as explained previously, there were no dermal or inhalation toxicity endpoints identified.  Therefore, no short-term aggregate assessment is needed for adults.  For children, the pathways that lead to exposure are dietary oral (background) as well as dermal and oral routes.  The most conservative exposure estimate for child oral hand to-mouth exposure is 0.08805 mg/kg/day.  For a description of the residential exposure scenarios considered in the aggregate assessment, see Section 6.0.

The aggregate MOE for 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
                                    0.03857
                                    0.08805
                                    0.12662
                                      790
[1] LOC includes standard inter- (10X) and intra- (10X) species uncertainty factors totaling 100.
[2] Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC
[3] Residential Exposure = [Oral Exposure].  Source of residential exposure values used in aggregate assessment (Tables 6.2.1 and 6.2.2).
[4] Total Exposure = Avg Food & Water Exposure + Residential Exposure)
[5] Aggregate MOE = [NOAEL/ (Avg Food & Water Exposure + Residential Exposure)], NOAEL=99.7 mg/kg/day.

7.3	Intermediate-Term Aggregate Risk

Intermediate-term exposure is not expected for the adult residential exposure pathway.  Therefore, the intermediate-term aggregate risk would be equivalent to the 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.  Since incidental oral short- and intermediate-term toxicity endpoints and points of departure are the same, the short-term aggregate risk estimate, which includes the highest residential exposure estimate, is protective of any intermediate-term exposures.

7.4	Chronic Aggregate Risk

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

7.5	Cancer Aggregate Risk

Dinotefuran is considered "not likely to be carcinogenic to humans;" therefore, an aggregate cancer risk assessment has not been conducted.


7.0 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 by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that dinotefuran has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

8.0 Occupational Exposure/Risk Characterization

Application methods, maximum application rates and use sites are summarized in Section 3.3.  Based on the proposed use patterns of dinotefuran, there is a potential for occupational short- and intermediate-term dermal and inhalation exposures during handling (mixing & loading) and post-application activities.  Chronic exposure is not expected for the proposed use patterns.

As previously discussed in Section 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 polyethylene or polyvinyl chloride, and shoes plus socks.  Risk estimates for occupational 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-Term Post-Application Risk

Occupational workers performing typical post-application activities such as scouting, irrigation, harvesting, etc. may receive dermal exposure to dinotefuran residues.  However, since no hazard was identified for the short- or intermediate-term dermal route of exposure, dermal risks were not assessed.

Technical dinotefuran has a Toxicity Category IV for acute dermal, primary skin irritation, and primary eye irritation.  Per the WPS, a 12 hour REI is required for chemicals classified under Toxicity Category IV.  Therefore, the REI of 12 hours appearing on the dinotefuran label (EPA Reg. No. 86203-25) for the proposed use on rice is adequate. 

10.0	References

C. Walls, DP398050.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, DP397490, 8/7/12. Tier I Drinking Water Concentrations for Dinotefuran for Section 3 new use on rice.  

L. Cheng, DP397469, 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 Analytical Chemistry and Residue Data.

B. O'Keefe, DP391885, 7/20/12. Dinotefuran: Human Health Risk Assessment for Proposed Section 3 Uses on Tuberous and Corm Vegetables Subgroup 1C, Onion Subgroup 3-07A, Onion Subgroup 3-07B, Small Fruit Subgroup 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 13-07F, 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'Keefe, DP398247, 8/31/2012. Dinotefuran: Occupational and Residential Exposure Assessment for Proposed New Total Release Fogger Use. 


Appendix A.  Toxicology Profile 

A.1	Toxicology Data Requirements

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

                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Primary Eye Irritation	
870.2500    Primary Dermal Irritation	
870.2600    Dermal Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)	
870.3150    Oral Subchronic (nonrodent)	
870.3200    21-Day Dermal	
870.3250    90-Day Dermal	
870.3465    90-Day Inhalation	
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                       -
                                      Yes
870.3700a  Developmental Toxicity (rodent)	
870.3700b  Developmental Toxicity (nonrodent)	
870.3800    Reproduction	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (nonrodent)	
870.4200a  Oncogenicity (rat)	
870.4200b  Oncogenicity (mouse)	
870.4300    Chronic/Oncogenicity	
                                      n/a
                                      no
                                      n/a
                                      yes
                                      yes
                                       -
                                      yes
                                       -
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial	
870.5300    Mutagenicity -- Gene Mutation - mammalian	
870.5xxx    Mutagenicity -- Structural Chromosomal Aberrations	
870.5xxx    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)	
870.6100b  90-Day Neurotoxicity (hen)	
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Develop. Neurotoxicity	
                                      no
                                      no
                                      yes
                                      yes
                                      yes
                                       -
                                       -
                                      yes
                                      yes
                                      yes
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes



A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Test Substance 
Guideline No.
Study Type
MRID(s)
                                    Results
                               Toxicity Category
870.1100
Acute oral, rat
                                   45639823
LD50= 2804/2000 [M/F]
                                      III
870.1100
Acute Oral, mouse
                                   45639824
LD50=2450/2275 [M/F]
                                      III
870.1200
Acute dermal, rat
                                   45639901
LD50 > 2000 mg/kg
                                      IV
870.1300
Acute inhalation, rat
                                   45639902
LC50 > 4.09 mg/L
                                      IV
870.2400
Acute eye irritation, rabbit
                                   46301601
no positive effects
                                      IV
870.2500
Acute dermal irritation, rabbit
                                   45639904
low level of irritation
                                      IV
870.2600
Skin sensitization, guinea pig
                                   45639905
not a sensitizer
                                      n/a


Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

                           Guideline No./ Study Type

                    MRID No. (year)/ Classification /Doses

                                    Results

870.3100
90-Day oral toxicity in rats

MRID: 45654205, 45654203 (range-finding) (1997)

Acceptable/Guideline

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

NOAEL: 336/384 [M/F] mg/kg	

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

870.3100
90-Day oral toxicity in mice

MRID: 45654206, 45654204 (range-finding) (1997)

Acceptable/Guideline

Dose Levels: 0, 500, 5000, 25,000, 50,000 ppm (dietary); M/F= 81/102, 884/1064, 4442/5414, 10,635/11,560 mg/kg/day

NOAEL: 4442/5414 [M/F] mg/kg/day

LOAEL: 10,635/11,560 [M/F] mg/kg/day, based on decreased body weight and body weight gain

870.3150
90-Day oral toxicity in dogs

MRID: 45639906 (main study), 45639915, 45639916 (range-finding studies) (1999)

Acceptable/Guideline

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

NOAEL: 307 mg/kg/day

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

870.3200
28-Day dermal toxicity (rats)

MRID: 45639908, 45639907 (range-finding) (2001)

Acceptable/Guideline

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


Systemic: 
NOAEL: 1000 mg/kg/day

LOAEL: Not Established. 

Dermal: 
NOAEL: 1000 [M], 200 [F] mg/kg/day

LOAEL: not determined/1000 [M/F] mg/kg/day based on lack of effects in males, and acanthosis/ hyperkeratosis in high dose females (lower doses not evaluated histopathologically).

870.3465
28-Day inhalation toxicity (rat)

MRID: 45639909, 46072401 (2002)

Acceptable/Guideline

Dose Levels: 0, 0.22, 0.66, 2.08 mg/L (nose-only); M/F= 0, 60, 179, 565 mg/kg/day

NOAEL: 2.08 [M/F] mg/L or 565 mg/kg/day; HDT	

LOAEL: not identified

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

870.3700a
Prenatal developmental toxicity study (rats)

MRID: 45654207, 45639910 (range-finding) (1998) 

Acceptable/Guideline

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

Maternal
NOAEL: 1000 mg/kg/day, HDT
LOAEL:  Not Established

Developmental 
NOAEL: 1000 mg/kg/day
LOAEL: Not Established 

870.3700b
Prenatal developmental toxicity study (rabbits)

MRID: 45654208 (main study), 45639911, 45639912 (range-finding studies) (1998)

Acceptable/Guideline

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

Maternal 
NOAEL: 125 mg/kg/day
LOAEL: 300 mg/kg/day based on clinical signs indicative of neurotoxicity (i.e., hypoactivity, prone position, tremors) 

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

870.3800
Reproduction and fertility effects (rats)

MRID: 45639913, 45639914 (range-finding) (2002)

Acceptable/Guideline

Dose Levels: 0, 300, 1000, 3000, 10,000 ppm (dietary); M/F: 0, 24.1/26.8, 79.9/90.1, 241.0/267.9, 822.1/907.0 mg/kg/day

Parental/systemic
NOAEL: 241/268[M/F] mg/kg/day
LOAEL: 822/907[M/F] mg/kg/day, based on a transient decrease in food consumption and decreased premating weight gain in F0 males, observations of soft feces in F0 females and decreased thyroid weights in F1 females.

Offspring  
NOAEL: 241/268 [M/F] mg/kg/day
LOAEL: 822/907 [M/F] based on decreased body weights, body weight gains, and decreased forelimb grip strength (F1 males) or hindlimb grip strength (F1 females). 

Reproductive 
NOAEL: 241/268 [M/F] mg/kg/day
LOAEL: 822/907 [M/F] mg/kg/day, based on decreased uterine weights and microscopic alterations in the uterus and vagina of F0 females, decreased numbers of primordial follicles in F1 females, altered estrous cyclicity in F0 and F1 females, slight increases in abnormal sperm morphology in F0 and F1 males, and slight decreases in testicular sperm count in F0 males and sperm motility in F1 males.

870.4100b
Chronic toxicity (dogs)

MRID: 45654209 (1999)

Acceptable/Guideline

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

NOAEL: 559/512 [M/F] mg/kg/day; HDT
LOAEL: Not Established


870.4200b
Carcinogenicity (mice)

MRID: 45639917 (2000)

Acceptable/Guideline

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

NOAEL: 3694/4728 [M/F] mg/kg/day
LOAEL: Not Established

870.4300
Combined chronic toxicity/ carcinogenicity (rats)

MRID: 45640001 (2000)

Acceptable/Guideline

Dose Levels: 0, 60, 200, 2000, 20,000 ppm (dietary); M/F: 3.0/3.9, 9.9/12.5, 99.7/127.3, 991/1332 mg/kg/day

NOAEL: 99.7/127.3 [M/F] mg/kg/day
LOAEL: 991/1332 [M/F] mg/kg/day based on decreased body weight gain and nephrotoxicity. 

870.5100
Bacterial reverse mutation test



MRID: 45640003 (1996)

Acceptable

Negative.  +- S9 up to 16,000 ug/plate

870.5100
Bacterial reverse mutation test

MRID: 45654210 (1996)

Acceptable

Negative.  +- S9 up to limit dose of 5000 ug/plate


870.5300
In vitro mammalian cell gene mutation test

MRID: 45640002 (2002)

Acceptable

Negative, +- S9 up to 2002 ug/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 ug/mL

(CHL/IU cells)

870.5395
In vivo mammalian cytogenics -micronucleus assay

MRID: 45654212 (1995)

Acceptable

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

870.6200a
Acute neurotoxicity screening battery

MRID: 45640005 (2001)

Acceptable/Guideline

Dose Levels: 0, 325, 750, 1500 [M/F] mg/kg/day

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

870.6200b
Subchronic neurotoxicity screening battery

MRID: 45640004 (2001)

Acceptable/Guideline

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

NOAEL: 33/40 [M/F] mg/kg/day	
LOAEL: 327/400 [M/F] mg/kg/day based on decreased motor activity. 

870.6300
Developmental neurotoxicity study (rats)

MRID 48291601 (2010)

Acceptable/Guideline

Dose:  0, 1000, 3000 or 10000
Gestation/Lactation = 0, 79.4/158, 237.4/500.7 or 784.1/1642.9 mg/kg/day

Maternal NOAEL: 784  mg/kg/day 
Maternal LOAEL: Not Established

Offspring NOAEL = 784 mg/kg/day. Offspring LOAEL: Not Established.


870.7485
Metabolism and pharmacokinetics (rats)

MRID: 45640006

Acceptable/Guideline
Dose: single 50 or 1000 mg/kg oral or 50 mg/kg IV treatments or multiple oral 50 mg/kg treatments with MTI-446 (dinotefuran, >98% a.i., batch numbers VB9304, VB9302 (radiolabeled in the guanidine and furan positions) and 22-00210 & OFU-1265 (unlabeled)

Absorption was > 90% regardless of dose.  The radiolabel was widely distributed through the body and was completely excreted within 168 hours of treatment.  Urine was the primary elimination route, accounting for 88-99.8%.  Excretion into the urine was rapid, being 84-99% complete within 24 hours of treatment.  Absorption of the radioactivity was linear within the dose range of 50 and 1000 mg/kg.  Elimination of radioactivity was fast for all groups with a T(1/2) 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 Cmax for milk and fetal tissues was detected 0.5 hours after maternal treatment.  The concentra - tions of radioactivity in fetal tissue and maternal milk declined quickly and were below detection limits 24 hours post-treatment. After IV or oral treatment, 75- 93% of the administered radiolabeled test material, or nearly 93-97% of total urinary radiolabel, was excreted unchanged in the urine.  The parent compound was also the primary component in the plasma, milk, bile, feces, and most tissues collected 4-8 hours after treatment and at both dose levels.  Less than 10% of the 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/cm[2]

870.7800
Immunotoxicity in Rats
MRID 48442101 (2010)

Acceptable/Guideline

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

Systemic 
NOAEL: 425/430 [M/F] mg/kg/day.
LOAEL:  992/1018 [M/F] mg/kg/day based on decreased body weight, body weight gain, and food consumption.
Immunotoxicity 
NOAEL: 992/1018 [M/F] mg/kg/day  LOAEL: Not Established 

870.7800
Immunotoxicity in Mice
MRID 48442102 (2010)

Acceptable/Guideline

Dose:  0, 1120, 2800 or 7000 ppm
M/F= 0, 153/223, 405/581, 1053/1438 mg/kg/day
Systemic 
NOAEL: 1053/1438 [M/F] mg/kg/day.
LOAEL: Not Established

Immunotoxicity  
NOAEL: 1053/1438 [M/F] mg/kg/day.
LOAEL: Not Established

Special study: 
Neonatal rat metabolism study (12-day old rat pups)

MRID: 45640007

Acceptable/Non-guideline

Dose: 50 mg/kg radiolabeled MTI-446 (dinotefuran, Lot No. VB9304, labeled on the central guanidine portion of the mole - cule, purity and radio purity >99%

After a single oral 50 mg/kg dose of [G-[14]C] MTI-446 to 12-day-old rats, absorption was high (absorption could not be adequately determined but may have approached 80%) and the radio - label was widely distributed within the body.  Approximately 32-36% of the administered dose was excreted within 4 hours of treatment.  Urine was the primary elimination route as indirectly evidenced by finding high radioactive areas in the kidneys and bladder by whole body autoradiography.  No areas of tissue seques - tration were found and no gender-related differences were identified.  The test material was essentially not metabolized, the parent 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 Established



Appendix B.  Physical/Chemical Properties

TABLE B.  Physicochemical Properties of the Test Compound: Dinotefuran. 
Parameter
Value
Reference (MRID)
Melting point/range
107.5ºC
45639702
pH
5.6 @ 25ºC
45654201
Density
1.40 g/cm[3] @ 20ºC
45639702
Water solubility ( 20°C)
39.83 x 10[3] mg/L (pH 6.98)
45639702
Solvent solubility (mg/L at 20°C)
                               g/100 mL Solvent
45639702

Hexane
9 x 10[-7]


Heptane
1.05 x 10[-6]


Xylene
0.0072


Toluene
0.0149


Dichloromethane
6.45


Acetone
6.13


Methanol
6.00


Ethanol
2.01


Ethyl Acetate
0.52

Vapor pressure at 30°C
< 1.7 x 10[-6] Pa @ 25ºC
45639702
Dissociation constant (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
Euromax: 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
11,700




 Appendix C.  International Residue Limit Status Sheet.

                 Dinotefuran (044312, Requested 25April, 2012)
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 byproducts
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.




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

N
H
N
N
H
O
C
H
3
N
O
2


UF

1-methyl-3-(tetrahydro-3-furylmethyl)-urea

N
H
O

N
H
O
C
H
3



\* MERGEFORMAT
DN

1-methyl-3-(tetrahydro-3-furylmethyl)-guanidine

N
H
N H
N
H
O
C
H
3



\* MERGEFORMAT
PHP
6-hydroxy-5-(2-hydroxyethyl)-1-methyl-1,3-diazinane-2-ylidene-N-nitroamine

FNG
2-nitro-1-(tetrahydro-3-furylmethyl)guanidine

MNG
2-nitro-1-methylguanidine



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. Environmental Protection Agency. Released June 21, 2011. 

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

