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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

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. 
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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
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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
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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 broadspectrum 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 
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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. 
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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
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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.
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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.
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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 μg for dinotefuran in inert food surface items.

For tolerance setting in livestock commodities, dinotefuran is the residue of concern in livestock 

commodities for tolerance setting. A liquid 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.
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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.
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(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”.
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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 
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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/nonagricultural 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-touse (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 
Page 14 of 49

presented in Table 3.1.

TABLE 3.1. Dinotefuran Nomenclature.

Compound Chemical Structure

Common name dinotefuran

Company experimental 

name

MTI-446

IUPAC name (EZ)-(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine

CAS name N-methyl-N ́-nitro-N ̋-[tetrahydro-3-furanyl)methyl]guanidine

CAS # 165252-70-0

End-Use Products 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

Common name DN

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

Compound Chemical Structure

Common name UF

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

3.2 Physical/Chemical Characteristics

The 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 

N

H

O

N

O H

CH3

N

H

N H

N

O H

CH3

N

H

N

N

O H

CH3

NO2
Page 15 of 49

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 • M3/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

PHI1

(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 
Page 16 of 49

labels [i.e., TC 267 (EPA Reg. No. 499-531), TC 259 (EPA Reg. No. 499-526), and TC 249 

(EPA Reg. No. 499-527)]. TC 267 is a 0.5% pressurized liquid injection product. TC 259 is 

0.025% foam product. 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 

ft3

(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 ft2for 

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 ft2)

NS NS NA Apply lightly and uniformly to 

infested areas. Repeat treatments 

as necessary. 
Page 17 of 49

Table 3.3.2 Summary of Directions for Use of Dinotefuran in Food/Feed Handling Establishments.

Applic. 

Timing, Type, 

and Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. 

Rate

PHI

(days)

Use Directions and Limitations

Spot treatment,

Hand/bulbous 

or powder 

duster

NS NS NS NA Apply lightly and uniformly to 

infested areas. Limit individual 

treatments to ≤20% of total 

surface area or ≤2 ft2for 

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. 
Page 18 of 49

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new uses of dinotefuran on rice, in food/feed handling establishments, as a horse spoton 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.
Page 19 of 49

4.0 Hazard Characterization and Dose-Response Assessment

Dinotefuran is in the neonicotinoid class of pesticides and acts as an agonist on insect nicotinic 

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 nonpregnant 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 concentrationtime 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 postdosing. 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.
Page 20 of 49

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 radiolabel 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/cm2(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.
Page 21 of 49

Dinotefuran was well tolerated at high doses following dietary administration for ninety days to 

mice, rats and dogs. The most sensitive effects were decreases in body weight and/or body 

weight gain, but even these effects occurred at or near the Limit Dose. Changes in spleen and 

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 postweaning 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.
Page 22 of 49

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 
Page 23 of 49

chronic exposure estimates in this analysis are unlikely to underestimate actual exposure. The 

residential exposure assessment uses the 2012 Residential SOPs and is considered healthprotective.

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 ShortTerm (1-30 days) 

and IntermediateTerm (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.
Page 24 of 49

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. 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 Needed1 Not Needed1

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 
Page 25 of 49

adjusted the residue values from these five trials before inputting into the OECD calculation 

procedures for deriving a tolerance for rice grain. 

The available data support a tolerance of 9 ppm for rice grain with the requested registration of 

the 20% SG formulation on rice. Rice straw is no longer considered to be a significant livestock 

feedstuff; therefore, no tolerance is needed.

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.

LAFT2 HAFT2 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

UF30.458 0.519 0.488 0.488 0.488 0.488 N/A

DN30.397 0.490 0.444 0.444 0.444 0.444 N/A

Combined44.09 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

UF30.19 0.95 0.23 0.89 0.49 0.51 0.22

DN30.21 1.20 0.24 1.07 0.45 0.56 0.30

Combined41.53 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

UF30.75 0.75 0.75 0.75 0.75 0.75 NA

DN30.63 0.65 0.64 0.64 0.64 0.64 NA

Combined45.06 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

UF30.22 0.38 0.22 0.36 0.33 0.30 0.07

DN30.30 0.44 0.32 0.43 0.37 0.37 0.06

Combined42.21 4.07 2.29 3.97 3.56 3.27 0.88

Combined results - All MRIDs

Rice Grain4 Combined 0.264-0.435 6-8 16 1.53 5.14 1.81 5.10 3.56 3.41 0.99

Rice Grain5 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 
Page 26 of 49

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.
Page 27 of 49

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 
Page 28 of 49

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 
Page 29 of 49

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). SCIGROW 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.
Page 30 of 49

1.0 for the use of dinotefuran on rice. The peak concentration is 269 μg/L and the longer term 

concentration (≈average) would depend upon retention time (10 to 30 days).

Table 5.3. Tier 1 Surface Water EDWCs (μg/L) for Drinking Water Risk Assessment for the Use of 

Dinotefuran on Rice. Based upon total toxic 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 

μg/L for both the acute and chronic exposures. Since the application rate for turf (1 application 

at 0.54 lb ai/A) is higher than for rice, and since SCI-GROW is not site or crop dependent, the 

concentration would be conservative and was not included in the dietary risk assessment.

5.4 Dietary Risk Assessment

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

The acute and chronic dietary exposure 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 μg/L was used in the DEEM-FCID. Thus, 

the results obtained from the present analyses may be considered highly conservative. At the 

95th 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 μg/L was used in the DEEM-FCID. No population 
Page 31 of 49

subgroups were of concern: the general U.S. population accounted for 1.4% of the chronic 

population-adjusted dose (cPAD), while the most 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.
Page 32 of 49

6.1 Residential Handler Exposure

Exposure for adult residential handlers activating the total release fogger is not expected because 

the label instructs handlers to exit the area immediately after initiating application. Also, the 

horse spot-on product can be used by a residential handler, but exposure is expected to be 

negligible. Therefore no residential handler exposures were assessed. 

6.2 Post-Application Exposure

There is potential for both short- and intermediate-term adult and child post-application exposure 

from the total release fogger product; however, no dermal hazard was identified in the routespecific 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, postapplication 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.

Scenario1

Deposited 

Residue 

(μg/cm2)

Children 

Ages

(yrs)

Activity Daily Dose 

(mg/kg/day) MOE1

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: 
Page 33 of 49

Hand-to-Mouth Daily Dose (mg/kg/day) = hand residue loading (mg/cm2) x fraction of hand mouthed (0.13) x surface area of 1 

hand (150 cm2) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x number of replenishment intervals per hour 

(4) x (1- (1-fraction saliva extraction (0.48) / (number of contact events per hour (20 events/hr) / number of replenishment 

intervals per hour (4 intervals/hr))) / 11 kg body weight; where

Hand Residue Loading (mg/cm2) = fraction ai on hands (0.15) compared to total surface residue from Jazzercise studies (gloves) 

x dermal exposure (mg) / 2 x surface area of 1 hand (150 cm2);

Object-to-Mouth Daily Dose (mg/kg/day) = deposited residue (14.6 μg/cm2) x fraction of residue transferred to object (0.06 for 

carpets, or 0.08 for hard surfaces) x conversion factor (0.001 mg/μg) x object surface area mouthed per event (10 cm2/event) x

exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x number of replenishment intervals per hour (4 intervals/hr) x 

(1- (1-fraction saliva extraction (0.48) / (number of object-to-mouth contact events per hour (14 events/hr) / number of 

replenishment intervals per hour (4 intervals/hr))) / 11 kg body weight

Dermal Exposure (mg) = deposited residue (14.6 μg/cm2) x fraction transferred (0.06 for carpets, or 0.08 for hard surfaces) x 

transfer coefficient (1,800 cm2/hr) x exposure time (4 hr/day for carpets, or 2 hr/day for hard surfaces) x conversion factor (0.001 

mg/μg); where 

Deposited Residue (14.6 μg/cm2) = Active Ingredient Applied (340,194 μg) / Area Treated (23,225 cm2); where 

Active Ingredient Applied (340,194 μg) = 6 oz fogger x % ai (0.2%) x conversion factor (28,349,526 μg/oz), and 

Area Treated (23,225 cm2) = volume treated (200 ft3) / ceiling height (8 ft) x conversion factor (929 cm2/ft2); 

Table 6.2.2 lists the residential post-application exposures and risk estimates from the existing 

residential uses of dinotefuran. Because no dermal or inhalation endpoints were chosen for 

dinotefuran post-application residential dermal and inhalation exposure 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) MOE1

Turf

Granular 0.52 lb ai/A 0.5 A

Oral ingestion of granules 0.11 1100

Oral hand-to-mouth 0.00076 1.3E+5

Oral object-to-mouth 0.00027 4.3E+5

Oral ingestion of soil 1.7E-5 5.9E+6

Liquid 0.54 lb ai/A 0.5 A

Oral hand-to-mouth 0.0079 1.3E+4

Oral object-to-mouth 0.00024 4.1E+5

Oral ingestion of soil 1.8E-5 5.7E+6

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

RTU Garden 

Trigger 

Sprayer

Liquid 0.042 lb ai/gal 1 gal No post-application exposure NA2 NA

Dog Spot-On Liquid

80.7 mg ai/treatment 1 tube

Oral hand-to-mouth

0.00066 1.5E+5

161.6 mg ai/treatment 1 tube 0.00057 1.8E+5

193.8 mg ai/treatment 1 tube 0.00043 2.3E+5

Cat Spot-On Liquid 192 mg ai/treatment 1 tube Oral hand-to-mouth 0.0019 5.3E+4

320 mg ai/treatment 1 tube 0.002 5.1E+4

Indoor 

Broadcast

0.25% 

Aerosol

0.0033 lb ai/can or 

0.61 μg ai/cm2or 

1.24E-6 lb ai/ft2

1 20-oz 

can/2646 

ft2

Oral hand-to-mouth on carpet 0.0036 2.8E+4

Oral hand-to-mouth on hard surface 0.0012 8.3E+4

Object-to-mouth on carpet 0.00046 2.2E+5

Object-to-mouth on hard surface 0.00034 3.2E+5

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

Table 6.2.2. Residential Post-Application Short-Term Oral Exposure and Risk Estimates for Children to Dinotefuran.

Scenario Formulation Application Rate Amount 

Treated Activity

Current Assessment

Daily Dose 

(mg/kg/day) MOE1

& Crevice 0.3 ug ai/cm2 Oral hand-to-mouth on hard surface 0.00059 1.7E+5

Object-to-mouth on carpet 0.00024 4.2E+5

Object-to-mouth on hard surface 0.00016 6.4E+5

Dust 0.25 μg ai/cm2 NA

Oral hand-to-mouth on carpet 0.0015 6.8E+4

Oral hand-to-mouth on hard surface 0.00049 2.0E+5

Object-to-mouth on carpet 0.00020 5.1E+5

Object-to-mouth on hard surface 0.00013 7.6E+5

1

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

scenarios use the short-term incidental oral point of departure of 99.7 mg/kg/day.

2 NA = not applicable

6.3 Combined Exposure

FQPA requires that residential exposures that could 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
Page 35 of 49

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).

7.2 Short-Term Aggregate Risk

There is potential short-term exposure to dinotefuran via dietary (which is considered 

background exposure) and residential (which is considered primary exposure) pathways. For 

adults, these pathways lead to exposure via dietary oral (background) as well as dermal and 

inhalation routes. However, as explained previously, there were no dermal or inhalation toxicity

endpoints identified. Therefore, no short-term 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 
Page 36 of 49

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 LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

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

3Residential 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.
Page 37 of 49

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to dinotefuran and any other substances and dinotefuran does not appear to produce a toxic 

metabolite produced 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/.

9.0 Occupational Exposure/Risk Characterization

Application methods, maximum application rates and use sites are summarized in Section 3.3. 

Based on the proposed use patterns of dinotefuran, there is a potential for occupational short- and 

intermediate-term dermal and inhalation exposures during handling (mixing & loading) and postapplication 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.
Page 38 of 49

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. 
Page 39 of 49

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
Page 40 of 49

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Test Substance 

Guideline No.

Study Type MRID(s) Results Toxicity 

Category

870.1100 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 (rangefinding) (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 (rangefinding) (1997)

Acceptable/Guideline

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

ppm (dietary); M/F= 81/102, 884/1064, 

4442/5414, 10,635/11,560 mg/kg/day

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

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

based on decreased body weight and body

weight gain

870.3150

90-Day oral toxicity 

in dogs

MRID: 45639906 (main study), 45639915, 

45639916 (range-finding studies) (1999)

Acceptable/Guideline

Dose Levels: 0, 1600, 8000, 24,000 ppm 

(dietary); M/F= 0, 58/58, 307/323, 

862/950 mg/kg/day

NOAEL: 307 mg/kg/day

LOAEL: 862 mg/kg/day, based on decreased 

body weight gain in males and decreased 

body weight and body weight gain in 

females.

870.3200 MRID: 45639908, 45639907 (range- Systemic: 
Page 41 of 49

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

28-Day dermal 

toxicity (rats)

finding) (2001)

Acceptable/Guideline

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

NOAEL: 1000 mg/kg/day

LOAEL: Not Established. 

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 (rangefinding) (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 (rangefinding) (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.
Page 42 of 49

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

Offspring 

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

LOAEL: 822/907 [M/F] based on decreased 

body weights, body weight gains, and 

decreased forelimb grip strength (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 μg/plate
Page 43 of 49

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

870.5100

Bacterial reverse 

mutation test

MRID: 45654210 (1996)

Acceptable

Negative. ± S9 up to limit dose of 5000 

μg/plate

870.5300

In vitro mammalian 

cell gene mutation 

test

MRID: 45640002 (2002)

Acceptable

Negative, ± S9 up to 2002 μg/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 μg/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 

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 
Page 44 of 49

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

(dinotefuran, >98% a.i., batch numbers 

VB9304, VB9302 (radiolabeled in the 

guanidine and furan positions) and 22-

00210 & OFU-1265 (unlabeled)

urine was rapid, being 84-99% 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 

T1⁄2 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 concentrations 

of radioactivity in fetal tissue and maternal 

milk declined quickly and were below

detection limits 24 hours post-treatment. 

After IV or oral treatment, 75- 93% of the 

administered radiolabeled test material, or 

nearly 93-97% of total urinary radiolabel, 

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 doserelated differences or label position effects 

were found.

870.7600

Dermal penetration

47013401 A dermal absorption factor (DAF) of 1.71% 

represents the radioactivity absorbed and 

remaining on the skin after removal of the 

stratum corneum, following a 10 hour 

exposure to 3.2 g/cm2

870.7800

Immunotoxicity in 

Rats

MRID 48442101 (2010)

Acceptable/Guideline

Dose: 0, 2240, 5600 or 14000 ppm

M/F= 0, 164/179, 425/430, 992/1018

mg/kg/day

Systemic 

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

LOAEL: 992/1018 [M/F] mg/kg/day based 

on decreased body weight, body weight gain, 

and food consumption.

Immunotoxicity 

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

LOAEL: Not Established 

870.7800

Immunotoxicity in 

Mice

MRID 48442102 (2010)

Acceptable/Guideline

Systemic 

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

LOAEL: Not Established
Page 45 of 49

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

Dose: 0, 1120, 2800 or 7000 ppm

M/F= 0, 153/223, 405/581, 1053/1438

mg/kg/day

Immunotoxicity 

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

LOAEL: Not Established

Special study: 

Neonatal rat 

metabolism study 

(12-day old rat pups)

MRID: 45640007

Acceptable/Non-guideline

Dose: 50 mg/kg radiolabeled MTI-446 

(dinotefuran, Lot No. VB9304, labeled on 

the central guanidine portion of the molecule, purity and radio purity >99%

After a single oral 50 mg/kg dose of [G14C] 

MTI-446 to 12-day-old rats, absorption was 

high (absorption could not be adequately 

determined but may have approached 80%) 

and the radiolabel 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 sequestration were found 

and no gender-related differences were 

identified. The test material was essentially 

not metabolized, the parent compound 

accounting for >97% of the radiolabel in the 

excreta, plasma, kidneys, and stomach, and

nearly 61-83% in intestines (and contents), 

and liver.

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
Page 46 of 49

Appendix B. Physical/Chemical Properties

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

Parameter Value Reference (MRID)

Melting point/range 107.5oC 45639702

pH 5.6 @ 25oC 45654201

Density 1.40 g/cm3 @ 20oC 45639702

Water solubility ( 20°C) 39.83 x 103 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 10-6Pa @ 25oC 45639702

Dissociation constant (pKa) 12.6 @ 20oC (estimated) 45639702

Octanol/water partition coefficient Log(KOW) -0.549 (Kow = 0.283) @ 25oC 45639702

UV/visible absorption spectrum Media Absorbance 

Maximum 

268 nm

€max: Molar

Absorbance 

Coefficient

45639702

Acidic 1.0469 12,600

1.0180 12,300

Neutral 1.3017 12,500

1.2668 12,300

Basic 0.8869 10,700

0.9662 11,700
Page 47 of 49

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 Mexico2 Codex3

40 CFR 180.603:

Plant: Combined residues of dinotefuran, ( RS )-1-methyl2-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

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

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.
Page 48 of 49

Appendix D. Dinotefuran and Metabolites

Common name/code Chemical name Chemical structure

Dinotefuran; MTI446N-methyl-N ́-nitro-N ̋-

[(tetrahydro-3-furanyl)-

methyl]-guanidine

UF 1-methyl-3-(tetrahydro-3-

furylmethyl)-urea

DN 1-methyl-3-(tetrahydro-3-

furylmethyl)-guanidine

N

H

N H

N

O H

CH3

N

H

O

N

O H

CH3

N

H

N

N

O H

CH3

NO2
Page 49 of 49

Common name/code Chemical name Chemical structure

PHP 6-hydroxy-5-(2-

hydroxyethyl)-1-methyl-1,3-

diazinane-2-ylidene-Nnitroamine

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

furylmethyl)guanidine

MNG 2-nitro-1-methylguanidine H

H N 2N

N

CH3

N

+ O

O

–

Appendix E. Review of Human Research

Studies reviewed for ethical conduct:

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. 

Electronic Database. Task Force members Health Canada, U. S. Environmental Protection 

Agency, and the National Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler 

Unit Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released 

June 21, 2011.

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