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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

DATE: 5/2/13

SUBJECT: Dinotefuran ID#: 13MI04 Section 18 Emergency Exemption for Use on Pome 

Fruits and Stone Fruits in Michigan to Control Brown Marmorated Stink Bugs.

PC Code: 044312 DP Barcode: D409855

MRID No.: None Registration No.: 59639-135, 10163-317

Petition No.: None Regulatory Action: Section 18

Assessment Type: Single Chemical/Aggregate Reregistration Case No.: NA

TXR No.: NA CAS No.: 165252-70-0

40 CFR: 180.603

FROM: Nancy Dodd, Chemist, Risk Assessor

Barry O’Keefe, Senior Biologist

Sheila Healy, Ph.D, Toxicologist

Risk Assessment Branch III (RAB3)

Health Effects Division (HED) (7509P)

THROUGH: Christine Olinger, Branch Chief

RAB3/HED (7509P)

TO: Tawanda Maignan/Andrea Conrath, RM #9

Minor Use, Inerts and Emergency Response Branch

Registration Division (7505P)

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

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

(MI). This document and attachments provide an assessment of the human health risk resulting 

from the proposed and registered uses of dinotefuran. The toxicology evaluation was performed 

by Sheila Healy, the drinking water assessment was conducted by Jim Wolf and Jim Hetrick of 

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

assessment was conducted by Barry O’Keefe, and the review of the residue chemistry data, 

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

Dodd. 
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1.0 Executive Summary ................................................................................................................4

2.0 HED Recommendations.........................................................................................................7

2.1 Tolerance Considerations ..................................................................................................7

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

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

3.0 Introduction .............................................................................................................................7

3.1 Chemical Identity................................................................................................................8

3.2 Physical/Chemical Characteristics...................................................................................9

3.3 Pesticide Use Pattern ..........................................................................................................9

3.4 Anticipated Exposure Pathways.....................................................................................10

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

4.0 Hazard Characterization and Dose-Response Assessment ............................................11

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

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

4.3 Toxicological Effects .........................................................................................................12

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) .................................13

4.4.1 Completeness of the Toxicology Database .............................................................14

4.4.2 Evidence of Neurotoxicity.........................................................................................14

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal .....14

4.4.4 Residual Uncertainty in the Exposure Database ..................................................14

4.5 Toxicity Endpoint and Point of Departure Selections.................................................15

5.0 Dietary Exposure and Risk Assessment ............................................................................16

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

5.2 Food Residue Profile........................................................................................................16

5.3 Water Residue Profile.......................................................................................................17

5.4 Dietary Risk Assessment ..................................................................................................18

5.4.1 Description of Residue Data & Percent Crop Treated ........................................18

5.4.2 Acute Dietary Risk Assessment ...............................................................................18

5.4.3 Chronic Dietary Risk Assessment...........................................................................18

5.4.4 Summary Table..........................................................................................................18

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ...............................19

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

6.2 Post-Application Exposure .............................................................................................19

6.3 Combined Exposure ........................................................................................................22

6.4 Residential Bystander Post-Application Inhalation Exposure .................................22

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

7.0 Aggregate Exposure/Risk Characterization .....................................................................22

7.1 Acute Aggregate Risk .......................................................................................................23

7.2 Short-Term Aggregate Risk ............................................................................................23

7.3 Intermediate-Term Aggregate Risk...............................................................................24

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

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

8.0 Cumulative Exposure/Risk Characterization...................................................................24

9.0 Occupational Exposure/Risk Characterization................................................................24

10.0 References...............................................................................................................................25

Appendix A. Toxicology Profile.....................................................................................................26
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A.1 Toxicology Data Requirements.......................................................................................26

A.2 Toxicity Profiles.................................................................................................................27

Appendix B. Physical/Chemical Properties.................................................................................33

Appendix C. Dinotefuran and Metabolites..................................................................................34

Appendix D. Review of Human Research....................................................................................36
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1.0 Executive Summary

Dinotefuran ((RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine) is a broad-spectrum 

insecticide belonging to the nitroguanidine sub-class of the 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 thereafter. The mode of action is interference with the 

acetylcholine receptor on the post-synaptic side of the nerve cells. 

Dinotefuran is currently registered for use on various agricultural commodities. It is also 

registered on many residential/non-agricultural use sites, including: turf, indoor (including 

residential and food/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, nonbearing fruit and nut trees, plantations reforestation nurseries, forests, and woodland areas. 

Registered dinotefuran formulations include baits, gels, soluble concentrates, granulars, soluble 

granules, and ready-to-use (RTU) products.

Use Profile

The Michigan Department of Agriculture and Rural Development requested a Section 18 

emergency specific exemption to use dinotefuran to control the brown marmorated stink bug on 

pome fruit and stone fruit in MI. Dinotefuran will be used on apples, peaches and nectarines on 

up to a total of approximately 40,200 acres in MI. The applications would be made from April 

through November, 2013. The dinotefuran products to be used are Venom Insecticide (EPA 

Reg. No. 59639-135) or Scorpion 35SL (EPA Reg. No. 10163-317).

Foliar applications will be made with ground equipment at a maximum application rate of 0.304 

lb ai/A with a maximum of two applications per season for a total of 0.608 lb ai/A/season. The 

minimum retreatment interval (RTI) is 7 days. The preharvest interval (PHI) is 3 days. The 

restricted entry interval (REI) is 12 hours.

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

and stone fruits in MI. Section 18s have been previously granted to other states for use of 

dinotefuran to control stink bugs on pome and stone fruits; the previous Section 18 tolerances 

were based on data extrapolated from an apple metabolism study. A Section 3 tolerance of 1.0 

ppm has been established on peach reflecting a lower seasonal rate than that proposed for this 

Section 18.

Toxicity/Hazard

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

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

hazard characterization. The nervous system is the main target of dinotefuran toxicity. After a 

single dose in rats and rabbits, neurotoxicity was manifested as clinical signs (hypoactivity, 

prone position, panting, tremors, and erythema) and decreased motor activity and changes in 

motor activity. These acute effects are consistent with effects seen on the nicotinic cholinergic 

nervous system after repeated dosing. Dinotefuran was well tolerated at high doses following 

dietary administration for 90 days to mice, rats and dogs. The principal toxicological findings 
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were decreases in body weight and/or body weight gain at or near the limit dose; but for acute 

dietary exposure the endpoint is neurotoxicity. No systemic or neurotoxicity was seen following 

repeated dermal applications at the limit dose to rats for 28 days. No systemic or portal of entry 

effects were seen following repeated inhalation exposure at the maximum obtainable 

concentrations to rats for 28 days. No evidence of functional immunotoxicity was observed in 

guideline immunotoxicity or developmental immunotoxicity studies of dinotefuran. There are 

also no indications of perturbed reproductive function. No adverse effects in fetuses were seen 

in the developmental toxicity studies in rats or rabbits, at maternally toxic doses, and offspring 

effects in the reproduction study occurred at the same doses causing parental effects. There are 

no concerns of developmental neurotoxicity. There was no evidence of carcinogenicity in male 

and female mice and in male and female rats fed diets containing dinotefuran at the limit dose. 

Dinotefuran was non-mutagenic in both in vivo and in vitro assays.

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

for pre- and/or post-natal toxicity, or in the exposure database, and the Food Quality Protection 

Act (FQPA) Safety Factor can be reduced to 1X.

For acute dietary risk to the general population, including infants and children, an acute 

population adjusted dose (aPAD) of 1.25 mg/kg/day was derived from a maternal no observed 

adverse effect level (NOAEL) of 125 mg/kg/day in a developmental toxicity study in rabbits 

based on clinical signs indicative of neurotoxicity in does (hypoactivity, prone position, panting, 

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

LOAEL).

For chronic dietary risk to all populations, a chronic population adjusted dose (cPAD) of 1.0 

mg/kg/day was derived from a NOAEL of 99.7 mg/kg/day from the chronic 

toxicity/carcinogenicity study in rats, based on decreased body weight gain and food efficiency 

in females and increased incidences of kidney pelvic mineralization and ulceration in males at 

991 mg/kg/day (LOAEL).

To assess short- and intermediate-term incidental oral exposures, an oral point of departure 

(POD) was selected. The POD (NOAEL = 99.7 mg/kg/day) was based on decreased body 

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

mineralization and ulceration in males seen at the lowest observed adverse effect level (LOAEL) 

of 991 mg/kg/day seen in the chronic toxicity/carcinogenicity study in rats. 

Quantification of short- or intermediate-term dermal and inhalation risks are not required 

because no systemic or developmental toxicity was seen up to the limit dose in route-specific 

toxicity studies. 

Dietary Exposure (Food and Water)

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

acute dietary risk estimates are well below the Agency’s level of concern (LOC; <100% of the 

acute population adjusted dose (aPAD)) for all population subgroups and were estimated at 3.7% 

of the aPAD for the general U.S. population and 12% of the aPAD for the most highly exposed 

population subgroup (children 1-2 years old). The results of the unrefined chronic dietary 
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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 1.7% of the cPAD for the general U.S. population 

and 5.7% 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

There is potential for exposure in residential settings during the application of currently 

registered products containing dinotefuran, and from entering areas previously treated with 

dinotefuran, such as lawns where children might play, pets children might play with, or golf 

courses and home gardens that could lead to exposures for adults. As a result, risk assessments 

were previously completed for both residential handler and postapplication scenarios 

(DP398048, B. O’Keefe, 8/31/12; DP285650, J. Arthur, 4/27/2004; DP318728, B. O’Keefe, 

8/2/04; and DP347177, S. Recore, 5/7/08). The proposed Section 18 uses of dinotefuran do not 

add any additional residential exposures or risks.

Aggregate Exposure

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

and chronic aggregate risk estimates for all populations, resulting from exposure to dinotefuran 

in food and drinking water, are not of concern. A short-term aggregate risk assessment was 

performed for children to assess the potential for co-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 690, 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.

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 studies (listed in Appendix D) have 

been determined to require a review of their ethical conduct, and have received that review.

Environmental Justice

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

assessment. Refer to Section 3.5 for details.
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2.0 HED Recommendations

HED has no concerns regarding human health exposure and risk from the proposed Section 18 

use of dinotefuran on stone fruit and pome fruit for control of the brown marmorated stink bug in 

MI. The specific tolerance recommendations are discussed in Section 2.1.

2.1 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Plants

Adequate analytical methods are available for enforcement of the proposed tolerances. The 

methods include a high performance liquid chromatography/tandem mass spectrometry 

(HPLC/MS/MS) method for determination of residues of dinotefuran, DN, and UF; an 

HPLC/ultraviolet (UV) detection method for the determination of residues of dinotefuran; and 

HPLC/MS and HPLC/MS/MS methods for determination of residues of DN and UF. Analytical 

Chemistry Branch/Biological and Economic Analysis Division (ACB/BEAD) found the methods 

to be adequate (D288743, 10/22/2003, D. Swineford, ACB/BEAD). The lowest level of method 

validation (LLMV) was reported as 0.01 ppm for dinotefuran (m/z 203 →129) and metabolites 

DN (m/z 158 →102) and UF (m/z 159 →102).

Multiresidue Methods

Dinotefuran was not adequately recovered using any of the multiresidue methods. HED does not 

expect any of the FDA Protocols to recover these metabolites due to the structural similarities of 

the metabolites as compared to the parent.

2.2.2 Recommended Tolerances

HED recommends Section 18 tolerances be established on the following crop groups, for 

residues of dinotefuran, (RS)-1-methyl-2-nitro-3-((tetrahydro-3-furanyl)methyl)guanidine, 

including its metabolites and degradates, in or on the commodities listed below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the sum of 

dinotefuran and its metabolites DN, 1-methyl-3-(tetrahydro-3-furylmethyl)guanidine, and UF, 1-

methyl-3-(tetrahydro-3-furylmethyl)urea, calculated as the stoichiometric equivalent of 

dinotefuran:

Fruit, pome, group 11-10............................................................................................... 2.0 ppm

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

3.0 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.
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Dinotefuran is currently registered for use on various agricultural commodities. It is also 

registered on many residential/non-agricultural use sites, including: turf, indoor (including 

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

outdoor (lawns, ornamentals, flower gardens, vegetable gardens, surfaces of buildings, porches, 

patios, etc.), ant baits, fire ant baits, pet spot-on, foggers, Christmas trees, ornamental trees, nonbearing fruit and nut trees, plantations reforestation nurseries, forests, and woodland areas. 

Registered dinotefuran formulations include baits, gels, soluble concentrates, granulars, soluble 

granules, and ready-to-use (RTU) products.

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

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

3.1 Chemical Identity

The chemical structure and nomenclature of dinotefuran and its metabolites DN and UF are 

presented in Table 3.1. Structures of additional metabolites are shown in Appendix C.

TABLE 3.1. Dinotefuran Nomenclature.

Compound Chemical Structure

Common name dinotefuran

Company experimental 

name

MTI-446

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

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

CAS # 165252-70-0

End-Use Products Scorpion 35 SL (EPA Reg. No. 10163-317); Venom (EPA Reg. No. 59639-135)

Compound Chemical Structure

Common name DN

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

N

H

N H

N O H

CH3

N

H

N

N O H

CH3

NO2
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TABLE 3.1. Dinotefuran Nomenclature.

Compound Chemical Structure

Common name UF

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

3.2 Physical/Chemical Characteristics

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

a molecular weight of 202.2 g/mole, a very high water solubility (39,830 ppm), and a low 

octanol/water partition coefficient (KOW = 0.283), suggesting the potential for runoff and low 

bioaccumulation. The low vapor pressure (1.28 x 10-8 mm Hg) and a low Henry’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.

3.3 Pesticide Use Pattern

The Michigan Department of Agriculture and Rural Development requested a Section 18 

emergency specific exemption to use dinotefuran to control the brown marmorated stink bug on 

pome fruit and stone fruit in MI. Dinotefuran will be used on apples, peaches and nectarines on 

up to a total of approximately 40,200 acres in MI. The applications would be made from April 

through November, 2013. The dinotefuran products to be used are Venom Insecticide (EPA 

Reg. No. 59639-135) or Scorpion 35SL (EPA Reg. No. 10163-317).

As shown in Table 3.3 below, the use pattern for the proposed Section 18 on pome and stone 

fruits in MI to control the brown marmorated stink bug is foliar application with ground 

equipment at a maximum application rate of 0.304 lb ai/A with a maximum of two applications 

per season for a total of 0.608 lb ai/A/season. The minimum retreatment interval is 7 days. The 

preharvest interval (PHI) is 3 days. The restricted entry interval (REI) is 12 hours.

N

H

O

N O H

CH3
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Table 3.3. Summary of Proposed Directions for Use of Dinotefuran.

Applic. 

Timing, Type, 

and Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)1, 2

Max. No. 

Applic. 

per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Pome Fruit and Stone Fruit

Foliar;

Broadcast;

Ground 

equipment

Scorpion 

35 SL3

[10163-317]

0.203-

0.304 2 0.608 3 Do not apply until after 

petal fall.

The minimum 

retreatment interval is 7 

days.

The REI is 12 hours.

Venom

70 SG4

[59639-135]

0.179-

0.302 2 0.604 3

1 Scorpion 35SL: Apply 8-12 fl oz/A/application. The formulation contains 3.24 lb ai/gallon. 2 Venom 70 SG: Apply 4-6.75 oz/A/application. The formulation contains approx. 70% ai. 3 SL = soluble liquid. 4 SG/SDG = soluble granule/soluble dispersible granule.

3.4 Anticipated Exposure Pathways

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

from applications in food handling establishments. Humans may also be exposed to dinotefuran 

in drinking water, since application may result in dinotefuran reaching surface and ground water 

sources of drinking water. There are residential uses of dinotefuran, so exposure to dinotefuran 

may occur in residential or non-occupational settings during application and as a result of 

residues present after application. In an occupational setting, handlers may be exposed while 

handling the pesticide prior to application, as well as during application. There is also a potential 

for post-application exposure for workers re-entering treated sites. 

Risk assessments have been completed for the existing uses of dinotefuran. This risk assessment 

considers all of the aforementioned exposure pathways based on the proposed new uses of 

dinotefuran, but also considers existing uses of dinotefuran, 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 and region of the country. Additionally, 
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OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure 

assessments are performed when conditions or circumstances warrant. Whenever appropriate, 

non-dietary exposures based on home use of pesticide products and associated risks for adult 

applicators and for children 3 to < 6 years old, youths and adults entering or playing on treated 

areas post-application are evaluated. Further considerations are currently in development as OPP 

has committed resources and expertise to the development of specialized software and models 

that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

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

acetylcholine receptors. Consistent with its neurotoxic pesticidal mode of action (MOA), 

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

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

and pre-natal developmental toxicity study in rabbits. A summary of the toxicology profile of 

dinotefuran is presented in Appendix A.

4.1 Toxicology Studies Available for Analysis

The toxicology database for dinotefuran is adequate for hazard characterization. Available 

studies include subchronic and chronic oral toxicity studies in rats, mice and dogs, 

developmental toxicity studies in rats and rabbits, a 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%). 
Page 12 of 36

Elimination was rapid with plasma half-life of about 3.6 hours for males and about 2-fold longer 

for female rats at 7.9 hours following a single oral dose of dinotefuran. Upon repeated daily 

dosing, plasma elimination half-life estimates increased slightly to 5.6 hrs for males, but 

remained about the same for females at 6.9 hrs. The predominant species detected in excreta was 

the parent chemical (75-93% of the administered radiolabel) in both oral and IV administration 

studies. Minor metabolites identified accounted for only 2-6% of the administered radiolabel.

The ADME data collected from the single oral dose study with pregnant rats at GD18 suggests 

that dinotefuran readily crosses the placenta as evidenced by parallel profiles exhibited by 

maternal blood and fetal tissues. Peak levels of radioactivity in maternal blood and fetal tissues 

were comparable and both reported at the first time measurement of 0.5 hours. When lactating 

rats at 12 days postpartum were similarly dosed with a single dose of radiolabeled dinotefuran, 

there was also a comparable profile between maternal blood radioactivity content and maternal 

milk; both matrices achieved comparable peak levels at the same first time measurement of 0.5 

hours. The clearance of radioactivity from fetal tissues and milk paralleled that of maternal 

plasma, decreasing by ≥ 80% by 4 hours post-dosing. No measurement of radioactivity was 

made in nursing pups.

PND 12 rat pups exhibited a similar ADME profile following a single oral dose of 50 mg/kg bw 

radiolabeled dinotefuran. Absorption could not be accurately quantified but was noted to be high 

(~80%). The 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.

4.3 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 13 of 36

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

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

weight gain, but even these effects occurred at or near the 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 effects 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 14 of 36

4.4.1 Completeness of the Toxicology Database

The toxicity database for dinotefuran is complete, comprehensive, of good quality and 

considered adequate to support toxicity endpoint selection for risk assessment and for FQPA 

evaluation.

4.4.2 Evidence of 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 and chronic dietary analyses are unrefined analyses using tolerance-level 

residues and assuming100% crop treated. The dietary drinking water assessment utilized water 

concentration values generated by model and associated modeling parameters which are 

designed to provide conservative, health protective, high-end estimates of water concentrations.

HED concludes that the acute and chronic exposure estimates in this analysis are unlikely to 

underestimate actual exposure. The residential exposure assessment uses the 2012 Residential 

SOPs and is considered health-protective.
Page 15 of 36

4.5 Toxicity Endpoint and Point of Departure Selections

The dinotefuran hazard profile was updated in a recent risk assessment (DP391885, B. O’Keefe, 

7/20/12), and nothing has changed since this update. Please refer to that assessment for 

extensive details. The toxicology database is adequate for characterization of hazard. In 

accordance with the EPA’s 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 1 summarizes the toxicological doses and 

endpoints for dinotefuran for use in human health risk assessments. For further details refer to 

Appendix A.

Table 4.5. Summary of Toxicological Doses and Endpoints for Dinotefuran for Use in Human Health Risk 

Assessments

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.

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.
Page 16 of 36

5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

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

Section 18. Metabolism studies in rape, potato, rice, apple, and lettuce were submitted in 

conjunction with an earlier dinotefuran petition, PP#2F06427 (DP285648, L. Cheng, 2/26/04). 

The database is adequate for determining dinotefuran residues of concern. A listing of the 

dinotefuran metabolites/degradates is provided in Appendix C.

Table 5.1. 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

Residue data previously submitted to support a Section 3 on peach and nectarine (D389492, L. 

Cheng, 4/12/12) were used to estimate the Section 18 tolerances on pome and stone fruits.

The residue data are summarized in the following table:

TABLE 5.2. Summary of Residue Data from Peach Crop Field Trials with Dinotefuran.

CommodityAnalyte Total 

App. 

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Foliar Application

Peach Dinotefuran 0.352-

0.365

2-3 12 0.08 0.54 0.09 0.50 0.21 0.25 0.13

UF3 12 <0.01 0.07 0.01 0.07 0.01 0.02 0.02

DN3 12 <0.01 0.05 0.01 0.04 0.01 0.02 0.01

Total Residues 12 <0.11 0.66 0.11 0.62 0.24 0.29 0.16 1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and 

standard deviation, the LOQ (0.01 ppm for all analytes) was used for any results reported as <LOQ in Table C.3 2

 LAFT = lowest average field trial; HAFT = highest average field trial. 3 Residues of UF and DN are reported in parent equivalents as calculated by the study reviewer.

Assuming residues increase proportionally with increasing rate, total residues of 0.66 ppm from 

a seasonal rate of 0.365 lb ai/A would be 1.1 ppm from the proposed seasonal rate of 0.608 lb 

ai/A. A tolerance of 2.0 ppm is adequate.
Page 17 of 36

HED has concluded that no changes are needed to the existing tolerances for livestock

commodities as a result of the proposed Section 18 uses on pome and stone fruits.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the 

Environmental Fate and Effects Division (EFED) in the following memorandum: “ Tier I 

Drinking Water Concentrations for Dinotefuran for Section 3 New Use on Rice” (D397490, J. 

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

were incorporated in the DEEM-FCID into the food categories “water, direct, all sources” and 

“water, indirect, all sources.” 

There are no drinking water monitoring data available on the concentration of parent dinotefuran 

or any of its degradates. EFED provided a Tier 1 dinotefuran drinking water assessment with 

estimated drinking water concentrations (EDWCs) for dinotefuran and its metabolite/degradate 

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

Groundwater EDWCs were obtained with the Tier 1 SCI-GROW model v.2.3 using the turf 

scenario. 

Table 5.3 summarizes the surface water EDWCs for dinotefuran and DN degradate. The peak 

concentration is 269 μg/L and the longer term concentration (≈average) would depend upon 

retention time (10 to 30 days).

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

Dinotefuran on Rice. Based upon total toxic 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 EDWC, obtained using the Tier 1 SCI-GROW, is the same value for the turf 

use and the Section 18 rice use; 4.90 μg/L for both the acute and chronic exposures. Since the 

application rate for turf (1 application at 0.54 lb ai/A) is higher than for rice and since SCIGROW is not site or crop dependent, the resulting water concentration is considered to be 

conservative.

Because the surface water estimates are higher than the groundwater estimates, the surface water 

values, expressed to two significant figures and converted to ppm, were directly incorporated in 

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

sources.” The peak value of 269 ug/L (ppb) was used in the acute assessment and the 10 day 

retention time value of 257 ug/L was used in the chronic assessment.
Page 18 of 36

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data & Percent Crop Treated

The acute and chronic dietary exposure assessments of dinotefuran are unrefined since it is 

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

tolerance-level residues, adjusted for additional residues which are not included in the tolerance 

but are included in the risk assessment. Default processing factors were used as appropriate. 

According to current HED policy, only the chronic dietary assessment included the food 

handling establishment use with 0.01 ppm tolerances for all food commodities without other 

tolerances.

5.4.2 Acute Dietary Risk Assessment

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

from the Tier 1 Rice model v. 1.0 and the 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 3.7% of the acute population-adjusted dose (aPAD), while the most 

highly exposed population subgroup, children 1-2 years old, accounted for 12% of the aPAD.

5.4.3 Chronic Dietary Risk Assessment

Potential residues in drinking water were included in the 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 

subgroups were of concern: the general U.S. population accounted for 1.7% of the chronic 

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

1-2 years old, accounted for 5.7% of the cPAD.

5.4.4 Summary Table

Table 5.4.4. Summary of Dietary (Food and Drinking Water) Exposure and Risk 

for Dinotefuran.

Population Subgroup

Acute Dietary

(95 th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure

(mg/kg/day) % cPAD

General U.S. Population 0.046286 3.7 0.016633 1.7

All Infants (< 1 year old) 0.132460 11 0.047675 4.8
Page 19 of 36

Table 5.4.4. Summary of Dietary (Food and Drinking Water) Exposure and Risk 

for Dinotefuran.

Population Subgroup

Acute Dietary

(95 th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure

(mg/kg/day) % cPAD

Children 1-2 years old* 0.152112 12 0.056650 5.7

Children 3-5 years old 0.099267 7.9 0.037044 3.7

Children 6-12 years old 0.051696 4.1 0.018991 1.9

Youth 13-19 years old 0.031125 2.5 0.011261 1.1

Adults 20-49 years old 0.034765 2.8 0.013944 1.4

Adults 50-99 years old 0.031484 2.5 0.013404 1.3

Females 13-49 years old 0.033791 2.7 0.013432 1.3

*The subpopulation with the highest risk estimates is bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

This document addresses agricultural uses on pome and stone fruits, which will not contribute to 

residential exposure. There are currently registered uses of dinotefuran on several residential use 

sites, including turf, ornamentals, vegetable gardens, pet spot-ons, indoor aerosol sprays, foggers, 

crack and crevice sprays. Each of these existing residential use patterns were reassessed in 

recent HED human health risk assessments using the updated 2012 Residential SOPs and body 

weights (D398048, B. O’Keefe, 8/31/12; DP391885, B. O’Keefe, 7/20/12). The new exposure 

and risk estimates for all residential post-application scenarios resulted in risk estimates that are 

not of concern.

6.1 Residential Handler Exposure

As indicated in Section 4.0, there are no dermal or inhalation toxicity concerns. Therefore, no 

residential handler exposures were assessed.

6.2 Post-Application Exposure

Residential post-application exposures and risk estimates from the existing uses of dinotefuran

are shown in the following tables.

Table 6.2.1 presents these anticipated exposures from the total release fogger and their associated 

risk estimates. Residential incidental oral risk estimates ranged from 1,200 to 13,000, and were 

not of concern to HED. 
Page 20 of 36

Table 6.2.1. Residential Post-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: 

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-tomouth 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 other 

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
Page 21 of 36

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

Liquid 0.54 lb ai/A 0.5 A

Oral hand-to-mouth 0.0079 1.3E+4

Oral object-to-mouth 0.00024 4.1E+5

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

Ant Bait Granular 0.00005 Fraction of ai in 

granular

Oral ingestion of 

granules 0.0011 1.1E+5

RTU Garden 

Trigger 

Sprayer

Liquid 0.042 lb ai/gal 1 gal No post-application 

exposure

NA2 NA

Dog Spot-On Liquid

80.7 mg 

ai/treatment 1 tube

Oral hand-to-mouth

0.00066 1.5E+5

161.6 mg 

ai/treatment 1 tube 0.00057 1.8E+5

193.8 mg 

ai/treatment 1 tube 0.00043 2.3E+5

Cat Spot-On Liquid

192 mg 

ai/treatment 1 tube

Oral hand-to-mouth

0.0019 5.3E+4

320 mg 

ai/treatment 1 tube 0.002 5.1E+4

Indoor 

Broadcast

0.25% 

Aerosol

0.0033 lb 

ai/can or 0.61 

μg ai/cm2 or 

1.24E-6 lb 

ai/ft2

1 20-oz 

can/2646 

ft2

Oral hand-to-mouth on 

carpet 0.0036 2.8E+4

Oral hand-to-mouth on 

hard surface 0.0012 8.3E+4

Object-to-mouth on 

carpet 0.00046 2.2E+5

Object-to-mouth on hard 

surface 0.00034 3.2E+5

Indoor Crack 

& Crevice

0.5% 

Aerosol

0.00626 lb 

ai/can or 0.3 ug 

ai/cm2

NA

Oral hand-to-mouth on 

carpet 0.0018 5.6E+5

Oral hand-to-mouth on 

hard surface 0.00059 1.7E+5

Object-to-mouth on 

carpet 0.00024 4.2E+5

Object-to-mouth on hard 

surface 0.00016 6.4E+5

Dust 0.25 μg ai/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
Page 22 of 36

6.3 Combined Exposure

FQPA requires that residential exposures that could reasonably be expected to occur on the same 

day be combined and compared to the appropriate toxicity endpoint. The exposure estimates 

from use of the total release fogger product are higher than those from other existing residential 

uses. Additionally, co-occurrence with the existing cat spot-on use is possible, since both uses 

can be for the treatment of fleas. Co-occurrence with the existing indoor broadcast use would 

not be probable, because if you 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 combined exposure 

estimate provides the worst case residential exposure estimate and is recommended for use in the 

dinotefuran aggregate risk assessment.

6.4 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation bystander 

exposure assessment was not performed for dinotefuran at this time. Although volatilization of 

pesticides may be a potential source of post-application inhalation exposure to individuals nearby 

to pesticide applications, quantification of short- or intermediate-term inhalation risk is not 

required for dinotefuran because no systemic toxicity or portal of entry effects were seen 

following repeated inhalation exposure at the highest practical concentration obtainable in the 

respirable range.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application (a method proposed to be employed for 

dinotefuran), but, to a lesser extent, could also be a potential source of exposure from the ground 

application method also employed for dinotefuran. The Agency has been working with the 

Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift management practices. On a chemical by 

chemical basis, the Agency is now requiring interim mitigation measures for aerial applications 

that must be placed on product labels/labeling. The Agency has completed its evaluation of the 

new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide 

registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT 

computer model to its risk assessments for pesticides applied by air, orchard airblast and ground 

hydraulic methods. After the policy is in place, the Agency may impose further refinements in 

spray drift management practices to reduce off-target drift with specific products with significant 

risks associated with drift. Also, note that the residential uses of dinotefuran resulted in risk 

estimates of no concern, i.e., incidental oral MOEs range from of 1100 to 5,900,000.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 
Page 23 of 36

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. 

The most recent assessments have considered the changes in the new residential SOPs 

implemented in January of 2012. HED found no changes that would affect the aggregate safety 

finding and confirms that there are no risks of concern resulting from the existing occupational 

and residential uses nor from utilizing the new residential SOPs to estimate residential exposure 

and risk.

7.1 Acute Aggregate Risk

The aggregate acute risk estimates include exposure to residues of dinotefuran in food and 

drinking water, and does not include dermal, inhalation, or other incidental oral exposure. The 

acute risk estimate for the U.S. 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 3.7% of the aPAD for the general U.S. population, and 

12% for the most highly exposed subgroup, children 1-2 years old. 

7.2 Short-Term Aggregate Risk

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

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

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

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

endpoints identified. Therefore, no short-term aggregate assessment is needed for adults. For 

children, the pathways that lead to exposure are dietary oral (background) as well as dermal and 

oral routes. The most conservative exposure estimate for child oral hand to-mouth exposure is 

0.08805 mg/kg/day. For a description of the residential exposure scenarios considered in the 

aggregate assessment, see Section 6.0.

The aggregate MOE for children 1-2 years old is 690, 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 0.056650 0.08805 0.14470 690

1 LOC includes standard inter- (10X) and intra- (10X) species uncertainty factors totaling 100. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral Exposure]. Source of residential exposure values used in aggregate assessment 

(Tables 6.2.1 and 6.2.2).
Page 24 of 36

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

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

7.3 Intermediate-Term Aggregate Risk

Intermediate-term exposure is not expected for the adult residential exposure pathway. 

Therefore, the intermediate-term aggregate risk would be equivalent to the 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.

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.
Page 25 of 36

As previously discussed in Section 4.0, dermal and inhalation exposures were not assessed 

because no hazard was identified.

10.0 References

B. O’Keefe, DP398048, 8/31/12. Dinotefuran: Human Health Risk Assessments for Proposed 

Section 3 Uses on Rice and Food/Feed Handling Establishments, and New Horse Spot-On and 

Total Release Fogger Products.

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

Section 3 Uses on Tuberous and Corm Vegetables Subgroup 1C, Onion Subgroup 3-07A, Onion 

Subgroup 3-07B, Small Fruit Subgroup 13-07F, Berry Subgroup 13-07H, Peach, and Watercress, 

And a Tolerance on Imported Tea.

B. O’Keefe, DP388993, 5/31/11. Dinotefuran ID#: 11VA02 Section 18 Emergency Exemption 

for Use on Pome Fruits and Stone Fruits in Virginia, New Jersey, Pennsylvania, Maryland, 

Delaware, West Virginia, and North Carolina to Control Stink Bugs.

C. Walls, DP398050, 8/20/12. Dinotefuran: Acute and Chronic Aggregate (Food and Drinking 

Water) Dietary Exposure and Risk Assessments for a Section 3 Registration Action on Rice and 

Uses in Food-Handling Establishments.

J. Wolf, J. Hetrick, DP397490, 8/7/12. Tier I Drinking Water Concentrations for Dinotefuran for 

Section 3 New Use on Rice. 

L. Cheng, D389492, 4/12/12. Dinotefuran. Petition for the Establishment of Permanent 

Tolerances on Tuberous and Corm Vegetables Subgroup 1C, Onion Subgroup 3-07A, Onion 

Subgroup 3-07B, Small Fruit Subgroup 13-07F, Berry Subgroup 13-07H, Peach, Watercress, and

Tea (Import). Summary of Analytical Chemistry and Residue Data.
Page 26 of 36

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 27 of 36

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Test Substance 

Guideline No.

Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral, rat 45639823 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

28-Day dermal 

toxicity (rats)

MRID: 45639908, 45639907 (rangefinding) (2001)

Acceptable/Guideline

Systemic: 

NOAEL: 1000 mg/kg/day

LOAEL: Not Established. 
Page 28 of 36

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

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

NOAEL: 1000 [M], ≤200 [F] mg/kg/day

LOAEL: not determined/≤1000 [M/F] 

mg/kg/day based on lack of effects in males, 

and acanthosis/ hyperkeratosis in high dose

females (lower doses not evaluated 

histopathologically).

870.3465

28-Day inhalation 

toxicity (rat)

MRID: 45639909, 46072401 (2002)

Acceptable/Guideline

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

(nose-only); M/F= 0, 60, 179, 565 

mg/kg/day

NOAEL: 2.08 [M/F] mg/L or 565 

mg/kg/day; HDT

LOAEL: not identified

Note: The concentration tested is the highest 

practical concentration obtainable in the 

respirable 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.

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). 
Page 29 of 36

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

Reproductive

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

LOAEL: 822/907 [M/F] mg/kg/day, based 

on decreased uterine weights and 

microscopic alterations in the uterus and 

vagina of 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

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 

MRID: 45640002 (2002)

Acceptable

Negative, ± S9 up to 2002 μg/mL

(Mouse lymphoma L5178Y cells)
Page 30 of 36

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

test

870.5375 

In vitro mammalian 

chromosome 

aberration test

MRID: 45654211 (1996)

Acceptable

Negative for clastogenic/aneugenic activity 

up to 2000 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 

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

VB9304, VB9302 (radiolabeled in the 

guanidine and furan positions) and 22-

00210 & OFU-1265 (unlabeled)

Absorption was > 90% regardless of dose. 

The radiolabel was widely distributed 

through the body and was completely 

excreted within 168 hours of treatment. 

Urine was the primary elimination route, 

accounting for 88-99.8%. Excretion into the 

urine was rapid, being 84-99% complete 

within 24 hours of treatment. Absorption of 

the radioactivity was linear within the dose 

range of 50 and 1000 mg/kg. Elimination of 

radioactivity was fast for all groups with a 

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 
Page 31 of 36

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

milk and fetal tissues was detected 0.5 hours 

after maternal 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 μg/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

Dose: 0, 1120, 2800 or 7000 ppm

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

mg/kg/day

Systemic 

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

LOAEL: Not Established

Immunotoxicity 

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

LOAEL: Not Established

Special study: 

Neonatal rat 

metabolism study 

(12-day old rat pups)

MRID: 45640007

Acceptable/Non-guideline

Dose: 50 mg/kg radiolabeled MTI-446 

(dinotefuran, Lot No. VB9304, labeled on 

the central guanidine portion of the 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
Page 32 of 36

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

finding high radioactive areas in the kidneys 

and bladder by whole body autoradiography. 

No areas of tissue 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 33 of 36

Appendix B. Physical/Chemical Properties

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

Parameter Value Reference (MRID)

Melting point/range 107.5oC 45639702

pH 5.6 @ 25oC 45654201

Density 1.40 g/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 10-6 Pa @ 25oC 45639702

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

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

UV/visible absorption spectrum Media Absorbance 

Maximum 

268 nm

€max: Molar

Absorbance 

Coefficient

45639702

Acidic 1.0469 12,600

1.0180 12,300

Neutral 1.3017 12,500

1.2668 12,300

Basic 0.8869 10,700

0.9662 11,700
Page 34 of 36

Appendix C. Dinotefuran and Metabolites

Common name/code Chemical name Chemical structure

Dinotefuran; MTI-446 N-methyl-N ́-nitro-N ̋-[(tetrahydro3-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 35 of 36

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
Page 36 of 36

Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, including studies from the 

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the 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.

The following studies were reviewed for ethical conduct:

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

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

Agency, and the 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).