Page 3 of 69

5.1.2 Summary of Environmental Degradation .......................................................... 24

5.1.3 Comparison of Metabolic Pathways.................................................................... 24

5.1.4 Residues of Concern Summary............................................................................ 25

5.2 Food Residue Profile .................................................................................................... 25

5.3 Water Residue Profile.................................................................................................. 29

5.4 Dietary Risk Assessment.............................................................................................. 31

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

Assessment........................................................................................................................... 31

5.4.2 Acute Dietary Risk Assessment ........................................................................... 31

5.4.3 Chronic Dietary Risk Assessment ....................................................................... 31

5.4.4 Summary Table..................................................................................................... 31

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 32

6.1 Residential Handler Exposure .................................................................................... 32

6.2 Post-Application Exposure .......................................................................................... 33

6.3 Combined Exposure..................................................................................................... 34

6.4 Residential Bystander Post-Application Inhalation Exposure ................................ 34

6.5 Spray Drift.................................................................................................................... 34

7.0 Aggregate Exposure/Risk Characterization.................................................................. 34

7.1 Acute Aggregate Risk................................................................................................... 35

7.2 Short-Term Aggregate Risk ........................................................................................ 35

7.3 Intermediate-Term Aggregate Risk ........................................................................... 36

7.4 Chronic Aggregate Risk .............................................................................................. 36

7.5 Cancer Aggregate Risk ................................................................................................ 36

8.0 Cumulative Exposure/Risk Characterization ............................................................... 36

9.0 Occupational Exposure/Risk Characterization ............................................................ 36

9.1 Short-/Intermediate-Term Handler Risk................................................................... 37

9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 37

10.0 References......................................................................................................................... 37

Appendix A. Toxicology Profile................................................................................................ 38

A.1 Toxicology Data Requirements................................................................................... 38

A.2 Toxicity Profiles............................................................................................................ 39

A.3 Hazard Identification and Endpoint Selection .......................................................... 44

A.4 Executive Summaries................................................................................................... 47

Appendix B. Physical/Chemical Properties............................................................................. 66

Appendix C. International Residue Limit Status Sheet. ........................................................ 67

Appendix D. Dinotefuran and Metabolites.............................................................................. 68

Appendix E. Review of Human Research................................................................................ 69
Page 4 of 69

1.0 Executive Summary

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

insecticide belonging to the nitroguanidine sub-class of the neonicotiniod class of insecticides. It 

is insecticidal by contact and ingestion, resulting in the cessation of insect feeding within hours 

of contact and death shortly thereafter by interfering with the acetylcholine receptor on the postsynaptic side of the nerve cells.

The Interregional Research Project No. 4 (IR-4) submitted a petition (#1E7863) proposing new 

uses and requesting the establishment of tolerances for the residues of dinotefuran on the 

following crops and crop groups: berry, low growing, except strawberry, subgroup 13-07H; fruit, 

small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F; onion, bulb, subgroup 3-07A; 

onion, green, subgroup 3-07B; vegetable, tuberous and corm, subgroup 1C; peach; and 

watercress. Additionally, the IR-4 petition requested the establishment of a tolerance on 

imported tea.

The most recent human health risk assessment was conducted for a Section 18 use on pome fruits 

and stone fruits to control stink bugs (B. O’Keefe, DP388993, 5/31/11). Since the last risk 

assessment, HED has re-evaluated the dinotefuran toxicological database and updated the hazard 

characterization and dose response assessment. This toxicology database reevaluation has 

resulted in changes to the toxicity endpoints, points of departure, and safety factors for several 

routes of exposure from those presented in previous HED risk assessments.

Use Profile

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

(WDG) formulations (DINOTEFURAN 20SG, EPA Reg. No. 86203-12; STARKLE 70SG,

EPA Reg. No. 86203-23; DINOTEFURAN 70SG, EPA Reg. No. 59639-135) to control 

sucking and chewing insects infesting the following crops and crop groups: low growing berry 

subgroup, except strawberry; small fruit vine climbing, except fuzzy kiwifruit; bulb and green 

onions; peach and nectarine; tuberous and corm vegetables; and watercress. The proposed 

maximum rates are 0.338 lb ai/A per application and per season when applied to the soil using 

ground equipment or 0.18 lb ai/A per application and 0.36 lb ai/A per season when applied to 

the foliage using aerial or ground equipment. The proposed labels also state that “Regardless 

of application method, the maximum application rate is 0.54 lb ai/A/season.” Pre-harvest 

intervals (PHIs) range from 1 to 21 days. Retreatment intervals (RTIs) range from ≥7 to ≥14 

days. For handlers, personal protective equipment (PPE) includes long-sleeved shirt and long 

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

shown in Section 3.3.

Toxicity/Hazard

The toxicology database is adequate for characterization of hazard. The main target of toxicity is 

the nervous system. Nervous system toxicity was manifested as clinical signs and decreased 

motor activity seen after acute dosing (in both rats and rabbits) and changes in motor activity 

which are consistent with effects on the nicotinic cholinergic nervous system seen after repeated 
Page 5 of 69

dosing. Dinotefuran was well tolerated at high doses following dietary administration for ninety 

days to mice, rats and dogs. The principal toxicological findings were decreases in body weight 

and/or body weight gain at or near the Limit Dose. No systemic or neurotoxicity was seen 

following repeated dermal applications at the Limit Dose to rats for 28 days. No systemic or 

portal of entry effects were seen following repeated inhalation 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 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 NOAEL of 

125 mg/kg/day in a developmental toxicity study in rabbits based on clinical signs indicative of 

neurotoxicity (hypoactivity, prone position, panting, tremors) observed at 300 mg/kg/day 

(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 (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).

For incidental oral exposure scenarios, the NOAEL of 99.7 mg/kg/day established in the 

combined chronic toxicity/carcinogenicity study was selected to assess risk from both short-and 

intermediate term exposures. 

Quantification of short- or intermediate-term dermal risk is not required. No systemic toxicity 

was seen at the Limit Dose in an acceptable dermal toxicity study in rats and there are no 

developmental or reproductive toxicity concerns. Additionally, the potential for neurotoxicity 

was evaluated in the dermal study and no treatment-related effects were seen in any of the 

neurological parameters. Further, no increase in toxicity with duration was observed throughout 

the toxicology database for dinotefuran. Therefore, it is reasonable to attribute no hazard to 

intermediate-term exposure based on a 28-day dermal toxicity study.

Quantification of short- or intermediate-term inhalation risk is not required. No systemic toxicity 

or portal of entry effects were seen following repeated inhalation exposure at the highest 
Page 6 of 69

practical concentration obtainable in the respirable range. No effects were seen at doses 

approximately 100,000 times greater than the greatest expected human exposure. Although 

neurotoxicity was not specifically evaluated in this study, effects of increased/decreased motor 

activity, panting, tremor and prone position would be evident with clinical observation if present. 

Since no increase in toxicity with duration was observed throughout the toxicology database for 

dinotefuran this study is also appropriate for intermediate-term inhalation exposure.

Dietary Exposure (Food and Water)

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

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

adjusted dose (aPAD)) for all population subgroups and were estimated at 2.2% of the aPAD for 

the U.S. general population and 5.8% of the aPAD for the most highly exposed population 

subgroup (children 1-2 years 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 level 

of concern (<100% of the chronic population adjusted dose (cPAD)) for all population subgroups

and were estimated at <1% of the cPAD for the U.S. general population and 2.6% 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

All of the existing residential use patterns have been reassessed for residential handler and postapplication exposures using the new residential standard operating procedures (SOPs) and body 

weights used in all human health risk assessments. There are currently registered uses of 

dinotefuran on several residential use sites, including turf, ornamentals, vegetable gardens, pets, 

indoor aerosol sprays, crack and crevice sprays, etc. Short-term incidental oral exposures were 

assessed using the short-term point of departure of 99.7 mg/kg/day. The new exposure and risk 

estimates for all residential post-application scenarios are not of concern to HED (MOEs ranged 

from 1100 to 5,900,000).

Aggregate Exposure

The aggregate acute and chronic dietary risk estimates for all populations, resulting from 

aggregate exposure to dinotefuran in food and drinking water are not of concern. For children, a 

short-term aggregate risk assessment was performed for the post-application scenario resulting in 

the greatest exposure, resulting in a MOE of 3,000, which is greater than 100, and therefore not 

of concern. For adults, no aggregate risk assessment was performed, since no toxicity endpoints 

were identified for 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.
Page 7 of 69

Occupational post-application dermal exposures are possible following applications to the 

proposed crops. However, since no hazard was identified for the dermal route of exposure

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 has a Toxicity Category IV for acute dermal, primary skin irritation, and 

primary eye irritation. Per the Worker Protection Standard (WPS), a 12 hour restricted entry 

interval (REI) is required for chemicals classified under Toxicity Category IV. Therefore, the 

REI of 12 hours appearing on the proposed dinotefuran label is adequate.

2.0 HED Recommendations

HED recommends the registration request be granted for dinotefuran use on berry, low growing, 

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

subgroup 13-07F; onion, bulb, subgroup 3-07A; onion, green, subgroup 3-07B; vegetable, 

tuberous and corm, subgroup 1C; peach; and watercress. Additionally, HED recommends the 

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

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

tolerance revisions requested in Section 2.2.3. 

2.1 Data Deficiencies/Prior Conditions of Registration

There are no data deficiencies at this time.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method 

Parent dinotefuran and the metabolites DN and UF are the residues of concern in plant 

commodities for tolerance setting purpose. There are analytical methods available for 

enforcement: a high performance liquid chromatography/tandem mass spectrometry 

(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.

Dinotefuran is the residue of concern in livestock commodities for tolerance setting. A liquid 

chromatography/mass spectrometry/ mass spectrometry (LC/MS/MS) method is adequate for the 

determination of residues of dinotefuran, DN, and UF in livestock commodities. Method 

validation data demonstrated acceptable recoveries of dinotefuran and its metabolites DN and UF 
Page 8 of 69

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

adequate for tolerance enforcement. 

Dinotefuran is not adequately recovered using any of FDA’s multi-residue methods. Although 

no multi-residue method data have been submitted for the DN and 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. An International Residue Limits (IRL) Status sheet is attached to this 

review as Appendix C.

2.2.3 Recommended Tolerances 

Pending submission of a revised Section F, there are no residue chemistry issues that will 

preclude establishment of permanent tolerances for dinotefuran in/on the following crops or crop 

groups/subgroups:

Table 2.2.3. Tolerance Summary for Dinotefuran.

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments (correct commodity definition)

Berry, low growing, 

except strawberry, 

subgroup 13-07H

0.2 0.2

Fruit, small, vine 

climbing, except fuzzy 

kiwifruit, subgroup 13-

07F

0.9 0.9

A revised Section F must be submitted to 

delete the grape tolerance at 0.9 ppm. Fruit, 

small vine climbing, except fuzzy kiwifruit, 

subgroup 13-07F

Onion, bulb, subgroup 

3-07A 0.07 0.15 A revised Section F must be submitted to 

propose a tolerance at 0.15 ppm.

Onion, green, subgroup 

3-07B

6.0 5.0 A revised Section F must be submitted to 

propose a tolerance at 5.0 ppm.

Peach 0.9 1.0 A revised Section F must be submitted to 

propose a tolerance at 1.0 ppm.

Tea, plucked leaves 25 50 Tea, dried

Vegetable, tuberous and 

corm, subgroup 1C

0.05 0.05 A revised Section F must be submitted to 

delete the potato tolerance at 0.05 ppm.

Watercress 5.0 8.0 A revised Section F must be submitted to 

propose a tolerance at 8.0 ppm.

Note to RD: Concomitant with the establishment of crop group tolerances for the small fruit 

subgroup 13-07F and tuberous and corm vegetable subgroup 1C, the individual tolerances 

already established in/on grape and potato should be deleted.
Page 9 of 69

2.2.4 Revisions to Petitioned-For Tolerances

Adequate field trial data are available to support this petition. HED concurs with the tolerance 

level of 0.2 ppm for the low growing berry (except strawberry) subgroup 13-07H as proposed by 

the registrant. HED concurs with the registrant’s proposal for the establishment of tolerances for 

the tuberous and corm vegetable subgroup 1C at 0.05 ppm and for the small fruit except fuzzy 

kiwifruit subgroup 13-07F at 0.9 ppm, and concomitant removal of the tolerances for potato and 

grape. Use of the Organization for Economic Cooperation and Development tolerance

calculation procedures indicates that the tolerances for residues in/on the onion subgroup 3-07A, 

onion subgroup 3-07B, peach, and watercress should be established at 0.15 ppm, 5.0 ppm, 1.0 

ppm, and 8.0 ppm, respectively, instead of those values proposed by the registrant. 

For imported tea, the ChemSAC (ChemSAC Meeting Minutes, 3/7/12) noted that residue decline 

studies were conducted. The ChemSAC decided that two tea trials were sufficient for setting a

tolerance on import tea, and the level should be based on dried tea leaves. From the study report 

it was unclear whether the tea samples analyzed for residues had been dried beforehand. An 

answer was provided through a contact with a JMPR colleague in Japan. According to a string 

of email correspondence, the tea leaves in Japan are routinely dried before residue analysis. This 

information agrees well with a phrase of “covered with the sunshade for 10 days before gather” 

stated in the table of results of the “Dinotefuran: Pesticide Residue Analysis in Tea”, IR-4 PR 

No. 10838. Application of the OECD tolerance calculation procedure to the four residue values 

available (duplicate sample analysis from two trials) results in a recommended tolerance level of

50 ppm. The ChemSAC concurs with the calculator result. The ChemSAC also concluded that 

since dried tea is the commodity in commerce, the proper commodity definition should be tea, 

dried. Additionally, HED notes that the use pattern must stipulate a seasonal maximum rate of 

0.356 lb ai/A (0.4 kg/ha) with a 7-day PHI. 

2.3 Petition Recommendations 

860.1550 Proposed Tolerances

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

Table 2.2.3.

2.4 Label Recommendations

2.4.1 Recommendations from Residue Reviews

OPPTS 860.1200 Directions for Use

The petitioner must submit proposed labels (with English translations) for dinotefuran 

use on tea in any country from which the treated tea may be imported into the U.S. The 

available data support application of an SG formulation at a seasonal rate of 0.356 lb ai/A 

(0.4 kg/ha) with a 7-day retreatment interval (RTI) and a 7-day pre-harvest interval 

(PHI). 
Page 10 of 69

With the exception of the cranberry and watercress trials, crop field trials were conducted 

without an adjuvant added in the spray mixtures. Thus, a statement is needed on the label 

that prohibits use of adjuvants when applications are made to the proposed crops except 

cranberry and watercress. For cranberry and watercress, the label needs to specify that a 

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

respectively.

For the EPA Reg. No. 59639-135, the 70SG label, the petitioner needs to revise the PHI 

for soil application to peach and nectarine from 3 days to 21 days, since there are only 

soil residue data for the 21-day PHI.

3.0 Introduction

Dinotefuran is a broad-spectrum insecticide belonging to the nitroguanidine sub-class of the 

neonicotiniod class of insecticides. It is insecticidal by contact and ingestion, resulting in the 

cessation of insect feeding within hours of contact and death shortly thereafter by interfering 

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. Dinotefuran formulations 

include baits, gels, soluble concentrates, granulars, soluble granules, and ready-to-use (RTU) 

products, including total-release foggers and RTU sprays. 

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

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

establishment of tolerances for the residues of dinotefuran on the following crops and crop 

groups: berry, low growing, except strawberry, subgroup 13-07H; fruit, small, vine climbing, 

except fuzzy kiwifruit, subgroup 13-07F; onion, bulb, subgroup 3-07A; onion, green, subgroup 

3-07B; vegetable, tuberous and corm, subgroup 1C; peach; and watercress. Additionally, the IR4 petition requested the establishment of a tolerance on imported tea.

The proposed uses of dinotefuran are expected to result in occupational exposure only; no 

residential exposure is expected from the proposed uses of dinotefuran. Only short- and 

intermediate-term occupational exposures were assessed for the proposed uses of dinotefuran. 
Page 11 of 69

3.1 Chemical Identity

The chemical structure and nomenclature of dinotefuran are 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 Product DINOTEFURAN 20SG (EPA Reg. No. 86203-12), STARKLE 70SG (EPA Reg. No. 86203-

23), DINOTEFURAN 70 SG (EPA Reg. No. 59639-135)

Compound Chemical Structure

Common name DN

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

Compound Chemical Structure

Common name UF

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

N

H

O

N

O H

CH3

N

H

N H

N

O H

CH3

N

H

N

N

O H

CH3

NO2
Page 12 of 69

3.2 Physical/Chemical Characteristics

The physicochemical properties of dinotefuran are summarized in Appendix B. 

3.3 Pesticide Use Pattern

The IR-4, on behalf of the Agricultural Stations of HI, FL, OR, MA, UT, GA, NJ, MI, SC, ID, 

TX, OK, and NM, submitted a petition (#1E7863) requesting the establishment of tolerances 

for the residues of dinotefuran on berry, low growing, except strawberry, subgroup 13-07H;

fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F; onion, bulb, subgroup 3-

07A; onion, green, subgroup 3-07B; peach; watercress; and vegetable, tuberous and corm, 

subgroup 1C. 

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

(WDG) formulations (DINOTEFURAN 20SG, EPA Reg. No. 86203-12; STARKLE 70SG, EPA 

Reg. No. 86203-23; DINOTEFURAN 70SG, EPA Reg. No. 59639-135) to control sucking and 

chewing insects infesting low growing berry subgroup, except strawberry; small fruit vine 

climbing, except fuzzy kiwifruit; bulb and green onions; peach and nectarine; tuberous and corm 

vegetables; and watercress. Dinotefuran is proposed for foliar application by ground or aerial 

methods. Additionally it is proposed for application to soil for onions and peaches. For 

handlers, PPE includes long-sleeved shirt and long pants, shoes plus socks, and chemical 

resistant gloves. There is a rotational crop restriction that imposes a 120-day plant-back interval 

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

directions for use.
Page 13 of 69

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

Applic. 

Timing, 

Type, and 

Equip.

Formulation 

[EPA Reg.

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. 

Rate 

(lb ai/A)

PHI 

(days)

Use Directions and Limitations

Onion, bulb and green: (bulb) – Daylily, Fritillaria, Garlic, Garlic (Great-headed, serpent), Lily, Onion, Onion (Chinese, pearl, 

potato), Shallot, and Cultivars of these; (green) – Chive (fresh leaves), Chive (Chinese, fresh leaves), Elegans hosta, Fritillaria 

leaves, Kurrat, Leady’s leek, Leek, Leek (wild), Onion (Beltsville bunching), Onion (fresh), Onion (green), Onion (macrostem), 

Onion (tree, tops), Onion (Welsh, tops), Shallot (fresh leaves), Cultivars of these 

Foliar,

Broadcast

Ground and 

Aerial

Soil, Ground

20% SG

[86203-12]

70% SG

[86203-23]

70% SG

[59639-135]

0.09-0.18 

(foliar)

0.225-

0.27 

(soil)

Not 

specified 

(NS)

0.27 

(foliar)

0.27 (soil)

1 

(foliar)

NS 

(soil)

Begin applications when first pest activity is 

noticed or when insects reach threshold levels. 

Apply at 7-day retreatment intervals. 

Applications may be made in a minimum of 5 

gal/A by air and 20 gal/A by ground.

Apply at planting or immediately after 

transplanting in a minimum of 10 gal/A.

Regardless of application method, the

combined (soil & foliar) maximum seasonal 

rate is 0.383 lb ai/A/season.

Small Fruit Vine Climbing, Except Fuzzy Kiwifruit; also known as Berry and Small Fruit (Subgroup 13-07F): Amur river 

grape, Gooseberry, Grape, Kiwifruit hardy, Maypop, Schisandra berry, Cultivars, Varieties and/or hybrids of these

Foliar,

Broadcast

Ground, 

Aerial, and 

Airblast

20% SG

[86203-12]

70% SG

[86203-23]

70% SG

[59639-135]

0.045 -

0.135 

(foliar)

0.225 –

0.338 

(soil)

NS (foliar)

1 (soil)

0.27 

(foliar)

0.338 (soil)

1 

(foliar)

28 

(soil)

Begin applications when first pest activity is 

noticed or when insects reach threshold levels. 

Apply at 14-day retreatment intervals. 

Applications may be made in a minimum of 5 

gal/A by air and 50 gal/A by ground. 

Regardless of application method, the 

combined (soil & foliar) maximum application 

rate is 0.54 lb ai/A/season. 

Low Growing Berry Subgroup, Except Strawberry; also known as Berry and Small Fruit (Subgroup 13-07H): Bearberry, 

Bilberry, Blueberry lowbush, Cloudberry, Cranberry, Lingonberry, Muntries, Partridgeberry, Cultivars of these

Foliar,

Broadcast

Ground, 

Aerial, and 

Airblast

20% SG

[86203-12]

70% SG

[86203-23]

70% SG

[59639-135]

0.09-0.18 

(foliar) NS 0.36 7

Begin applications when first pest activity is 

noticed or when insects reach threshold levels. 

Apply at 14-day retreatment intervals. 

Applications may be made in a minimum of 5 

gal/A by air and 30 gal/A by ground. 

Peach and Nectarine

Foliar,

Broadcast

Ground, 

Aerial, and 

Airblast

Soil, Ground

20% SG

[86203-12]

70% SG

[86203-23]

70% SG

[59639-135]*

0.090-

0.18 

(foliar)

0.27 

(soil)

NS 0.27 

(foliar)

0.27 (soil)

3 

(foliar)

21 

(soil)

Begin applications when first pest activity is 

noticed or when insects reach threshold levels. 

Apply at 7-day retreatment intervals. 

Applications may be made in a minimum of 5 

gal/A by air and 50 gal/A by ground. 

For soil treatment, apply in a minimum of 100 

gal/A. Regardless of application method, the 

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

Regardless of application method, the

combined (soil & foliar) maximum application 

rate is 0.36 lb ai/A/season. 
Page 14 of 69

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

Applic. 

Timing, 

Type, and 

Equip.

Formulation 

[EPA Reg.

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. 

Rate 

(lb ai/A)

PHI 

(days)

Use Directions and Limitations

Tuberous and Corm Vegetables (Subgroup 1C): Arracacha, Arrowroot, Artichoke, Chinese, Artichoke, Jerusalem, Cana, 

edible, Cassava, bitter and sweet, Chayote (root), Chufs, Dasheen (taro), Ginger, Leren, Potato, Sweet Potato, Tanier, Turmeric, 

Yam bean, Yam, true

Foliar,

Broadcast

Ground, 

Aerial, and 

Airblast

20% SG

[86203-12]

70% SG

[86203-23]

70% SG

[59639-135]

0.045 -

0.068 

(foliar)

0.293 –

0.338 

(soil)

NS (foliar)

NS (soil)

0.203 

(foliar)

0.338 (soil)

7 

(foliar)

NS 

(soil)

Do not combine foliar applications with soil 

applications, or vice versa. Only use one 

application method. Begin applications when 

first pest activity is noticed or when insects 

reach threshold levels. Apply at 14-day 

retreatment intervals. Applications may be 

made in a minimum of 3 gal/A by air and 10 

gal/A by ground. 

Watercress

Foliar,

Broadcast

Ground and 

Aerial

20% SG

[86203-12]

70% SG

[86203-23]

70% SG

[59639-135]

0.09-0.18 NS 0.36 1

Begin applications when first pest activity is 

noticed or when insects reach threshold levels. 

Apply at 7-day retreatment intervals. 

Applications may be made in 5-10 gal/A by air 

and 50-300 gal/A by ground. 

* Label indicates a 3-day PHI for soil application.

3.4 Anticipated Exposure Pathways

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

proposed new uses of dinotefuran on the low growing berry subgroup, except strawberry; small 

fruit vine climbing, except fuzzy kiwifruit; bulb and green onions; peach and nectarine; tuberous 

and corm vegetables; and watercress; and the import tolerance for tea. Humans may be exposed 

through their diet from applications to agricultural commodities. 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. 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. 
Page 15 of 69

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part 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 Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for children 3 to < 6 years old, youths and adults entering or playing on treated areas postapplication 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 also affected as 

demonstrated in the acute neurotoxicity (ACN), subchronic neurotoxicity (SCN) studies in rats, 

and developmental toxicity study in rabbits.

4.1 Toxicology Studies Available for Analysis

The toxicology database for dinotefuran is adequate for the characterization of its hazard. 

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

developmental toxicity studies in rats and rabbits, a reproductive toxicity study in rats, acute and 

subchronic neurotoxicity 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 
Page 16 of 69

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 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, probably reflective of the predominant 

route of excretion being via the urine ( 93%). Elimination was rapid with plasma half-life of 

about 3.6 hours for males and about 2-fold longer for female rats at 7.9 hours following a single 

oral dose of dinotefuran. Upon repeated daily dosing, plasma elimination half-life estimates 

increased slightly to 5.6 hrs for males, but remained about the same for females at 6.9 hrs. The 

predominant species detected in excreta was 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 and at the same first time measurement of 

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

plasma, decreasing by 80% by 4 hours post-dosing. No measurement of 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 
Page 17 of 69

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

The main target of toxicity is the nervous system. Nervous system toxicity was manifested as 

clinical signs and decreased motor activity seen after acute dosing (in both rats and rabbits) and 

changes in motor activity which are consistent with effects on the nicotinic cholinergic nervous 

system seen after repeated dosing. In the subchronic neurotoxicity study (SCN), increased motor 

activity and habituation was observed at the mid-dose while decreased activity was observed at 

the high-dose. Typically, low to moderate activation of nicotinic acetylcholine receptors 

(nAChR) causes stimulation of the peripheral nervous system (PNS). Whereas high levels of 

neonicotinoids (agonists) can over stimulate the PNS, maintaining cation channels in the open 

state which blocks the action potential and leads to paralysis. It is pertinent to note that the 

developing nervous system is not more sensitive to the effects of dinotefuran than the adult 

nervous system; no neurotoxic effects were observed in offspring exposed to dinotefuran 

perinatally (maternal doses: 748 mg/kg/day, gestation; 1643 mg/kg/day, lactation).

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

mice, rats and dogs. The principal toxicological findings were decreases in body weight and/or 

body weight gain at or near the Limit Dose. Changes in spleen and thymus weights were seen in 

mice, rats and dogs following subchronic and chronic 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 

data base contains immunotoxicity studies in mice and rats and a developmental immunotoxicity 

study in rats. In the immunotoxicity studies there were no effect on T-cell dependent antibody 

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

female rats. There were no changes in spleen and thymus weight and there were no 

histopathological lesions in these organs in those studies. In the developmental immunotoxicity 

study, there was no evidence of an effect on the functionality of the immune system in rats that 

were exposed to dinotefuran at the Limit Dose during the prenatal, postnatal, and post-weaning 

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

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

No systemic or neurotoxicity was seen following repeated dermal applications at the Limit Dose 

to rats for 28 days. No systemic or portal of entry effects were seen following repeated 

inhalation exposure at the maximum obtainable concentrations to rats for 28 days. 
Page 18 of 69

In the pre-natal studies, no maternal or developmental toxicity was seen at the Limit Dose in rats. 

In rabbits, maternal toxicity manifested as clinical signs of neurotoxicity but no developmental 

toxicity was seen. In the reproduction study, parental, offspring, and reproductive toxicity was 

seen at the Limit Dose. Parental toxicity included decreased body weight gain, transient decrease 

in food consumption, and decreased thyroid weights. Offspring toxicity was characterized as 

decreased forelimb grip strength or hindlimb grip strength in the F1 pups. There was no adverse 

effect on reproductive performance at any dose. In the developmental neurotoxicity study, no 

maternal or offspring toxicity was seen at any dose including the Limit Dose.

There was no evidence of carcinogenicity in male and female mice and in male and female rats 

fed diets containing dinotefuran at the Limit Dose for 78 weeks to mice and 104 weeks to rats. 

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

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

Based on the hazard and exposure data, the dinotefuran risk assessment team has recommended 

that the FQPA Safety Factor be reduced to 1X. The rationale for this recommendation is 

provided in the following sections.

4.4.1 Completeness of the Toxicology Database

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

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

evaluation.

4.4.2 Evidence of Neurotoxicity

The neurotoxic potential of dinotefuran has been adequately considered. Dinotefuran is a 

neonicotinoid and has a neurotoxic mode of pesticidal action. Consistent with the mode of 

action, changes in motor activity was seen in repeat-dose studies, including the subchronic 

neurotoxicity study (SCN). Additionally, decreased grip strength and brain weight was observed 

in the offspring of a multi-generation reproduction study albeit at doses close to the limit dose. 

For these reasons, a developmental neurotoxicity (DNT) study was required. Upon submission 

of the DNT, it was concluded that there is no evidence of a unique sensitivity to the developing 

nervous system since no effects on neurobehavioral parameters were seen in the offspring at 

doses that approached or exceeded the Limit Dose.

4.4.3 Evidence 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 
Page 19 of 69

toxicity was seen. In the reproduction study, offspring toxicity characterized as decreased 

forelimb grip strength or hindlimb grip strength in the F1 pups was seen at the same dose (Limit 

Dose) that caused parental toxicity (decreased body weights). The concern is low for the 

observed qualitative increase in sensitivity since the 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 and 100% crop 

treated assumptions for all commodities. The chronic dietary analysis included tolerance level 

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

minimum pre-harvest intervals (PHIs). The dietary drinking water assessment utilized water 

concentration values generated by model and associated modeling parameters which are 

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

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

underestimate actual exposure. 

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

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

scenarios are presented in the Appendix A. Briefly, neurotoxic effects are the most sensitive 

endpoint (seen in rabbits and rats). Beyond neurotoxicity, the only other consistently observed 

effect (in all species) is decreased body weight gain (≤ 10%) which in the absence of body 

weight decrements per se was not regarded as biologically significant or adverse even at nearLimit Doses. The toxicological database indicates that dinotefuran toxicity does not progress 

with duration of exposure (i.e., NOAELs/LOAELs are not lower with longer exposure durations 

nor are the effects seen progressed in severity).

The Agency has selected Points of Departures (PODs) based on the most sensitive toxicological 

endpoint of concern observed in the most sensitive species for assessing risks via dietary and 

non-dietary exposure scenarios. 

For the general population, an acute Reference Dose (aRfD) of 1.25 mg/kg/day was derived from 

a maternal NOAEL of 125 mg/kg/day and the application of an Uncertainty Factor of 100 which 

includes 10X for inter-species extrapolation and intra-species variation. The NOAEL was 

established in a developmental toxicity study in rabbits based on clinical signs indicative of 
Page 20 of 69

neurotoxicity (hypoactivity, prone position, panting, tremors) observed at 300 mg/kg/day 

(LOAEL). This study/endpoint is appropriate for assessing acute dietary risk since the signs 

were seen following administration of the first dose on Gestation Day 6. This PoD would 

address the concern for the decreased motor activity seen on Day 1 in females at 750 mg/kg/day 

and in males at 1500 mg/kg/day in the acute neurotoxicity study.

In previous risk assessments, decreased thymus weight seen in the chronic toxicity study in dogs 

was selected as the toxicity endpoint for chronic exposure. Since then, immunotoxicity studies 

in mice and rats as well as a developmental immunotoxicity study were submitted and reviewed 

by the Agency. In the immunotoxicity studies there were no effects on T-cell dependent 

antibody response (TDAR) at the Limit Dose in male and female mice and in male and female 

rats. There were no changes in spleen and thymus weight and there were no histopathological 

lesions in these studies. In the developmental immunotoxicity study, there was no evidence of 

an effect on the functionality of the immune system in rats that were exposed to dinotefuran at 

the Limit Dose during the prenatal, postnatal, and post-weaning periods in a developmental 

immunotoxicity study. Consequently, the thymus weight changes seen in the dog study were not 

considered to be toxicologically relevant and appropriate for endpoint selection/risk assessment.

A chronic RfD of 1.0 mg/kg/day was derived from a NOAEL of 99.7 mg/kg/day (chronic 

toxicity/carcinogenicity study in rats) and the application of an Uncertainty Factor of 100, which 

includes 10X for inter-species extrapolation and 10X for intra-species variation. The NOAEL 

was established based on decreased body weight gain, and food efficiency in females and 

increased incidences of kidney pelvic mineralization and ulceration in males at 991 mg/kg/day 

(LOAEL). This study/endpoint is appropriate for this exposure scenario since the effects of 

concern were seen following chronic exposure in the most sensitive species. This NOAEL 

would also address the concern for the decreased motor activity seen in rats at 327 mg/kg/day in 

the subchronic neurotoxicity study as well as the clinical signs of neurotoxicity (prone position, 

panting, tremors) seen at 300 mg/kg/day in the does in the pre-natal developmental toxicity study 

with rabbits. 

For incidental oral exposure scenarios, the NOAEL of 99.7 mg/kg/day established in the 

combined chronic toxicity/carcinogenicity was selected to assess risk from both short-and 

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

established based decreased motor activity seen in two weeks at 327 mg/kg/day in the subchronic 

neurotoxicity (SCN) study. This study with a lower NOAEL was not selected for these exposure 

scenarios because the lower NOAEL in the SCN is an artifact of dose selection. The higher 

NOAEL would still be protective of the neurotoxicity seen not only in the SCN but also the 

clinical signs of neurotoxicity (prone position, panting, tremors) seen at 300 mg/kg/day in does 

in the developmental toxicity study and the decreased motor activity seen in female rats at 750 

mg/kg/day in the acute neurotoxicity study. The pattern of motor activity seen with single and 

repeated exposure is consistent with the neonicotinic mode of action. Thus, the selected PoD 

would protect for neurotoxicity, the principal toxicological effect of dinotefuran. This endpoint 

is appropriate for the population (infants and children) and durations (short to intermediate term) 

of concern since the decrease in motor activity was seen two weeks after initiation of treatment 
Page 21 of 69

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

database. The Level of Concern is a Margin of Exposure of 100 which includes 10X for interspecies extrapolation and 10X for intra-species variation. 

Quantification of dermal and inhalation risks were not required since no systemic toxicity or 

neurotoxicity was seen following repeated dermal applications at the Limit Dose in a 28-day 

dermal toxicity study in rats and no systemic or portal of entry effects following repeated 

inhalation exposures at the highest practical concentration obtainable in a 28-day inhalation 

toxicity study in rats. Furthermore, the inhalation NOAEL (2.08 mg/L or 565 mg/kg/day) 

represents an exposure approximately 105times greater than the maximum human exposure via 

inhalation for registered and currently proposed uses (5.85 x10-3 mg/kg/day for belly grinder 

application of granular formulations). Additionally, there are no concerns for developmental or 

reproductive toxicity. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregate 

risk assessment must consider exposures from three major sources: oral, dermal and inhalation 

exposures. In the case of dinotefuran, dermal and inhalation risk assessments are not performed 

as there is no identifiable hazard via these routes of exposure at excessive dose.

4.5.3 Cancer Classification and Increased Tumor Incidence Risk Assessment 

Recommendation

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

Dinotefuran is classified as “Not Likely to be Carcinogenic to Humans” based on the lack of 

evidence for carcinogenicity in mice and rats. 

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

Assessment

The most recent human health risk assessment was conducted for a Section 18 use on pome fruits 

and stone fruits to control stink bugs (B. O’Keefe, DP388993, 5/31/11). Since the last risk 

assessment, HED has re-evaluated the dinotefuran toxicological database and updated the hazard 

characterization and dose response assessment. This toxicology database re-evaluation has 

resulted in changes to the toxicity endpoints, points of departure, and safety factors for several 

routes of exposure from those presented in previous HED risk assessments. Table 4.5.4.1 

summarizes these changes. For further details refer to Appendix A.
Page 22 of 69

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Dinotefuran for Use in Dietary Human 

Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

Acute Dietary 

(General Population, 

including Infants 

and Children)

NOAEL=125 

mg/kg/day

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 in does (prone 

position, panting, tremor and 

erythema) seen following the first 

dose on Gestation Day 6.

Chronic Dietary (All 

Populations)

NOAEL=99.

7 mg/kg/day

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.

5.0 Dietary Exposure and Risk Assessment 

References: 

- Dinotefuran: Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk 

Assessments for a Section 3 Registration Action on Tuberous and Corm Vegetables Subgroup 1C, Onion 

Subgroup 3-07A, Onion Subgroup 3-07B, Small Fruit Subgroup 13-07F, Berry Subgroup 13-07H, Peach, 

Watercress, and Tea (Import). C. Walls, DP391889, 7/17/12. 

- Tier I Human Health Drinking Water Assessment of Dinotefuran and its Transformation Products of 

Concern (MNG, DN, UF and DN-2-OH + DN-3-OH) in Support of Proposed IR-4 New Uses (Onion, Bulb 
Page 23 of 69

and Green; Berry and Small Fruit; Tuberous and Corm Vegetables; Peach; and Watercress). R. Parker, 

DP394848, 12/12/11. 

- Dinotefuran. Petition for the Establishment of Permanent Tolerances on Tuberous and Corm Vegetables 

Subgroup 1C, Onion Subgroup 3-07A, Onion Subgroup 3-07B, Small Fruit Subgroup 13-07F, Berry 

Subgroup 13-07H, Peach, Watercress, and Tea (Import). Summary of Analytical Chemistry and Residue 

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

5.1 Metabolite/Degradate Residue Profile

5.1.1. Summary of Plant and Animal Metabolism Studies

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

the IR-4 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 is provided in Appendix D.

Primary Crops

The nature of the residue in plants is adequately understood. Metabolism was found to be 

similar in the crops studied (rape, potato, rice, apple, and lettuce) and proceeds through 

hydrolysis of the nitroimino moiety of dinotefuran, loss of the nitro group, intra-molecular ring 

formation, and tetrahydrofuran ring hydroxylation and ring opening. Parent dinotefuran and the 

metabolites DN and UF are the residues of concern in plant commodities for tolerance setting 

purpose, and dinotefuran, DN, UF and PHP are the residues of concern for risk assessment 

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

Rotational Crops

In a previously submitted petition, PP#2F06427 (DP285648, L. Cheng, 2/26/04), the petitioner 

did not propose a metabolic profile for rotational crops; however, metabolites that were 

identified in rotational crop commodities were consistent with those identified in primary crops. 

Based on the results of the study, the petitioner concluded that no dinotefuran residues of 

concern would accumulate at levels >0.01 ppm in rotational crops planted 120 days after 

treatment. If the plant back interval of 120 days is shortened in the future, additional rotational 

crop data will be required. 

Livestock 

Adequate metabolism studies with dinotefuran on ruminants and laying hens were submitted in 

PP#2F06427. The metabolism of dinotefuran was observed to be similar in the goat and hen 

studies. The primary metabolic pathways of dinotefuran in plants were also found similar to 

those described for livestock, with certain extensions of the pathway in plants. Dinotefuran is 

the residue of concern in livestock commodities for tolerance setting. For risk assessment, parent 

and metabolites UF and FNG are the residues of concern in ruminants, and parent and metabolite 

FNG are the residues of concern in poultry (MARC report, TXR #0052304, DP293759, L. 

Cheng, 1/20/04).
Page 24 of 69

5.1.2 Summary of Environmental Degradation

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

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

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

Constant (8.63 x 10-14 Atm • 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.

5.1.3 Comparison of Metabolic Pathways

In rats after intravenous (IV) or oral treatment, 75-93% of the administered radiolabeled test 

material, or nearly 93-97% of total urinary radiolabel dinotefuran, was excreted unchanged in the 

urine. The parent compound was also the primary component in the plasma, milk, bile, feces, 

and most tissues collected 4-8 hours after treatment and at both dose levels. Less than 10% of 

the parent compound was metabolized into numerous minor metabolites that were not well 

resolved by HPLC or 2D-thin layer chromatography (TLC).

In plants, dinotefuran is metabolized through hydrolysis of the nitroimino moiety of dinotefuran, 

loss of the nitro group, intra-molecular ring formation, and tetrahydrofuran ring hydroxylation 

and ring opening. Parent dinotefuran and the metabolites DN, UF, and PHP are the major 

metabolites identified in plant commodities.

In livestock, dinotefuran is metabolized in a manner similar to that in plants with certain 

extensions of the pathway in plants. Parent dinotefuran and metabolites UF and FNG are the

major metabolites identified in ruminants, and parent dinotefuran and metabolite FNG are the 

major metabolites identified in poultry.
Page 25 of 69

5.1.4 Residues of Concern Summary 

Table 5.1.4. Residues of Concern in Crops, Livestock, Rotational Crops, and Water

Matrix Residues for Tolerance Expression Residues for Risk Assessment

Plants Dinotefuran, DN, UF Dinotefuran, DN, UF, and PHP

Ruminants Dinotefuran Dinotefuran, UF, FNG

Poultry Dinotefuran Dinotefuran, FNG

Rotational Crops Not Needed1 Not Needed1

Drinking Water Not applicable Dinotefuran, MNG, DN, UF, DN-2-OH, and 

DN-3-OH

1

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

5.2 Food Residue Profile

Adequate residue data are available to support dietary risk assessment as well as the proposed 

tolerances/expansions of crop groups/subgroups of the insecticide dinotefuran in/on berry, low 

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

subgroup 13-07F; onion, bulb, subgroup 3-07A; onion, green, subgroup 3-07B; vegetable, 

tuberous and corm, subgroup 1C; peach; watercress; and imported tea.

The submitted residue data for bulb onion, green onion, cranberry, peach, watercress, and tea are 

adequate to fulfill data requirements. The number and locations of the field trials are in 

accordance with OCSPP Guideline 860.1500 for bulb onion, green onion, cranberry, peach, 

watercress, and tea. Field trials were conducted at ~1x the proposed maximum seasonal rate and 

samples were harvested at the proposed PHI for all crops.

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

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

are stable for 7 to 25 months (at -40 to -2oC). Previously submitted storage stability data also 

indicate these compounds are stable in tomato, melon, broccoli, grape, potato, lettuce, apple and 

cotton for up to 12 months.

Proposed Uses 

Onion, bulb, subgroup 3-07A

IR-4 has submitted residue data for bulb onion, the representative crop for subgroup 3-07A. The 

results from the bulb onion field trials are summarized in Table 5.2.1. 
Page 26 of 69

TABLE 5.2.1. Summary of Residue Data from Dry Bulb Onion Crop Field Trials with Dinotefuran.

Commodity Analyte Total App. 

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Drench/In-furrow Application

Dry onion bulbs Dinotefuran 0.258-0.346 71-156 8 <0.01 0.01 0.01 0.01 0.01 0.01 N/A

UF38 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

DN38 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

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

Foliar Application

Dry onion bulbs Dinotefuran 0.352-0.370 1-2 8 <0.01 0.06 0.01 0.05 0.02 0.02 0.02

UF38 <0.01 0.02 0.01 0.01 0.01 0.01 <0.01

DN38 <0.01 0.02 0.01 0.01 0.01 0.01 <0.01

Total Residues 8 <0.03 0.09 0.03 0.08 0.04 0.04 0.02

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

standard deviation, the LOQ (0.01 ppm for all analytes) was used for any results reported as <LOQ in Table C.3; N/A = Not 

applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.

3 Residues of UF and DN are reported in parent equivalents as calculated by the study reviewer.

Onion, green, subgroup 3-07B

IR-4 has submitted residue data for green onion, the representative crop for subgroup 3-07B. 

The results from the green onion field trials are summarized in Table 5.2.2.

TABLE 5.2.2. Summary of Residue Data from Green Onion Crop Field Trials with Dinotefuran.

Commodity Analyte Total App. 

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Foliar Application

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

UF35 <0.01 0.162 0.01 0.149 0.060 0.072 0.060

DN35 0.017 0.352 0.022 0.343 0.266 0.204 0.136

Total Residues 5 <0.115 2.63 0.118 2.37 0.906 1.09 0.864

Post-plant Application to Soil

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

UF31 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

DN31 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

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

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

standard deviation, the LOQ (0.01 ppm for all analytes) was used for any results reported as <LOQ in Table C.3. N/A = Not 

applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.

3 Residues of UF and DN are reported in parent equivalents as calculated by the study reviewer.
Page 27 of 69

Berry, low growing, except strawberry, subgroup 13-07H

IR-4 has submitted residue data for cranberry, the representative crop for subgroup 13-07H. The 

results from the cranberry field trials are summarized in Table 5.2.3.

TABLE 5.2.3. Summary of Residue Data from Cranberry Crop Field Trials with Dinotefuran.

Commodity Analyte Total App. 

Rate

(lb ai/A)

PHI

(days)

Residue Levels (ppm)1

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Cranberry Dinotefuran 0.348-0.362 6-8 4 0.01 0.06 0.01 0.05 0.04 0.04 0.02

UF34 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

DN34 <0.01 0.02 0.01 0.02 0.01 0.01 <0.01

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

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

standard deviation, the LOQ (0.01 ppm for all analytes) was used for any results reported as <LOQ in Table C.3. N/A = Not 

applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.

3 Residues of UF and DN are reported in parent equivalents using a molecular weight conversion factor of 1.3 for each analyte as 

calculated by the study reviewer.

Peach

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

summarized in Table 5.2.4.

TABLE 5.2.4. Summary of Residue Data from Peach Crop Field Trials with Dinotefuran.

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

UF312 <0.01 0.07 0.01 0.07 0.01 0.02 0.02

DN312 <0.01 0.05 0.01 0.04 0.01 0.02 0.01

Total Residues 12 <0.11 0.66 0.11 0.62 0.24 0.29 0.16

Soil Drench Application

Peach Dinotefuran 0.268-

0.269

21 2 <0.01 0.01 0.01 0.01 0.01 0.01 N/A

UF32 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

DN32 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

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

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

standard deviation, the LOQ (0.01 ppm for all analytes) was used for any results reported as <LOQ in Table C.3. N/A = Not 

applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.

3 Residues of UF and DN are reported in parent equivalents as calculated by the study reviewer.
Page 28 of 69

Watercress

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

summarized in Table 5.2.5.

TABLE 5.2.5. Summary of Residue Data from Watercress Field Trials with Dinotefuran.

Commodity Analyte Total 

App. Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Without Adjuvant

Watercress Dinotefuran 0.355-

0.363

1 3 1.23 3.47 1.25 3.38 1.88 2.17 1.09

UF33 0.042 0.119 0.044 0.118 0.069 0.077 0.038

DN33 0.273 0.397 0.287 0.385 0.301 0.324 0.053

Total 

Residues

3 1.55 3.85 1.58 3.74 2.38 2.57 1.10

With Adjuvant

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

UF32 0.044 0.170 0.049 0.161 0.105 0.105 0.079

DN32 0.314 0.687 0.338 0.650 0.494 0.494 0.220

Total 

Residues

2 1.80 2.99 2.00 2.93 2.46 2.46 0.656

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

2 LAFT = lowest average field trial; HAFT = highest average field trial.

3 Residues of UF and DN are reported in parent equivalents as calculated by the study reviewer.

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

13-07H

Potato is the representative crop for the tuberous and corm vegetable subgroup 1C. Therefore, 

the previously submitted potato residue data (DP290191, L. Cheng, 11/23/04) are adequate to 

support the establishment of a subgroup 1C tolerance at the level set for potato (0.05 ppm). 

Also, grape is the representative crop for the small vine climbing fruit except fuzzy kiwifruit 

subgroup 13-07F. Therefore, the previously submitted grape residue data (DP290191, L. Cheng, 

11/23/04) are adequate to support the establishment of a subgroup 13-07F tolerance at the level 

set for grape (0.9 ppm).

Tea (import)

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

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

ai/A seasonal rate, with a 7-day RTI and a 7-day PHI. The submitted residue data for tea support 

a tolerance of 50 ppm in tea, dried.
Page 29 of 69

TABLE 5.2.6. Summary of Residue Data from Tea 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.

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

14 2 4.34 5.10 4.55 4.89 4.72 4.72 0.24

21 2 0.68 1.64 0.68 1.62 1.15 1.15 0.66

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

2 LAFT = lowest average field trial; HAFT = highest average field trial.

Processed Food and Feed

There are no processed commodities associated with the proposed crops. 

Livestock

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

feed items. The existing dinotefuran tolerances for milk and the fat, meat, and meat byproducts 

of cattle, goat, hog, horse, and sheep are adequate; no revision to the existing tolerances is 

needed to support the proposed uses of dinotefuran. The proposed uses of dinotefuran addressed 

in this document do not alter the Agency’s previous conclusion that there is no reasonable 

expectation of finite residues in poultry commodities [Category 3 of §180.6(a)]. No tolerances 

are needed for poultry tissues or eggs. 

Rotational Crops

Adequate confined field rotational crop data are 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 plantback interval is 

specified on the label. 

5.3 Water Residue Profile

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

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

assessment with estimated drinking water concentrations (EDWCs) for dinotefuran and its 

metabolites/degradates (MNG, DN, UF, DN-2-OH, and DN-3-OH) (DP394848, R. Parker, 

12/12/11). The EDWCs for the metabolites/degradates were reported in parent dinotefuran 

equivalents. The degradates UF and DN-2-OH are photolysates and are not likely to be formed 

in the fields of most crops. The formation of these degradates would be a result of direct 

exposure of parent dinotefuran to surface waters through spray drift, or through direct application 

to water, followed by photolysis. The estimated values for DN, UF, and DN-2-OH+DN-3-OH 

photolysates are considered to be the upper bound estimates, since these degradates are likely to 

form only in puddles or small water pockets in the field through photolysis, and therefore, these 

EDWCs should be considered an unrefined assessment. The surface water EDWCs were derived 
Page 30 of 69

using the FQPA Index Reservoir Screening Tool (FIRST) simulation model. The Screening 

Concentration in Ground Water (SCIGROW) model was used to derive the ground water 

EDWCs.

For the proposed crops, resulting EDWCs for parent dinotefuran for the two terrestrial crop 

groups with the highest annual application amount are 33.4 μg/L for surface water acute risk, 5.5 

μg/L for surface water chronic risk, and 1.07 μg/L for ground water. These values are all less 

than the previous EDWC values calculated by EFED for pome and stone fruits (DP389034, R. 

Parker, 5/26/11). Therefore, the pome and stone fruit EDWCs are still recommended for 

assessing dinotefuran residues in drinking water. The drinking water assessment was conducted 

for total dinotefuran residues including parent, MNG, DN, UF, DN-2-OH, DN-3-OH as 

recommended by HED. Total EDWCs for dinotefuran residues in surface source drinking water 

are not expected to exceed 91.31 μg/L for the 1 in 10 year daily peak concentration and 25.16 for 

the 1 in 10 year annual average concentration. In ground water, the EDWC for dinotefuran 

residues is not expected to exceed 3.5 μg/L. Because the surface water estimates are higher than 

the ground water estimates, the surface water values, expressed to two significant figures and 

converted to ppm, were directly incorporated in the DEEM-FCID into the food categories 

“water, direct, all sources” and “water, indirect, all sources.” EDWCs recommended for use in 

the human health risk assessment for all proposed/registered crops are listed in Table 5.3. 

EFED noted that a qualitative assessment was performed for the proposed use on watercress 

which is typically cultivated in shallow, flowing water. The Agency does not currently have a 

methodology for exposure assessment for crops cultivated in flowing water. The EFED Tier 1 

rice model was therefore used as the basis of the exposure assessment and the results were

characterized to reflect differences between the conditions represented in the rice model and the 

actual methods of watercress cultivation. The three main differences are (1) simulation of 

application efficiency (fraction of amount applied which is intercepted by the crop), (2) 

simulation of degradation of the pesticide in water after application, and (3) simulation of flow 

through and downstream from the area of cultivation. Consideration of these three differences 

from the rice model plus extensive runoff dilution from areas of the watershed which are not 

used for watercress cultivation would be expected to produce concentration values substantially 

less than those of other labeled crops.

Table 5.3 Summary of Estimated Surface Water Concentrations for Dinotefuran.

Scenario Surface Water Concentration (ppb)

Acute 91.31

Chronic (non-cancer) 25.16
Page 31 of 69

5.4 Dietary Risk Assessment

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

The acute and chronic dietary exposure 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.

5.4.2 Acute Dietary Risk Assessment

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

from the screening-level FIRST model as these values were higher than the ground water 

estimates from the SCIGROW model (DP394848, R. Parker, 12/12/11). 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 U.S. population accounted for just 

2.2% of the acute population-adjusted dose (aPAD), while the most highly exposed population 

subgroup, children 1-2 years old, accounted for 5.8% of the aPAD.

5.4.3 Chronic Dietary Risk Assessment

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

from the screening-level FIRST model as these values were higher than the ground water 

estimates from the SCIGROW model (DP394848, R. Parker, 12/12/11). No population 

subgroups were of concern: the U.S. population accounted for <1% of the chronic populationadjusted dose (cPAD), while the most highly exposed population subgroup, children 1-2 years 

old, accounted for 2.6% of the cPAD.

5.4.4 Summary Table

Table 5.4.4. Result of Acute and Chronic Dietary Exposure and Risk Estimates for 

Dinotefuran using DEEM-FCID (food and water).

Population Subgroup*

Acute Dietary

(95 th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day) % aPAD**

Dietary 

Exposure

(mg/kg/day) % cPAD**

General U.S. Population 0.027173 2.2 0.008041 <1

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

Children 1-2 years old 0.072092 5.8 0.025775 2.6

Children 3-5 years old 0.052397 4.2 0.018474 1.8
Page 32 of 69

Table 5.4.4. Result of Acute and Chronic Dietary Exposure and Risk Estimates for 

Dinotefuran using DEEM-FCID (food and water).

Population Subgroup*

Acute Dietary

(95 th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day) % aPAD**

Dietary 

Exposure

(mg/kg/day) % cPAD**

Children 6-12 years old 0.028815 2.3 0.009781 1.0

Youth 13-19 years old 0.019797 1.6 0.006209 <1

Adults 20-49 years old 0.019742 1.6 0.006311 <1

Adults 50+ years old 0.020109 1.6 0.006453 <1

Females 13-49 years old 0.019914 1.6 0.006307 <1

*The values for the highest exposed population for each type of risk assessment are bolded.

** Report %PADs to 2 significant figures.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

References: 

- 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, DP391888, 7/20/2012.

This document addresses the proposed new domestic agricultural uses of dinotefuran. These 

proposed uses do not involve applications by homeowners or commercial applicators in 

residential settings. Therefore, no new residential exposure is expected. There are currently 

registered uses of dinotefuran on several residential use sites, including turf, ornamentals, 

vegetable gardens, pets, indoor aerosol sprays, crack and crevice sprays, etc. Each of these 

existing residential use patterns has previously been assessed and the resulting exposures and 

risk estimates that were not of concern. However, HED has recently updated the residential 

standard operating procedures (SOPs) and body weights used in all human health risk 

assessments. Therefore, all of the existing residential use patterns have been reassessed for 

residential handler and post application exposures using the new procedures and data.

All existing residential use patterns were reassessed using the new residential SOPs and new 

body weight designations. The new exposure and risk estimates for all residential postapplication scenarios result in risk estimates that are also not of concern.

6.1 Residential Handler Exposure

As previously discussed in Section 4.0, dermal and inhalation risks were not assessed because no 

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

6.2 Post-Application Exposure

When determining the potential for residential exposure, the Agency considers residues, leaf to 

skin/hand residue transfer, children’s hand-to-mouth residue transfer and exposure time. 

Because no dermal or inhalation endpoints were chosen for dinotefuran post-application 

residential dermal and inhalation exposure scenarios are not assessed. As a result, risk 

assessments have only been completed for post-application scenarios in which incidental oral 

exposures are expected. Short-term incidental oral exposures were assessed using the short-term 

point of departure of 99.7 mg/kg/day. Additionally, the acute dietary point of departure of 125 

mg/kg/day was used to assess the incidental oral ingestion of granules.

Table 6.2 lists the residential post-application exposures and risk estimates. The post-application 

exposure and risk estimates for all residential uses result in risk estimates that are not of concern 

(MOEs ranged from 1,100 to 5,900,000).

Table 6.2. 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 NA NA

Dog Spot-On Liquid

80.7 mg ai/treatment 1 tube

Oral hand-to-mouth

0.00066 1.5E+5

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

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

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

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

Indoor 

Broadcast

0.25% 

Aerosol

0.0033 lb ai/can or 

0.61 μg ai/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 

& 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

NA = not applicable

1

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

scenarios use the short-term incidental oral point of departure of 99.7 mg/kg/day.
Page 34 of 69

6.3 Combined Exposure

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

be combined and compared to the appropriate toxicity endpoint. While it is possible for children 

to be exposed to indoor broadcast sprays on hard surfaces/carpets and to spot-on treatment to 

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

because incidental oral hand-to-mouth exposure from treatment turf is higher and still results in 

an MOE that does not exceed HED’s LOC.

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, for dinotefuran quantification of short- or intermediate-term inhalation 

risk is not required, because no systemic toxicity or portal of entry effects were seen following 

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

range.

6.5 Spray 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 (add) pesticide exposures and 

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

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When 
Page 35 of 69

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. For dinotefuran, potential exposures from food, drinking 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 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 2.2% of the aPAD for the U.S. general population, and 5.8% 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 scenario was chosen; i.e., oral hand to-mouth exposure from 

turf following application of a liquid formulation. For a description of the residential exposure 

scenario considered in the aggregate assessment, see Section 6.0.

The aggregate MOE for children 1-2 years old is 3,000, 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 from 

treated turf

99.7 100 0.997 0.025775 0.0079 0.033675 3,000

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 (Table 6.2).
Page 36 of 69

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

5 Aggregate MOE = [NOAEL , 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 (from turf), 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

References:

- 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, DP391888, 7/20/2012.
Page 37 of 69

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

Based on the proposed use patterns of dinotefuran, 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 on the proposed labels include long-sleeved shirt and long pants, shoes plus 

socks, and chemical resistant gloves.

Risk estimates for occupational handlers were not assessed because no hazard was identified for 

either the dermal or inhalation route of exposure.

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 proposed dinotefuran 

labels is adequate.

10.0 References

C. Walls, DP391889, 7/17/12. Dinotefuran: Acute and Chronic Aggregate (Food and Drinking 

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

and Corm Vegetables Subgroup 1C, Onion Subgroup 3-07A, Onion Subgroup 3-07B, Small 

Fruit Subgroup 13-07F, Berry Subgroup 13-07H, Peach, Watercress, and Tea (Import).

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

Dinotefuran and its Transformation Products of Concern (MNG, DN, UF and DN-2-OH + DN-3-

OH) in Support of Proposed IR-4 New Uses (Onion, Bulb and Green; Berry and Small Fruit; 

Tuberous and Corm Vegetables; Peach; and Watercress). 

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

Tolerances on 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 38 of 69

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.

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. 

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
Page 39 of 69

Study

Technical

Required Satisfied

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

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

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

yes

-

-

yes

yes

yes

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes

yes

yes

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Test Substance 

Guideline No.

Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral, rat 45639823 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 

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
Page 40 of 69

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

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

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

870.3150

90-Day oral toxicity 

in dogs

MRID: 45639906 (main study), 45639915, 

45639916 (range-finding studies) (1999)

Acceptable/Guideline

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

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

862/950 mg/kg/day

NOAEL: 307 mg/kg/day

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

body weight gain in males and decreased 

body weight and body weight gain in 

females.

870.3200

28-Day dermal 

toxicity (rats)

MRID: 45639908, 45639907 (rangefinding) (2001)

Acceptable/Guideline

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

Systemic: 

NOAEL: 1000 mg/kg/day

LOAEL: Not Established. 

Dermal: 

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

LOAEL: not determined/ 1000 [M/F] 

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

and acanthosis/ hyperkeratosis in high dose

females (lower doses not evaluated 

histopathologically).

870.3465

28-Day inhalation 

toxicity (rat)

MRID: 45639909, 46072401 (2002)

Acceptable/Guideline

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

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

mg/kg/day

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

mg/kg/day; HDT

LOAEL: not identified

Note: The concentration tested is the highest 

practical concentration obtainable in the 

respirable range. 

870.3700a

Prenatal 

developmental 

toxicity study (rats)

MRID: 45654207, 45639910 (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)
Page 41 of 69

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

Developmental

NOAEL: 300 mg/kg/day

LOAEL: Not Established

870.3800

Reproduction and 

fertility effects (rats)

MRID: 45639913, 45639914 (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). 

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

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

Combined chronic 

toxicity/ 

carcinogenicity (rats)

Acceptable/Guideline

Dose Levels: 0, 60, 200, 2000, 20,000 

ppm (dietary); M/F: 3.0/3.9, 9.9/12.5, 

99.7/127.3, 991/1332 mg/kg/day

LOAEL: 991/1332 [M/F] mg/kg/day based 

on decreased body weight gain and 

nephrotoxicity.

870.5100

Bacterial reverse 

mutation test

MRID: 45640003 (1996)

Acceptable

Negative. ± S9 up to 16,000 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 

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 

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

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

neurotoxicity study

Acceptable/Guideline

Dose: 0, 1000, 3000 or 10000

Gestation/Lactation = 0, 79.4/158, 

237.4/500.7 or 784.1/1642.9 mg/kg/day

Maternal LOAEL: Not Established

Offspring NOAEL = 784 mg/kg/day.

Offspring LOAEL: Not Established.

870.7485

Metabolism and 

pharmacokinetics 

(rats)

MRID: 45640006

Acceptable/Guideline

Dose: single 50 or 1000 mg/kg oral or 50 

mg/kg IV treatments or multiple oral 50 

mg/kg treatments with MTI-446 

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

VB9304, VB9302 (radiolabeled in the 

guanidine and furan 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 

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 
Page 44 of 69

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ Classification /Doses Results

exposure to 3.2 g/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

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.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

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

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

A.3.2 Acute Reference Dose (aRfD) - General Population

Selected Study: Developmental Toxicity Study in Rabbits

MRID No.: 45654208

Executive Summary: See Appendix A, Guideline 870.3700b

Dose and Endpoint for Establishing aRfD: NOAEL = 125 mg/kg based on clinical signs (prone 

position, panting, tremors) seen in does at 300 mg/kg/day (LOAEL). This endpoint is 

appropriate because the clinical signs were seen following the first day of dosing (Gestation Day 

6). This NOAEL would also address the concern for the decreased motor activity seen in female 

rats at 750 mg/kg/day and in male rats at 1500 mg/kg on Day 1 of dosing in the acute 

neurotoxicity study.

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

A.3.3 Chronic Reference Dose (cRfD) `

Study Selected: Combined Chronic Toxicity/Carcinogenicity Study in Rats 

MRID No.: 45640001

Executive Summary: See Appendix A, Guideline 870.4300 

Dose and Endpoint for Establishing cRfD: NOAEL=99.7 mg/kg/day based on decreased body 

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

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

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

Comments about Study/Endpoint/Uncertainty Factor: This study and endpoint is appropriate for 

this exposure scenario since the endpoint of concern was seen following chronic exposure to the 

most sensitive species. This NOAEL would also address the concern for the decreased motor 

activity seen in rats at 327 mg/kg/day in the subchronic neurotoxicity study as well as the clinical 

signs of neurotoxicity (prone position, panting, tremors) seen at 300 mg/kg/day in the does in the 

pre-natal developmental toxicity study with rabbits. In previous risk assessments, decreased 

thymus weight seen in the chronic toxicity study in dogs was selected as the toxicity endpoint for 

chronic exposure. Since then, immunotoxicity studies in mice and rats as well as a 

developmental immunotoxicity study were submitted and reviewed by the Agency. There was 

no evidence of adverse effects on functional immunotoxicity when tested up to the Limit Dose in 

these studies. Additionally, there were no changes in spleen and thymus weight and there were 

no histopathological lesions in these studies. Consequently, the thymus weight changes seen in 
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the dog study were not considered to be toxicologically relevant and appropriate for endpoint 

selection/risk assessment.

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Selected Study: Combined Chronic Toxicity/Carcinogenicity Study in Rats 

MRID No.: 45640001

Executive Summary: See Appendix A, Guideline 870.4300b

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

endpoints of concern.

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

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

the NOAEL of 99.7 mg/kg/day established in the combined chronic toxicity/carcinogenicity 

study was selected to assess risk from both short-and intermediate term exposures. In a 

subchronic neurotoxicity study, a NOAEL of 33 mg/kg/day was established based on decreased 

motor activity seen in two weeks at 327 mg/kg/day in the subchronic neurotoxicity (SCN) study. 

This study with a lower NOAEL was not selected for these exposure scenarios because the lower 

NOAEL in the SCN is an artifact of dose selection. The higher NOAEL would still be protective 

of the neurotoxicity seen not only in the SCN but also the clinical signs of neurotoxicity (prone 

position, panting, tremors) seen at 300 mg/kg/day in does in the developmental toxicity study 

and the decreased motor activity seen in female rats at 750 mg/kg/day in the acute neurotoxicity 

study. The pattern of motor activity seen with single and repeated exposure is consistent with 

the neonicotinic mode of action. Thus, the selected POD would protect for neurotoxicity, the 

principal toxicological effect of dinotefuran. This endpoint is appropriate for the population 

(infants and children) and durations (short to intermediate term) of concern since the decrease in 

motor activity was seen two weeks after initiation of treatment and there is no increased toxicity 

observed with increased duration throughout the database. The Level of Concern is a Margin of 

Exposure of 100 which includes 10X for inter-species extrapolation and 10X for intra-species 

variation. 

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)

Quantification of short- or intermediate-term dermal risk is not required. No systemic toxicity 

was seen at the Limit Dose in an acceptable dermal toxicity study in rats (MRID 45639908) and 

there are no developmental or reproductive toxicity concerns. Additionally, the potential for 

neurotoxicity was evaluated in the dermal study and no treatment-related effects were seen in 

any of the neurological parameters. Further, no increase in toxicity with duration was observed 

throughout the toxicology database for dinotefuran. Therefore, it is reasonable to attribute no 

hazard to intermediate-term exposure based on a 28-day dermal toxicity study.
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A.3.6 Inhalation Exposure (Short- and Intermediate-Term) 

Quantification of short- or intermediate-term inhalation risk is not required. No systemic toxicity 

or portal of entry effects were seen following repeated inhalation exposure at the highest 

practical concentration obtainable in the respirable range (MRID 45639909). No effects were 

seen at doses approximately 100,000 times greater than the greatest expected human exposure. 

Although neurotoxicity was not specifically evaluated in this study, effects of 

increased/decreased motor activity, panting, tremor and prone position would be evident with 

clinical observation if present. Since no increase in toxicity with duration was observed 

throughout the toxicology database for dinotefuran this study is also appropriate for 

intermediate-term inhalation exposure.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat

In a 90-day oral toxicity study (MRID 45654205), Dinotefuran (96.5% a.i., lot number 22-

00110) was administered to 10 Crl:CD (SD) BR VAF/Plus rats/sex/dose in the diet at 

concentrations of 0, 500, 5000, 25,000, or 50,000 ppm (equivalent to 0, 34, 336, 1623, and 3156 

mg/kg bw/day for males and 0, 38, 384, 1871, and 3616 mg/kg bw/day for females). All animals 

survived until scheduled sacrifice, and no treatment-related clinical signs were noted. Body 

weights of both sexes in the 25,000 and 50,000 ppm groups were significantly lower than those 

of controls from week 2 until termination. Overall body weight gain was 84% of control values 

in the 5000 ppm females, 68% of the control values in the 25,000 ppm females and 60% and 

48% of the control values in the 50,000 ppm males and females, respectively. Food consumption 

was significantly lower for the 25,000 and 50,000 ppm groups throughout the study. Food 

efficiency was negative for the 50,000 ppm group during week 1, but generally similar for all 

groups afterward. 

No treatment-related effects were seen on survival, clinical signs, hematology, clinical 

chemistry, and urinalysis, parameters and gross pathology. Decreased body weight gain was 

seen in females at the 25,000 ppm group (68% of the control value) and in males (60%) and 

females (48%) at the 50,000 ppm group. Additionally, although not significant, decreases (12-

16%) in absolute body weight were also seen in females at the 25,000 ppm dose group. Based 

on these observations, the decreases in body weight/body weight gain were attributed to 

treatment. Histopathology revealed a dose-dependent increase in the incidence and/or severity of 

vacuolization in the adrenal zona glomerulosa and zona fasciculata at 25,000 ppm.

Under the conditions of this study, the LOAEL was 25,000 ppm (1623/1871 [M/F] 

mg/kg/day) based on decreased body weight and body weight gain and histopathological 
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lesions of the adrenal glands in female rats. The NOAEL is 5000 ppm ((336/384 [M/F] 

mg/kg/day) for males and females. 

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

requirement for a 90-day oral toxicity study (OPPTS 870.3100; OECD 408) in rats.

870.3100 90-Day Oral Toxicity – Mouse

In a 90-day oral toxicity study (MRID 45654206), Dinotefuran (96.5% a.i., lot number 22-

00110) was administered to 10 Crl:CD-1(ICR)BR VAF/Plus mice/sex/dose in the diet at 

concentrations of 0, 500, 5000, 25,000 or 50,000 ppm (equivalent to 0, 81, 844, 4442, and 10,635 

mg/kg bw/day for males and 0, 102, 1064, 5414, and 11,560 mg/kg bw/day for females). All 

animals survived until the scheduled sacrifice, and there were no treatment-related clinical signs 

of toxicity. Body weights of the 50,000 ppm animals were significantly lower (11-16% for 

males, 14-22% for females) than those of controls beginning at week 3 until termination, except 

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

males and 72% in females. There were no adverse treatment-related effects on hematology, 

clinical chemistry, urinalysis, organ weight, or gross or macroscopic pathology. 

Under the conditions of this study, the LOAEL for Dinotefuran in mice was 50,000 ppm 

(10,635 mg/kg/day for males, and 11,560 mg/kg/day for females), based on decreased body 

weight and body weight gain. The corresponding NOAEL was 25,000 ppm (4442 

mg/kg/day for males, and 5414 mg/kg/day for females). 

This 90-day oral toxicity study in the mouse is Acceptable/Guideline and satisfies the guideline 

requirement for a 90-day oral toxicity study (OPPTS 870.3100; OECD 408) in mice. 

870.3150 90-Day Oral Toxicity – Dog

In a 90-day oral toxicity study (MRID 45639906), Dinotefuran (MTI-446) (99.1% a.i., lot # 

2200210)] was administered to 4 beagle dogs/sex/dose in diet at dose levels of 0, 1600, 8000, or 

24,000 ppm [mean equivalents: 0, 58, 307, or 862 mg/kg bw/day (males), and 0, 58, 323, or 950 

mg/kg bw/day (females)]. An initial high-dose of 40,000 ppm MTI-446 was offered to the highdose group from days 1-4, but the concentration was reduced on day 5 to 30,000 ppm, and again 

on day 12 to 24,000 ppm, due to in appetence and general deteriorating condition of at least 2 of 

the animals (vomiting, diarrhea, red feces, subdued behavior, and/or pale gums).

The initial high doses of the test compound (40,000 ppm and 30,000 ppm) adversely affected 

food efficiencies and body weight gains in the high-dose animals for the first 2 weeks. At study 

termination, body weight gain was reduced for high dose males (71% of control values), and 

body weight and body weight gain were reduced for females at all doses (88-92% and 66-71% of 

control values, respectively), though not in a dose-dependent manner. 
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No treatment-related changes were seen in: survival, hematology, clinical chemistry or 

urinalyses parameters; absolute and/or relative organ weights; gross pathology; and 

histopathology in either sex at any dose level. The areas of hemorrhage seen in the mesenteric 

and mandibular lymph nodes were not considered to be of toxicological significance since no 

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

and female mice and adult male and female rats. There were no changes or histopathological 

lesions of the spleen and thymus in either species in these studies. Additionally, there was no 

evidence of an effect on the functionality of the immune system in rats that were exposed to 

dinotefuran during the prenatal, postnatal, and post-weaning periods in a developmental 

immunotoxicity study.

Under the conditions of this study, the LOAEL for dinotefuran is 24,000 ppm (equivalent 

to 862 mg/kg bw/day), based on decreased body weight gain in males and decreased body 

weight and body weight gain in females. The NOAEL is 8000 ppm (equivalent to 307 

mg/kg/day).

This 90-day oral toxicity study in the dog is classified as Acceptable/Guideline and satisfies the 

guideline requirement for a 90-day oral toxicity study (OPPTS 870.3150; OECD 409) in dogs.

870.3200 21/28-Day Dermal Toxicity – Rat

In a 28-day dermal toxicity study (MRID 45639908; range-finding study MRID 45639907), 

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

rats/sex/dose at dose levels of 0 (5% CMC in reverse osmosis water), 40, 200, or 1000 mg/kg 

bw/day, 6 to 7 hours/day, 7 days/week for 29 days. 

One male treated with 40 mg/kg/day died during week 4; however, in the absence of clinical 

observations and macroscopic or microscopic compound-related pathology and no deaths at 

other doses, this death is not considered treatment-related. All other animals survived until 

scheduled sacrifice, and there were no compound-related dermal observations, clinical signs, or 

adverse effects on motor activity, opthalmoscopic observations, body weights or body weight 

gain, food consumption, organ weights, or gross or histopathology. 

Under the conditions of this study, the NOAEL for systemic toxicity for Dinotefuran is 

1000 mg/kg/day, the highest dose tested; a LOAEL is not established.

Under the conditions of this study, for NOAEL dermal toxicity for Dinotefuran is 1000 

mg/kg/day; a LOAEL was not established.

870.3465 90-Day Inhalation – Rat

In a 28-day inhalation toxicity study (MRID 45639909) [MTI 446 (Batch 5400610, 99.1 % 

purity)] four groups of rats consisting of 10 males and 10 females per group were administered 

the test material by nose-only exposure at concentrations of 0, 0.22, 0.66, and 2.08 mg/L 
Page 50 of 69

(approximately 60, 179, and 565 mg/kg/day). The exposures were for six hours per day for a 

total of 29 days for males and 30 days for females. There were no compound-related effects on 

survival, clinical signs, body weight/body weight gain, hematology, clinical chemistry, gross 

pathology, or histologic pathology. The NOAEL is 2.08 mg/L (approximately 565 mg/kg/day), 

the highest concentration obtainable. A LOAEL was not established.

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 45654207), MTI-446 (92.9% a.i., Lot #2200210) was 

administered to 24 pregnant Sprague-Dawley rats/dose in aqueous 0.5% Carmellose-sodium by 

gavage at dose levels of 0, 100, 300, 1000 mg/kg bw/day on gestation days (GD) 6-15, inclusive. 

Doses were based on the results of a range-finding study (MRID 45639910). On GD 20, dams 

were sacrificed, subjected to gross necropsy, and all fetuses examined externally. One-half of 

the fetuses were examined viscerally, and the other one-half of the fetuses were examined for 

skeletal malformations/variations. The total numbers of fetuses (number of litters) examined 

was 298 (22), 309 (22), 272 (20), and 236 (20) for the 0, 100, 300, and 1000 mg/kg bw/day 

groups, respectively.

No effects of treatment were observed in survival, clinical signs, body weight/body weight gain, 

water intake, or gross necropsy at doses up to and including the Limit Dose.

Under the conditions of this study, the maternal toxicity NOAEL for Dinotefuran in rats is 

1000 mg/kg bw/day. A maternal toxicity LOAEL was not established. 

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

pre- or post-implantation losses, resorptions/dam, fetuses/litter, fetal body weights, or fetal sex 

ratios were observed in the treated groups as compared with the controls. No treatment related 

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

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

rats is 1000 mg/kg bw/day. A developmental LOAEL was not established.

This developmental toxicity study in the rat is classified Acceptable/Guideline and satisfies the 

guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rats.

870.3700b Prenatal Developmental Toxicity Study – Rabbit

In a developmental toxicity study (MRID 45654208), MTI-446 (92.9% a.i., Lot #2200210) was 

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

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

(GD) 6-18, inclusive. Doses were based on the results of range-finding studies (MRID 

45639911, 45633912). On GD 28, does were sacrificed and subjected to gross necropsy. All 
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fetuses were examined for external, visceral, and skeletal malformations/variations. The total 

numbers of fetuses (litters) examined was 151(20), 153(19), 170(21), and 147(19) for the 0, 30, 

60, and 120 mg/kg bw/day groups, respectively, except the number of fetuses (litters) examined 

for visceral alterations in the high-dose group was 138(19). No maternal toxicity adverse effects 

were observed in the low-dose group (52 mg/kg/day).

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

the dosing interval (GD 6-18; 80% of controls) and a transient decrease in food consumption 

during the first few daily intervals following initiation of dosing (84-90% of controls during 

daily intervals of GD 6-10). Gross necropsy findings in the mid-dose group included a doserelated increase in the incidence of pale brown discoloration of the liver (8/22 affected) and gray 

white plaques in the fundic region of the stomach (14/22 affected). However, in the absence of 

corroborating histopathology the toxicological significance of these findings is unclear. 

Moreover, these effects are not consistent with dinotefuran’s mode of action.

Maternal toxicity was evident at the high doses of 300 mg/kg/day. Does in the high-dose group 

had a number of transient clinical signs indicative of neurotoxicity including hypoactivity 

(number of animals affected/number of observations: 21/91), prone position (20/74), panting 

(20/63), tremor (9/16), and erythema of nose/auricle (10/14). The signs were noted following 

administration of the first dose on GD 6 and were not observed by GD 14. High-dose does had 

decreased body weight gain over the treatment interval of GD 6-18 (41% of controls), 

accompanied by decreases in daily food consumption (50-84% of controls), and daily water 

consumption (generally 90% or less than the controls). Gross necropsy revealed almost all 

animals had pale brown discoloration of the liver (19/21 affected) and gray white plaques in the 

fundic region of the stomach (20/21 affected). The doe not affected with white plaques in the 

fundic region of the stomach instead had gray white discoloration of the mucosa in the fundic, 

pyloric region of the stomach. Additionally, one doe had enlargement of the liver.

Under the conditions of this study, the maternal toxicity LOAEL for Dinotefuran in rabbits 

is 300 mg/kg bw/day based on clinical signs indicative of neurotoxicity (hypoactivity, prone 

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

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

pre- or post-implantation losses, resorptions/doe, fetuses/litter, fetal body weights, or fetal sex 

ratios were observed in the treated groups as compared with the controls. No treatment-related 

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

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

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

established.

The developmental toxicity study in the rabbit is classified Acceptable/Guideline and satisfies 

the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in 

rabbits.
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A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

In a 2-generation reproduction study (MRID 45639913) MTI-446 (Dinotefuran; 98.9% a.i., batch 

# 5400810) was administered to 25 Han Wistar [Hanlbm:WIST (SPF)] rats/sex/dose in feed at 

dietary concentrations of 0, 300, 1000, 3000, or 10,000 ppm. Premating doses were respectively 

0, 24.1, 79.9, 241.0, or 822.1 mg/kg bw/day for F0 males, 0, 26.8, 90.1, 267.9, or 907.0 

mg/kg bw/day for F0 females, 0, 27.2, 90.5, 269.0, or 934.7 mg/kg bw/day for F1 males, and 0, 

29.6, 96.5, 292.6, or 1004.8 mg/kg bw/day for F1 females. F0 and F1 parental animals were 

administered the treated or control diets for at least 70 days prior to mating, throughout mating, 

gestation, and lactation, and until necropsy, and one litter was produced by each generation. 

Additional groups of 20 F1 pups/sex/dose were selected for post-weaning functional evaluations, 

including a functional observational battery, and quantitative grip strength and motor activity 

measurement, at approximately 6 weeks of age. Dose selection was based on a range-finding 1-

generation reproduction study in rats (MRID 45639914).

Death of one high-dose F0 female on LD 21 may have been related to gross and microscopic 

renal abnormalities (bilateral dilatation of the pelves, tubular mineralization, and pyelitis), and 

not a treatment-related effect. Treatment-related clinical signs were limited to observations of 

soft feces from all high-dose F0 females and one high-dose F1 female beginning on LD 11-16 and 

continuing through the end of lactation. Body weight gains of high-dose F0 males were marginally decreased during the first three weeks of premating and for the cumulative premating 

interval (90 and 91% of controls, respectively), and this group also had a transient reduction in 

food consumption during the first week of premating (90% of controls). Biologically significant 

decreases in absolute body weight were seen in high-dose F1 males during the first 5 weeks of 

premating and in F1 females during the first 2 weeks of premating (85-90% and 88-90% of 

controls, respectively), and both groups also had decreased body weight gains during the first 

week of premating (83-84% of controls) and decreased food consumption during the first 2

weeks of premating (84-88% and 88-92% of controls, for males and females respectively). 

However, the effects on body weight and food consumption in the F1 animals represented a 

continuation of an offspring effect rather than a parental effect. High-dose F0 males and females 

had decreased absolute spleen weights (90% and 84% of controls, respectively; p<0.05) and 

decreased spleen/brain weight ratios (90% and 86% of controls; p<0.05).

Under the conditions of this study, the Parental/ Systemic Toxicity NOAEL is 3000 ppm 

(241.0 mg/kg bw/day in males and 267.9 mg/kg bw/day in females) and the Parental 

Systemic Toxicity LOAEL is 10,000 ppm (822.1-934.7 mg/kg bw/day in males and 907.0-

1004.8 mg/kg bw/day in females), based on a transient decrease in food consumption and 

decreased premating weight gain in F0 males, observations of soft feces in F0 females and 

decreased thyroid weights in F1 females.
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There were no treatment-related effects on mean litter size, numbers of live and dead pups, sex 

ratio at birth, or the birth, viability, and weaning indices, and no treatment-related clinical signs 

were observed in offspring during lactation of either generation. In both generations, mean pup 

weights of the treated groups were similar to those of controls on LD 1. F1 high-dose male and 

female pups had decreased body weight gains during LD 4-21 (80-88% and 84-87% for males 

and females, respectively), which resulted in significantly decreased absolute body weights on 

LD 14 and 21 for males (86-89%; p<0.01) and on LD 21 for females (88%; p<0.05). In highdose F2 pups, the decreased body weight gains occurred during LD 7-21 (77-85% of controls), 

and significantly decreased absolute body weights were noted on LD 14 and 21 for both sexes 

(85-87% of controls; p<0.01). 

High-dose F1 and F2 pups of both sexes had decreased mean absolute spleen weights and 

spleen/brain weight ratios (72-77% and 75-81% of controls, respectively). Significant decreases 

in absolute and relative thyroid weight were observed at 300, 1000 and 10,000 ppm but not at an 

intermediate dose of 3,000 ppm. Though not dose-dependent at lower doses, a 25% decrease in 

absolute organ weight at 10,000 ppm (822 mg/kg/day) is considered adverse. High-dose F2 male 

and female pups had decreased mean absolute thymus weights (76% and 82% of controls for 

males and females, respectively) and decreased thymus/brain weight ratios (83% and 85% of 

controls). There was also a slight decrease in brain weight (96-98% of controls). There were no 

treatment-related FOB observations, and the motor activity results from the treated F1 groups 

were similar to those of controls. High-dose F1 males had significantly decreased forelimb grip 

strength (82% of controls), and high-dose F1 females had significantly decreased rearlimb grip 

strength (79%).

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

269.0 mg/kg bw/day for males and 267.9-292.6 mg/kg bw/day for females and the Offspring 

Toxicity LOAEL is 10,000 ppm (822.1-934.7 mg/kg bw/day for males and 907.0-1004.8 

mg/kg bw/day for females), based on decreased body weights, body weight gains, and 

decreased forelimb grip strength (F1 males) or hindlimb grip strength (F1 females). 

Ovaries from high-dose F1 females had decreased numbers of primordial follicles (37.2 vs. 62.0 

for controls). There were no treatment-related effects on estrous cyclicity during premating. 

However, estrous staging from vaginal smears collected at necropsy indicated a trend towards 

increased numbers of high-dose females in diestrus (F0: 15/25 vs. 9/25 controls; F1: 16/25 vs. 

12/25 controls) and an absence of high-dose F0 or F1 females in metestrous (vs. 3 controls for 

both generations). High-dose F0 females had increased incidences of atrophy of the uterus 

(19/25 vs. 11/25 controls) and atrophy of the vaginal mucosa (18/25 vs. 8/25 controls). Uterine 

atrophy may be related to decreased absolute uterine weights and uterus/brain weight ratios 

noted in high-dose F0 females (79% and 80% of controls). Microscopic lesions were not 

observed in F1 females.

High-dose F0 males had an increased percentage of intact sperm with an abnormally curved hook 

(2.0% vs. 1.1% in controls), and high-dose F1 males had increased percentages of intact sperm 

with a misshapen hook (1.0% vs. 0.5% in controls) and sperm with a normal head and a detached 
Page 54 of 69

tail (1.8 vs. 1.3% in controls). A marginally decreased testicular sperm count was noted in highdose F0 males (91% of controls), and high-dose F1 males had decreased percentages of progressive sperm and increased percentages of stationary sperm (86% and 125% of controls, respectively). There were no treatment-related effects on mating performance, fertility, gestation 

length, or precoital intervals. There were also no treatment-related effects on the mean ages and 

weights at which preputial separation or vaginal perforation was observed in F1 offspring or the 

mean anogenital distances in F2 offspring.

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

269.0 mg/kg bw/day in males and 267.9-292.6 mg/kg bw/day in females) and the 

Reproductive Toxicity LOAEL is 10,000 ppm (822.1-934.7 mg/kg bw/day in males and 

907.0-1004.8 mg/kg bw/day in females), based on decreased uterine weights and 

microscopic alterations in the 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. 

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

generation reproductive study in rats [OPPTS 870.3800; OPP §83-4; OECD 416].

A.4.4 Chronic Toxicity

870.4100b Chronic Toxicity – Dog

In a chronic toxicity study (MRID 45654209), Dinotefuran (98.9% a.i., lot # 2200210) was 

administered to 4 beagle dogs/sex/dose in the diet at concentrations of 0, 640, 3200, or 16,000 

ppm (equivalent to 0, 20, 111, or 559 mg/kg bw/day (males) and 0, 22, 108, or 512 mg/kg 

bw/day (females) for 52 weeks. Treatment had no adverse effect on survival or clinical signs of 

toxicity. The reduced overall body weight gains, final body weights, and reduced food 

efficiencies in the high-dose males and mid- and high-dose females were marginal and did not 

follow a pattern of dose-response nor showed statistical significance when compared to controls. 

There were no treatment-related changes in hematology, clinical chemistry and urinalysis 

parameters, organ weights, gross or histopathology. The decrease in thymus weight observed at 

the mid and high dose groups were not considered to be treatment related due to lack of 

histopathological changes of the thymus in this study, in other studies in the data base, and in the 

immunotoxicity studies in mice and rats. Additionally, there was no evidence of impairment of 

functional immunotoxicity at the Limit Dose in adult mice and rats and during the prenatal, 

postnatal, and post-weaning periods in a developmental immunotoxicity study.

Under the conditions of this study, the NOAEL for Dinotefuran in dogs is 16000 ppm (512 

mg/kg bw/day), the highest dose tested. A LOAEL was not established.

This chronic study in the dog is classified as Acceptable/Guideline and satisfies the guideline 

requirement for a chronic oral study [OPPTS 870.4100, OECD 452] in dogs.
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A.4.5 Carcinogenicity

870.4300 Combined Chronic Toxicity/Carcinogenicity Study – rat

In a combined chronic toxicity/carcinogenicity study (MRID 45640001), MTI-446 (Dinotefuran, 

98.9% a.i., Lot/Batch # 2200210) was administered to groups of 60 male and 60 female rats per 

group at dietary concentrations of 0, 60, 200, 2000, or 20,000 ppm (2.98, 9.89, 99.7, and 991 

mg/kg bw/day, respectively, for males and 3.91, 12.5, 127.3, and 1332 mg/kg bw/day, 

respectively, for females) for 104 weeks. Additional groups of ten rats/sex/group were 

administered the same dietary concentrations of test material for 26, 52, and 78 weeks for interim 

evaluations. Groups of ten rats/sex also were administered basal or 20,000-ppm diets for 26 

weeks followed by 6 weeks on basal diet to assess the reversibility of any treatment-related 

effects (recovery study). 

No treatment-related or adverse effects occurred on survival, clinical signs, hematology 

parameters, clinical chemistry parameters, urinalysis parameters, organ weights; or the eyes in 

male or female rats administered any dose of the test material at any time during the study. Male 

rats in the 20,000-ppm group weighed 4-9% (p 0.05) less than controls from weeks 2-90 and 4% 

(not significant) less at study termination; they also gained 20% less weight than controls 

between weeks 26 and 54, but only 5% less over the entire study. Females in the 20,000-ppm 

group weighed up to 17% (p 0.05) less than controls during the first year of the study and up to 

32% (p 0.05) less during the second year. Females in the 20,000-ppm group gained 52-58% less 

weight than controls between weeks 26-52 and 52-78 and 36% (p 0.05) less weight than 

controls over the entire study. Food consumption was 7-12% (p<0.05) less than that of controls 

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

males in the control and 20,000-ppm group, respectively, for weeks 26-52, 1.84% and 0.95% for 

females in the control and 20,000-ppm groups, respectively, for weeks 26-52 and 1.49% and 

0.70%, respectively, for females in the control and 20,000-ppm groups for weeks 52-78. 

Therefore, reduced food consumption likely contributed to the decreased weight gain in the 

males, but is not sufficient to explain the decreased weight gain in females. No treatment-related 

decreases in body weight, weight gain, food consumption, or food efficiency were observed in 

either sex at 60 or 2000 ppm dose groups.

The only treatment-related gross finding was increased incidence of thinness (49% vs 28% for 

controls, p 0.05) in 20,000-ppm group females that died or were killed moribund before study 

termination. Microscopic findings considered treatment related included pelvic mineralization 

(22/60 rats vs. 5/60 for controls) and ulceration (5/60 rats vs 0/60 for controls) in 20,000-ppm 

group males.

The incidence of C-cell adenomas of the thyroid gland was increased (p=0.053) in male rats at 

the high dose (15/60; 25%) when compared to controls (7/59; 12%). This increase was not 

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

in benign tumors (i.e., adenomas); 2) absence of corroborative pre-non-neoplastic lesions in the 
Page 56 of 69

thyroids (e.g., hypertrophy or hyperplasia); 3) lack of progression to malignancy (i.e., no 

carcinomas were seen); 4) no reduction in the latency period (i.e., not a fatal tumor); and 5) the 

incidence (25%) was numerically comparable to the high end (24%) of the historical control 

range (1.7 – 24%). The incidences of C-cell adenomas at the other dose levels were within the 

historical controls range. 

Under the conditions of this study, the lowest-observed-adverse-effect level (LOAEL) for 

Dinotefuran in rats is 20,000 ppm (991 and 1332 mg/kg bw/day, respectively) based on 

decreased body weight gain and increased incidences of kidney pelvic mineralization, 

tubular basophilia, lymphocytic infiltration and ulceration in males. The no-observedadverse-effect level (NOAEL) is 2000 ppm (99.7 and 127.3 mg/kg bw/day, for males and 

females, respectively).

This chronic/carcinogenicity study in the rats is classified as Acceptable/Guideline and satisfies 

the guideline requirement for a chronic toxicity/carcinogenicity study in rats (OPPTS 870.4300; 

OECD 453].

870.4200b Carcinogenicity (feeding) – Mouse

In a carcinogenicity study (MRID 45639917) MTI-446 (93% a.i., lot # 2200210) was 

administered to 70 Crl:CD-1® (ICR)BR VAF/Plus® mice/sex/dose in the diet at concentrations 

of 0, 25, 250, 2500, or 25,000 ppm (equivalent to 0, 3, 34, 345, or 3694 mg/kg bw/day for males 

and 0, 4, 45, 441, or 4728 mg/kg bw/day for females) for 78 weeks. Ten mice/sex/dose were 

sacrificed at week 53.

Treatment had no adverse effects on survival, clinical sings, body weight, body weight gain, food 

consumption, organ weights, gross pathology or histopathology. The high dose of 25,000 ppm in 

the diet affected body weights and body weight gains of both male and female mice. Final mean 

body weights of male and female mice administered 25,000 ppm in the diet were 95 and 91% of 

the respective control group body weights. Respective overall weight gains were 82 and 75% of 

the control weight gains. There was no evidence of carcinogenicity in either sex at any dose 

including the highest dose tested which was three-fold the Limit Dose.

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

The NOAEL for dinotefuran in mice is 25,000 ppm in the diet (3,694/4,728 [M/F] 

mg/kg/day), the highest dose tested. A LOAEL was not established.

This carcinogenicity study is classified as Acceptable/Guideline and satisfies guideline 

requirements for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice.
Page 57 of 69

A.4.6 Mutagenicity

Gene Mutation

870.5100 and 870.5300

MRID 45640003, 45654210, 45640002

Negative ±S9 up to 16,000 μg/plate

Negative ±S9 up to 5000 μg/plate

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

Cytogenetics

870.5395

MRID 45654212

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

Other Genotoxicity

870.5375

MRID 45654211

Negative for clastogenic/aneugenic activity up to 2000 μg/mL.

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity

In an acute neurotoxicity study (MRID 45640005), groups of fasted, 48-54 day old Crl:CD (SD) 

IGS BR rats (10 animals/sex/group) were given a single oral dose of MTI-446 (93% [98.9% 

purity of dried matter]; lot # 2200210) in 0.5% carboxymethylcellulose in reverse osmosis water 

at doses of 0, 325, 750, or 1500 mg/kg bw and observed for 15 days. Neurobehavioral 

assessment (functional observational battery and motor activity testing) was performed in 10 

animals/sex/group one week prior to treatment, approximately 3 hours post-dosing (time of peak 

effect) on Day 1, and on Days 8 and 15. At study termination, all animals were euthanized and 

perfused in situ for gross pathology examination. Of the perfused animals, 6 animals/sex in the 

control and high-dose groups were subjected to neuropathologic evaluation of brain and 

peripheral nervous system tissues. 

There were no treatment-related effects on mortality, clinical observations, body weight, 

functional observational battery parameters, gross pathology or neuropathology. Motor activity 

was decreased on day 1 at the high dose in both males and females. This decrease was 

statistically significant for males in the first subsession (0-10 min, 68% of control values) and for 

females in the first and last subsession (33-56% of control values), as well as for total activity 

(53% of control values). Total activity for males was also reduced on day 1 (70% of control

values, n.s.). For females only, motor activity was also reduced at the mid-dose (28-80% of 

controls for subsessions, 68% of controls for total activity). Although the decreases at the middose was not statistically significantly different when compared to the controls, it was considered 

to be biologically significant due to the magnitude of the effect, presence of dose-response, and 

consistency across all subsessions. The decreases in motor activity observed were observed on 

Day 1 in both sexes at the high dose and in female at the mid dose were attributable to treatment. 

On days 8 and 15, motor activity in all treated groups was comparable to control values.
Page 58 of 69

Under the conditions of this study, the LOAEL for Dinotefuran in rats is 1500 mg/kg in 

males and 750 mg/kg/day in females based on decreases in motor activity on Day 1. The 

NOAEL is 750 mg/kg/day in males and 325 mg/kg/day in females.

870.6200 Subchronic Neurotoxicity

In a subchronic neurotoxicity study (MRID 45640004), groups of 10 Crl:CD®(SD)IGS BR 

rats/sex/dose were administered Dinotefuran [93.0% a.i., Lot No. 2200210 (dried matter 98.9% 

a.i.)] at dietary dose levels of 0, 500, 5,000, or 50,000 ppm (equivalent to 0, 33, 327, or 3,413 

mg/kg/day for males and 0, 40, 400, or 3,806 mg/kg/day for females) for 13 weeks. All animals 

were observed twice daily. Individual body weights and food consumption were determined 

weekly. Neurobehavioral assessment (functional observational battery and motor activity 

testing) was performed in all animals/sex/group prior to treatment and once during weeks 2, 4, 8, 

and 13. At study termination, all animals/sex/group were euthanized and perfused in situ for 

neuropathological examination. Of the perfused animals, six rats/sex in the control and highdose groups were subjected to microscopic examination of brain and peripheral nervous system 

tissues. 

No deaths occurred and there were no clinical signs attributable to treatment. Body weights were 

significantly (p 0.05) reduced in high-dose males and females throughout the 13-week 

treatment period. The final body weights for males and females in the high-dose group were 

79% and 81% of the respective controls. Total body weight gains over the entire study period 

were 62% and 46% of controls for high-dose males and females, respectively (p 0.05). Food 

consumption was significantly (p 0.05) reduced during most treatment weeks in high-dose 

animals, with average daily food consumption 87% and 82% of control males and females, 

respectively. Overall food efficiency was 70% and 58% of controls for high-dose males and 

females, respectively. Relative to controls, there were no treatment-related effects on body 

weight, body weight gain, food consumption, or food efficiency in the lower dose groups.

At 50,000 ppm, FOB assessments revealed significantly decreased body temperature (0.5oC 

below controls) and decreased rearing (35% of control values) in high dose females during week 

2. In addition, motor activity was decreased in high dose females; the decrease was statistically 

significant during week 2 (55% of control levels), and remained below control levels (72-84% of 

control values) throughout the treatment period (during assessments at weeks 4, 8, and 13).

At 5000 ppm, there were significant increases in subsession motor activity in both males and 

females during week 2 (220-429% of control levels). This inverted U pattern of activity –

increased activity at mid dose and decreased activity at high-dose, compared to control - is 

consistent with the mode of action of neonicotinoids. Typically, low to moderate activation of 

nicotinic acetylcholine receptors (nAChR) causes stimulation of the peripheral nervous system 

(PNS). Whereas high levels of neonicotinoids (agonists) can over stimulate the PNS, 

maintaining the voltage-gated sodium channels in the open state which blocks the action 

potential and leads to paralysis. 
Page 59 of 69

Under the conditions of this study, the LOAEL for Dinotefuran in rats is 5000 ppm (327 

mg/kg/day for males and 400 mg/kg/day for females) based on changes in motor activity 

during week 2. The corresponding NOAEL is 500 ppm (33 mg/kg/day and 40 mg/kg/day, 

respectively, for males and females).

870.6300 Developmental Neurotoxicity Study

One hundred presumed pregnant Cr1:CD(SD) rats were randomly assigned to four exposure 

groups, 25 rats per group (MRID 48291601). The test substance in the diet, MTI-446 

(Dinotefuran), or vehicle were offered continuously on days 6 of gestation (GD 6) through day 

21 of lactation (PND 21) until sacrifice at exposures of 0 , 1000, 3000 or 10000 ppm. Dietary 

exposures were equivalent to 0, 79.4, 237.4 or 784.1 mg/kg/day during gestation and 0, 158.0, 

500.7 or 1642.9 mg/kg/day during lactation. All maternal rats were sacrificed after completion 

of the 21-day postpartum period and a gross necropsy was performed. The following parameters 

were evaluated: viability, clinical observations, detailed clinical observations, maternal body 

weight and body weight changes, maternal behavior, feed consumption values, necropsy 

observations, the number and distribution of corpora lutea, implantation sites, uterine contents, 

litter size and pup viability. 

On day 4 (PND 4) all litters were reduced to ten pups each by random selection; 25 appropriately 

sized litters per group were selected for examination on study. Ten pups of each sex and dosage 

group were randomly selected for brain weight/dimensions determination and 

neurohistopathology (Subsets 1 and 4). Litters with fewer than nine pups were not assigned to 

study, but retained until not needed. One male and one female pup/litter (up to 25/sex/subset) 

were assigned to each evaluation as follows: PND 21 brain weight/gross dimensions (all dose 

groups) and neurohistopathology and microscopic brain measurements (0 and 10000 ppm dose 

groups only); water maze and passive avoidance; motor activity and acoustic startle habituation; 

brain weight/gross dimensions (all dose groups) and neurohistopathology and microscopic brain 

measurements (0 and 10000 ppm dose groups); one pup per sex used for replacement of rats 

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

Rats were observed for viability at least twice daily during the postweaning period and clinical 

observations and general appearance once weekly during the postweaning period. Additionally, 

rats assigned to Subsets 2 and 3 were examined for gross signs of toxicity and clinical 

observations; and rats assigned to Subset 4 were examined by an individual unaware of each rat's 

dosage group for detailed clinical observations. Body weights for male and female rats were 

recorded weekly during the postweaning period and prior to sacrifice. Pup body weights were 

recorded on PNDs 0, 4, 7, 11, 13, 17 and 21. Food consumption values for male and female rats 

were recorded weekly during the postweaning period and on the day of preputial separation or 

vaginal patency for subsets 2 through 4.

Subset I pups selected for brain weight/dimension determination and neurohistopathological 

evaluations were sacrificed and processed on PND 21. All pups in Subset I were examined for 

gross lesions. Subsets 2 and 3 rats were sacrificed after completion of the postweaning 
Page 60 of 69

behavioral evaluations. Subset 4 rats randomly selected for neurohistopathological evaluations 

were sacrificed on PND 69 and those not selected for these procedures were sacrificed and 

examined for gross lesions. Subset 5 pups were sacrificed on PND 21 and examined for gross 

lesions.

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

related to exposure to MTl-446 occurred. Body weight gains for intervals GD 6 to 9and GD 6 to 

20 were significantly reduced, 45% and 11%, respectively, in the 10000 ppm exposure group 

compared to the control group value; however, this body weight decrement was not sustained 

and body weights on GD 20 in all treatment groups were essentially equivalent to control values. 

Body weight gains during the lactation period did not differ significantly among the treatment 

groups. While maternal body weights were significantly reduced in the 10000 ppm exposure 

group on days 11 and 16 of lactation (LD 11 and 16), this ~4% decrement is not considered 

toxicologically significant. Exposure to MTI-446 at up to 3000 ppm during gestation and 

lactation did not affect body weight gains or body weights. Absolute and relative food 

consumption values were generally comparable among the exposure groups. No maternal gross 

lesions related to exposure to MTI-446 occurred.

The maternal NOAEL for dinotefuran in rats was 10,000 ppm (784 mg/kg/day gestation;

1643 mg/kg/day, lactation), the highest dose tested.

No clinical and no necropsy observations in the Fl generation pups were attributed to maternal 

exposure to the test substance at doses as high as 10,000 ppm. No mortality related to maternal 

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

survived to scheduled sacrifice. One female rat in the 10,000 ppm maternal exposure group was 

found dead on postnatal day PND23, another was found dead on PND 26 and two female rats in 

the 0 ppm exposure group were missing on PND 21 or 22 and another was sacrificed due to 

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

MTl-446. All other rats survived to scheduled sacrifice.

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

considered to be unrelated to the test substance. Average body weights, body weight gains and 

absolute and relative feed consumption values in the male and female offspring were unaffected 

by maternal exposure to MTI-446 at exposures up to 10,000 ppm. There were no microscopic 

changes in the tissues evaluated histologically that were considered to have been the result of test 

substance administration. No statistically significant inter-group differences were noted for brain 

weights or for gross brain dimensions on days 21 and 69 postpartum. No treatment-related 

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

nervous systems at 10,000 ppm. Maternal exposure to MTI-446 at concentrations as high as 

10,000 ppm did not affect the day of vaginal patency or preputial separation. Motor activity was 

not affected by maternal exposures to MTI-446 as high as 10,000 ppm. Maternal exposure to 

MTI-446 as high as 10,000 ppm did not affect learning and memory in offspring as evaluated in 

a passive avoidance paradigm.
Page 61 of 69

The offspring NOAEL for dinotefuran in rats was 10,000 ppm (784 mg/kg/day gestation; 

1643 mg/kg/day, lactation), the highest dose tested.

This study is classified acceptable/guideline and satisfies the guideline requirement for a 

developmental neurotoxicity in rats

A.4.8 Metabolism

870.7485 Metabolism – Rat

In a metabolism study (MRID 45640006), MTI-446 (dinotefuran, >98% a.i., batch numbers 

VB9304, VB9302 (radiolabeled in the guanidine and furan positions) and 22-00210 & OFU1265 (unlabeled) was administered to multiple groups of 5 or more male and female rats. The 

rats received single 50 or 1000 mg/kg oral or 50 mg/kg IV treatments or multiple oral 50 mg/kg 

treatments and were killed 0.5 to 168 hours after treatment.

Absorption was > 90% regardless of dose. The radiolabel was widely distributed through the 

body and was completely excreted within 168 hours of treatment. Urine was the primary 

elimination route, accounting for 88-99.8% with <5% of the radiolabel recovered in the feces, 

cage wash, expired air, carcass, and tissues of treated animals. Excretion into the urine was 

rapid, being 84-99% complete within 24 hours of treatment. Less than 0.1% of the radiolabel 

was retained by the tissues and carcass 168 hours after treatment. 

The pharmacokinetic parameters confirmed rapid absorption with a Cmax of 40.8-47.4 ppm 

reached in 0.25-0.625 hours in low-dose rats. In high-dose rats, a Cmax of 471-566 ppm was 

reached ~2 hours after treatment. The AUC0- ranged from 69.0-110 ppm hr for low-dose rats 

and 2370-2660 ppm hr for high dose rats. Absorption of the radioactivity was linear within the 

dose range of 50 and 1000 mg/kg. Elimination of radioactivity was fast for all groups with a 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. Of the 

limited metabolism that occurred, MTI-446 initially underwent enzymatic hydroxylation of the 

furan ring to form 6-hydroxy-5-(2-hydroxyethyl)-1-methyl-1,3-diazinane-2-ylidene-Nnitroamine (PHP) isomers. Further oxidation, reduction and acetylation of PHP occurred to form 

1-methyl-2-nitro-3-(2-oxotetrahydro-3-furylmethyl)guanidine (446-CO), 1-[4-hydroxy-2-

(hydroxymethyl)butyl]-3-methyl-2-nitroguanidine (446-DO) and its acetyl conjugate, and 3-
Page 62 of 69

hydroxymethyl-4-(-3-methyl-2-nitroguanidino)butyric acid (446-OH + COOH). A minor 

pathway involves the C-N bond cleavage to yield the furan and guanidine moieties; the free 

guanidine is represented by trace amounts of MNG, MG, and MG-Ac. For all parameters 

measured in this study, no sex- or dose-related differences or label position effects were found.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity - Rat

In an immunotoxicity study (MRID 48442101) Dinotefuran (MTI-446, 97.9% a.i., batch# 

K09C3718) was administered to 10 Crl:CD (SD) rats/dose/sex via diet at dose levels of 0, 2240, 

5600, or 14000 ppm (0/0, 164/179, 425/430, or 992/1018; males/females respectively) for 4-

weeks. The positive control group consisting of 8 Crl:CD (SD) rats/sex were administered 50 

mg/kg cyclophosphamide via intraperitoneal injection on Day 27. On Day 25, all test animals 

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

concentration of 2x108cells/mL. On Day 29, T-cell dependent antibody response (TDAR) was 

determined with a plaque forming cell (PFC) assay. Parameters evaluated include mortality, 

clinical signs of toxicity, body weight, body weight gain, food consumption, water consumption, 

organ weights (i.e. spleen and thymus), macroscopic pathology, and assay-specific parameters.

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

no treatment-related effects on water consumption or organ weights (i.e. spleen and thymus); and 

there were no treatment-related findings for clinical signs of toxicity or macroscopic pathology. 

At the 14000 ppm dose (M: 992 mg/kg/day), the treatment-related effects observed were 

decreased body weight, body weight gain, and food consumption.

The systemic toxicity NOAEL is 5600 ppm (425/430 mg/kg/day for males and females 

respectively) and the LOAEL is the HDT, 14000 ppm (992/1018 mg/kg/day for males and 

females respectively), based on decreased body weight, body weight gain, and food 

consumption.

The plaque forming cell (PFC) assay results showed that there were no statistical differences in 

quantity of cells/spleen, PFC/106viable cells, or PFC/spleen in any treatment group when 

compared with the vehicle controls. A high inter-individual variability was noted in all the 

treatment groups as well as in the control group. Evaluation of individual animal data did not 

show any trend or distribution that would demonstrate significant suppression of SRBC antibody 

response.

The Natural Killer (NK) cells activity assay was not performed in this study. In a previous 

developmental immunotoxicity study in rats (MRID 47677501), it was concluded that 

dinotefuran showed no evidence of an effect on the functionality of the immune system in rats 

that were exposed to dinotefuran during the prenatal, postnatal, and post-weaning period (TXR# 

0055238). The overall weight of evidence suggests that this chemical does not directly target the 
Page 63 of 69

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

The immunotoxicity NOAEL is the HDT, 14000 ppm (992/1018 mg/kg/day for males and 

females respectively), based on results of a PFC assay and the LOAEL was not established.

870.7800 Immunotoxicity – Mouse

In an immunotoxicity study (MRID 48442102) Dinotefuran (MTI-446, 97.9% a.i., batch# 

K09C3718) was administered to 10 Crl:CD1 (ICR) mice/dose/sex via diet at dose levels of 0, 

1120, 2800, or 7000 ppm (0/0, 153/223, 405/581, or 1053/1438; males/females respectively) for 

4-weeks. The positive control group consisting of 8 Crl:CD1 (ICR) mice/sex were administered 

20 mg/kg/day cyclophosphamide via gavage (oral) on Days 22-26. On Day 25 of the study, all 

animals were immunized with a 0.2 mL intravenous injection of sheep red blood cells (SRBCs) 

at a concentration of 2x109cells/mL. On Day 29, T-cell dependent antibody response (TDAR) 

was determined with a plaque forming cell (PFC) assay. Parameters evaluated include mortality, 

clinical signs of toxicity, body weight, body weight gain, food consumption, water consumption, 

organ weights (i.e. spleen and thymus), macroscopic pathology, and assay-specific parameters.

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

no treatment-related effects on body weight, body weight gain, food consumption, water 

consumption, or organ weights (i.e. spleen and thymus); and there were no treatment-related 

findings for clinical signs of toxicity or macroscopic pathology.

The systemic toxicity NOAEL is the HDT, 7000 ppm (1053/1438 mg/kg/day for males and 

females respectively), and the LOAEL was not established.

The plaque forming cell (PFC) assay results showed that there were no statistical differences in 

quantity of cells/spleen, PFC/106viable cells, or PFC/spleen in any treatment group when 

compared with the vehicle controls. A high inter-individual variability was noted in all the 

treatment groups as well as in the control group. Evaluation of individual animal data did not 

show any trend or distribution that would demonstrate significant suppression of SRBC antibody 

response.

The Natural Killer (NK) cells activity assay was not performed in this study. In a previous 

developmental immunotoxicity study in rats (MRID 47677501), it was concluded that 

dinotefuran showed no evidence of an effect on the functionality of the immune system in rats 

that were exposed to dinotefuran during the prenatal, postnatal, and post-weaning period (TXR# 

0055238). The overall weight of evidence suggests that this chemical does not directly target the 

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

The immunotoxicity NOAEL is the HDT, 7000 ppm (1053/1438 mg/kg/day for males and 

females respectively), based on results of a PFC assay and the LOAEL was not established.
Page 64 of 69

A.4.10 Special/Other Studies

Non-guideline

In a developmental immunotoxicity study and a dose-range finding for a developmental 

neurotoxicity study (DNT) (MRID 47677501), MTI-446 (dinotefuran; 94.7%; Lot # 2200210) 

was administered in the diet to presumed pregnant Sprague Dawley (Crl:CD[SD]) rats (10/dose) 

at dietary levels of 0, 1000, 3000, or 10,000 ppm (equivalent to 0, 105.4, 317.8, or 1035.4 

mg/kg/day, respectively) beginning on gestation day (GD) 6, and continuing through lactation 

day (LD) 21. The F1 generation was potentially exposed through the maternal milk and the 

dam’s dose formulation through weaning. On PND 21, the F1 generation were selected (up to 

three pups/sex/litter) randomly for immunotoxicity assays. F1 pups (20/sex/dose) were fed the 

same dietary concentrations as their dams beginning on PND 21 until termination (PND 42). 

Systemic toxicity parameters were evaluated in the P and F1 generations, and immunotoxicity 

was evaluated in the F1 generation. Ten F1 pups/sex/dose group were examined for humoral 

immune response by measuring IgM antibody forming cell responses following immunization 

with sheep red blood cell (SRBC); the remaining ten F1 pups/sex/dose group were examined for 

innate immune response by performing a natural killer (NK) cell assay. The splenocytes of the 

pups used for the NK cell assay were also phenotyped by flow cytometry.

For maternal toxicity, no treatment-related adverse effects were observed on mortality, clinical 

signs, body weights, body weight gains, food consumption, reproductive performance, or gross 

pathology.

The maternal toxicity LOAEL was not observed. The NOAEL for maternal toxicity is 

10,000 ppm (equivalent to 1035.4 mg/kg bw/day).

For offspring toxicity, no treatment-related effects were observed on the birth, live birth, 

viability, or lactation indices or on sex ratio on PND 21. There were no clinical signs of toxicity, 

and all pups sacrificed on PND 4 and PND 21 appeared normal at necropsy. At 10,000 ppm, pup 

body weights were decreased (p≤0.01) by 13-18% during PND 13-21. After weaning, no 

treatment-related adverse effects were observed on mortality, clinical signs, food consumption, 

or gross pathology in the post-weaning F1 generation. At 10,000 ppm, post-weaning body 

weights were decreased (p≤0.05) by 7-22% during PND 22-57 in the males, and by 7-11% 

during PND 22-36 and PND 57-64 in the females. 

The offspring toxicity LOAEL was 10,000 ppm (equivalent to 1035.4 mg/kg bw/day), based 

on decreased body weights in both sexes. The NOAEL for offspring toxicity is 3000 ppm 

(equivalent to 317.8 mg/kg bw/day).

For dose-range finding of a developmental neurotoxicity study, this diet concentration (10000 

ppm) is considered suitable as a high dose level for the DNT study.
Page 65 of 69

For developmental immunotoxicity, there were no treatment-related effects on antibody forming 

cell response (humoral immunity) and Natural Killer Cell activity (innate immunity). No 

differences that attributable to treatment were noted in the distribution of splenocyte 

subpopulations. Increased spleen weights were observed in the 1000 and 3000 ppm males, but 

this finding was not dose-dependent and was considered incidental.

Under conditions of this study, there were no immunologically adverse effects on antibody 

forming cell response or Natural Killer cell activity in male and female rats that exposed to 

dinotefuran during the prenatal, postnatal and post-weaning period. The LOAEL for 

developmental immunotoxicity was not observed. The NOAEL is 10,000 ppm (equivalent to 

1035.4 mg/kg bw/day).

Non-Guideline

In a neonatal metabolism study (MRID 45640007), radiolabeled MTI-446 (dinotefuran, Lot No. 

VB9304, labeled on the central guanidine portion of the molecule, purity and radiopurity >99%) 

was administered to 12-day old male and female Sprague Dawley pups. The pups were divided 

into two groups. Group 1, consisting of 25 male and 25 female pups, received a single oral dose 

of 50 mg/kg labeled test material. Five pups of each sex were sacrificed 0.5 and 1.5 after 

treatment and 15 pups of each sex were sacrificed 4 hours after treatment. At sacrifice, blood, 

plasma, intestinal tract with contents, kidney, liver, stomach and contents, the residual carcass, 

and pooled excreta were collected. Three male and 3 female pups in Group 2 received a single 

oral dose of 50 mg/kg labeled test material and one pup of each sex was sacrificed 0.5, 1.5, and 4 

hours after treatment and subjected to whole body autoradiography (WBA). 

After a single oral 50 mg/kg dose of [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 WBA. No areas of 

tissue sequestration were found and no gender-related differences were identified. The test 

material was essentially not metabolized, the parent compound accounting for >97% of the 

radiolabel in the excreta, plasma, kidneys, and stomach, and nearly 61-83% in intestines (and 

contents), and liver.

This neonatal metabolism study is classified Acceptable/Non-guideline, and satisfies the intent of 

the study to investigate the absorption, distribution, metabolism and excretion of radiolabeled 

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

12-day-old neonatal rats were used; a single dose was used (50 mg/kg); urine and feces were not 

collected separately, excreta were not collected individually for the determination of the percent 

of dose contained in each; the study duration was 4 hours; no expired air was collected; and no 

biliary studies were done.
Page 66 of 69

Appendix B. Physical/Chemical Properties

1 DP# TABLE B. Physicochemical Properties of the Test Compound: Dinotefuran.

Parameter Value Reference (MRID)

Melting point/range 107.5oC 45639702

pH 5.6 @ 25oC 45654201

Density 1.40 g/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 67 of 69

Appendix C. International Residue Limit Status Sheet.

Dinotefuran (044312; 11/03/2011)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.603

Plant (a) General (1) dinotefuran, sum of dinotefuran 

and its metabolites DN, 1-methyl-3-(tetrahydro-3-

furylmethyl)guanidine, and UF, 1-methyl-3-

(tetrahydro-3-furylmethyl)urea

None None

Commodity1

Tolerance (ppm) /Maximum Residue Limit 

(mg/kg)

US Canada Mexico2 Codex3

Berry, low growing, except strawberry, 

subgroup 13-07H 0.2

Fruit, small vine climbing, except fuzzy 

kiwifruit, subgroup 13-07F 0.9

Onion, bulb, subgroup 3-07A 0.15

Onion, green, subgroup 3-07B 5.0

Peach 1.0

Tea, plucked leaves 25

Vegetable, tuberous and corm, subgroup 1C 0.05

Watercress 8.0

Completed: M. Negussie; 11/03/11

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

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

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated 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 68 of 69

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

PHP 6-hydroxy-5-(2-

hydroxyethyl)-1-methyl-1,3-

diazinane-2-ylidene-Nnitroamine

N

H

N H

N

O H

CH3

N

H

O

N

O H

CH3

N

H

N

N

O H

CH3

NO2
Page 69 of 69

Common name/code Chemical name Chemical structure

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

furylmethyl)guanidine

Appendix E. Review of Human Research

Studies reviewed for ethical conduct:

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

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

Agency, and the National Agricultural Chemicals 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).