Document ID: EPA-HQ-OPP-2009-0013-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-12-18T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 11/17/2009

MEMORANDUM

SUBJECT:	Second Amendment: Dinotefuran: Human Health Risk Assessment for
Proposed Uses on Brassica Leafy Vegetables Subgroup 5B and Turnip Greens

PC Code: 044312	DP Barcode: D371573

Decision No.: 400299	Registration Nos.: 33657-17, 33657-38, 59639-135

Petition No.: 8F7433 	Regulatory Action: Section 3 Registration Action

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

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

MRID Nos.: NA	40 CFR: 180.603

FROM:	Barry O’Keefe, Risk Assessor

		Amelia Acierto, Chemist

		Whang Phang, Toxicologist

		Risk Assessment Branch 3 (RAB3)

		Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief

		Risk Assessment Branch 3 (RAB3)

		Health Effects Division (7509P)

TO:		Rita Kumar, Senior Regulatory Specialist

		Fungicide Branch

		Registration Division (7505P)

This document amends the Human Health Risk Assessment for Dinotefuran
dated 10/15/09 (DP370643, B. O’Keefe) to include an aggregate risk
assessment including the indoor uses and to provide additional
information from the recently-received range-finding developmental
neurotoxicity (DNT) study.

The Registration Division (RD) of the Office of Pesticide Programs (OPP)
has requested that the Health Effects Division (HED) evaluate toxicology
and residue chemistry data and conduct dietary, aggregate, and
occupational exposure and risk assessments, as needed, to estimate the
risk to human health that will result from existing and proposed uses of
dinotefuran.

On behalf of Valent U.S.A. Corporation and Mitsui Chemicals, Inc., the
Interregional Research Project Number 4 (IR-4) is proposing this active
ingredient (ai) for selective control of insects on turnip greens and on
a broad spectrum of the following crops within the turnip greens and
Brassica (cole) leafy vegetables, crop subgroup 5 (broccoli raab,
collards, kale, mizuna, Chinese cabbage (bok choy), mustard greens,
mustard spinach, and rape greens).

HED has conducted a human health risk assessment for these proposed
uses.  HED has high confidence in the quality of the toxicology,
chemistry, and exposure databases used to assess risk from dinotefuran.

A summary of the findings and an assessment of human risk resulting from
the registered and proposed tolerances for dinotefuran are provided in
this document.  The risk assessment and the occupational/residential
exposure assessment were provided by Barry O’Keefe.  The residue
chemistry data review and dietary risk assessment were provided by
Amelia Acierto. The toxicology update was provided by Whang Phang.  

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc243366599 \h  4 

2.0	Ingredient Profile	  PAGEREF _Toc243366600 \h  9 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc243366601 \h  9 

2.2	Physical and Chemical Properties	  PAGEREF _Toc243366602 \h  10 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc243366603 \h  11 

3.1	Hazard Characterization and FQPA Considerations	  PAGEREF
_Toc243366604 \h  11 

3.1	FQPA Safety Factor for Infants and Children	  PAGEREF _Toc243366605
\h  14 

3.3	Summary of Toxicological Doses and Endpoints for Use in Human Health
Risk Assessments	  PAGEREF _Toc243366606 \h  14 

3.4	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc243366607 \h  16 

3.5	Endocrine disruption	  PAGEREF _Toc243366608 \h  17 

4.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc243366609 \h 
18 

4.1  Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc243366610 \h  18 

4.1.1	Metabolism in Primary Crops	  PAGEREF _Toc243366611 \h  18 

4.1.2	Metabolism in Livestock	  PAGEREF _Toc243366612 \h  18 

4.1.3	Analytical Methodology	  PAGEREF _Toc243366613 \h  19 

4.1.4	Storage Stability Data	  PAGEREF _Toc243366614 \h  19 

4.1.5	Magnitude of the Residue in Plants	  PAGEREF _Toc243366615 \h  20 

4.1.6	Magnitude of the Residue in Processed Food/Feed	  PAGEREF
_Toc243366616 \h  21 

4.1.7	Confined and Field Accumulation in Rotational Crops	  PAGEREF
_Toc243366617 \h  21 

4.1.8	Drinking Water Residue Profile	  PAGEREF _Toc243366618 \h  21 

4.1.9	Proposed Tolerances	  PAGEREF _Toc243366619 \h  22 

4.2  Dietary Exposure and Risk	  PAGEREF _Toc243366620 \h  23 

5.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc243366621 \h  25 

6.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc243366622 \h  25 

7.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc243366623
\h  27 

8.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc243366624 \h  28 

8.1	Short-/Intermediate-Term Handler Risk	  PAGEREF _Toc243366625 \h  31

8.2	Short-/Intermediate-Term Postapplication Risk	  PAGEREF
_Toc243366626 \h  33 

9.0	Data Needs and Label Recommendations	  PAGEREF _Toc243366627 \h  35 

9.1	Toxicology Data Needs	  PAGEREF _Toc243366628 \h  35 

9.2	Residue Chemistry Data Needs and Label Recommendations	  PAGEREF
_Toc243366629 \h  35 

10.0	International Residue Limit Status	  PAGEREF _Toc243366630 \h  36 

11.0	Appendix A: Dinotefuran and its Metabolites	  PAGEREF _Toc243366631
\h  37 

12.0	Appendix B: Toxicity Profile	  PAGEREF _Toc243366632 \h  38 

12.1	Appendix B1.: Acute Toxicity Data on Dinotefuran Technical	 
PAGEREF _Toc243366633 \h  38 

12.2	Appendix B2.: Subchronic, Chronic and Other Toxicity Profile	 
PAGEREF _Toc243366634 \h  39 

13.0	Appendix C: Executive Summary of Dose Range-Finding Developmental
Neurotoxicity and Immunotoxicity Study	  PAGEREF _Toc243366635 \h  44 

 1.0	Executive Summary  TC \l1 "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 post-synaptic side of the nerve cells.

On behalf of Valent U.S.A. Corporation and Mitsui Chemicals, Inc., the
IR-4 is proposing this ai for selective control of insects (whitefly,
flea beetle and aphids) on turnip greens and on a broad spectrum of the
following crops within the Brassica (cole) leafy vegetables, crop
subgroup 5 (broccoli raab, collards, kale, mizuna, Chinese cabbage (bok
choy), mustard greens, mustard spinach, and rape greens).  The proposed
use is to apply by aerial or ground equipment using Dinotefuran 20SG
(EPA Reg. No. 33657-17), Dinotefuran 70SG (EPA Reg. No. 59639-135), or
Starkle 70SG (EPA Reg. No. 33657-38) as a foliar spray at 0.088 to 0.141
lb ai/A.  Up to a maximum of three applications per season can be made
with a minimum 7 day reapplication interval.  The proposed maximum
seasonal application rates are 0.262 to 0.268 lb ai/A by foliar
application, depending on the product used.

Hazard Assessment Summary

The quality of the toxicology database for dinotefuran is good and the
confidence in the hazard and dose-response assessments is high.  The
toxicity database for dinotefuran is considered adequate to support
toxicity endpoint selection for risk assessment and for FQPA evaluation.
 However, under the current 40 CFR §158.500 data requirement
guidelines, immunotoxicity data (OPPTS 780.7800) are now required.  In
2004, prior to this requirements, the registrant was required to submit
a developmental neurotoxicity study, including immunotoxicity parameters
as a condition of registration.  In response, the registrant submitted a
dose-range finding developmental neurotoxicity and immunotoxicity study
on dinotefuran in rats (MRID47677501).  In this study, dinotefuran
showed no evidence of an effect on the functionality of the immune
system.  The results of this dose-range finding study provide
information regarding the potential immunotoxic effects in offspring
rats after exposure to dinotefuran during prenatal, postnatal, and
post-weaning periods.  Dinotefuran did not affect the various parameters
examined.  The parameters examined are comparable to those measured in a
definitive immunotoxicity study.  The study is considered
acceptable/non-guideline.  When the results of this study are considered
with the entire toxicity data base of dinotefuran, this study fulfills
the requirement for an immunotoxicity study, at this time.

Dinotefuran has low acute toxicity by the oral, dermal, and inhalation
routes.  It is not a dermal sensitizer, but causes a low level of skin
irritation.  The main target tissues are the nervous system and the
immune system, with effects seen in several species.  Nervous system
toxicity is manifested as changes in motor activity observed in acute
and subchronic neurotoxicity studies in the rat, decreased grip strength
in adult offspring in the 2-generation rat study and maternal clinical
signs (prone position and tremor) in the rabbit developmental study.  
Immune system toxicity is manifested as decreases in spleen and thymus
weights, seen in multiple studies and species (including dogs, rats, and
mice).  There are also indications of endocrine-related toxicity,
manifested in the reproductive toxicity study (in rats) as decreases in
primordial follicles and altered cyclicity in females and abnormal sperm
parameters in males at the Limit Dose; changes in testes or ovary weight
were also seen in several species (mouse, dog, and rat).  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. 
Review of acceptable oncogenicity and mutagenicity studies provide no
indication that dinotefuran is carcinogenic or mutagenic.  Dinotefuran
is characterized as “not likely to be carcinogenic to humans” based
on the absence of significant tumor increases in two adequate rodent
carcinogenicity studies.

HED concluded that the toxicology database for dinotefuran is adequate
for FQPA assessment.  Available studies include developmental toxicity
studies in rats and rabbits, a reproductive toxicity study in rats, and
acute and subchronic neurotoxicity studies in rats.  Additionally, a
dose-range finding developmental neurotoxicity and immunotoxicity study
was also available.  There was no evidence of increased susceptibility
following in utero exposures in the prenatal developmental toxicity
studies in rats and rabbits.  In the reproduction toxicity study, there
was evidence for increased qualitative susceptibility.  The level of
concern for the observed susceptibility is low since 1) clear NOAELs and
LOAELs are established for the endpoints of concern for parental and
offspring toxicity; 2) the effects in the offspring were seen in the
presence of parental toxicity; and 3) the effects were seen only at the
highest dose tested which was the Limit Dose (1000 mg/kg/day).

In the range-finding developmental neurotoxicity and immunotoxicity
study, dinotefuran did not affect the distribution of splenocyte
subpopulations (total B cell, total T cells, helper/DTH T cells,
cytotoxic T cells, and natural killer cells) in the weanlings of F1
generation.  It did not affect the anti-SRBC antibody forming cell
response (humoral immunity) and NK cell activity (innate immunity). 
Therefore, 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
periods.

In the range-finding DNT study, no developmental neurotoxicity was seen.
 The offspring LOAEL was the Limit Dose (1035 mg/kg/day) based on
decreased body weight and the offspring NOAEL was 317 mg/kg/day. 
Establishment of such a high LOAEL in the range-finding study clearly
indicates that in order to elicit toxicity, dose selection for the
definitive DNT study will likely result in a point of departure much
higher than those currently used for overall risk assessment (range from
2.0 to 33.0 mg/kg/day).  These results are consistent with DNT studies
for other compounds in this chemical class (i.e., neonicotinoids).  The
results of the DNT studies on these structurally related compounds
(thiacloprid, clothianidin, and imidacloprid) indicate that while the
DNT study with dinotefuran will enhance hazard characterization (i.e.,
potential dinotefuran-induced neurotoxicity in developing animals), the
study will not provide points of departures lower than those currently
used for the overall risk assessments.  Therefore, a database
uncertainty factor (UFDB) is not applied for the lack of the DNT study. 
Based on these weight-of-evidence considerations, HED has concluded that
there are no residual uncertainties for pre- and or post- natal toxicity
and that the FQPA Safety Factor can be removed (i.e., 1X) for acute
dietary and non-dietary (incidental oral, and dermal) risk assessments. 
For the chronic dietary and short- and intermediate-term inhalation risk
assessments, however, the 10X FQPA Safety Factor is retained for the use
of a LOAEL (UFL) (i.e., lack of a NOAEL in the critical studies).

Dietary (Food & Drinking Water) Exposure Assessment

Acute dietary (food and drinking water) exposure estimates for the total
U.S. population and all population subgroups were below the HED’s
level of concern at the 95th percentile of exposure.  The assessment was
unrefined and assumed 100% crop treated and tolerances level residues. 
The estimated acute dietary exposure is <2% of the aPAD for the general
U.S. population and <4% of the aPAD for children 1-2 years old, the most
highly exposed population subgroup.

Chronic dietary (food and drinking water) exposure estimates for the
total U.S. population and all population subgroups were below the
HED’s level of concern.  The assessment was unrefined and assumed 100%
crop treated and tolerances level residues.  The estimated chronic
dietary exposure is 30% of the cPAD for the general U.S. population and
68% of the cPAD for children 1-2 years old, the most highly exposed
population subgroup.

Residential Exposure and Risk

This document only presents the assessment of the proposed new
agricultural uses of dinotefuran.  No residential uses are being
requested at this time; therefore, no residential risk assessment has
been conducted.  However, the aggregate risk assessment utilizes
residential exposure assessments conducted previously (DP285650, J.
Arthur, 04/27/04).

Aggregate Exposure Assessment

Because there are existing residential uses of dinotefuran, short- and
intermediate-term aggregate risk assessments based on exposure from
oral, inhalation, and dermal routes were considered.  However, the
toxicological effects for oral and inhalation routes of exposure are
different (i.e., neurotoxicity for oral and decrease in body weight for
inhalation); and therefore, these exposure scenarios have not been
combined.  Also, because no systemic toxicity was seen at the limit dose
in a 28-day dermal toxicity study, no quantification of short-term
dermal risk is required.  Therefore, a short-term aggregate risk
assessment was not performed.

Short- and intermediate-term aggregate risk assessments were performed
for adults and children.  For children, the subgroup with the highest
estimated chronic dietary exposure (children 1-2 years old) was
aggregated with residential exposures to children playing on treated
lawns (dermal and oral hand-to-mouth exposures) in order to calculate
the worst case intermediate-term aggregate risk to children.  The
reciprocal MOE method was used to conduct the intermediate-term
aggregate risk assessment for children, since the levels of concern are
identical for all MOEs in the calculation.  For adults, the aggregate
risk index (ARI) method was used, since levels of concern are not
identical for all types of exposure in the calculation.  For children,
the aggregate MOE is 160 which is greater than 100, and therefore does
not exceed HED’s level of concern.  For adults, the total aggregate
ARI is 5.9 which is greater than 1, and therefore does not exceed
HED’s level of concern.

Occupational Handler Exposure Assessment

No chemical-specific handler exposure data were submitted in support of
this registration.  It is the policy of the HED to use data from the
Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in
PHED Surrogate Exposure Guide (8/98) to assess handler exposures for
regulatory actions when chemical-specific monitoring data are not
available (HED Science Advisory Council for Exposure Standard Operating
Procedure (SOP) No. 7, dated 1/28/99).  

The short- and intermediate-term inhalation risk estimates to handlers
do not exceed HED’s level of concern at baseline (no respirator) for
any of the handler scenarios where baseline data are available.  Only
engineering control (enclosed cockpit) data are available to assess
inhalation risks to handlers operating aircraft.  The inhalation risks
do not exceed HED’s level of concern for pilots using enclosed
cockpits and wearing no respirator.

The intermediate-term dermal and combined intermediate-term dermal plus
intermediate-term inhalation risks to handlers do not exceed HED’s
level of concern with baseline attire (i.e., long-sleeve shirt, long
pants, shoes, and socks) where baseline data are available.  Only
engineering control (enclosed cockpit) data are available to assess
dermal (and therefore combined risks) to handlers operating aircraft. 
The dermal and combined risk estimates do not exceed HED’s level of
concern for pilots using enclosed cockpits and wearing baseline attire. 

Occupational Postapplication Exposure Assessment

HED assumes that inhalation exposures are minimal following outdoor
applications of an ai with low vapor pressure.  Since the proposed use
of dinotefuran includes only outdoor applications and dinotefuran has a
low vapor pressure, postapplication inhalation exposures and risks were
not assessed.

No short-term dermal point of departure (PoD) was identified for
dinotefuran.  Postapplication occupational risks were assessed using the
intermediate-term dermal PoD.

Data from chemical-specific residue dissipation studies were previously
submitted for use in completing the postapplication risk assessments for
ornamental, turf and agricultural (leafy vegetable) applications.  These
studies were summarized in a previous review (DP285650, 04/27/04, J.
Arthur).  Dissipation data from the study on leafy vegetables (DP300464,
06/09/04, MRID 45640008, B. O’Keefe) were used in this risk
assessment.  

All scenarios resulted in MOEs greater than 100 on day 0 (12 hours after
application) and therefore are not of concern to HED.  

Since systemic postapplication risks do not exceed HED’s level of
concern on day 0 (12 hours following application), the restricted entry
interval (REI) is based on the acute toxicity of dinotefuran technical
material.  Dinotefuran is classified as Toxicity Category IV for acute
dermal toxicity and for skin irritation and eye irritation potential. It
is not a dermal sensitizer. Acute toxicity Category III and IV chemicals
require a 12 hour REI under the Worker Protection Standard (WPS).  

Recommendations for Tolerances

HED has completed a human health risk assessment for the proposed new
uses of the active ingredient dinotefuran.  Pending submission of a
revised Section F to reflect the recommended tolerance level and revised
Section B labels for the end-use products to reflect the appropriate
maximum total in ounces corresponding to the stated limit in lbs
ai/A/season, there are no residue chemistry issues that would preclude
granting tolerances and registration for the requested use of
dinotefuran as stated below.

Note: The tolerance expression has been revised to meet current HED
policy.  Tolerances are established for residues of dinotefuran
((RS)-1-methyl-2-nitro-3-((tetrahydro-3-furanyl)methyl)guanidine),
including its metabolites and degradates, in or on the commodities
listed below.  Compliance with the tolerance levels specified below is
to be determined by measuring only the sum of dinotefuran and its
metabolites DN, 1-methyl-3-(tetrahydro-3-furylmethyl)guanidine, and UF,
1-methyl-3-(tetrahydro-3-furylmethyl)urea, calculated as the
stoichiometric equivalent of dinotefuran, in or on the commodities.  

HED recommends establishment of permanent tolerances for residues of
dinotefuran, as expressed and calculated above, under 40 CFR
§180.603(a) as follows:

		Brassica, leafy greens, subgroup 5B …………….15 ppm

		Turnip greens …………………………………….15 ppm

Recommendations for Labels

860.1200 Directions for Use

The application rate for the 20% formulation must be revised to reflect
the application rate in oz/A.

The maximum seasonal use rates for mustard greens for all labels must be
revised to reflect the maximum proposed seasonal use rate.

The additional directions for “foliar application” with the
restriction not to apply more than a total of 6 oz of Dinotefuran (0.268
lb ai) per acre per season applies to all three formulations.  Since the
20SG formulation contains only 20% active ingredient, 6 oz would not be
sufficient to provide the required seasonal rate.  The statement that
pertains to the 20SG formulation should be corrected.

Environmental Justice Considerations

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,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
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
toddlers, 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.

Review of Human Research

This risk assessment relies in part on data from Pesticide Handlers
Exposure Database (PHED) studies in which adult human subjects were
intentionally exposed to a pesticide or other chemical.  These studies
have been determined to require a review of their ethical conduct, have
received that review, and have been determined to be ethical.

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

2.1	Summary of Registered/Proposed Uses  TC \l2 "2.1	Summary of
Registered/Proposed Uses 

The proposed new use of dinotefuran is for control of whitefly, flea
beetle, and aphids on turnip greens and Brassica (cole) leafy
vegetables, crop subgroup 5 (broccoli raab, collards, kale, mizuna,
Chinese cabbage (bok choy), mustard greens, mustard spinach, and rape
greens).  The proposed use is to apply by aerial or ground equipment
using Dinotefuran 20SG (EPA Reg. No. 33657-17), Dinotefuran 70SG (EPA
Reg. No. 59639-135), or Starkle 70SG (EPA Reg. No. 33657-38) as a foliar
spray at 0.088 to 0.141 lb ai/A.  Up to a maximum of three applications
per season can be made with a minimum 7 day reapplication interval.  The
proposed maximum seasonal application rates are 0.262 to 0.268 lb ai/A
by foliar application, depending on the product used.  Applications may
not be made to vegetables grown for seed.  Applications may not be made
within one (1) day of harvest.  The proposed new uses of dinotefuran
evaluated in this assessment are summarized in Table 1.



Table 1.  Proposed Use Pattern for Dinotefuran

Crop	Product, Formulation	Treatment Type/Target of Application

	Application Equipment	Maximum Application Rate 

(lb ai/A)	Treatment Interval	Preharvest Interval

Turnip Greens and Brassica (cole) leafy vegetables, including broccoli
raab, cabbage, Chinese (bok choy), collards, kale, mizuna; mustard
greens mustard spinach, and rape greens. 	Soluble Granule

Dinotefuran 20SG

(20% a.i.)

Reg # 33657-17	Foliar application when first pest activity is noticed or
when insects reach State and County Extension Service recommendations
aerial or groundboom	0.141 lb ai/acre	Do not treat more often than every
7 days.  Do not apply more than a total of 0.268 lb ai per acre per
season.  No more than 3 applications of Dinotefuran 20SG are allowed per
season.	1 day

	Soluble Granule

Starkle 70SG

(70% a.i.)

Reg # 33657-38	Foliar application when first pest activity is noticed or
when insects reach State and County Extension Service recommendations
aerial or groundboom	0.131 lb ai/acre	Do not treat more often than every
7 days.  Do not apply more than a total of 0.262 lb ai per acre per
season.  No more than 3 applications of Starkle 70SG are allowed per
season.	1 day

	Soluble Granule

Dinotefuran 70SG

(70% a.i.)

Reg # 59639-135	Foliar application when first pest activity is noticed
or when insects reach State and County Extension Service recommendations
aerial or groundboom	0.134 lb ai/acre	Do not treat more often than every
7 days.  Do not apply more than a total of 0.268 lb ai per acre per
season.  No more than 3 applications of Dinotefuran 70SG are allowed per
season.	1 day

2.2	Physical and Chemical Properties  TC \l2 "2.2	Physical and Chemical
Properties 

The chemical structure of dinotefuran and its metabolites are presented
in Appendix A.  Please refer to a previous risk assessment document
(DP309412, 12/08/04, B. O’Keefe) for a detailed listing of the
physical and chemical properties of dinotefuran.



3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment 

3.1	Hazard Characterization and FQPA Considerations  TC \l2 "3.1	Hazard
Characterization and FQPA Considerations 

The quality of the toxicology database for dinotefuran is good and the
confidence in the hazard and dose-response assessments is high.  The
toxicity database for dinotefuran is considered adequate to support
toxicity endpoint selection for risk assessment and for FQPA evaluation.
 However, under the current 40 CFR §158.500 data requirement
guidelines, immunotoxicity data (OPPTS 780.7800) are now required.  In
2004, prior to this new requirement, the registrant was required to
submit a developmental neurotoxicity study including immunotoxicity
parameters as a condition of registration.  In response, the registrant
submitted a dose-range finding developmental neurotoxicity and
immunotoxicity study on dinotefuran in rats (MRID 47677501).  This study
has been reviewed (W. Phang, DP# 366688, 8/5/09, TXR# 0055238), and the
executive summary for the Data Evaluation Report for this study is
presented in the Appendix C.  Briefly, under the conditions of the
study, dinotefuran did not affect the distribution of splenocyte
subpopulations (total B cell, total T cells, helper/DTH T cells,
cytotoxic T cells, and natural killer cells) in the weanlings of F1
generation. It did not affect the anti-SRBC antibody forming cell
response (humoral immunity) and NK cell activity (innate immunity). 
Therefore, 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
periods.  Although, this study was a dose-range-finding study for a
developmental immunotoxicity study, it examined all the parameters which
would have been required in a regular developmental immunotoxicity study
and the highest tested dose (1035 mg/kg) was slightly greater than the
limit dose (1000 mg/kg).

Considering the results and conduct of the study, HED believes that this
range-finding study provides sufficient data for understanding the
immunotoxic potential of dinotefuran in young animals and satisfies the
data requirement for a developmental immunotoxicity study.  With respect
to the requirement for an adult immunotoxicity study under the new rule
(FR 158.500, 10/26/2007), HED has analyzed the entire data base of
dinotefuran and that of a structurally related chemical, clothianidin. 
Clothianidin was found to produce similar effects on the thymus and
spleen as dinotefuran in the repeated dosing studies, and an
immunotoxicity study was conducted in both adult and the offspring
animals.  No immunotoxicity was found in either the adults or the
offspring treated with clothianidin.  Based on the available
information, HED believes that conducting an immunotoxicity study in
adult rats would probably not provide additional information on the
immunotoxicity of dinotefuran and certainly would not impact the risk
assessment of this pesticide.  An immunotoxicity study in adult rats is
not needed at this time. 

No concerns for developmental neurotoxicity were seen in the
range-finding DNT study where the offspring LOAEL was the Limit Dose
(1035 mg/kg/day) based on decreased body weight and the offspring NOAEL
was 317 mg/kg/day.  Establishment of such a high LOAEL in the
range-finding study clearly indicates that in order to elicit toxicity,
dose selection for the definitive DNT study will likely result in a
point of departure much higher than those currently used for overall
risk assessment (range from 2.0 to 33.0 mg/kg/day). 

Dinotefuran has low acute toxicity by the oral, dermal, and inhalation
routes.  It is not a dermal sensitizer, but causes a low level of skin
irritation.  The main target tissues are the nervous system and the
immune system, with effects seen in several species.  Nervous system
toxicity is manifested as changes in motor activity observed in acute
and subchronic neurotoxicity studies in the rat, decreased grip strength
in adult offspring in the 2-gen rat study and maternal clinical signs
(prone position and tremor) in the rabbit developmental study.  These
effects occurred at doses ranging from ~300 to ~1500 mg/kg/day.  Immune
system toxicity is manifested as decreases in spleen and thymus weights,
seen in multiple studies and species (including dogs, rats, and mice). 
There are also indications of endocrine-related toxicity, manifested in
the reproductive toxicity study (in rats) as decreases in primordial
follicles and altered cyclicity in females and abnormal sperm parameters
in males at the Limit Dose; changes in testes or ovary weight were also
seen in several species (mouse, dog, and rat).  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. 
Review of acceptable oncogenicity and mutagenicity studies provide no
indication that dinotefuran is carcinogenic or mutagenic.  Dinotefuran
is characterized as “not likely to be carcinogenic to humans” based
on the absence of significant tumor increases in two adequate rodent
carcinogenicity studies.

HED concluded that the toxicology database for dinotefuran is adequate
for FQPA assessment.  Available studies include developmental toxicity
studies in rats and rabbits, a reproductive toxicity study in rats, and
acute and subchronic neurotoxicity studies in rats.  Additionally, a
dose-range finding developmental neurotoxicity and immunotoxicity study
was also available.  There was no evidence of increased susceptibility
following in utero exposures in the prenatal developmental toxicity
studies in rats and rabbits.  In the reproduction toxicity study, there
was evidence for increased qualitative susceptibility.  The level of
concern for the observed susceptibility is low since 1) clear NOAELs and
LOAELs are established for the endpoints of concern for parental and
offspring toxicity; 2) the effects in the offspring were seen in the
presence of parental toxicity; and 3) the effects were seen only at the
highest dose tested which was the Limit Dose (1000 mg/kg/day).  In the
range-finding developmental neurotoxicity and immunotoxicity study,
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 periods.  Further, no concerns for
developmental neurotoxicity were seen in the range-finding DNT study
where the offspring LOAEL was the Limit Dose (1035 mg/kg/day) based on
decreased body weight and the offspring NOAEL was 317 mg/kg/day.  These
results are consistent with other compounds in this chemical class
(i.e., neonicotinoids thiacloprid, imidacloprid, clothainadin) where
neurotoxicity (in the presence of decreased pup body weight) was seen in
only one compound (imidacloprid) and the DNT was not used in the
imidacloprid risk assessment.

In the current risk assessment for dinotefuran, the lowest point of
departure for neurotoxicity is a NOAEL of 33 mg/kg/day, which is used
for assessment of short-term incidental oral risk.  Lower points of
departure for systemic toxicities are used for the other risk assessment
scenarios:  The chronic RfD an extrapolated NOAEL of 2.0 mg/kg/day based
decreased thymus weight, the intermediate term incidental oral exposure
is based on a NOAEL of 22 mg/kg/day based on changes in body weight/body
weight gain, and the short and the intermediate inhalation exposure
endpoints are based on an extrapolated NOAEL of 6.0 mg/kg/day based on
decreased body weight and food consumption.

In summation, dose selection for the definitive DNT study will likely
result in a point of departure much higher than those currently used for
overall risk assessment (range from 2.0 to 33.0 mg/kg/day).  Thus, there
are reliable toxicity data showing that the points of departures used
for the overall risk assessment of dinotefuran are protective of infants
and children.  Therefore, a database uncertainty factor (UFDB) is not
needed to account for the lack of a dinotefuran DNT.

Based on these weight-of-evidence considerations, HED has concluded that
there are no residual uncertainties for pre- and or post- natal toxicity
and that the FQPA Safety Factor can be removed (i.e., 1X) for acute
dietary and non-dietary (incidental oral, and dermal) risk assessments. 
For the chronic dietary and for short- and intermediate-term inhalation
risk assessments, however, the 10X FQPA Safety Factor is retained for
the use of a LOAEL (UFL) (i.e., lack of a NOAEL in the critical
studies).

A 10X Uncertainty Factor for the use of a LOAEL (UFL) was retained in
deriving the chronic Reference Dose (RfD) and the MOE for long-term
inhalation exposure risks since a NOAEL was not established in the
1-year toxicity study in dogs selected for these exposure scenarios. 
The endpoint of concern for these scenarios is the decreased thymus
weight in male dogs.  The default 10X UF was deemed to be adequate based
on the magnitude and the nature of response at the LOAEL in the study:
1) at the LOAEL, the decreased thymus weight was limited to one sex
(males) with no corroborative histopathological lesions in the thymus
glands; 2) this appears to be a species specific effect since no
treatment-related effects on the thymus (weight or histopathology) was
seen following chronic exposures to mice or rats; and 3) there is high
confidence that the extrapolated NOAEL of 2.0 mg/kg/day (LOAEL 20 ÷ 10
UF = 2.0) will be protective of the systemic toxicity seen at higher
doses in mice (LOAEL = 34 mg/kg/day) and rats (LOAEL = 991 mg/kg/day)
following chronic exposures.

A 10X (UFL) was also retained for the use of a LOAEL in deriving the
MOEs for short and intermediate term inhalation exposures since a NOAEL
was not established in the 28-day inhalation toxicity study in rats
selected for these exposure scenarios.  The default 10X UF is deemed to
be adequate since: 1) Following exposures for 28-days, no toxicity to
the target organ (respiratory system) was seen at any concentration; 2)
the endpoint of concern was generalized systemic toxicity characterized
by decreased body weight gain and food consumption in one sex (males);
and 3) the extrapolated NOAEL of 6.0 mg/kg/day will be protective of the
potential toxicity via this route of exposure.

Risk assessments were conducted for acute and chronic dietary,
intermediate-term dermal, and short- and intermediate-term oral and
inhalation exposures.  The HED/RAB3 risk assessment team made
recommendations for acute and chronic Reference Doses (RfDs),
toxicological endpoint selections, uncertainty factors (UFs), and
appropriate margins of exposure (MOEs) for use as appropriate in
occupational/residential exposure risk assessments.  The endpoints that
were selected for dinotefuran are presented in the endpoint summary
tables, Tables 2 and 3.

3.2	FQPA Safety Factor for Infants and Children  TC \l2 "3.1	FQPA Safety
Factor for Infants and Children 

As explained above, HED has concluded that the FQPA Safety Factor can be
removed (i.e., 1X) for acute dietary and non-dietary (incidental oral,
and dermal) risk assessments.  For the chronic dietary and for short-
and intermediate-term inhalation risk assessments, however, the 10X FQPA
Safety Factor is retained for the use of a LOAEL (UFL) (i.e., lack of a
NOAEL in the critical studies).  The recommendation is based on the
following: 

The toxicity database is adequate and there are no residual
uncertainties for pre- and/or postnatal toxicity.  The doses chosen as
quantitative risk estimates are adequately protective for infants and
children.

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 contribution
from drinking water is minimal.  HED concludes that the acute exposure
estimates in this analysis are unlikely to underestimate actual
exposure.

The chronic dietary analysis included tolerance level residues and 100%
crop treated.  The field trials represent maximum application rates and
minimum PHIs.  The contribution from drinking water is minimal.  HED
concludes that the chronic exposure estimates in this analysis are
unlikely to underestimate actual exposure.

The dietary drinking water assessment utilizes water concentration
values generated by model and associated modeling parameters which are
designed to provide conservative, health protective, high-end estimates
of water concentrations which will not likely be exceeded.

While there is potential for postapplication residential exposure, the
best data and approaches currently available were used in the
dinotefuran residential assessment.  HED used the current conservative
approaches for residential assessment.  HED believes that the calculated
risks represent conservative estimates of exposure because maximum
application rates are used to define residue levels upon which the
calculations are based.  Exposures are unlikely to be underestimated
because the assessment was a screening level assessment.

3.3	Summary of Toxicological Doses and Endpoints for Use in Human Health
Risk Assessments  TC \l2 "3.3	Summary of Toxicological Doses and
Endpoints for Use in Human Health Risk Assessments 

HED previously completed a comprehensive Section 3 human health risk
assessment for the use of dinotefuran on many crops (Memo B. O’Keefe,
et. al., 12/08/04, DP# 309412).  Since then HED received and reviewed a
developmental immunotoxicity range-finding study and a DNT range-finding
study.  This current assessment considers the results from these
studies.  Additionally, the FQPA safety factor terminology has been
revised to reflect current policy.  All other hazard characterization
and endpoint selection information from the previous risk assessment are
applied directly to this action.  Below are the up-to-date tables.  

Table 2.  Summary of Toxicological Doses and Endpoints for Dinotefuran
for Use in Dietary and Non-Occupational 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,
tremor, erythema) seen following a single dose.

Chronic Dietary (All Populations)	LOAEL=20 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 10x, which is a UFL	Chronic RfD = 0.02

mg/kg/day

cPAD = 0.02 mg/kg/day	Chronic Toxicity in Dogs

LOAEL = 20 mg/kg/day based on decreased thymus weight in males.

Incidental Oral Short-Term (1-30 days)	NOAEL=33 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x 	Residential LOC for MOE = 100	Subchronic Neurotoxicity
Study in Rats

LOAEL = 327 mg/kg/day based on increased motor activity during week two.

Incidental Oral Intermediate-Term (1-6 months)	NOAEL=22 mg/kg/day	UFA=
10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100	Chronic Toxicity in Dogs

LOAEL = 108 mg/kg/day based on decreased body weight and body weight
gains in females.

Dermal Short-Term (1-30 days)	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 this exposure scenario.

Dermal Intermediate-Term (1-6 months)	NOAEL=22 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100

	Chronic Toxicity in Dogs

LOAEL = 108 mg/kg/day based on decreased body weight and body weight
gains in females.

Inhalation Short- Term (1-30 days)	LOAEL=60 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 10x, which is a UFL	Residential LOC for MOE = 1000	28-day
Inhalation Toxicity Study in Rats

LOAEL = 60 mg/kg/day based on decreased body weight gain in males.

Inhalation Intermediate-Term (1-6 months)	LOAEL=60 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 10x, which is a UFL	Residential LOC for MOE = 1000

	28-day Inhalation Toxicity Study in Rats

LOAEL = 60 mg/kg/day based on decreased body weight gain in males.

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 (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

Table 3.  Summary of Toxicological Doses and Endpoints for Dinotefuran
for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal Short-Term (1-30 days)	NA	NA	NA

	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 this
exposure scenario 

Dermal Intermediate-Term (1-6 months)	NOAEL=22 mg/kg/day	UFA= 10x

UFH= 10x	Occupational LOC for MOE = 100

	Chronic Toxicity in Dogs

LOAEL = 108 mg/kg/day based on decreased body weight and body weight
gains in females.

Inhalation Short-Term (1-30 days)	LOAEL=60 mg/kg/day	UFA=10x

UFH=10x

UFL= 10x	Occupational LOC for MOE = 1000	28-day Inhalation Toxicity
Study in Rats

LOAEL = 60 mg/kg/day based on decreased body weight gain in males.

Inhalation Intermediate-term (1-6 months)	LOAEL=60 mg/kg/day	UFA=10x

UFH=10x

UFL= 10x	Occupational LOC for MOE = 1000	28-day Inhalation Toxicity
Study in Rats

LOAEL = 60 mg/kg/day based on decreased body weight gain in males.

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 (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.

3.4	Recommendation for Aggregate Exposure Risk Assessments  TC \l2 "3.4
Recommendation for Aggregate Exposure Risk Assessments 

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.  The toxicity
endpoints selected for these routes of exposure may be aggregated as
follows:

For short-term aggregate exposure assessment, incidental oral and
inhalation cannot be combined due to differences in the endpoint, i.e.
neurotoxicity for incidental oral and decreases in body weight for
inhalation.  No quantification of dermal risk is required.

For intermediate-term aggregate exposure, incidental oral and dermal and
inhalation endpoints can be aggregated because of the use of a common
endpoint (decreased body weight gain).

For long-term aggregate exposure, incidental oral and dermal and
inhalation endpoints can be aggregated because of the use of oral
equivalents and a common endpoint (decreased thymus weight).

3.5	Endocrine disruption  TC \l2 "3.5	Endocrine disruption 	

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations.  As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP).

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, dinotefuran
may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.



4.0	Dietary Exposure/Risk Characterization  TC \l1 "4.0	Dietary
Exposure/Risk Characterization 

Reference: Dinotefuran.  IR-4 Petition for the Establishment of
Tolerances for Residues of Dinotefuran in/on Brassica, Leafy Greens,
Subgroup 5B and Turnip Greens. 01/31/09, A. Acierto, DP358024.

Table 4 lists the conclusions of the HED Metabolism Assessment Review
Committee (MARC) concerning the dinotefuran residues of concern in
crops, livestock, rotational crops and drinking water (MARC report, TXR
# 52304, D293759, L. Cheng, 20-Jan-2004).  The MARC determined that the
residue of concern in plants for tolerance setting and risk assessment
are different.  Plant metabolism data indicated that PHP was found to be
a major metabolite (>10% total radioactive residues) only in apples, but
not in the other plants studied (lettuce, potato, rape, and rice), and
hence the use of the recommended tolerance level residues for the
existing and proposed crops, except grapes, will not underestimate the
exposure in the risk assessment.

Table 7. Residues of Concern in Crops, Livestock, Rotational Crops, and
Water

Matrix	

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 decided	

Not decided

Water	

Not applicable	

Dinotefuran, MNG, DN, UF, DN-2-OH, and DN-3-OH

4.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "4.1 
Pesticide Metabolism and Environmental Degradation 

4.1.1	Metabolism in Primary Crops  TC \l3 "4.1.1	Metabolism in Primary
Crops 

The nature of the residues in plants is adequately understood for the
purpose of this petition, based on previously submitted metabolism
studies with rape, potato, rice, apple, and lettuce.  The main metabolic
reactions in plants are the hydrolysis of the nitroimino moiety of
dinotefuran, loss of the nitro group, intramolecular ring formation, as
well as tetrahydrofuran ring hydroxylation and ring opening.  The
residues of concern in plants for tolerance enforcement are parent, DN
and UF, and for risk assessment are parent, DN, UF, and PHP
[6-hydroxy-5-(2-hydroxyethyl)-1-methyl-1,3-diazinane-2-lidene-N-nitroami
ne (MARC report, D293759, L. Cheng, 01/20/2004). 

4.1.2	Metabolism in Livestock  TC \l3 "4.1.2	Metabolism in Livestock 

Dinotefuran metabolism in livestock is similar to the progression found
in plants.  For ruminants and poultry, the residue of concern for the
tolerance expression is primarily dinotefuran.  For risk assessment, the
residues of concern in ruminants are parent, UF and FNG, and the
residues of concern in poultry are dinotefuran and FNG (MARC report,
D293759, L. Cheng, 01/20/2004).

4.1.3	Analytical Methodology  TC \l3 "4.1.3	Analytical Methodology 

Enforcement Method for Plants

Three methods for plants have been available for enforcement of
tolerances: an HPLC/MS/MS method (MRID 45639811) for the determination
of residues of dinotefuran, DN, and UF; an HPLC/UV method (MRID
45639808) for the determination of dinotefuran; and an HPLC/MS and
HPLC/MS/MS method (MRID 45639809) for the determination of DN and UF. 
ACB/BEAD found the methods to be adequate (DP#331831, P. Savoia,
4/17/2007).  

An additional LC/MS/MS method (MRID 47545401) was developed by Wildlife
International, Ltd. (Project No. 236C-113), entitled “Laboratory
Validation of Method(s) for the Analysis of MTI-446 and its metabolites
DN and UF in Multiple Crop Substrates”, to quantitate residues in
mustard greens.  The method was validated using untreated mustard greens
fortified separately with dinotefuran, DN and UF at 0.01 for each
analyte.  Adequate recovery data were provided.  Based on the method
validation data and concurrent recovery data, the submitted LC/MS/MS
method for leafy Brassica greens is adequate for enforcement and data
collection purposes. 

Analytical Methods - Livestock

No livestock feed items are associated with the proposed uses on
Brassica leafy vegetables subgroup 5B and turnip greens.  However,
Mitsui Chemicals, Inc previously submitted an adequate LC/MS/MS method
for the determination of residues of dinotefuran and its metabolites DN
and UF in livestock commodities (MRID 46132901).  This method was the
data collection method used in the analysis of samples collected from
the dairy cattle feeding study (MRID 45891613).  The validated limit of
quantitation (LOQ) is 0.01 ppm for each analyte, and the reported limit
of detection (LOD) is 0.002 ppm for each analyte in milk, cream,
livestock tissues, and poultry egg.

Multiresidue Methodology (860.1360)

Dinotefuran (parent) was not adequately recovered using any of the
multiresidue methods (FDA Multi-Residue Method Test Guidelines, PAM,
Vol. I, Appendix II).  Although no multiresidue 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 as compared to the parent.

4.1.4	Storage Stability Data  TC \l3 "4.1.4	Storage Stability Data 

Adequate storage stability data for mustard greens are available.  The
data demonstrate that residues of dinotefuran, DN and UF are stable
under frozen storage for 637 days.  The data support the storage
intervals and durations of samples of mustard greens from the crop field
trials.  No correction for decline during storage is necessary.  The
storage durations and conditions of samples from the crop field trials
submitted to support this petition are presented in Table 5.  

TABLE 5.	Summary of Storage Conditions.  

Matrix 	Analyte	Storage Temperature

 (°C)	Actual Storage Duration (days)	Interval of Demonstrated Storage
Stability

 (days)

Mustard Greens	Dinotefuran

UF

DN	<- 40 to -1	436 - 602	Dinotefuran is stable for up to 637 days with
recoveries of 90-98% for dinotefuran, 78-102% for UF, and 80-98% for
DN.*

*Three storage study samples fortified at 0.1 ppm with each analyte were
extracted after 637 days of frozen storage.  Concurrent recoveries were
96% for dinotefuran and UF, and106% for DN.  No 0-time was reported.

4.1.5	Magnitude of the Residue in Plants  TC \l3 "4.1.5	Magnitude of the
Residue in Plants 

In support of the proposed use on crop subgroup 5B, IR-4 has submitted
field trial data for dinotefuran on mustard greens.  Nine field trials
were conducted during the 2003 growing season in the United States
encompassing Regions 2, 3, 4, 5, 6, and 10.  The treated plots received
two foliar applications of dinotefuran formulated as a 20% soluble
granule.  Each application was made at a rate of 0.179 lb ai/A for a
total seasonal rate of 0.36 lb ai/A (~1.3x the proposed rate) and the
retreatment interval was 7 ± 1 days.  No adjuvant was added to the
spray mixture.  At each trial location, untreated and treated raw
agricultural commodity (RAC) samples were harvested 1 day following the
last test substance application.  At one of the test sites, untreated
and treated RAC samples were harvested at 0, 1, 7, and 14 days after the
last application to determine residue decline.

Samples of mustard greens were analyzed for residues of dinotefuran
(parent) and its metabolites DN and UF using an LC/MS/MS method
developed by Wildlife International, Ltd.  

The maximum residues in/on mustard greens harvested 1 day after the last
of two applications of the 20% SG formulation at a total rate of 0.35 to
0.36 lb ai/A were 6.5 ppm for dinotefuran (parent), 0.77 ppm for DN and
1.9 for UF.  The maximum combined residues of dinotefuran, DN and UF
from the field trials was 7.8 ppm.  The results from these field trials
are summarized in Table 6.  

TABLE 6.	Summary of Residue Data from Crop Field Trials

Commodity	Total Applic. Rate,

lb a.i./A	

PHI (days)	Residue Levels (ppm)

	

n	

Min.	

Max.	

HAFT*	

Median

(STMdR)	

Mean

(STMR)	

Std. Dev.

DINOTEFURAN

Mustard greens	

0.35-0.37	1	16	0.784	5.79	2.77	4.38	3.74	1.7

DN

Mustard greens	

0.35-0.37	

1	

16	0.504	1.90	1.73	0.95	1.22	1.0

UF

Mustard greens	

0.35-0.37	

1	

16	0.071	0.774	0.734	0.20	0.27	0..2

*HAFT = Highest average field trial.

Conclusions:  The submitted residue data are adequate to fulfill data
requirements for the establishment of tolerances of dinotefuran in/on
mustard greens.  The submitted field trial data reflect the use of two
foliar applications of the 20% SG formulation at total rates of 0.35 to
0.36 lb ai/A on mustard greens grown in the United States with 1-day
PHI.  An acceptable method was used for quantitation of residues on
mustard greens.  The submitted storage stability data indicate that
residues of dinotefuran, DN, and UF are stable in/on mustard greens
stored frozen for up to 637 days at <-40 to -1oC.  The available data
support the storage intervals of samples from the mustard greens field
trials. The residue decline studies show that the residue of dinotefuran
and its metabolites decline with increasing harvest intervals.  

HED has concluded that turnip greens will be moved to the Brassica leafy
greens subgroup 5B.  Therefore, crop field trial data for mustard greens
(the representative commodity of leafy Brassica greens subgroup 5B) are
sufficient to support the proposed use on turnip greens.  Until the
regulation has been finalized in the Federal Register, a separate
tolerance must be established for turnip greens at the same level as the
leafy Brassica greens tolerance.

The locations of the mustard green field trials are in accordance with
OPPTS Guideline 860.1500 to support a tolerance for the leafy Brassica
greens subgroup 5B and turnip greens except that one field trial in
Region 2 had 3 foliar applications instead of the proposed 2
applications.  The sample from that trial had higher residues as a
result of the extra treatment.  Therefore, the data from that field
trial was not included in the tolerance setting for mustard greens. 
However, the remaining number of field trials (8) is adequate.  An
additional field trial in Region 2 will not be required. 

4.1.6	Magnitude of the Residue in Processed Food/Feed  TC \l3 "4.1.6
Magnitude of the Residue in Processed Food/Feed 

No processing data were submitted with this petition and none are
required since there are no processed food/feed items associated with
Brassica, leafy greens, Subgroup 5B and turnip greens.

4.1.7	Confined and Field Rotational Accumulation in Rotational Crops  TC
\l3 "4.1.7	Confined and Field Accumulation in Rotational Crops 

The Agency has previously concluded that a confined rotational crop
study with dinotefuran reflecting a 120-day plantback interval for
rotated crops is adequate.  However, if the petitioner wishes to support
a plantback interval less than 120 days, then, a new confined rotational
crop study reflecting a 1x application rate will be required  (D290191,
L. Cheng, 11/23/2004).

The petitioner did not submit any field rotational crop data.  The
Agency has previously concluded that based on the available confined
rotational crop data, a 120-day plantback interval is appropriate for
all rotational crops other than cotton, leafy vegetables, fruiting
vegetables, cucurbits, potatoes, and head and stem Brassica (D290191, L.
Cheng, 11/23/2004).

4.1.8	Drinking Water Residue Profile TC \l3 "4.1.8	Drinking Water
Residue Profile 

Reference: Tier I Estimated Drinking Water Concentrations of Dinotefuran
and its Transformation Products of Concern MNG, DN, UF and DN-2-OH +
DN-3-OH, for Use in Human Health Risk Assessment, Proposed New (IR-4)
Use of the Chemical on Leafy Brassica Greens and Turnip Greens. J.
Melendez, DP357111, 01/23/09.

The EFED determined that the maximum estimated Drinking Water
Concentration (EDWCs) for parent dinotefuran and its
metabolites/degradates MNG, DN, UF, and DN-2-OH + DN-3-OH for the food
crop use pattern are much lower in comparison to the turf grass use
pattern.  Therefore, the EDWCs from the previous drinking water
assessment for turf grass were used in this assessment as described
below.  EFED calculated screening level surface water and ground water
estimates for dinotefuran and its degradates using linked PRZM/EXAMS
models and the SCI-GROW model, respectively.  EDWCs are presented in
Table 7.  

Table 7. Tier I Estimated Drinking Water Concentrations for Dinotefuran
& its Metabolites/Degradates.

Chemical1	

Acute (peak) Surface Water Concentration (ppb)	

Annual Average Surface Water Concentration (ppb)	

Ground Water Concentration (ppb)

Dinotefuran	

48.20	

8.00	

2.75

MNG	

3.86	

1.63	

0.86

DN	

7.77	

3.32	

0.19

UF	

4.07	

2.07	

0.32

DN-2-OH2	

11.88	

5.95	

0.94

1Residues of concern for water as recommended by the Metabolism
Assessment Review Committee (1/7/2004)

2 DN-2-OH represents DN-2-OH+DN-3-OH.  These two were reported jointly
in the study.

HED used the total acute (peak) surface water concentration of 75.78 ppb
and the total annual average of 20.97 ppb for acute and chronic dietary
risk analyses, respectively.  This approach may significantly
overestimate dietary exposure to dinotefuran from drinking water;
however, since estimated aggregate food and drinking water exposures
using this approach are well below HED’s levels of concern, additional
refinements were not deemed necessary.  For the acute and chronic
dietary assessments, EDWCs were incorporated directly as a point
estimate in the DEEM analysis to assess exposure to dinotefuran from
drinking water.

4.1.9	Proposed Tolerances TC \l3 "4.1.9	Proposed Tolerances 

Adequate field trial data are available to support this petition. 
Results indicate that the proposed tolerance (17 ppm) for leafy Brassica
greens subgroup 5B is too high based on the data generated from the crop
field trials after 2 foliar treatments of dinotefuran and a 1-day PHI. 
HED recommends revision of Section F to reflect a tolerance level of 15
ppm for leafy Brassica greens subgroup 5B.  

There are currently no established Codex, Canadian, or Mexican MRLs for
dinotefuran.  An International Residue Limit Status is attached to this
review.

HED has concluded that turnip greens will be moved from the leaves of
the root and tuber vegetables crop group (group 2) to the Brassica leafy
vegetables crop group 5, subgroup 5B: (Memorandum,  B. Schneider,
6/14/2002).  Until the regulations have been finalized in the Federal
Register, a separate tolerance is needed for turnip greens, at the same
level as the leafy Brassica greens tolerance, 15 ppm.  The tolerance
expression has been revised to meet current HED policy.  Tolerances are
established for residues of dinotefuran
((RS)-1-methyl-2-nitro-3-((tetrahydro-3-furanyl)methyl)guanidine),
including its metabolites and degradates, in or on the commodities in
the table below.  Compliance with the tolerance levels specified below
is to be determined by measuring only the sum of dinotefuran and its
metabolites DN, 1-methyl-3-(tetrahydro-3-furylmethyl)guanidine, and UF,
1-methyl-3-(tetrahydro-3-furylmethyl)urea, calculated as the
stoichiometric equivalent of dinotefuran, in or on the commodities.  A
summary of the recommended tolerances for the current petition is
presented in Table 8.

Table 8.  Tolerance Summary for Dinotefuran

Commodity or Subgroup	Proposed Tolerance (ppm)	Established Tolerance
(ppm)	Recommended Tolerance (ppm)	Comments; Correct Commodity Definition

Tolerances for combined residues of Dinotefuran [(RS)
-1-methyl-2-nitro-3-(tetrahydro-3-furanylmethyl)guanidine] and its
metabolites DN [1-methyl-3-(tetrahydro-3-furylmethyl)guanidine], and UF
[1-methyl-3-(tetrahydro-3-furylmethyl)-urea), calculated as the
stoichiometric equivalent of dinotefuran, in or on the commodities]

40 CFR 180.603(a)

Brassica, leafy greens, subgroup 5B	17	--	15

	Turnip, greens	17	--	15

	

4.2	Dietary Exposure and Risk TC \l2 "4.2  Dietary Exposure and Risk 

Reference: Dinotefuran: Acute and Chronic Aggregate (Food and Drinking
Water) Dietary Exposure and Risk Assessments for a Section 3
Registration Action on Leafy Brassica Greens Subgroup 5B and Turnip
Greens. A. Acierto, DP358025, 04/09/09. 

Dietary risk assessment incorporates both exposure and toxicity of a
given pesticide.  The risk is expressed as a percentage of a maximum
acceptable dose (i.e., the dose which HED has concluded will result in
no unreasonable adverse health effects).  This dose is referred to as
the population adjusted dose (PAD).  HED is concerned when estimated
dietary risk exceeds 100% of the PAD.  

DEEM-FCID™ Program and Consumption Information

Dinotefuran acute and chronic dietary exposure assessments were
conducted using the Dietary Exposure Evaluation Model software with the
Food Commodity Intake Database (DEEM-FCID™, Version 2.03), which
incorporates consumption data from USDA’s Continuing Surveys of Food
Intakes by Individuals (CSFII), 1994-1996 and 1998.  The 1994-96, 98
data are based on the reported consumption of more than 20,000
individuals over two non-consecutive survey days.  Foods “as
consumed” (e.g., apple pie) are linked to EPA-defined food commodities
(e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour
- cooked; fresh or N/S, baked) using publicly available recipe
translation files developed jointly by USDA/ARS and EPA.  For chronic
exposure assessment, consumption data are averaged for the entire U.S.
population and within population subgroups, but for acute exposure
assessment are retained as individual consumption events.  Based on
analysis of the 1994-96, 98 CSFII consumption data, which took into
account dietary patterns and survey respondents, HED concluded that it
is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

Acute Dietary (Food and Drinking Water) Exposure Results and
Characterization

The acute dietary exposure assessment was unrefined.  The analysis
assumed 100% crop treated and tolerance level residues.  Acute dietary
exposure of the general US population and all population subgroups are
below the Agency’s level of concern (i.e., <100% of the aPAD).  The
risk estimates were 1.6% of the aPAD for the general U.S. population and
3.5% of the aPAD for children 1-2- years old, the most highly exposed
population subgroup based on analysis at the 95th percentiles of
exposure.

Chronic Dietary (Food and Drinking Water) Exposure Results and
Characterization

The chronic dietary exposure analysis was unrefined.  The assessment
assumed 100% crop treated and tolerance level residues.  Based on the
assumptions described above (section II and III), chronic dietary
exposure of the general US population and all population subgroups are
below the Agency’s level of concern (i.e., <100% of the cPAD).  The
combined chronic dietary exposure estimates are 30% of the cPAD for the
general U.S. population and 68% of cPAD for children 1-2 years old, the
most highly exposed population subgroup.

The results of the acute and chronic dietary (food+drinking water)
exposure analysis are summarized in Table 9 below.  

Table 9.  Summary of the Acute and Chronic Dietary (Food and Drinking
Water) Exposure and Risk for      Dinotefuran.

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD*	Dietary Exposure

(mg/kg/day)	% cPAD*	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	0.02	1.6	0.006	30

All Infants (< 1 year old)	0.027	2.1	0.006	30	N/A	N/A

Children 1-2 years old	0.044	3.5	0.014	68

Children 3-5 years old	0.034	2.7	0.011	54

Children 6-12 years old	0.021	1.7	0.007	33

Youth 13-19 years old	0.016	1.3	0.005	24

Adults 20-49 years old	0.017	1.4	0.005	26

Adults 50+ years old	0.018	1.4	0.005	27

Females 13-49 years old	0.018	1.4	0.005	26

*The population subgroup with the highest estimated chronic dietary
(food + drinking water) 

  exposure and risk is indicated by bold text.

  NA = not applicable

Conclusions

Acute and chronic exposures and risks do not exceed HED’s level of
concern for the U.S. population and for all relevant population
subgroups.  Of note is that contribution from drinking water is minimal.
 HED concludes that the acute and chronic exposure estimates are
unlikely to underestimate actual acute or chronic exposure.

5.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "5.0	Residential (Non-Occupational) Exposure/Risk Characterization 

There is potential for exposure to homeowners in residential settings
during the application of currently registered products containing
dinotefuran, and from entering areas previously treated with
dinotefuran, such as lawns and carpets where children might play, or
golf courses and home gardens that could lead to exposures for adults. 
As a result, risk assessments were previously completed for both
residential handler and postapplication scenarios (J. Arthur, DP285650,
4/27/2004 and S. Recore, DP347177, 5/7/08).  The proposed uses of
dinotefuran on turnip greens and Brassica leafy vegetables do not add
any additional residential exposures or risks.

6.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "6.0
Aggregate Risk Assessments and Risk Characterization 

In accordance with the FQPA, HED must consider and aggregate pesticide
exposures and risks from three major sources: food, drinking water, and
residential exposures.  In an aggregate assessment, exposures from
relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.

Based on the proposed and existing Section 3 uses, acute, short-term,
intermediate-term and chronic aggregate exposures are anticipated. 
Aggregate exposure assessments were performed for acute aggregate
dietary exposure (food + drinking water), chronic aggregate dietary
exposure (food + drinking water), and residential intermediate-term
exposure to children (from dermal and incidental oral exposures) and
adults (from dermal and inhalation exposures).  A cancer aggregate risk
assessment was not performed because dinotefuran is not carcinogenic. 
All potential exposure pathways were assessed in the aggregate risk
assessment.  Dietary (food and drinking water) exposures were considered
because there is a potential for individuals to be exposed concurrently
through these routes.

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.  Since the acute dietary
exposure assessment already includes the highest acute exposure from the
drinking water modeling data, no further calculations are necessary. 
The acute risk estimate for all populations, resulting from aggregate
exposure to dinotefuran in food and drinking water is below HED’s
level of concern.  The food and drinking water exposure estimates for
the most highly exposed subgroup, children 1-2 yrs old, is 3.5% of the
aPAD.

Chronic Aggregate Risk

The aggregate chronic risk estimates include exposure to residues of
dinotefuran in food and drinking water, and does not include dermal,
inhalation or incidental oral exposure.  Since the chronic dietary
exposure assessment already includes the highest chronic exposure from
the drinking water modeling data, no further calculations are necessary.
 The chronic risk estimate for all populations, resulting from aggregate
exposure to dinotefuran in food and drinking water is below HED’s
level of concern.  The food and drinking water exposure estimates for
the most highly exposed subgroup, children 1-2 yrs old, is 68% of the
aPAD.

Short- & IntermediateTerm Aggregate Risk

Because there are existing residential uses of dinotefuran, short- and
intermediate-term aggregate risk assessments based on exposure from
oral, inhalation, and dermal routes were considered.  However, the
toxicological effects for oral and inhalation routes of exposure are
different (i.e., neurotoxicity for oral and decrease in body weight for
inhalation); and therefore, these exposure scenarios have not been
combined.  Also, because no systemic toxicity was seen at the limit dose
in a 28-day dermal toxicity study, no quantification of short-term
dermal risk is required.  Therefore, only short-term oral residential
hand-to-mouth exposures for toddlers need to be aggregated with chronic
food and drinking water exposures.  These exposures were aggregated and
are presented in Table 10.  Additionally, as a worse-case estimate of
risk, intermediate-term dermal and oral residential hand-to-mouth
exposures for toddlers were aggregated with chronic food and drinking
water exposures.  Also, the point of departure for intermediate-term
dermal and oral exposures is a NOAEL of 22 mg/kg/day versus the point of
departure for short-term oral exposures which is 33 mg/kg/day.

Table 10. Aggregate Risk for Short-Term Exposure of Children (1-2 yrs)
to Dinotefuran

Residential Use Site	NOAEL mg/kg/day	Level of Concern MOE1	Average Food
+ Water Exposure2	Oral Residential Exposure3	Aggregate MOE (Food +
Residential)4

Turf	33	100	0.014	0.005827	1700

Indoor Carpets	33	100	0.014	0.080	350

1The level of concern MOE of 100 is based on the standard inter- and
intra-species safety factors, 10x for intra-species variability and 10x
for inter-species extrapolation.

2Average food and drinking water exposure

3Residential oral exposure to children playing on treated lawns (oral
hand-to-mouth + oral object-to-mouth + oral soil ingestion), or treated
carpets

4Aggregate MOE = NOAEL/[(average food + drinking water exposure) +
(residential oral exposure)]

An intermediate-term aggregate risk assessment was performed as a
screening level assessment.  Intermediate-term aggregate risk
assessments were performed for adults and children.  For children, the
subgroup with the highest estimated chronic dietary exposure (children
1-2 years old) was aggregated with residential exposures to children
playing on treated lawns (dermal and oral hand-to-mouth exposures) in
order to calculate the worst case intermediate-term aggregate risk to
children.  The reciprocal MOE method was used to conduct the
intermediate-term aggregate risk assessment for children, since the
levels of concern are identical for all MOEs in the calculation.  For
adults, the aggregate risk index (ARI) method was used, since levels of
concern are not identical for all types of exposure in the calculation. 
For children, the aggregate MOE is 430 for playing on turf and 160 for
playing on carpets, which are greater than 100, and therefore do not
exceed HED’s level of concern.  For adults, the total aggregate ARI is
5.9 which is greater than 1, and therefore does not exceed HED’s level
of concern.

Table 11. Aggregate Risk for Intermediate-Term Exposure of Children (1-2
yrs) to Dinotefuran

Residential Ues Site	NOAEL mg/kg/day	Level of Concern MOE1	Average Food
+ Water Exposure2	Oral Residential Exposure3	Dermal Residential
Exposure4	Aggregate MOE (Food + Residential)5

Turf	22	100	0.014	0.005827	0.031	430

Indoor Carpets	22	100	0.014	0.080	0.041	160

1The level of concern MOE of 100 is based on the standard inter- and
intra-species safety factors, 10x for intra-species variability and 10x
for inter-species extrapolation.

2Average food and drinking water exposure

3Residential oral exposure to children playing on treated lawns (oral
hand-to-mouth + oral object-to-mouth + oral soil ingestion), or treated
carpets

4Residential dermal exposure to children playing on treated lawns

5Aggregate MOE = NOAEL/[(average food + drinking water exposure) +
(residential oral exposure) + (residential dermal exposure)]

Table 12. Aggregate Risk for Intermediate-Term Exposure of Adults to
Dinotefuran

Population	Level of Concern ARI1	ARI (Food + Water)2	Residential ARIs3
Total Aggregate ARI4

	Handlers	Post Application Dermal Exposure

Dermal Exposure	Inhalation Exposure

General U.S. Population	1	37	17	970	12	5.9

1ARI (Aggregate Risk Index) = MOECalculated / MOEAcceptable 

2ARIFood + Water = (22 mg/kg/day/0.006 mg/kg/day) / 100 = 37

3ARIDermal =MOE / 100 and, ARIInhalation = MOE / 1000

4ARITotal Aggregate = 1/[(1/ARIFood + water) + (1/ARIResidential Handler
Deraml ) + (1/ARIResidential Handler Inhalation) + (1/ARIPost
Application Dermal)]

7.0	Cumulative Risk Characterization/Assessment  TC \l1 "7.0	Cumulative
Risk Characterization/Assessment 

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  
HYPERLINK "http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

8.0	Occupational Exposure/Risk Pathway  TC \l1 "8.0	Occupational
Exposure/Risk Pathway 

Reference: Dinotefuran: Occupational and Residential Exposure Assessment
for proposed new uses of dinotefuran on turnip greens and Brassica
(cole) leafy vegetables, crop subgroup 5 (broccoli raab, collards, kale,
mizuna, Chinese cabbage (bok choy), mustard greens, mustard spinach, and
rape greens). DP358026; B. O’Keefe; 06/19/09.

Dinotefuran may be applied to turnip greens and Brassica leafy
vegetables using a variety of application equipment. The application
methods, maximum application rates, and use sites are summarized in
Table 1.  Handler exposure is expected to be short- or intermediate-term
based on information provided on the proposed labels.  

Five occupational handler scenarios were identified for which exposure
to dinotefuran is expected.  The quantitative exposure and risk
assessment developed for occupational handlers is based on the following
exposure scenarios (note: dry flowable PHED unit exposures were used as
surrogate to assess soluble granular):

Mixer/Loaders

Mixing/loading dry flowables to support aerial applications, 

Mixing/loading dry flowables to support groundboom applications,

Applicators

Applying sprays aerially using an enclosed cockpit,

Applying sprays with groundboom equipment, and

Flaggers 

Flagging to support aerial spray applications.

Data and Assumptions for Occupational Handler Exposure Scenarios	

Unit Exposures:

Chemical-specific data for assessing exposure during pesticide handling
activities (mixing/loading, applying, and flagging) were not submitted
to the Agency in support of application.  It is HED policy to use data
from the PHED Version 1.1 to assess handler exposures for regulatory
actions when chemical-specific data are not available (HED Science
Advisory Council for Exposure, SOP No.7, January 1999).  

	

Mitigation Approaches:

There are three basic risk mitigation approaches considered appropriate
for controlling occupational exposure.  These include administrative
controls, use of personal protective equipment (PPE), and the use of
engineering controls.  Occupational handler exposure assessments were
completed by HED using baseline PPE, and engineering controls.

The baseline clothing level for occupational exposure scenarios is an
individual wearing long pants, a long-sleeved shirt, shoes, socks, no
chemical-resistant gloves, and no respirator.  The first level of
mitigation generally applied is PPE, which may include addition of
chemical resistant-gloves, an additional layer of clothing, and/or a
respirator.  The next layer of mitigation considered in the risk
assessment process is the use of appropriate engineering controls,
which, by design, attempt to eliminate the possibility of human
exposure.  Examples of engineering controls include enclosed tractor
cabs or cockpits, closed mixing/loading systems, and water-soluble
packets.   

Area Treated:

Based on HED Exposure Science Advisory Committee SOP No. 9.1, the area
treated in a day was assumed to be:

80 acres for mixing/loading to support groundboom applications,  

350 acres for applying sprays aerially,

80 acres for applying with groundboom equipment, and

350 acres for flagging to support aerial spray applications.  

Application Rate:

A maximum application rate of 0.14 lb ai/acre is proposed for
application to turnip greens and Brassica leafy vegetables.

Body Weight:

The average adult body weight of 70 kg was used for estimating dermal
and inhalation dose, since the toxicological endpoints of concern are
not sex-specific.

Absorption Factor:

The intermediate-term dermal endpoint was based on an oral study;
therefore, a dermal absorption factor of 30 percent was used to estimate
dermal exposure for intermediate-term durations.  

Since the short- and intermediate-term inhalation endpoint was based on
an oral study and no inhalation absorption data are available, toxicity
by the inhalation route is considered to be equivalent to the estimated
toxicity by the oral route of exposure.

Equations and Calculations:

Daily Dose:  Daily dose (inhalation or dermal) was calculated by
normalizing the daily dermal or inhalation exposure value by body weight
and accounting for dermal and inhalation absorption. 

Average Daily Dose = Daily Exposure (mg ai/day) x {Absorption Factor
(%/100)}

   (mg/kg/day)                                                  Body
Weight (kg)  

	Where:

	Average Daily Dose = Absorbed dose received from exposure to a
pesticide in a given scenario (mg pesticide active ingredient/kg body
weight/day),

	Daily Exposure = Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption,

	Absorption Factor = A measure of the amount of chemical that crosses a
biological boundary such as the skin or lungs, and 

	Body Weight 	= Body weight (kg) determined to represent the population
of interest in a risk assessment

Margin of Exposure (MOE): The daily dermal and daily inhalation doses
received by handlers were compared to the appropriate point of departure
(i.e., NOAEL or LOAEL) to assess the risk to occupational handlers for
each exposure route. All MOE values were calculated separately for
dermal and inhalation exposure levels using the following formula:

	MOE = 		NOAEL or LOAEL (mg/kg/day)_      

				Average Daily Dose (mg/kg/day)

Where:

MOE = Margin of exposure value used by HED to represent risk or how
close a chemical exposure is to being a concern (unitless),

	ADD = Average daily dose (ADD) is absorbed dose received from exposure
to pesticide, 

NOAEL =	Dose level in a toxicity study, where no observed adverse
effects occurred in the study, and

	LOAEL =	Dose level in a toxicity study, where the lowest level of
adverse effects occurred in the study.

Combined Risks: Combined risk was estimated by calculating an aggregate
risk index (ARI) because, while dermal and inhalation toxicological
endpoint effects are the same, they have different associated levels of
concern for the MOE.  Calculated ARIs of ( 1 do not cause concern to
HED.  The following formula is used to calculate the ARI:  

  SEQ CHAPTER \h \r 1  Aggregate Risk Index (ARI) = 1 / ((1 / (Dermal
MOE/LOC) + (1 / (Inhalation MOE/LOC))  	

8.1	Short-/Intermediate-Term Handler Risk  TC \l2 "8.1
Short-/Intermediate-Term Handler Risk 

Occupational handlers may be exposed by the dermal and inhalation routes
during mixing, loading, applying, flagging, and otherwise handling
dinotefuran.  Handler exposure is expected to be short- or
intermediate-term based on information provided on the proposed labels. 

Since a short-term dermal endpoint was not identified, only
intermediate-term dermal risks were assessed for handlers.  Also,
because the short- and intermediate-term inhalation endpoints and PoDs
are the same they are assessed as the same risk estimates. Further,
because common toxicity endpoints were identified for both dermal and
inhalation routes, a combined intermediate-term risk from both routes of
exposure was assessed.  

HED’s level of concern for the MOE is defined by the uncertainty
factors that are applied to the assessment.  HED applies a 10X factor to
account for inter-species extrapolation and a 10X factor to account for
intra-species sensitivity.  An additional 10X factor has been applied to
the inhalation risks to account for the use of an LOAEL in the MOE
calculation.  The total uncertainty factors that have been applied to
the non-cancer risk assessment for dinotefuran are 100 for
intermediate-term dermal occupational exposure and 1000 for short- and
intermediate-term inhalation occupational exposure.  

Combined risk was estimated by calculating an ARI because, while dermal
and inhalation endpoint effects are the same, they have different
associated levels of concern for the MOE.  Calculated ARIs of ( 1 do not
cause concern to HED.  

Summaries of the risks for occupational handlers are included in Table
12.  The maximum application rate for each exposure scenario is
presented as the worst case scenario.  All handler scenarios resulted in
MOEs greater than the level of concern (MOEs ≥ 100 for dermal risk and
MOEs ≥ 1000 for inhalation risk) at some level of mitigation. 

The inhalation risks to handlers do not exceed HED’s level of concern
at baseline (no respirator) for any of the handler scenarios where
baseline data are available.  Only engineering control (enclosed
cockpit) data are available to assess inhalation risks to handlers
operating aircraft.  The inhalation risks do not exceed HED’s level of
concern for pilots using enclosed cockpits and wearing no respirator.

The intermediate-term dermal and combined intermediate-term dermal plus
intermediate-term inhalation risks to handlers do not exceed HED’s
level of concern with baseline attire (i.e., long-sleeve shirt, long
pants, shoes, and socks) where baseline data are available (ARIs ≥ 1).
 Only engineering control (enclosed cockpit) data are available to
assess dermal exposures (and therefore combined risks) to handlers
operating aircraft.  The intermediate-term dermal and combined
intermediate-term dermal plus intermediate-term inhalation risks to
handlers do not exceed HED’s level of concern for pilots using
enclosed cockpits and wearing baseline attire.



	Table 12.  Dinotefuran Occupational Handler Risks - Intermediate-Term
Dermal Risks, Short- and Intermediate-Term Inhalation Risks, and
Combined Intermediate-Term Dermal and Inhalation Risks   

Exposure Scenario	Crop or Target	Application Rate

(lb ai/A)	Area Treated Daily

(acres) 	Unit Exposures	Doses a,b	MOEs c,d,,f,g,	ARIe,f,g

Baseline Dermal (mg/lb ai)	Baseline Inhalation (ug/lb ai)	Baseline

Absorbed Dermala 	Baseline Inhalationb 	Baseline Dermalc 

LOC=100	Baseline Inhalationd

LOC = 1000 	Baseline Dermal + Baseline Inhalatione 

LOC = 1

Mixer/Loader

Mixing/Loading Dry Flowables for Aerial Applications	Turnip greens and
Brassica leafy vegetables, 	0.14	350	0.066	0.77	0.014	0.00054	1,600
110,000	14

Mixing/Loading Dry Flowables for Groundboom Applications

0.14	80	0.066	0.77	0.0032	0.00012	6,900	490,000	61

Applicator

Applying Sprays via Aerial Equipment with Enclosed Cockpit	Turnip greens
and Brassica leafy vegetables, 	0.14	350	0.005 g

(Eng cont)	0.068 g 

(Eng cont)	0.0011 g 

(Eng cont)	0.000048 g

(Eng cont)	21,000 g 

(Eng cont)	1,300,000 g 

(Eng cont)	180 g

(Eng cont)

Applying Sprays via Groundboom Equipment

0.14	80	0.014	0.74	0.00067	0.00012	33,000	510,000	200

Flagger

Flagging for Aerial Sprays Applications	Turnip greens and Brassica leafy
vegetables, 	0.14	350	0.011	0.35	0.0023	0.00025	9,500	240,000	69

a.	Absorbed Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x
application rate (lb ai/acre) x acres treated * dermal absorption (30%)
/ body weight (70 kg).

 unit exposure (μg/lb ai) x application rate (lb ai/acre) x acres
treated * inhalation absorption (100%) x conversion factor (1 mg/1,000
μg) / body weight (70 kg). 

c.	Intermediate-term dermal MOE = NOAEL (22 mg/kg/day) / dermal daily
dose (mg/kg/day).  Level of concern = 100.

d.	Short- and Intermediate-Term Inhalation MOE = LOAEL (60 mg/kg/day) /
inhalation daily dose (mg/kg/day). Level of concern = 1000.

e.	ARI (aggregate risk index) = 1/((1/(Dermal MOE/100) + 1/(Inhalation
MOE/1000)).  Level of Concern = 1.

f.	Baseline Dermal:  Long-sleeve shirt, long pants, and no gloves;
Baseline Inhalation: no respirator.

g.	Only engineering control (enclosed cockpit) data are available to
assess dermal and inhalation risks to handlers operating aircraft.  



8.2	Short-/Intermediate-Term Postapplication Risk  TC \l2 "8.2
Short-/Intermediate-Term Postapplication Risk 

8.2.1	Data and Assumptions for Postapplication Exposure Scenarios	

Inhalation:  HED assumes that inhalation exposures are minimal following
outdoor applications of an active ingredient with low vapor pressure. 
Since the proposed uses of dinotefuran include only outdoor applications
and dinotefuran has a low vapor pressure, postapplication inhalation
exposures and risks were not assessed. 

Dermal:  The proposed use on leafy Brassica greens is for a postemergent
application. Postapplication exposures and risks were assessed for these
uses.  

The transfer coefficients (TCs) used in this assessment were taken from
the Agency’s revised Agricultural Transfer Coefficient SOP.  Many of
the TCs in this SOP are based on work of the Agricultural Re-Entry Task
Force (ARTF).  It is the intention of HED’s Science Advisory Council
for Exposure that the transfer coefficient SOP will be periodically
updated to incorporate additional information about agricultural
practices in crops and new data on TCs.  Much of this information will
originate from exposure studies currently being conducted by the ARTF,
from further analysis of studies already submitted to the Agency, and
from studies in the published scientific literature.  There may be data
compensation issues with the use of ARTF data in this assessment,
because Mitsui Chemicals, Inc. is not a member of the task force.

Data from chemical-specific residue dissipation studies were previously
submitted for use in completing the postapplication risk assessments for
ornamental, turf and agricultural (leafy vegetable) applications.  These
studies were summarized in a previous review (DP285650, 04/27/04, J.
Arthur).  Dissipation data from the study on leafy vegetables (DP300464,
06/09/04, MRID 45640008, B. O’Keefe) were used in this risk
assessment.  Table 13 summarizes the transfer coefficients and related
activities for turnip greens and Brassica leafy vegetables.  

Equations/Calculations:

The following equations were used to calculate risks for workers
performing postapplication activities:

Daily dermal dose t = DFRt (µg/cm2) x 1E-3 mg/µg x Tc (cm2/hr) x DA x
ET (hrs)		(mg/kg/day)				BW (kg)

	Where,

	t	= 	number of days after application day (days)

	DFRt 	=	dislodgeable foliage residue on day "t" (µg/cm2)

	TC	=	transfer coefficient (cm2/hr)					

     	DA	=     	dermal absorption factor (unitless)

	ET	=	exposure time (hr/day)

	BW	=	body weight (kg)

The daily dermal doses received by handlers were compared to the
appropriate PoD (i.e., NOAEL) to assess the risk to occupational
postapplication workers. All MOE values were calculated using the
following formula:

	MOE = 	______NOAEL (mg/kg/day)_               ___      

			Average Daily Dermal Dose (mg/kg/day)

Where:

MOE   =	Margin of exposure value used by HED to represent risk or how
close a chemical exposure is to being a concern (unitless),

ADD =		Average daily dermal dose (ADD) is absorbed dose received from
exposure to pesticide, and

	NOAEL	 =	Dose level in a toxicity study, where no observed adverse
effects occurred in the study.

	8.2.2 Agricultural Postapplication Exposure and Risk

The postapplication exposure associated with agricultural crops is
summarized in Table 13.  All scenarios resulted in MOEs greater than 100
on day 0 (12 hours after application) and therefore are not of concern
to HED.  

Table 13.  Occupational Postapplication Exposure and Risk for
Dinotefuran

Crop	Activity	Transfer

Coefficient1

(cm2/hr)	DAT2	DFR 3

(μg/cm2)	Intermediate-Term Exposure

	Daily Dermal Dose4 (mg/kg/day)	MOE5

LOC = 100

Turnip greens and Brassica leafy vegetables 	Hand Weeding, Irrigating,
Scouting, and Thinning at minimum foliage development.	500	0

(12 hours)	0.323	0.0058	3,800

	Irrigating and Scouting at full foliage development	1,500	0

(12 hours)	0.323	0.0173	1,300

	Hand Pruning, Hand Harvesting, and Thinning at full foliage
development.	2,500	0

(12 hours)	0.323	0.0289	760

Transfer coefficients and associated activities from ExpoSAC Policy Memo
#003.1 “Agricultural Transfer Coefficients”, 8/17/2000.

2	DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = the
day of treatment after sprays have dried; assumed to be approximately 12
hours.

3	The estimated "day 0" residue value (0.323 µg/cm2) from the leafy
vegetables DFR study conducted in Pennsylvania (MRID 45640008) is the
highest of the three sites studied and is used as a screen for estimated
day "0" values.  Values are normalized for differences in maximum foliar
application rates.

4	Daily Dermal Dose = [(DFR x TC x Dermal absorption x 8-hr Exposure
Time)] / [(CF: 1000 µg/mg) x (70-kg Body Weight)] (Intermediate-term
dermal absorption factor = 30%).

5	MOE = NOAEL / Daily Dermal Dose   (Intermediate-term Dermal NOAEL = 22
mg/kg/day).

Occupational postapplication risks do not exceed HED’s level of
concern on Day 0 (12 hours following application).

Since systemic postapplication risk estimates do not exceed HED’s
level of concern on day 0 (12 hours following application), the
restricted entry interval (REI) is based on the acute toxicity of
dinotefuran technical material.  Dinotefuran is classified as Toxicity
Category IV for acute dermal toxicity and for skin irritation and eye
irritation potential. Acute toxicity Category III and IV chemicals
require a 12 hour REI under the Worker Protection Standard (WPS).  

9.0	Data Needs and Label Recommendations  TC \l1 "9.0	Data Needs and
Label Recommendations 

9.1	Toxicology Data Needs  TC \l2 "9.1	Toxicology Data Needs 

870.6300  Developmental Neurotoxicity

A developmental neurotoxicity study in rats is required.

9.2	Residue Chemistry Data Needs and Label Recommendations  TC \l2 "9.2
Residue Chemistry Data Needs and Label Recommendations 

860.1200  Directions for Use

The application rate for the 20% formulation must be revised to reflect
the application rate in oz/A.

The maximum seasonal use rates for mustard greens for all labels must be
revised to reflect the maximum proposed seasonal use rate.

The label directions for “foliar application” with the restriction
not to apply more than a total of 6 oz of Dinotefuran (0.268 lb ai) per
acre per season applies to all three formulations.  Since the 20SG
formulation contains only 20% active ingredient, 6 oz would not be
sufficient to provide the required seasonal rate.  The statement that
pertains to the 20SG formulation should be corrected.

860.1550  Proposed Tolerances

A revised Section F is required to reflect the recommended tolerance
level of 15 ppm for Brassica, leafy greens, subgroup 5B and 15 ppm for
turnip greens.  



10.0	International Residue Limit Status  TC \l1 "10.0	International
Residue Limit Status 

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: (RS)
-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine	Common Name:

Dinotefuran	X Proposed tolerance

   Reevaluated tolerance

   Other	Date:  01/29/2009

Codex Status (Maximum Residue Limits)	U. S. Tolerances

(No Codex proposal step 6 or above

⁯Codex proposal step 6 or above for the crops requested	Petition
Number:  8E7433

DP#:  358024

Other Identifier:  Decision #400299

Residue definition (step 8/CXL):  N/A	Reviewer/Branch:  Amelia Acierto,
RAB3

	Residue definition: Dinotefuran  (RS)
-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine and its
metabolites DN, 1-methyl-3-(tetrahydro-3-furylmethyl)guanidine, and UF,
1-methyl-3-(tetrahydro-3-furylmethyl)-urea) expressed as dinotefuran 
SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 

Crop (s)	MRL (mg/kg)	Crop(s) 	Tolerance (ppm)

Brassica, leafy greens, subgroup 5B	15

Turnip, greens	15

Limits for Canada	Limits for Mexico

  ( No Limits

   No Limits for the crops requested	  ( No Limits

   No Limits for the crops requested

Residue definition:  N/A 	Residue definition:  N/A

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

Notes/Special Instructions: S.Funk, 01/29/2009



11.0	Appendix A: Dinotefuran and its Metabolites  TC \l1 "11.0	Appendix
A: Dinotefuran and its Metabolites 

Common name/code	

Chemical name	

Chemical structure

Dinotefuran; MTI-446	

Guanidine, N-methyl-N’-nitro-N”-[(tetrahydro-3-furanyl)-methyl]-	

 

UF	

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

 

DN	

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

 

12.0	Appendix B: Toxicity Profile  TC \l1 "12.0	Appendix B: Toxicity
Profile 

12.1	Appendix B1.: Acute Toxicity Data on Dinotefuran Technical  TC \l2
"12.1	Appendix B1.: Acute Toxicity Data on Dinotefuran Technical 

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	

Primary Eye Irritation – Rabbit	

46301601	

no positive effects	

IV

870.2500	

Primary Skin Irritation – Rabbit	

45639904	

low level of irritation	

IV

870.2600	

Dermal Sensitization (Guinea Pig Maximization test)	

45639905	

not a sensitizer	



12.2	Appendix B2.: Subchronic, Chronic and Other Toxicity Profile  TC
\l2 "12.2	Appendix B2.: Subchronic, Chronic and Other Toxicity Profile 

Appendix B2. Toxicity Profile of Dinotefuran

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day oral toxicity in rats	

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

Acceptable/Guideline

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

NOAEL: 38/384 [M/F] mg/kg/day	

LOAEL: 384 [M] mg/kg/day based on adrenal histopathology; 1871 [F]
mg/kg/day based on ( body weight/body weight gain, changes in
hematology/clinical chemistry, changes in organ weights, and adrenal
histopathology

870.3100

90-Day oral toxicity in mice	

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

Acceptable/Non-guideline

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

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

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

870.3150

90-Day oral toxicity in dogs	

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

Acceptable/Guideline

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

NOAEL: 307/not determined [M/F] mg/kg/day

LOAEL: 862 [M] mg/kg/day, based on ( body weight gain, hemorrhagic lymph
nodes; <59 [F], based on ( body weight, body weight gain

870.3200

28-Day dermal toxicity (rats)	

MRID: 45639908, 45639937 (range-finding) (2001)

Acceptable/Guideline

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

	

Systemic: 

NOAEL: 1000 mg/kg/day

LOAEL: not determined (no effects seen)

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, ( in 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:<0.22 [M] mg/L, 0.22 [F] mg/L	

LOAEL: ( body weight gain, food consumption [M]; increased clinical
signs (protruding eyes) [F]

870.3700a

Prenatal developmental toxicity study (rats)	

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

Acceptable/Guideline

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

Maternal

NOAEL: 300 mg/kg/day

LOAEL: 1000 mg/kg/day based on ( body weight gain and food consumption

Developmental 

NOAEL: 1000 mg/kg/day

LOAEL: not determined (no effects seen)

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: 52 mg/kg/day

LOAEL: 125 mg/kg/day based on ( body weight gains, food consumption, and
necropsy findings

Developmental 

NOAEL: 300 mg/kg/day

LOAEL: = 300 mg/kg/day based on clinical signs in does (prone position,
panting, tremor, erythema) seen following a single dose.

870.3800

Reproduction and fertility effects (rats)	

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

Acceptable/Guideline

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

Parental/systemic

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

LOAEL: 822/907[M/F] mg/kg/day, based on ( food consumption, weight gain
in males, soft feces in females, and ( spleen weights in both sexes

Reproductive (tentative)a

NOAEL: ≤241/268 [M/F] mg/kg/day

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

Developmental 

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

LOAEL: 822-935/907-1,005 [M/F] mg/kg/day based on ( body weights, body
weight gains, and spleen weights in F1 and F2 males and females, (
thymus weights in F2 males and females, and ( forelimb grip strength (F1
males) or hindlimb grip strength (F1 females)

870.4100a

Chronic toxicity (rats)	

See 870.4300 Combined chronic toxicity/carcinogenicity (rats)	

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: <20/22 [M/F] mg/kg/day

LOAEL: 20/108 [M/F] mg/kg/day based on ( thymus weight, ( food
efficiency, body weight, and body weight gain in females, ( thymus
weight in males

870.4200a

Carcinogenicity (rats)	

See 870.4300 Combined chronic toxicity/carcinogenicity (rats)	

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: <3 [M], <4 [F] mg/kg/day

LOAEL: 3/4 [M/F] mg/kg/day based on ( spleen weights at week 79 terminal
sacrifice in males and increased ovarian weights at week 53 in females

870.4300

Combined chronic toxicity/ carcinogenicity (rats)	

MRID: 45640001 (2000)

Acceptable/Guideline

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

NOAEL: 99.7/127.3 [M/F] mg/kg/day

LOAEL: 991/1332 [M/F] mg/kg/day based on ( body weight gain, food
efficiency in females, ( incidences of kidney pelvic mineralization and
ulceration in males

870.5100

Bacterial reverse mutation test	

MRID: 45640003 (1996)

Acceptable	

Negative.  ± S9 up to 16,000 Fg/plate

870.5100

Bacterial reverse mutation test	

MRID: 45654210 (1996)

Acceptable	

Negative.  ± S9 up to limit dose of 5000 Fg/plate

870.5300

In vitro mammalian cell gene mutation test	

MRID: 45640002 (2002)

Acceptable	

Negative, ± S9 up to 2002 Fg/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 Fg/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)

Unacceptable/Guideline

(no positive control data; peak effect time not documented)

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 ( motor activity on day 1

870.6200b

Subchronic neurotoxicity screening battery	

MRID: 45640004 (2001)

Unacceptable/Guideline

(no positive control data, data re motor activity computer error)

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 ( motor activity during week 2

870.6300

Developmental neurotoxicity study	

Study not available	

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 T½ 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
dose-related differences or label position effects were found.

870.7600

Dermal penetration	

Study not available	

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
radiopurity >99%	

After a single oral 50 mg/kg dose of [G-14C] 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  The NOAEL for reproductive toxicity is “tentative” due to the
lack of evaluations of sperm morphology and histopathology of the
reproductive organs at the low and mid doses ( as recommended in the
Test Guidelines) due to effects observed in these parameters at the
highest dose.



13.0	Appendix C: Executive Summary of Dose Range-Finding Developmental
Neurotoxicity and Immunotoxicity Study  TC \l1 "13.0	Appendix C:
Executive Summary of Dose Range-Finding Developmental Neurotoxicity and
Immunotoxicity Study 

EXECUTIVE SUMMARY:  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 were 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).

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B≤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 (10,000 ppm) is considered suitable as a high dose level
for the DNT study.

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).

This study is classified acceptable/non-guideline and provides
information regarding the potential immunotoxic effect in offspring rats
after exposure to dinotefuran during the prenatal, postnatal, and
post-weaning periods. Additionally, it is a range-finding study for a
definitive developmental neurotoxicity study.

 PAGE   

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Page   PAGE  45  of   NUMPAGES  45 

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