Document ID: EPA-HQ-OPP-2009-0013-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-08T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

Docket ID No.:  EPA-HQ-OPP-2008-xxxx

EPA Registration Division Contact: Sidney Jackson (703-305-7610)

Pesticide Petition #: 8E7433  

EPA has received a pesticide petition (PP 8E7433) from the Interregional
Research Project Number 4 (IR-4), IR-4 Project Headquarters, 500 College
Road East, Suite 201 W, Princeton, NJ 08540 proposing pursuant to
Section 408(d) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C.
346a(d), to amend 40 CFR Part 180 by establishing a tolerance for
residues of dinotefuran,
(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine and its
major metabolites DN, 1-methyl-3-(tetrahydro-3-furylmethyl)guanidine,
and UF, 1-methyl-3-(tetrahydro-3-furylmethyl)-urea, in or on brassica,
leafy greens, subgroup 5B at 17.0 parts per million (ppm), and turnip,
greens at 17.0 ppm.  IR-4 submitted this petition on behalf of the
registrant, Mitsui Chemical, Inc., Chiyoda-ku, Tokyo, Japan.  EPA has
determined that the petition contains data or information regarding the
elements set forth in Section 408(d)(2) of the FDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of the petition. Additional data
may be needed before EPA rules on the petition.

A.	Residue Chemistry                                        

1. 	Plant metabolism.   

The primary metabolic pathways of dinotefuran in plants (rice, apple,
potato, oilseed rape and lettuce) were similar to those described for
animals, with certain extensions of the pathway in plants.  Parent
compound, dinotefuran, and two metabolites;
1-methyl-3-(tetrahydro-3-furymethyl) guanidine (DN) and
1-methyl-3-(tetrahydro-3-furymethyl)-urea (UF) were major metabolites in
all crops.  The metabolism of dinotefuran in plants and animals is
understood for the purposes of the proposed tolerances.  Parent
dinotefuran and the
metabolites,1-methyl-3-(tetrahydro-3-furymethyl)guanidine (DN) and
1-methyl-3-(tetrahydro-3-furymethyl)-urea (UF) are the residues of
concern for tolerance setting purposes. 

2. 	Analytical method.

Mitsui Chemicals, Inc., has submitted practical analytical methodology
for detecting and measuring levels of dinotefuran and its metabolites,
UF and DN, in or on raw agricultural commodities.  The HPLC method was
validated for determination of dinotefuran, DN and UF in or on tomatoes
and peppers, cucurbits, brassica, grapes, potatoes, and lettuce for raw
agricultural commodity matrices and in or on tomato paste and puree,
grape juice and raisins and potato chips, granules, and wet peel for
processed commodity matrices.  After extraction with a
water/acetonitrile mixture and clean up with hexane and extraction
columns, concentrations of dinotefuran and its metabolites were
quantified after HPLC separation by MS/MS detection.  The limit of
quantitation was 0.01 ppm for all matrices.

3.	 Magnitude of residues.

Crops in residue trials were treated at maximum label rates and
harvested at the specified minimum treatment to harvest intervals.  The
residue method for dinotefuran, DN and UF in all components utilized
HPLC separation with MS/MS detection.  Tolerances have been previously
proposed for combined residues of Dinotefuran, DN and UF in or on Leafy
Vegetables (Crop Group 4), Cotton Seed Undelinted and Cotton Gin
Byproducts, Cucurbit Vegetables (Crop Group 9), Grapes, Potatoes,
Fruiting Vegetables (Crop Group 8), Vegetables, brassica head and stem
crop subgroup (Crop Subgroup 5-A), and Meat, Milk and Byproducts.
ADVANCE \d1 

For Leafy Brassica Greens (Crop Subgroup 5-B), residue trials were
conducted for the representative crop, mustard greens. The proposed
tolerance in or on Leafy Brassica Greens for combined residues of
Dinotefuran, DN, and UF is 17 ppm. The maximum combined residue found
for the representative crop, mustard greens, was 7.834 ppm.

B.	 Toxicological Profile

1. 	Acute toxicity.  

Dinotefuran has low acute oral, dermal and inhalation toxicity.  The
oral LD50 in rats is 2450 mg/kg, the dermal LD50 is >2000 mg/kg and the
inhalation 4-hour LC50 is >4.09 mg/L air.  Dinotefuran is not a skin
sensitizer in guinea pigs but is slightly irritating to the skin and
eyes of rabbits.  End-use formulations of dinotefuran have similar low
acute toxicity profiles.

2. 	Genotoxicity. 

Dinotefuran and its metabolites do not induce gene mutations in
bacterial and mammalian cells, chromosome aberrations in mammalian cells
or DNA damage in bacterial cells in in vitro test systems.  Similarly,
it does not exhibit a clastogenic effect in vivo in the mouse
micronucleus test.  Therefore, there is no evidence to suggest a
genotoxic hazard at any of the 3 main levels of genetic organization.

3. 	Reproductive and developmental toxicity.

In rat and rabbit developmental toxicity studies with dinotefuran, there
was no evidence of teratogenicity or other embryotoxic effects at the
highest dose levels, although maternal toxicity was evident. There were
no treatment-related effects on litter parameters at any dose level in
either species.  In rats, 1000 mg/kg produced decreased food consumption
and body weight gain, and increased water intake. In rabbits, 300 mg/kg
produced hypoactivity, prone position, panting, flushing of the nose and
ears, tremors, and reduced weight gain, food consumption and water
intake.  Necropsy revealed pale brown discoloration of liver and
gray/white plaques in the stomach at 125 and 300 mg/kg.  The NOEL values
in maternal rats and rabbits were 300 and 52 mg/kg/day, respectively.
The NOEL values in rats and rabbits for embryonic development and
teratogenicity were the highest dose levels administered, 1000 and 300
mg/kg/day, respectively.  In a 2-generation study, parental animals of
both sexes and both generations showed reduced body weight gain and food
consumption at the highest dose level evaluated (10000 ppm), but there
was no effect of treatment at any dose level in either generation on
reproductive performance indicators. There were no treatment-related
effects at any dose level on the histopathological appearance of the
reproductive organs of either sex. Similarly, there were no effects at
any dose level in either generation on quantitative ovarian
histopathology or on sperm counts, motility and morphology.  Reduced
spleen weight in P generation animals and reduced thyroid weight in F1
generation parental females were apparent at 10000 ppm. F1 pup
behavioral and sexual development was unaffected by treatment at all
dose levels but pup weight gain during lactation was reduced at 10000
ppm in both generations. Furthermore, the spleen weight of F1 generation
progeny was reduced at 10000 ppm. Based on reduced weight gain and food
consumption in parental animals at 10000 ppm and reduced pre-weaning
weight gain in the offspring, the NOEL value for parental animals and
offspring is 241mg/kg.

 

4. 	Subchronic toxicity. 

Dinotefuran was evaluated in 13-week oral (diet) toxicity studies in
rats, mice, and dogs.  No specific target organs were identified in any
species. In the rat study, a NOEL of 500 ppm (34/38 mg/kg/day) for males
and females) was established, based on minimal growth retardation in
females and adrenal cortical vacuolation in males.  A NOAEL was
established at 5,000 ppm (336 / 384 mg/kg/day for males/females) based
on marked growth retardation at 25,000 ppm (adrenal cortical vacuolation
not adverse).  In the mouse study, a NOAEL of 25,000 ppm (4,442/5414
mg/kg/day for males/females) was established based on growth retardation
at 50,000 ppm.  In the dog study, a NOEL of 8,000 ppm (307/323/
mg/kg/day in males/females) was established based on growth retardation.
 Dinotefuran was also evaluated for dermal and inhalation toxicity for 4
weeks in rats.  Daily inhalation exposure of rats for 6 hours/day for 4
weeks did not elicit toxicologically significant effects at any exposure
concentration up to and including the highest technically achievable
concentration (2.08 mg/L) with a low MMAD(GSM of 2.03 um ( 3.60. 
Dinotefuran was well tolerated and there were no treatment related
effects on clinical condition, hematology, and clinical chemistry
profiles, organ weights, macroscopic and microscopic pathology.  Dermal
application for 4 weeks at dose levels up to 1000 mg/kg/day did not
elicit any local or systemic effects on any of the parameters examined. 
Therefore, no target organs were identified in the rat either by dermal
or inhalation exposure.

5. 	Neurotoxicity.

Dinotefuran did not produce any functional or histomorphological
evidence of neurotoxicity in acute (gavage) and 13-week (dietary)
neurotoxicity studies in rats. The NOEL for neurotoxicity in the acute
study was 1,500 mg/kg, the highest dose level administered. The NOEL for
neurotoxicity in the 13-week dietary study was 50,000 ppm (3413/3806
mg/kg/day for males and females). The NOEL for all effects in this study
was 5,000 ppm (327/400 mg/kg/day for males and females) based on reduced
body weight gain and food consumption.

6. 	Chronic toxicity. 

Chronic toxicity studies with dinotefuran have been conducted in rats,
mice, and dogs. In common with the subchronic studies in these species,
no specific target organs could be identified. In the 52-week dog study
a NOAEL of 559/512 mg/kg/day for males/females was established based on
decreased weight gain in both sexes and decreased food consumption in
females.  In the 78-week mouse study a NOAEL of 345/441 mg/kg/day for
males/females was established, based on decreased weight gain and a
decrease in circulating platelet counts.  In the 104-week rat study a
NOAEL of  991/127 mg/kg/day for males/females was established.  This was
based on a decrease in weight gain in females.

7. 	Carcinogenicity. 

The carcinogenic potential of dinotefuran has been evaluated in rats and
mice.  Survival incidences in the oncogenicity studies were unaffected
by treatment at all dose levels. There were no treatment-related effects
on the nature and incidence of neoplastic and adverse non-neoplastic
histomorphological findings in either species at any dose level.
Therefore, the NOAEL values for all effects, 991/127 mg/kg/day
(male/female rats) and 345/441 mg/kg/day (male/ female mice) are based
on reduced weight gain, and also on reduced numbers of platelets in
mice.

8. 	Animal metabolism. 

In the rat, dinotefuran is rapidly and almost completely absorbed from
the gastrointestinal tract into the general circulation, and is widely
distributed throughout the tissues and fluids of the body. Elimination
is rapid, predominantly by urinary excretion and almost complete within
7 days of administration. There is no evidence for tissue accumulation. 
Dinotefuran is rapidly transferred to maternal milk and widely
distributed into fetal tissues but rapidly eliminated from them.  More
than 90% of orally and intravenously administered dinotefuran is
eliminated as unchanged parent molecule, which is also the major
radioactive component in plasma, milk, bile and most tissues. The major
route of metabolism is an initial enzymatic hydroxylation of the
tetrahydrofuran ring to form isomers of
6-hydroxy-5-(2-hydroxyethyl)-1-methyl-1,3-diazinane-2-ylidine-N-nitroami
ne (PHP), followed by further oxidation, reduction and acetylation of
PHP to produce possible isomers of dinotefuran-CO, dinotefuran-DO,
PHP-Ac and dinotefuran-OH+COOH.  Several minor pathways of metabolism of
dinotefuran were identified in animals. The absorption, distribution,
metabolism and elimination of dinotefuran is unaffected by sex and
treatment regimen.  In hens and goats, the metabolite profile was
similar as in plant metabolism.

 

9. 	Metabolite toxicology. 

The metabolism profile for dinotefuran supports the use of an analytical
enforcement method that accounts for parent dinotefuran and
1-methyl-3-(tetrahydro-3-furymethyl)guanidine (DN) and
1-methyl-3-(tetrahydro-3-furymethyl)-urea (UF).  Other metabolites are
considered of equal or lesser toxicity than parent compound.

10. 	Endocrine disruption. 

Dinotefuran does not belong to a class of chemicals known or suspected
of having adverse effects on the endocrine system.  There is no evidence
that dinotefuran has any effect on endocrine function in developmental
or reproduction studies.  Furthermore, histological investigation of
endocrine organs in chronic dog, rat and mouse studies did not indicate
that the endocrine system is targeted by dinotefuran.

C.	 Aggregate Exposure

1. 	Dietary exposure. 

Chronic dietary exposure assessments were conducted using a Tier I
approach.  This Tier I assessment incorporated tolerance level residues
and 100% crop-treated in the DEEMTM (Dietary Exposure Evaluation Model;
Exponent, Inc., 2003) software system (Version 2.16).  DEEMTM utilized
the food consumption data derived from the 1994-1998 USDA Continuing
Surveys of Food Intake by Individuals (CSFII).   The resulting exposures
were compared to a RfD of 1.27 mg/kg/day, which was based on the female
NOAEL of 127 mg/kg/day from the 104-week rat study and a 100-fold
uncertainty factor.  Chronic dietary exposure estimates for the overall
US population and 25 population subgroups are well below the chronic
RfD.  Results of these analyses are summarized below.

Table H-1.     Chronic Dietary Risk (DEEM() Analysis of Dinotefuran

Population Subgroup	

mg/kg BW/day	

%RfD

US population	

0.003915	

0.30%

All infants ( < 1 year old)	0.002287	

0.20%

Non-Nursing infants	0.002796	

0.20%

Children (1-6)	0.006516	

0.50%

Children (7-12)	0.004183	

0.30%

Females (13-50)	0.003603	

0.30%

Males 13+ years	0.003559	

0.30%

There are no acute toxicity concerns with dinotefuran as there is no
toxicological endpoint attributable to a single exposure in the
dinotefuran toxicology database, including the rat and rabbit
developmental studies.  Therefore, only chronic dietary exposures have
been assessed.  

2. 	Non-dietary exposure. 

Mitsui has considered potential non-dietary and aggregate (non-dietary +
dietary) exposures to adults, adult females, and children (1-6 years of
age) for these uses. 

Applicator and post-application exposures can result from dermal and
inhalation routes for both adults and children.  Additionally, children
can be exposed through the post-application incidental ingestion route
via hand-to-mouth behavior.  Based on the label instructions and typical
use patterns of these product types, only short- and intermediate-term
exposure scenarios should be considered for dinotefuran products. 
However, since there are no toxicological endpoints attributable to a
single or possible multiple exposures in a very short duration, as in a
short-term scenario, only the intermediate-term exposure scenario has
been evaluated for this document.

Dermal exposures for applicator and post-application activities were not
assessed because the very high dermal NOAEL (>1,000 mg/kg/day) for
dinotefuran indicates that dermal exposures are not of concern.
Short-term oral (e.g., incidental ingestion) exposures for children, as
mentioned above, were not assessed because there are no toxicological
endpoints attributable to a single exposure or multiple exposures during
a very short-term time frame in the dinotefuran toxicology database. 
Since the oral endpoint is used to calculate inhalation risks,
short-term inhalation exposures for  children and adults were also not
evaluated since there is no toxicological endpoint attributable to a
short-term endpoint. Intermediate-term inhalation exposures for
applicator and post-application activities also were not assessed
because the very high inhalation NOAEL (>7,000 mg/kg/day) for
dinotefuran indicates that inhalation exposures are not of concern. 
Therefore, only intermediate-term oral (incidental ingestion) exposures
for  children were assessed.  These exposures were assessed for each
individual dinotefuran product, as well as for the aggregation of all
products.  In the aggregate assessment, it was assumed that the children
would be exposed to residues resulting from the agricultural uses
(chronic dietary), all within one day.  These non-dietary assessments
were conducted using equations and default parameters from EPA(s
Residential Standard Operation Procedures (SOPs) (US EPA, 1997 and 2001)
and maximum application rates. Although these exposures are based on the
intermediate-term time frame, the residue on the day of application was
used in the SOP equations in order to maintain an extra level of
conservatism.  This assumption implies that children are exposed to
residue levels, which are equivalent to levels resulting on the day of
application, every day over an intermediate-term time frame.   The
resulting oral and aggregate exposures were compared to the NOAEL of 307
mg/kg/day observed in the 13-week dog study. These risk estimates
(Margin of Exposures) for children (1-6 years of age) are summarized
below. From the results below, Mitsui concludes there is reasonable
certainty of no harm associated with the aggregate (dietary +
non-dietary) exposure to dinotefuran.

Table H-2.     Intermediate-Term Aggregate MOEs

 Exposure Routes	

Margin of Exposure	

mg/kg BW/day

Children (1-6 years old)	

 	

 

	

	

Dietary	 47,117	 0.006516

 	 	 

Aggregate	 1,410	0.217688

3.	Drinking water exposure

EPA uses the Drinking Water Level of Comparison (DWLOC) as a theoretical
upper limit on a pesticide(s concentration in drinking water when
considering total aggregate exposure to a pesticide in food, drinking
water, and residential uses.  DWLOCs are not regulatory standards for
drinking water; however, EPA uses DWLOCs in the risk assessment process
as a surrogate measure of potential exposure from drinking water.  In
the absence of monitoring data for pesticides, it is used as a point of
comparison against conservative model estimates of a pesticides
concentration in water.

An estimate of the drinking water environmental concentration (DWEC) in
ground and surface water for dinotefuran has been made for this Notice
of Filing.  The DWEC of dinotefuran in groundwater was estimated to be
0.94 ppb using SCI-GROW (the screening model for ground water), and the
DWEC for surface water was estimated to be 6.24 ppb (for chronic and
intermediate-term aggregate assessments) using FIRST (FQPA Index
Reservoir Screening Tool).

To calculate the DWLOC for chronic aggregate exposure relative to a
chronic toxicity endpoint, the chronic dietary food exposure from 
DEEMTM, as addressed above, was subtracted from the RfD to obtain the
acceptable chronic exposure to dinotefuran in drinking water.  DWLOC(s,
as presented below, were then calculated using default body weights and
drinking water consumption figures.

Table H-3.     Chronic Aggregate Drinking Water Assessment 

Population Subgroup	

Dietary mg/kg BW/day	

Maximum water exposure mg/kg BW/day	

kg BW	

SCI-GROW (ppb)	

FIRST (ppb)	

DWLOC (ppb)

US population	

0.003915	

1.266085	

70	

0.94	

6.24	44,340

All infants

 (< 1 year old)	

0.002287	

1.267713	

10	

0.94	

6.24	

12,677

Non-Nursing infants	

0.002796	

1.267204	

10	

0.94	

6.24	

12,672

Children (1-6)	

0.006516	

1.263485	

20	

0.94	

6.24	

25,270

Children (7-12)	

0.004183	

1.265817	

40	

0.94	

6.24	

50,633

Females (13-50)	

0.003603	

1.266397	

60	

0.94	

6.24	

37,992

Males (13+ years)	

0.003559	

1.266441	

70	

0.94	

6.24	

44,325

Chronic RfD used in assessments - 1.27 mg/kg BW/day 

DWLOC = (Maximum water exposure*BW)/water consumption

Water consumption for adults = 2L, water consumption for children = 1L

The estimated average concentration of dinotefuran in surface water is
6.24 ppb.  This value is less than the lowest DWLOC for dinotefuran as a
contribution to chronic aggregate exposure (12,672 ppb for non-nursing
infants, the most highly exposed population group for the chronic
scenario).  Therefore, taking into account the proposed uses, it can be
concluded with reasonable certainty that residues of dinotefuran in food
and drinking water will not result in unacceptable levels of human
health risk.

To calculate the DWLOC for the intermediate-term aggregate exposure
relative to a sub-chronic toxicity endpoint, the chronic dietary food
exposure from DEEMTM plus the intermediate-term non-dietary exposures
were subtracted from the NOAEL, divided by the target MOE (100), to
obtain the acceptable intermediate-term exposure to dinotefuran in
drinking water.  DWLOC(s, as presented below, were then calculated using
default body weights and drinking water consumption figures.

Table H-4.     Intermediate-term Aggregate Drinking Water Assessment 

Population Subgroup	

NOAEL/MOE mg/kg/day	

Aggregate Exposure mg/kg/day	

Max. Water Exposure mg/kg/day	

SCI-GROW (ppb)	

FIRST (ppb)	

DWLOC (ppb)

Toddlers (1-6)1	0.307	0.217	3.068	0.94	6.24	61,360

1 Assume 20kg bodyweight

The estimated average concentration of dinotefuran in surface water is
6.24 ppb.  This value is less than the DWLOC for dinotefuran as a
contribution to intermediate-term aggregate exposure (61,360 ppb). 
Therefore, taking into account the proposed uses, it can be concluded
with reasonable certainty that residues of dinotefuran in residential
environments and in food and drinking water will not result in
unacceptable levels of human health risk.

D.  	Cumulative Effects

The potential for cumulative effects of dinotefuran and other substances
that have a common mechanism of toxicity has also been considered. 
Dinotefuran belongs to a pesticide chemical class known as the
neonicotinoids and subclass nitroguanadines.  There is no reliable
information to indicate that toxic effects produced by dinotefuran would
be cumulative with those of any other chemical including another
pesticide. Therefore, Mitsui believes it is appropriate to consider only
the potential risks of dinotefuran in an aggregate risk assessment.

E.  	Safety Determinations

1.  	U.S. population

Using the chronic exposure assumptions and the proposed RfD described
above, the dietary exposure to dinotefuran for the U.S. population (48
states, all seasons) was calculated to be 0.30% of the reference dose of
1.27 mg/kg/day. The resulting DWLOC, 44,340 ppb, is much greater than
the estimated average concentration of dinotefuran in surface water,
6.24 ppb. Therefore, taking into account the proposed uses on Crop
Subgroup 5-B, Leafy Brassica Greens (broccoli raab; cabbage, Chinese
(bok choi); collards; kale; mizuna; mustard greens; mustard pinach; rape
greens), it can be concluded with reasonable certainty that residues of
dinotefuran in residential environments and in food and drinking water
will not result in unacceptable levels of human health risk.

2.  	Infants and children

FFDCA Section 407 provides that EPA shall apply an additional safety
factor for infants and children to account for prenatal and postnatal
toxicity and the completeness of the database.  Only when there is no
indication of increased sensitivity of infants and children and when the
database is complete, may the extra safety factor be removed.  In the
case of dinotefuran, the toxicology database is complete.  There is no
indication of increased sensitivity in the database overall, and
specifically, there is no indication of increased sensitivity in the
developmental and multi-generation reproductive toxicity studies. 
Therefore, Mitsui concludes that there is no need for an additional
safety factor; the RfD of 1.27 mg/kg/day and sub-chronic NOAEL of 307
mg/kg/day are protective of infants and children.

Using the chronic exposure assumptions and the proposed RfD described
above, the dietary exposure to dinotefuran for infants and children
(1-6) was calculated to be 0.50 % of the reference dose of 1.27 mg/kg
body-wt/day.  The resulting DWLOC for non-nursing infants, 12,672 ppb,
is much greater than the estimated average concentration of dinotefuran
in surface water, 6.24 ppb.  

Using the intermediate-term exposure assumptions and the proposed NOAEL
described above, the intermediate-term aggregate exposure to dinotefuran
for the children (1-6) resulted in an MOE of 1,410.  The resulting
DWLOC, 61,360 ppb, is much greater than the estimated average
concentration of dinotefuran in surface water, 6.24 ppb.  Therefore,
taking into account the proposed uses on Crop Subgroup 5-B, Leafy
Brassica Greens (broccoli raab; cabbage, Chinese (bok choi); collards;
kale; mizuna; mustard greens; mustard pinach; rape greens), it can be
concluded with reasonable certainty that residues of dinotefuran in
residential environments and in food and drinking water will not result
in unacceptable levels of human health risk

F.	 International Tolerances

No Codex Maximum Residue Levels (MRL(s) have been established for
residues of dinotefuran on any crops at this time.