 

Docket ID#: EPA HQ-OPP-2009-0890

COMPANY NOTICE OF FILING   

EPA Registration Division contact: Sidney Jackson, 703-305-7610

 

 Interregional Research Project Number 4 (IR-4)

PP# 9E7642

	EPA has received a pesticide petition 9E7642 from the Interregional
Research Project Number 4 (IR-4), IR-4 Project Headquarters, 500 College
Road East, Suite 201 W, Princeton, NJ 08540, in cooperation with
Chemtura Corp., 199 Benson Rd (2-5), Middlebury, CT 06749 proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.572 by establishing
a tolerance for residues of the insecticide bifenazate (1-methylethyl
2-(4-methoxy[1,1'-biphenyl]-3-yl)hydrazinecarboxylate) and
diazinecarboxylic acid, 2-(4-methoxy-[1,1’-biphenyl]-3-yl),
1-methylethyl ester (expressed as bifenazate) in or on the following
food  commodities: sugar apple, cherimoya, atemoya, custard apple,
ilama, soursop, and biriba at 1.5 parts per million (ppm); avocado at
7.0 ppm; fruit, small, vine climbing subgroup 13-07F, except fuzzy
kiwifruit at 0.75 ppm; and berry, low growing, subgroup 13-07G at 1.5
ppm.  EPA has determined that the petition contains data or information
regarding the elements set forth in section 408 (d)(2) of  FDDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the petition.
Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. The nature of the residues of bifenazate in plants
is adequately understood.  The major residue in all plant metabolism
studies is bifenazate.  A minor, but significant metabolite is the
diazene D3598, which was found to interconvert readily to/from
bifenazate in the plant matrix during the analytical procedure.

	2. Analytical method.  Chemtura Corporation has developed practical
analytical methodology for detecting and measuring residues of
bifenazate in or on raw agricultural commodities.   As D3598, a
significant metabolite, was found to interconvert readily to/from
bifenazate, the analytical method was designed to convert all residues
of D3598 to the parent compound (bifenazate) for analysis.  The method,
“Determination of Combined Bifenazate and D3598 Residues in Sugar
Apple”, utilizes reversed phase HPLC to separate the bifenazate from
matrix derived interferences, and oxidative coulometric electrochemical
detection for the identification and quantification of this analyte. 
The lowest level of method validation (LLMV) in this study was 0.05 ppm
for each analyte.  Based on recoveries of samples fortified at the LLMV,
the limit of detection (LOD) and limit of quantitation (LOQ) were
calculated as 0.0308 ppm and 0.0923 ppm, respectively, for bifenazate
and as 0.0332 ppm and 0.0997 ppm, respectively, for D3598.

3. Magnitude of residues. A complete crop residue program has been
completed for bifenazate in the major growing areas of the US for:

Sugar Apple:

A crop residue program has been completed for bifenazate using 
Acramite®- 50WS on sugar apple.  Three trials were conducted for this
study in accordance with U.S. EPA OPPTS 860 series guidelines in South
Florida (EPA Region 13) during the 2006 growing season.  Sugar apple is
a tropical fruit and can only be grown in Region 13.  Each trial site
included one untreated (control) plot and one treated plot.  At each
trial, two foliar applications of Acramite 50WS at a rate of
approximately 0.5 lb ai/A each were made for a total of approximately
1.0 lb ai/A to the treated plot. All applications were made 21 days
apart and timed so that commercially mature sugar apples could be
collected 1 day after the final application. 

Combined residues of bifenazate and D3598 in sugar apple harvested at a
1-day PHI showed residue levels between 0.04071 ppm to 1.313 ppm. 

A summary table is provided below:

Commodity	Application Rate

(lb ai/A)	PHI (days)	Residue Levels

(ppm)



	n	Min.	Max.	HAFT	Mean	Std. Dev.

Sugar Apple	0.98-1.04	1	12	0.04071	1.313	0.6658	0.3338	0.3539



Based on the results of the field trials on sugar apple, Chemtura
Corporation is proposing a crop specific tolerance of 1.5 ppm on sugar
apple (grouping also includes  cherimoya, atemoya, custard apple, ilama,
soursap, birida).

Avocado:

A ChemSAC decision stated that avocado can be assigned the highest
tropical fruit tolerance determined for either lychee (5.0 ppm), guava
(0.90 ppm), papaya (7.0 ppm) or sugar apple (1.5 ppm). Thus Chemtura is
also proposing a crop specific tolerance of 7.0 ppm on avocado.

Low growing berry subgroup 13-07G: 

In accordance with Federal Register Volume 72, December 7, 2007 (pp
69150-69158) Final Rule/Pesticide Tolerance Crop Grouping, it is
requested that strawberries be expanded to Low Growing Berry Subgroup
13-07G.  This subgroup contains strawberry, bearberry; bilberry;
blueberry, lowbush; cloudberry; cranberry; lingonberry; muntries;
partridgeberry; cultivars, varieties and/or hybrids of these.

Small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit:

In accordance with Federal Register Volume 72, December 7, 2007 (pp
69150-69158) Final Rule/Pesticide Tolerance Crop Grouping, it is
requested that grapes be expanded to ‘Small Fruit Vine Climbing
Subgroup 13-07F, Except Fuzzy Kiwifruit’. This subgroup contains
grape; Amur River grape; gooseberry; kiwifruit, hardy; maypop;
schisandra berry; cultivars, varieties, and/or hybrids of these.

B. Toxicological Profile

	1. Acute toxicity.  Bifenazate Technical, Acramite-50WS have low acute
oral, dermal, and inhalation toxicity in laboratory animals.  The oral
LD50 in rats and mice is greater than 5 g/kg for Acramite-50WS and the
technical material. The dermal LD50 in rats of Bifenazate Technical and
both formulations is greater than 5 g/kg.   The inhalation LC50 in the
rats of Bifenazate Technical and Acramite 50WS was found to be greater
than 4.4, 5.2 and 1.8 mg/l, respectively.  In eye irritation studies,
Acramite-50WS was a slight irritant, and Bifenazate Technical was
non-irritating. Acramite-50WS was found to be non-irritating to the skin
of rabbits and non-sensitizing on the skin of guinea pigs. Under the
test conditions for the M&K maximization test, bifenazate technical was
considered to be a sensitizer.

	2. Genotoxicty. Bifenazate was evaluated and found to be negative in
the Ames Reverse Mutation, Mouse Lymphoma, CHO Chromosome Aberration and
Mouse Micronucleus assays.

	3. Reproductive and developmental toxicity

Rabbit Teratology Study:  A range-finding study conducted in pregnant
New Zealand White rabbits at dosage levels of 125, 250, 500, 750 and
1,000 mg/kg/day demonstrated severe maternal toxicity at dosage levels
of ≥500 mg/kg/day and abortions at dosage levels of ≥250 mg/kg/day.
Bifenazate was then administered by oral gavage to pregnant New Zealand
White rabbits at dosage levels of 10, 50 and 200 mg/kg/day. No test
article related effects were seen at any dose level.  The NOAEL for
maternal and developmental toxicity was greater than 200 mg/kg/day, but
less than 250 mg/kg/day.

Rat Teratology Study: Bifenazate did not produce developmental toxicity
when administered by oral gavage to pregnant Sprague-Dawley CD rats at
dosage levels of 10, 100 and 500 mg/kg/day.  A reduction in maternal
body weight gain was seen at dosage levels of 100 and 500 mg/kg/day. 
Clinical observations at 500 mg/kg/day included red material/staining on
body surfaces, pale extremities and brown discharge. No developmental or
teratogenic effects were observed at any dosage level. The NOAEL for
maternal toxicity was 10 mg/kg/day and the NOAEL for developmental
toxicity was greater than 500 mg/kg/day.

Rat Reproduction Study: Bifenazate showed no effects on reproduction
upon dietary administration to two generations of male and female
Sprague-Dawley CD rats at dietary concentrations of 20, 80 and 200 ppm. 
At a dosage level of 200 ppm there was a reduction in body weight gain
in F0 males and females.  Food consumption was unaffected.  There was a
reduction in body weight gain in F1 females at all dosage levels and in
F1 males at 80 and 200 ppm in the absence of effects on food
consumption. Since the 20 ppm F1 males did not have a significant
reduction in body weight gain, this dosage level can be considered a
NOEL for systemic adult toxicity. The reduction in body weight gain in
the F1 females at 20 ppm would not be considered biologically
significant because no effects were observed on reproductive parameters
or in the F2 litter. The reproductive and developmental NOAEL was
greater than 200 ppm (10 mg/kg/day).

	4. Subchronic toxicity. Thirteen Week Rat Feeding Study:  Bifenazate
was fed to male and female Sprague Dawley CD rats for thirteen weeks at
dietary concentrations of 40, 200 and 400 ppm. At dosage levels of 200
and 400 ppm there was a reduction in red blood cell count and
hemoglobin. Food intake was reduced for 200 ppm females and 200 and 400
ppm males. Histopathological effects were seen in the liver, spleen and
adrenal cortex in males and females at 200 and/or 400 pm.  The maximum
tolerated dose (MTD) was exceeded in females at 200 ppm and in males and
females at 400 ppm. The NOAEL for subchronic toxicity in rats was 40 ppm
(2 mg/kg/day).

Neurotoxicity Assessment: No treatment related effects were seen on
neurobehavior in a standard Functional Observation Battery conducted at
weeks 8 and 13 of the thirteen-week rat feeding study. No overt signs of
anti-cholinergic activity, and no statistically significant effects on
cholinesterase activity were seen in rats in a two week feeding study at
dose levels up to 400 ppm.  Plasma, erythrocyte and brain cholinesterase
activity were evaluated in male and female rats fed bifenazate-treated
diet at 0, 20, 200, or 400 ppm for two weeks. All animals survived until
study termination and effects were only seen on body weight gain and
food consumption. The NOAEL for cholinergic inhibition was greater than
400 ppm (20 mg/kg/day).

Thirteen Week Dog Feeding Study:  Bifenazate was fed to male and female
Beagle dogs for thirteen weeks at dietary concentrations of 40, 400 and
1,000 ppm.  At dosage levels of 400 and 1,000 ppm there was a reduction
in red blood cell count, hemoglobin and hematocrit. Liver weights were
increased at 400 and 1,000 ppm and centrilobular hepatocellular
hypertrophy was seen in females at 400 ppm and males and females at
1,000 ppm. The NOAEL for subchronic toxicity in dogs was 40 ppm (1
mg/kg/day).

	5. Chronic toxicity. Dog Chronic Feeding Study: Bifenazate was fed to
male and female Beagle dogs for one year at dietary concentrations of
40, 400 and 1,000 ppm.  At dose levels of 400 and 1,000 ppm, there was a
reduction in food consumption in males and reduced body weight gain in
males and females.  There was a reduction in red blood cell count,
hemoglobin and hematocrit and an increase in bilirubin at 400 and 1,000
ppm.  Histopathological effects on bone marrow, kidney and liver were
also seen at these dose levels.  The NOAEL for chronic toxicity in dogs
was 40 ppm (1 mg/kg/day). 

Rat Chronic Feeding/Oncogenicity Study:  Bifenazate was not oncogenic in
rats when fed to male and female Sprague-Dawley CD rats for two years at
dietary concentrations of 20, 80 and 160 in females or 20, 80 and 200
ppm in males.  Body weight gain was reduced in males and females at the
high dosage levels. A reduction in red blood cell count and an increase
in splenic pigment were seen in females at 160 ppm, while high dose
males exhibited a reduction in total cholesterol and an increase in
splenic pigment. At a dose level of 80 ppm there was a reduction in body
weight gain, a decrease in red blood cell count and an increase in
splenic pigment in females. There was no increase in tumor incidence in
males or females as a result of bifenazate administration. The NOAEL for
chronic toxicity in rats was 20 ppm (1 mg/kg/day).

Mouse Oncogenicity Study:  Bifenazate was not oncogenic when fed to male
and female CD-1 mice for eighteen months at dietary concentrations of
10, 100 and 175 ppm in females and 10, 100 and 225 ppm in males. Body
weight gain was reduced in males and females at the high dose level. A
reduction in red blood cell, total leukocyte and lymphocyte counts was
seen in males at 225 ppm.  There was no increase in tumor incidence in
males or females as a result of bifenazate administration.

	6. Animal metabolism. In rat, [14C]-bifenazate, [14C-Phenyl] Hydrazine
carboxylic acid, 2-(4-methoxy-[1,1?-biphenyl]-3-yl)-1-methylethyl ester
was extensively metabolized when it was given orally in two dose levels
low (10 mg/kg), and high (1000 mg/kg). Although 2/3 of the dosed
radioactivity was excreted in the feces, bifenazate depicted a good
degree of absorption as indicated from the level of radioactivity in the
bile.  In the bile radioactivity study, about 70% of the C-14 was
collected from the cannulated bile ducts of low dosed rats indicating an
active level of absorption and enterohepatic circulation.

In general, the major metabolites present in feces, urine and bile
resulted from several well known metabolic reactions, including
hydrazine oxidation to diazene (D3598), molecular scission with loss of
the hydrazine carboxylic acid portion of the molecule to yield
4-methoxybiphenyl (D1989) followed by demethylation to form
4-hydroxybiphenyl (A1530). Metabolites resulted from aromatic
hydroxylation, and conjugation with glucuronic acid or sulfate were also
identified.

Pharmacokinetic parameters: The maximum plasma concentration (Cmax,
calculated as ppm D2341 equivalents) was reached much earlier following
the low dose (5-6 h) than the high dose (18-24 h). Elimination
half-lives (t1/2) were marginally longer at the high dose (12-16 h) than
at the low dose (12-13 h).  There were no obvious and consistent sex
differences in the pharmacokinetic parameters.

	

7. Metabolite toxicology. In a single dose oral toxicity limit test in
rats, the oral LD50 of the diazene product of bifenazate was estimated
to be approximately 5,000 mg/kg. At two hours and at seven days
post-dosing, no effects were seen on erythrocyte cholinesterase
inhibition in male or female rats.  In addition, no effect on plasma
cholinesterase inhibition was seen in male rats at seven days only.
Since this effect was seen only in plasma of females at one time point,
it is most likely a pseudocholinesterase effect without biological
significance.  In a dermal toxicity screen, the LD50 of the diazene was
estimated to be >2,000 mg/kg.

Mutagenicity screens with the diazene showed it to be weakly positive in
the Salmonella plate incorporation (Ames) assay in TA98 with activation
and negative in the L5178Y mouse lymphoma and mouse micronucleus assays.

	8. Endocrine disruption. There are no known reported adverse
reproductive or developmental effects in domestic animals or wildlife as
a result of exposure to this chemical.

A standard battery of required toxicity tests have been conducted on
bifenazate. No effects were seen in the reproduction or teratology
studies to indicate that bifenazate has an effect on the endocrine
system. Bifenazate administration to rats for 90 days at dose levels of
200 and 400 ppm resulted in an increased incidence of vacuolation in the
zona fasciculate of the adrenal cortex in male rats.  No effect was seen
at a dose level of 40 ppm (2 mg/kg/day). However, in the chronic rat
feeding study, no effect was seen on the adrenal cortex in male rats fed
200 ppm for one year. Furthermore, fasting glucose levels were not
reduced at any dose level in males or females in either study.  The zona
fasciculate is the site of cortisol production and cortisol is required
for gluconogenesis during fasting. The finding that fasting glucose
levels are not affected would suggest that adrenal cortex functionality
is not impaired at any dose level by bifenazate.

C. Aggregate Exposure

1. Dietary exposure. Based on dietary, drinking water, and
non-occupational exposure assessments, there is reasonable certainty of
no harm to the US population, any population subgroup, or infants and
children from chronic exposure to bifenazate.

Food. Chronic dietary exposures were estimated utilizing the Dietary
Exposure Evaluation Model software with Food Commodity Intake Database
(DEEM-FCID), version 2.16.  The most current and proposed crops are
included in EPA’s 2007 assessment assuming tolerance-level residues
and 100% crop treated.  EPA used anticipated residues for some crops
(i.e., average residues from field trials for squash, peach and tomato)
and percent crop treated estimates for some foods (i.e., almonds,
apples, apricots, cherries, cucumbers, grapes, nectarines, oranges,
peaches, pears, pecans, peppers, pistachios, prunes & plums,
strawberries, tomatoes, walnuts and watermelons).  Chemical-specific
processing factors are also included for apple juice (0.23), grape juice
(0.17), wine/sherry (0.17), tomato paste (1.0) and tomato puree (1.0).
The percent crop treated for soybeans is 0% because there was no use on
soybeans in 2005 or 2006 or 2007, and there are no plans to pursue
future use of bifenazate on soybeans.  Market projections are 1% for
tropical fruit (except avocados) group 6B and 10% for caneberries.  

Total chronic exposures to registered and proposed crops range from
0.001171 mg/kg/day (11.7% of cPAD) for youth aged 13-19 years to
0.005506 (55.1% of cPAD) for children aged 1-2 years old.  Chronic
dietary exposure for the U.S. population is estimated to be 0.001943
mg/kg/d (19.4% of cPAD).  Chronic dietary exposures less than 100% of
the cPAD are not of concern. The dietary exposures presented here are
only slightly greater than those estimated by EPA in the December 14,
2007, assessment supporting registration of caneberries (Subgroup 13A),
wild raspberry, Subgroups 6A and 6B, succulent-shelled soybeans and
assorted tropical fruit. It should be noted that assumption of 100% crop
treated on most crops in this assessment is extremely conservative. 
Chemtura projects a market share for most crops of approximately 1% for
minor crops in crop groups and the low susceptibility of the minor crops
to mites.  Unless mites are present, bifenazate will not be used.

The chronic exposures estimated here are conservative because
tolerance-level residues are also assumed for most crops and because the
percent crop treated assumption for most crops is 100%.  Existing crop
treated data show only minimal treatment of registered crops with
bifenazate.  Use on most crops, especially those significant in
children’s diets, is estimated to be 1% (apples, cherries), 5%
(grapes, plums) or 10% (peaches, pears).

ii. Drinking water. Exposure to bifenazate and potential residues in
drinking water is expected to be negligible. Bifenazate (half-life of 30
minutes) degrades rapidly under aerobic conditions to D3598 (half-life
of 7 hours), which degrades rapidly to D1989 (half-life of 96 days).
Photodegradation and other routes of dissipation of bifenazate do not
appear to be significant. Based on these data, the residue of concern
was considered to be D1989. Parent and D3598 were not included as
residues of concern in drinking later due to the short half-lives of
these compounds and the lack of an acute dietary endpoint. As reported
in the February 4, 2004 Federal Register (69 CFR 5289-5297), the annual
average estimated environmental concentrations (EECs) for bifenazate
(6.38 ppb in surface water and < 0.001 ppb in ground water) are based on
a single application of 0.75 lb ai/acre to strawberries, since the
application to grass was assumed not to impact the EECs estimated by
EPA. Chronic estimated environmental concentrations (EECs) of D1989 in
surface and ground water were generated using FIRST and SCI-GROW (1
application at 0.75 lbs ai/acre). The FIRST model generated an EEC of
6.4 ppb and SCI-GROW model generated an EEC of <0.001 ppb. These EEC
values are lower than the drinking water levels of concern (DWLOC) for
adults (260 ppb) and infants 1-2 years of age (8.8 ppb). Uses on
proposed crops were assumed not to impact the EEC estimates.

	2. Non-dietary exposure. As reported in the September 26, 2003 Federal
Register notice (68 FR 55494-55503), EPA estimated a combined MOE for
4200 for residents applying a product to home ornamental plants and
fruit trees.  Therefore, for the current short-term aggregate assessment
this MOE was included in estimating the short-term aggregate MOE
resulting from dietary and residential exposures.  Calculations were
performed for population subgroups that might apply bifenazate to
ornamentals and fruit trees (i.e., youth 13-19 years old, adults 20-49
years old, females 13-49 years old, adults 50+ years old and the general
population).  The short term oral endpoint for this scenario is 10
mg/kg/d.  MOEs range from 2300-2800.  Estimated aggregate MOEs in excess
of the target MOE (100) indicate reasonable certainty of no harm
resulting from aggregate bifenazate exposures from food, drinking water
and residential uses.

D. Cumulative Effects. The mechanism/mode of action of bifenazate on the
mammalian red blood cell, which is target organ in the species tested,
remains to be elucidated. The lack of information on bifenazate mode of
action precludes an assessment of cumulative effects. EPA has not made a
common mechanism of toxicity finding as to bifenazate and any other
substances and bifenazate does not appear to produce a toxic metabolite
produced by other substances.

E. Safety Determination

	1. U.S. population. Based on the toxicology database and available
information on anticipated residues, chronic dietary exposure to the
U.S. population (total) was 19.4% of the cPAD. The FIRST model generated
an EEC of 6.4 ppb and SCI-GROW model generated an EEC of <0.001 ppb.
These EEC values are lower than the drinking water levels of concern
(DWLOC) for adults (260 ppb). The combined MOE from the limited
potential for short-term exposure from residential uses is >1000. Based
on these assessments, it can be concluded that there is reasonable
certainty of no harm to the U.S. population or any population subgroup
from exposure to bifenazate.

	2. Infants and children. Based on the toxicology database and available
information on anticipated residues, chronic dietary exposure to infants
(under 1 year of age) was 40.7% of the cPAD and to children (1-2 years
of age) was 55.1% of the cPAD. The FIRST model generated an EEC of 6.4
ppb and SCI-GROW model generated an EEC of <0.001 ppb. These EEC values
are lower than the drinking water levels of concern (DWLOC) for infants
1-2 years of age (8.8 ppb). The combined MOE from the limited potential
for short-term exposure from residential uses is >1000. Based on these
assessments, it can be concluded that there is reasonable certainty of
no harm to the U.S. Population or any population subgroup from exposure
to bifenazate.

F. International Tolerances

	There are no CODEX or other international MRLs or tolerances for the
requested uses identified in this petition. In Argentina, the following
Tolerance/MRLs have been established: Apples 1 (mg/kg). In Australia,
Tolerance/MRL’s have been established: Apricot 0.5, Apple 2.0,
Nectarine 0.5, Peach 2.0, Pear 2.0, Plum including prune 0.5, and Pome
Fruits 2 (mg/kg). In Canada Tolerance/MRLs have been established: Apple
0.6, Cucumber 0.25, Grape 1.0, Pepper 1.1, Raisins 1.2 and Tomato 0.35
(ppm). An important tolerance is also published for strawberry (1.5
ppm). In Chile, Tolerance/MRLs have been established: Apple 0.75,
Nectarine 1.7, Peach 1.7, Pear 0.75, Plum 0.3 (mg/kg).  In Japan
Tolerance/MRLs have been established: Apple 2.0, Cherry 3.0, Citrus
Fruit 1.0, Cucumber 0.75, Eggplant 2.0, Grape 3.0, Melon 0.2, Peach 2.0,
Pear 2.0, Plum 3.0, Strawberry 5.0, Tea 2.0, Tomato 1.0, and Watermelon
0.3 (mg/kg). In Korea Tolerance/MRLs have been established: Apple 1.0,
Citrus 0.1, Eggplant 0.5, Peach 0.3, Pear 0.2, Rose N/A, Watermelon 0.1
(mg/kg). The EU commission has set MRLs of 2 mg/kg for Strawberries and
Peppers, 0.5 for Aubergines and Tomatoes and 0.3 for Cucurbits with
edible peel.

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