Document ID: EPA-HQ-OPP-2007-0302-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-27T04:00Z

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

Interregional Research Project Number 4 (IR-4)

PP#:6E7167

 	EPA has received a pesticide petition (PP) [6E7167] from the 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 (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part
180.572 by establishing a tolerance for residues of the miticide,
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 raw
agricultural commodities on/in papaya, star apple, black sapote, mango,
sapodilla, canistel, mamey sapote, lychee, longan, spanish lime,
rambutan, pulasan, guava, feijoa, jaboticaba, wax jambu, starfruit,
passionfruit, acerola, caneberry subgroup 13A, wild raspberry, edible
podded legume vegetable subgroup 6A, succulent shelled pea and bean
subgroup 6B, and succulent shelled soybean. EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408(d)(2) of the FFDCA; 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. Crompton 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 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.  Using this method the limit of
quantitation (LOQ) for bifenazate in stone fruit, pome fruit, grapes,
strawberries, and cotton was 0.01 ppm.  For hops the LOQ was 0.05 ppm. 
The limit of detection for this method, which varies with matrix, is
0.005 ppm.  The analytical method for bifenazate and its major
metabolite D3598 in animal samples was designed using the same
principles invoked in the plant method, with minor modifications. 
However, in animal samples, a separate aliquot of the extract was used
to determine residues of A1530 and its sulfate (combined) in milk and
meat samples (these metabolites appeared to be significant in goat
metabolism studies). The extract was subjected to acid hydrolysis to
convert the sulfate conjugate to A1530 before it was quantified by HPLC
using fluorescence or OCED detectors.

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

Edible podded legume vegetables (Subgroup 6A):  Chemtura is proposing to
expand the current 4 ppm tolerance for “pea, edible podded,
succulent” to all crops in subgroup 6A.

Succulent shelled peas and bean (Subgroup 6B):  Chemtura is proposing to
expand the current 0.2 ppm tolerance for “pea, garden, succulent” to
all crops in subgroup 6B.

Caneberries (Subgroup 13A):  Chemtura is proposing of tolerance of 6 ppm
for subgroup 13A and wild raspberries.

Tropical fruit:  Chemtura is proposing tolerances on several tropical
fruits:  6 ppm on papaya, star apple, black sapote, mango, sapodilla,
canistel, mamey sapote, and avocado;  4 ppm on lychee, longan, Spanish
lime, rambutan, and pulasan;  0.9 ppm on feijoa, guava, jaboticaba, wax
jambu, starfruit, passionfruit and acerola.

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.  Acramite 4SC
has been shown to be of low acute oral, dermal and inhalation toxicity
in laboratory animals.  The oral LD50 for male rats is greater than 5
g/kg in male rats and greater than 2 g/kg but less than 5 g/kg in female
rats for Acramite 4SC.   The dermal LD50 in rats is greater than 5g/kg
for Acramite 4SC.  The inhalation LC50 in rats is greater than 1.8 mg/L
for Acramite 4SC.   In eye irritation studies Acramite 4SC was
demonstrated to be a mild eye irritant.  In skin irritation studies,
Acramite 4SC was demonstrated to be non-irritating to the skin. 
Acramite 4SC was demonstrated to be non-sensitizing on the skin of
guinea pigs.      

2. Genotoxicity.  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
maternal toxicity at dosage levels of 500 mg/kg/day and greater and
abortions at dosage levels of 250 mg/kg/day and greater. 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
effets were seen at any dose level.  The NOAEL for maternal and
developmental toxicity was greater than 200 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
when  fed 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 NOEL 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.

9. Toxicology Endpoints (special sensitivities).  The following are the
toxicology endpoints for the exposure assessments:

a)	Acute Endpoint. An acute reference dose for dietary exposure was not
established, as there were no effects observed in any oral toxicity
studies that were attributable to a single dose.

b)	Short-Term Endpoint. The endpoint for acute dermal exposure is based
on the NOEL of 80 mg/kg/day from the 21-day dermal toxicity study in
rats. Use of a 100-fold safety factor, a margin of exposure (MOE) of
100, is appropriate and acceptable.

c)	Intermediate Endpoint. An intermediate exposure endpoint is not
required. Residential exposure from the landscape use is expected to be
very limited, and bifenazate is not used on turf.

d)	Chronic Endpoint. The endpoint for chronic exposure is based upon the
NOEL of 1 mg/kg/day which was obtained in the chronic rat and dog
feeding studies.  The RfD for chronic effects is 0.01 mg/kg/day using a
100-fold safety factor.

   The need for an additional safety factor for infants and children was
evaluated. Bifenazate was not carcinogenic in rodents and did not
produce reproductive effects in rats or developmental toxicity in rats
and rabbits. These data indicate that children would not be more
sensitive to dietary bifenazate than the general population, therefore,
a chronic RfD of 0.01 mg/kg/day, which is sufficient to protect the
general population, would provide adequate protection to infants and
children. Therefore, the application of an additional 10X safety factor
is not necessary.

   

   Due to the general inaccessibility of agricultural use sites to
children and given the low mammalian dermal and inhalation toxicity of
Acramite-50WS, both exposure and risk to children will be insignificant.

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.

i. Food.  Chronic dietary exposures were estimated utilizing the Dietary
Exposure Evaluation Model software with Food Commodity Intake Database
(DEEM-FCID), version 2.00. Default processing factors from DEEM 7.73
were used for all crops to estimate residues in foods consumed by humans
in accordance with standard EPA practice when processing studies are not
available.  EPA provided percent crop treated estimates for some
registered crops in the August 30, 2006, FR notice.  When a percent crop
treated estimate was not available in the August 30, 2006 FR notice,
Chemtura provided estimates of the percent crop treated for all other
registered and proposed crops. EPA’s percent crop treated estimates
were extrapolated for similar crops.  For some recently registered
crops, the percent crop treated was estimated by Chemtura as the maximum
of any available data and a consideration of future market penetration,
including 2.7% for cherries, 1% for cotton, 100% for hops, 1% for peas
(6A and 6B), 4.5% potatoes, 1% for root and tuberous vegetables (1C).
The percent crop treated for soybeans is 0% because there was no use on
soybeans in 2005 and there are no plans to pursue future use of
bifenazate on soybeans.  For proposed crops, market projections were
provided by Chemtura, including 1% for tropical fruit (except avocados)
group 6B and 10% for caneberries.  The percent crop treated for animal
products (meat and milk) was assumed to be 4.5% based on the percent
crop treated estimate for potatoes. ADVANCE \d4 Using existing %cPAD
for existing tolerances from 68 FR 55494-5503 (9/26/03) for the chronic
dietary exposure to the US Population (total) was estimated was 3.9% of
the cPAD (0.000390 mg/kg/day). The most highly exposed subpopulation,
non-nursing infant, has an estimated total bifenazate exposure equal to
9.7% of the cPAD. The total chronic dietary exposure associated with
current and proposed uses of bifenazate has been demonstrated to be less
than the cPAD (0.01 mg/kg/d) and are therefore not of concern. It is
important to remember that this assessment is quite conservative because
it includes tolerance level residues in all current and proposed crops
(with the exception of tomatoes, for which EPA used average residues
from field trials). 

ii. Drinking water. Exposure to bifenazate and potential residues in
drinking water is expected to be neglible. 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. 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). The EEC values discussed
were those reported in the 9-26-2003 Federal Register. Uses on proposed
crops were assumed not to impact the EEC estimates. 

2. Non-dietary exposure. [Food uses described in this petition are
strictly agricultural, and will not add to any residential non-dietary
exposure that may exist.

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 3.9% 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 8.1% of the cPAD and to children (1-2 years of
age) was 7.3% 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 

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).  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 2.0, Eggplant 2.0, Grape 3.0,
Melon 0.2, Peach 0.2, Pear 2.0, Plum 3.0, Strawberry 3.0, Tea 2.0,
Tomato 2.0, and Watermelon 0.2 (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 (ppm).