Notice of Filing of Pesticide Petition Number 8E7318

Prepared by Chemtura Corporation

[\<]{.mark}EPA Registration Division contact: Susan Stanton; (703)
305-5218[\>]{.mark}

[\<]{.mark} EPA has received a pesticide petition (PP#8E7318) from IR-4
Project Number 4 (IR-4), 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 tolerances for residues of bifenazate and its
metabolite, diazinecarboxylic acid,
2-(4-methoxy-\[1,1\'-biphenyl\]-3-yl), 1-methylethyl ester (expressed as
bifenazate), in or on the raw agricultural commodity bean dry, seed at
0.2 parts per million (ppm), in or on the raw agricultural commodity
grass, forage, fodder and hay, group 17, forage at 140 parts per million
(ppm), and in or on the raw agricultural commodity grass, forage, fodder
and hay, group 17, hay at 120 parts per million (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[\>]{.mark}

[\<]{.mark}*A. Residue Chemistry*[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 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
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.[\>]{.mark}

[\<]{.mark} 3. *Magnitude of residues.* A complete crop residue program
has been completed for bifenezate in the major growing areas of the US
for:

> [Dry Beans:]{.underline}

-   Chemtura Corporation is proposing a crop specific tolerance of 0.2
    ppm on dry beans (*Lupinus* spp. include grain lupin, sweet lupin,
    white lupin, and white sweet lupin; *Phaseolus* spp. include field
    bean, kidney bean, lima beans (dry), navy bean, and pinto bean;
    tepary bean; *Vigna* spp. include adzuki bean, blackeyed pea,
    catjang, cowpea, Crowder pea, moth bean, mung bean, rice bean,
    southern pea, and urd bean; broad bean; chickpea; guar; lablab bean;
    and lentil).

> [Grass Forage, Fodder, and Hay Group (Crop Group 17):]{.underline}

-   Chemtura Corporation is proposing a tolerance of 140 ppm on grass
    forage and fodder, and a tolerance of 120 ppm on grass hay. Crop
    Group 17 commodities include any grass, Graminaeae family (either
    green or cured) except sugarcane and those included in the cereal
    grains group, that will be fed to or grazed by livestock, all
    pasture and range grasses and grasses grown for hay or
    silage.[\>]{.mark}

[\<]{.mark}*B. Toxicological Profile*[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 2. *Genotoxicty.* Bifenazate was evaluated and found to be
negative in the Ames Reverse Mutation, Mouse Lymphoma, CHO Chromosome
Aberration and Mouse Micronucleus assays.[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

> 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
> NOEL was greater than 200 ppm (10 mg/kg/day).\]

[\<]{.mark} 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).[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

> [\<]{.mark}

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.[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark}*C. Aggregate Exposure*[\>]{.mark}

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.

[\<]{.mark} 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 and bean (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. Market projections are 1%
for tropical fruit (except avocados) group 6B and 10% for caneberries.
The predicted percent crop treated for grasses is expected to be less
than 1%, therefore, 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.

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 5.3% of the cPAD (0.000529 mg/kg/day). The most highly
exposed subpopulation, children 1-2 yrs, has an estimated total
bifenazate exposure equal to 13.5% 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).[\>]{.mark}

[\<]{.mark} 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.[\>]{.mark}

[\<]{.mark} 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 3400-3600. 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.[\>]{.mark}

[\<]{.mark}*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.[\>]{.mark}

[\<]{.mark}*E. Safety Determination*[\>]{.mark}

[\<]{.mark} 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 5.3% 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 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.[\>]{.mark}

[\<]{.mark} 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 9.7% 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.[\>]{.mark}

[\<]{.mark}*F. International Tolerances*[\>]{.mark}

[\<]{.mark} 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). 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
(mg/kg). In the United Kingdom Tolerance/MRL has been established:
Strawberry 1.0 (mg/kg). The Netherlands have national MRLs of 2.0 for
Strawberries and Chili Peppers, 0.5 for Sweet Peppers, Tomatoes and
Aubergines, 0.3 for Cucumbers and 0.2 for Melons and Watermelons. The
Dutch national MRLs are also import tolerances (MRLs) for Germany. The
EU commission have set MRLs of 2 for Strawberries and Peppers, 0.5 for
Aubergines and Tomatoes and 0.3 for Curcubits with edible
peel.[\>]{.mark}