Document ID: EPA-HQ-OPP-2007-0302-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-03-05T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

MEMORANDUM

Date:		01/11/2008

Subject:	PP#6E7167; Bifenazate; (000586).  Petition for Establishment of
Tolerances for Uses on Caneberry (Crop Subgroup Group 13A); Wild
Raspberry; Edible-podded Legume Vegetable (Crop Subgroup 6A);
Succulent-shelled Pea and Bean (Crop Subgroup 6B); Soybean,
Succulent-shelled; and Various Tropical Fruits Including Papaya, Star
Apple, Black Sapote, Mango, Sapodilla, Canistel, Mamey Sapote, Lychee,
Longan, Spanish Lime, Rambutan, Pulasan, Guava, Feijoa, Jaboticaba, Wax
Jambu, Starfruit, Passionfruit, and Acerola.  HED Human-Health Risk
Assessment. 

DP: No.	348242	Decision No:	373262

PC Code:	000586	MRID No.:	None

40 CFR §180.	572

Chemical Class:	Miticide/Insecticide

From:		William D. Wassell, Chemist 

P.V. Shah, Ph.D., Toxicologist 

Kelly M. Lowe, Environmental Scientist  

Registration Action Branch 1 (RAB1)

Health Effects Division (HED) (7509P)

Through:	Dana Vogel, Branch Chief

RAB1/HED (7509P)

To:			Daniel Rosenblatt RM 05

Registration Division (RD) (7505P)

Note to RD:  This document supersedes HED’s risk assessment of
12/14/2007 (Human-Health Risk Assessment, W. D. Wassell, et al.,
PP#6E7167, DP # 347497).  The document has been revised to modify the
discussion concerning the FQPA safety factor and to add information
concerning the percent crop-treated data which were used in the
assessment.

RD of the Office of Pesticide Programs (OPP) requested that HED evaluate
hazard and exposure data and conduct dietary, occupational, residential,
and aggregate exposure assessments, as needed, to estimate the risk to
human health that will result from all registered and proposed uses of
bifenazate.  A summary of the findings is provided in this document. 
The risk assessment, residue chemistry review, and dietary exposure
assessment were provided by William Wassell of RAB1; the hazard
characterization was provided by P.V. Shah of RAB1; the
occupational/residential exposure and risk assessment was provided by
Kelly Lowe of RAB1; and the drinking water assessment was provided by
Thuy Nguyen, of the Environmental Fate and Effects Division (EFED).  

NOTE:  In 2003, HED completed a Section 3 risk assessment for the
application of bifenazate to fruiting vegetables, cucurbit vegetables,
tree nuts pistachio, okra, and mint (D286170, T. Bloem et al.,
30-May-2003).  The current document contains only those aspects of the
risk assessment which are affected by the addition of the proposed
bifenazate uses.

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc142897337"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc142897337 \h  4  

2.0  PHYSICAL/CHEMICAL PROPERTIES	9

  HYPERLINK \l "_Toc142897338"  3.0  HAZARD CHARACTERIZATION	  PAGEREF
_Toc142897338 \h  10  

  HYPERLINK \l "_Toc142897339"  3.1  Endocrine Disruption	  PAGEREF
_Toc142897339 \h  12  

  HYPERLINK \l "_Toc142897340"  3.2  Residues of Concern for Dietary
Risk Assessment	  PAGEREF _Toc142897340 \h  12  

  HYPERLINK \l "_Toc142897341"  4.0  EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc142897341 \h  14  

  HYPERLINK \l "_Toc142897342"  4.1  Summary of Registered Uses	 
PAGEREF _Toc142897342 \h  14  

  HYPERLINK \l "_Toc142897343"  4.2  Summary of Proposed Uses	  PAGEREF
_Toc142897343 \h  14  

  HYPERLINK \l "_Toc142897344"  4.3  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc142897344 \h  16  

4.4  Water Exposure/Risk Pathway	28

  HYPERLINK \l "_Toc142897345"  4.5  Dietary Exposure Analysis	  PAGEREF
_Toc142897345 \h  28  

  HYPERLINK \l "_Toc142897346"  4.6  Residential Exposure and Risk
Assessment	  PAGEREF _Toc142897346 \h  29  

  HYPERLINK \l "_Toc142897347"  4.7  Non-occupational Off-Target
Exposure	  PAGEREF _Toc142897347 \h  29  

5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	29

  HYPERLINK \l "_Toc142897348"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc142897348 \h  30  

  HYPERLINK \l "_Toc142897349"  7.0  OCCUPATIONAL EXPOSURE AND RISK
ASSESSMENT	  PAGEREF _Toc142897349 \h  31  

  HYPERLINK \l "_Toc142897350"  7.1  Handler Exposure and Risk
Assessment	  PAGEREF _Toc142897350 \h  31  

  HYPERLINK \l "_Toc142897351"  7.2  Post-Application Exposure and Risk
Assessment	  PAGEREF _Toc142897351 \h  33  

  HYPERLINK \l "_Toc142897352"  7.3  REI	 35

  HYPERLINK \l "_Toc142897353"  8.0  DEFICIENCIES	  PAGEREF
_Toc142897353 \h  35  

  HYPERLINK \l "_Toc142897354"  8.1  Toxicology	  PAGEREF _Toc142897354
\h  35  

  HYPERLINK \l "_Toc142897355"  8.2  Residue Chemistry	  PAGEREF
_Toc142897355 \h  35  

  HYPERLINK \l "_Toc142897356"  8.3  Occupational/Residential	  PAGEREF
_Toc142897356 \h  35  

  HYPERLINK \l "_Toc142897357"  Attachment 1:  Chemical Structures	 
PAGEREF _Toc142897357 \h  37  

  HYPERLINK \l "_Toc142897357"  Attachment 2:  Toxicity Profile of
Bifenazate Technical	  PAGEREF _Toc142897357 \h  37  

  HYPERLINK \l "_Toc142897357"  Attachment 3:  Percent Crop-Treated Data
used for Bifenazate	 40

 1.0  EXECUTIVE SUMMARY

Bifenazate (1-methylethyl 2-(4-methoxy[1,1’-biphenyl]-3-yl)
hydrazinecarboxylate)) is a selective miticide/insecticide which
controls the motile stage of mites either by direct contact or through
contact with foliar residues.  Bifenazate blocks or closes the
GABA-(gamma-aminobutyric acid) activated-chloride channels of
susceptible pests resulting in over-excitation of the peripheral nervous
system.  

Bifenazate is the active ingredient (ai) in Floramite (various
formulations for use on ornamental plants) and Acramite (various
formulations for use on food/feed crops).  Bifenazate is currently
registered for application to ornamental plants, pome fruit, fruiting
vegetable, cucurbit vegetable, tree nut, nectarine, peach, plum, grape,
strawberry, cotton, hops, okra, and mint.  Tolerances are established
for residues of bifenazate and are expressed in terms of the combined
residues of bifenazate and D3598 (diazinecarboxylic acid,
2-(4-methoxy-[1,1’-biphenyl]-3-yl, 1-methylethyl ester)), expressed as
bifenazate, in/on plant commodities and livestock fat, under 40 CFR
§180.572(a)(1), range from 0.10 ppm (tuberous and corm vegetables,
subgroup 1C and fat of cattle, goat, hog, horse, and sheep) to 35 ppm
(cotton gin byproducts).  Tolerances are established (40 CFR
§180.572(a)(2)) for residues in milk, and meat and meat byproducts of
cattle, goat, hog, horse, and sheep at 0.02 ppm and are expressed in
terms of the combined residues of bifenazate, D3598 (expressed as
bifenazate), A1530, and A1530-sulfate (expressed as A1530).  In
addition, time-limited tolerances for residues of bifenazate and D3598
are established under 40 CFR §180.572(b) in connection with Section 18
Emergency Exemptions; these include tolerances for  residues in/on
potato at 0.05 ppm with a 12/31/06 expiration date; tart cherry at 5.0
ppm, soybean hulls at 20 ppm, soybean meal at 3.5 ppm, soybean refined
oil at 20 ppm, and soybean seed at 1.5 ppm with a 12/31/09 expiration
date; and timothy forage at 50 ppm and timothy hay at 150 ppm with a
12/31/07 expiration date.  

The Interregional Research Project No. 4 (IR-4), on behalf of the
Agricultural Experiment Stations of AR, CA, DE, FL, MI, NC, OR, PA, TN,
and WA, has submitted requests for Section 3 registrations for the
application of bifenazate to tropical fruits, caneberries, and peas and
beans.  A single broadcast application of Acramite 50WS (EPA Reg. No.
400-503) or Acramite 4SC (EPA Reg. No. 400-514) with 1 to 3 day
pre-harvest interval (PHIs) are proposed.  In conjunction with this
request, the petitioner has proposed the establishment of permanent
tolerances for residues of the insecticide bifenazate and its metabolite
D3598, expressed as bifenazate, in/on the following raw agricultural
commodities (RACs):



Papaya	6.0 ppm

Star apple	6.0 ppm

Black sapote	6.0 ppm

Mango	6.0 ppm

Sapodilla	6.0 ppm

Canistel	6.0 ppm

Mamey sapote	6.0 ppm

Lychee	4.0 ppm

Longan	4.0 ppm

Spanish lime	4.0 ppm

Rambutan	4.0 ppm

Pulasan	4.0 ppm

Guava	0.9 ppm

Feijoa	0.9 ppm

Jaboticaba	0.9 ppm

Wax jambu	0.9 ppm

Starfruit	0.9 ppm

Passionfruit	0.9 ppm

Acerola	0.9 ppm

Caneberry subgroup 13A	6.0 ppm

Wild raspberry	6.0 ppm

Vegetable, legume, edible-podded, subgroup 6A	4.0 ppm

Pea and bean, succulent-shelled, subgroup 6B*	0.3 ppm

Soybean, succulent-shelled	0.3 ppm

* -IR-4 previously submitted a relevant bifenazate petition (PP#5E6992;
DP# 324430, 7/19/06, T. Bloem) proposing uses on garden peas (succulent
and shelled pea) and edible-podded peas.

Hazard Assessment:  The acute toxicity data for bifenazate show that
this chemical is not acutely toxic by the oral, inhalation, or dermal
routes of exposure (Acute Toxicity Categories IV).  It is minimally
irritating to the eye (Acute Toxicity Category IV) and
slightly-irritating to the skin (Acute Toxicity Category IV). 
Bifenazate is a dermal sensitizer by the Magnusson/Kligman method, but
not the Buehler method. 

Subchronic and chronic studies in rats and dogs indicate that the liver
and hematopoietic system (spleen and/or bone marrow with associated
hematological findings) are the primary target organs in these species,
with additional toxicity in the kidney (chronic dog) and adrenal gland
(male rats) also identified.  Similarly, the hematopoietic system
(spleen) was the primary target organ in the repeat-dose dermal toxicity
study.  Also associated with this toxicity in several studies were
decreased body weight, body-weight gain, and food consumption.  No
evidence of carcinogenicity was seen in the rat and mouse studies and
the HED Hazard Identification Assessment Review Committee (HIARC)
classified bifenazate as "not likely" to be a human carcinogen by any
relevant route of exposure.  A full battery of mutagenicity studies were
negative for mutagenic or clastogenic activity.  The developmental
studies in rats and rabbits did not demonstrate increased sensitivity of
fetuses to bifenazate. Similarly, increased qualitative or quantitative
susceptibility to offspring were not observed with bifenazate during
pre- or postnatal development in the reproduction study.  There was no
evidence of neurotoxicity (clinical signs or neuropathology) in any of
the toxicology studies conducted with bifenazate.  A bifenazate
developmental neurotoxicity (DNT) study was not required by the HIARC.
It should be noted that bifenazate contains hydrazine as part of its
chemical structure.  This side chain is structurally similar to
unsymmetrical dimethyl hydrazine (UDMH), a B2 animal carcinogen
(possible human carcinogen).  Carcinogenicity studies performed with
bifenazate on rats and mice did not result in any carcinogenic effects
at a maximum dose of 10 mg/kg/day and 35 mg/kg/day, respectively.  The
rat, livestock, and plant metabolism studies indicate that metabolism of
bifenazate proceeds via oxidation of the hydrazine moiety of bifenazate
to form D3598 (diazene).  D3598 is then metabolized to D1989 (methoxy
biphenyl) and to bound residues by reaction with natural products.  The
petitioner proposed that the degradation route for D3598 to D1989
involved the formation of N2 and CO2 and not biphenyl hydrazine.  The
HED Metabolism Assessment Review Committee (MARC) reviewed the
petitioner’s proposed degradation route and agreed that formation of
free biphenyl hydrazine or other hydrazines is unlikely due to oxidation
of the parent to the conjugated diazene. The MARC did suggest that if a
future metabolism study is submitted, the petitioner should monitor for
biphenyl hydrazine.  Subsequently, Crompton Corporation submitted a
radish metabolism study which did not result in the identification of
biphenyl hydrazine.  Based on the radish metabolism study, the lack of
carcinogenic effects in the bifenazate carcinogenic studies, and since
biphenyl hydrazine was not identified in the excreta in the rat
metabolism study, RAB1 concluded that issues concerning the formation of
hydrazine(s) in plants and livestock have been addressed.  The
toxicological profile for bifenazate is included as Appendix 2.

Dose Response Assessment:  The HIARC met on four occasions to examine
the toxicology database for bifenazate and to determine the appropriate
toxicological endpoints for dietary and occupational/residential
exposure assessment (meeting dates - 21-Aug-2001 (TXR No. 0014658),
24-Apr-2001 (TXR No. 0014576), 13- Apr-1999 (TXR No. 0013335), and
4-Feb-1999 (TXR No. 0013277)).  The HIARC found the toxicological
database to be complete with the exception of a 28-day inhalation study.
 The HED Food Quality Protection Act Safety Factor Committee (FQPA SFC)
met on 27-Aug-2001 to evaluate the bifenazate toxicological database in
reference to the potential for enhanced sensitivity to infants and
children and concluded that the FQPA SF may be reduced to 1x (TXR No.
0014661); therefore, based on toxicological considerations and the
conservative assumptions used when generating the dietary, water, and
residential exposure estimates, HED concludes that the FQPA SF may be
reduced to 1x. 

Bifenazate has been classified as “not likely” to be a human
carcinogen by any relevant route of exposure and an acute dietary
endpoint was not identified for the general population including infants
and children; therefore, acute dietary and cancer exposure assessments
were not conducted.  Since the HIARC did not assign any additional
uncertainty factors to the endpoints selected for the various routes of
exposure assessment and since the FQPA SF has been reduced to 1x, the
total uncertainty factor for all exposure assessments is 100x (10x for
interspecies extrapolation, and 10x for intraspecies variation).  Oral
studies were selected for all durations of inhalation exposure
assessment and the HIARC determined that a 100% inhalation-absorption
factor is appropriate for route-to-route extrapolation.  Since a dermal
study was selected for all durations of dermal-exposure assessment, a
dermal-absorption factor is not necessary.  Oral, dermal, and inhalation
exposures can be aggregated based on common endpoints (changes in body
weights and body-weight gains, and hematological effects).  Exposure
assessments were conducted for the specific scenarios listed below.

Table 1.  Summary of Toxicological Endpoints used in the Current Risk
Assessment1.

Chronic dietary	NOAEL = 1.0 mg/kg/day	chronic RfD and cPAD = 0.01
mg/kg/day

Short-term oral	NOAEL = 10 mg/kg/day	LOC for MOEs ≤ 100

Short-term dermal	dermal NOAEL = 6.3 mg/kg/day	LOC for MOEs ≤ 100
(occupational/residential)1

Short-term inhalation	oral NOAEL = 10 mg/kg/day2	LOC for MOEs ≤ 100
(occupational/residential)1

1	NOAEL = no-observable-adverse-effect-level; RfD = reference-dose =
NOAEL ÷ 100; PAD = population-adjusted dose = RfD ÷ FQPA SF; LOC =
level-of-concern; MOE = margins of exposure = NOAEL ( exposure.

2	100% inhalation absorption factor.

Exposure Assessment

Residential Exposure:  HED reviewed and approved homeowner application
of FloramiteTM SC (EPA Reg. No. 400-508) to ornamentals and non-bearing
fruit trees.  Based on the proposed use patterns, only short-term dermal
and inhalation exposure are expected for homeowner applicators
(exposures calculated using the 18-Dec-1999 HED Draft Residential
Standard Operational Procedures (SOPs)).  The individual and aggregate
MOEs are not of concern. (aggregate MOE = 4200).  Post-application
exposure is anticipated to be negligible and was not assessed.  

Dietary Food Exposure:  Chronic dietary risk assessments were conducted
using the Dietary Exposure Evaluation Model - Food Consumption Intake
Database (DEEM-FCID(, ver. 2.03).  DEEM- FCID( incorporates the food
consumption data from the United States Department of Agriculture’s
(USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII;
1994-1996 and 1998).  The chronic analyses incorporated tolerance-level
residues for all commodities excluding squash, peach, and tomato
(average field-trial residues were assumed) and milk (the tolerance
level was adjusted upward to account for all of the residues of concern
for risk assessment).  The chronic analyses incorporated average percent
crop treated information provided by the Biological Economic Analysis
Division (BEAD; J. Carter, 13-Jul-2006).  The average percent
crop-treated estimates are summarized in Appendix 3.  DEEM( (ver. 7.81)
default processing factors were assumed for all commodities excluding
apple juice, grape juice, wine/sherry, tomato paste, and tomato puree. 
The processing factors for these commodities were reduced to 0.23, 0.17,
0.17, 1, and 1, respectively, based on data from processing studies. 
The analyses also included the chronic surface water point estimate
generated using the FQPA Index Reservoir Screening Tool (FIRST) and the
strawberry application scenario (2 x 0.50 lb ai/acre; 21-day retreatment
interval (RTI); highest registered/proposed rate).  The chronic exposure
estimates are (47% cPAD and are, therefore, not of concern to HED.  The
most highly-exposed population subgroup was children 1 to 2 years old.  

Occupational Exposure Estimates:  It is anticipated that the following
scenarios could result in handler exposure:  mixer/loader for groundboom
applications of water-soluble bags and applicators using airblast
equipment.  No chemical specific data were available with which to
assess potential exposure to pesticide handlers.  The estimates of
exposure to pesticide handlers are based upon surrogate study data
available in the PHED (August, 1998).  Exposures and risks were assessed
for both short- and intermediate-term durations.  HED has determined
that there are no risks of concern for all exposure scenarios (i.e.,
MOEs>100).  Exposures during postapplication activities were estimated
using dermal transfer coefficients from HED’s Science Advisory Council
(SAC) for Exposure (ExpoSAC) Policy Number 3.1: Agricultural Transfer
Coefficients, August 2000 and standard HED assumptions.  For caneberry
and tropical fruit applications, HED has determined that risks are not
of concern on day 0 (restricted entry interval (REI)=12 hours) for all
postapplication exposure activities (i.e., MOEs>100).  Bifenazate is
classified in Toxicity Category IV for acute dermal, oral and
inhalation, as well as for primary eye irritation and primary skin
irritation.  It is not a dermal sensitizer.  Therefore, the Worker
Protection Standard (WPS) interim REI of 12 hours, is adequate to
protect agricultural workers from postapplication exposures to
bifenazate.  This is the current REI listed on the product label.  

Aggregate Exposure Assessment:  In general, aggregate exposures are
calculated by summing dietary (food and water) and residential exposures
(residential or other non-occupational exposures).  Based on the
anticipated residential exposure scenarios and since acute and cancer
risk assessments are not required, only short-term (residential, food,
and water) and chronic (food and water) aggregate exposure assessments
were conducted.  Aggregate short-term (food, water, and residential)
exposures resulted in MOEs ≥3900 and aggregate chronic (food and
water) exposures were ≤47% the cPAD; therefore, as a result of all
registered/proposed uses, aggregate exposure to bifenazate is not of
concern.  

Recommendation for Tolerances and Registration:  Pending submission of
revised Sections B and F, the residue chemistry and toxicology databases
support conditional registration and establishment of permanent
tolerances for residues of bifenazate and D3598, expressed as
bifenazate, in/on the followings RACs:

Papaya	7.0 ppm

Star apple	7.0 ppm

Black sapote	7.0 ppm

Mango	7.0 ppm

Sapodilla	7.0 ppm

Canistel	7.0 ppm

Mamey sapote	7.0 ppm

Lychee	5.0 ppm

Longan	5.0 ppm

Spanish lime	5.0 ppm

Rambutan	5.0 ppm

Pulasan	5.0 ppm

Guava	0.90 ppm

Feijoa	0.90 ppm

Jaboticaba	0.90 ppm

Wax jambu	0.90 ppm

Starfruit	0.90 ppm

Passionfruit	0.90 ppm

Acerola	0.90 ppm

Caneberry subgroup 13A	5.0 ppm

Wild raspberry	5.0 ppm

Vegetable, legume, edible-podded, subgroup 6A	6.0 ppm

Pea and bean, succulent-shelled, subgroup 6B	0.70 ppm

Soybean, succulent-shelled	0.70 ppm

As a condition of registration, the petitioner should be required to
submit crop field trial data for the representative commodities of
edible-podded legume vegetables, subgroup 6a, (9 trials) and
succulent-shelled pea and bean, subgroup 6b, (12 trials).  The field
trials should be conducted according to the proposed use directions of
this petition (not at an exaggerated rate) and residue decline data
should be generated. 

2.0  PHYSICAL/CHEMICAL PROPERTIES

Bifenazate is a selective miticide which controls the motile stage of
mites either by direct contact or through contact with foliar residues. 
The petitioner indicated that bifenazate blocks or closes the GABA
activated chloride channels of susceptible pests resulting in
over-excitation of the peripheral nervous system.

Common name	Bifenazate

Company experimental name	D2341

IUPAC name	isopropyl 2-(4-methoxybiphenyl-3-yl)hydrazinoformate

CAS name	1-methylethyl
2-(4-methoxy[1,1′-biphenyl]-3-yl)hydrazinecarboxylate

CAS registry number	149877-41-8

End-use products (EPs)	Acramite®-50WS (50% WP; EPA Reg. No. 400-503)

Common name	None

Company experimental name	D3598

IUPAC name
isopropyl-(4-methoxy-[1,1’-biphenyl]-3-yl)diazenecarboxylate

CAS name	diazenecarboxylic acid, 2-(4-methoxy-[1,1’-biphenyl]-3-yl),
1-methylethyl ester

CAS registry number	149878-40-8

Table 3.  Physicochemical Properties of the Technical Grade of
Bifenazate.

Melting range	124-125 ºC	MRID 46064101

pH	6.78

	Density	1.19 g/cm3

	Water solubility	2.1 mg/L (20 °C)

	Solvent solubility	102 mg/mL ethyl acetate (20 °C)

	Vapor pressure	<1 x 10-8 atm M3/mole (25 °C)

	Dissociation constant, pKa	12.94 at 23 °C

	Octanol/water partition coefficient, Log(KOW)	3.4

	UV/visible absorption spectrum	Max 264 nm in water

	

3.0  HAZARD CHARACTERIZATION

A detailed hazard characterization for bifenazate was presented in a
previous HED risk assessment (D286170, T. Bloem et al., 30-May-2003) and
a summary of the bifenazate toxicological profile is provided in the
executive summary.  The HIARC met on four occasions to examine the
toxicology database for bifenazate and to determine the appropriate
toxicological endpoints for dietary and occupational/residential
exposure assessment (meeting dates - 21-Aug-2001 (TXR No. 0014658),
24-Apr-2001 (TXR No. 0014576), 13-Apr-1999 (TXR No. 0013335), and
4-Feb-1999 (TXR No. 0013277)).  The HIARC found the toxicological
database to be complete with the exception of a 28-day inhalation study.
 

Food Quality Protection Act Safety Factor Considerations:

There is no quantitative or qualitative evidence of increased
susceptibility of rats or rabbit fetuses to in utero exposure in
developmental studies, nor following pre/post-natal exposure to rats in
the two generation reproduction study.  The developmental neurotoxicity
study is not required because there is no evidence of neurotoxicity or
neuropathology in the bifenazate database.  The bifenazate toxicological
database is complete. The dietary food and drinking water exposure
assessments will not underestimate the potential exposures for infants
and children; and the residential use (ornamentals) is not expected to
result in post-application exposure to infants and children.  Therefore,
the FQPA SFC (27-August-2001, TXR No. 0014661) concluded that the FQPA
SF may be reduced to 1X.  The RAB1 risk assessment team concluded that 
based on toxicological considerations and the residue assumptions used
in the dietary (D330587, T. Bloem, 19-July-2006) and residential
(D284802, M. Dow and D.Vogel,15-Aug-2002) exposure analyses, the FQPA SF
may be reduced to 1x.  Table 4 is a summary of the endpoints used in the
current assessment.  



Table 4.  Summary of Toxicological Dose and Endpoints for Bifenazate.

Exposure

Scenario	Dose Used in Risk Assessment,

UF	FQPA SF and LOC for Risk Assessment	Study and Toxicological Effects

Acute Dietary; all populations	An acute dietary endpoint was not
selected based on the absence of an appropriate endpoint attributed to a
single dose.

Chronic Dietary;

all populations	NOAEL= 1.0 mg/kg/day

UF = 100

cRfD = 0.01  mg/kg/day	FQPA SF = 1x 

cPAD = 0.01 mg/kg/day	LOAEL = 8.9/10.4 mg/kg/day [M/F] based on changes
in hematological and clinical chemistry parameters, and histopathology
in bone marrow, liver, and kidney in the one-year dog feeding study.

Incidental Oral, Short Term (1 -30 days)	oral NOAEL = 10 mg/kg/day	LOC
for MOE ( 100

(residential and occupational)	maternal LOAEL = 100 mg/kg/day based on
clinical signs, decreased body weight and food consumption during the
dosing period in the rat developmental study.

Incidental Oral, Intermediate Term (30 days - six months)	oral NOAEL =
0.9 mg/kg/day	LOC for MOE ( 100

(residential and occupational)	LOAEL = 10.4/10.7 mg/kg/day [M/F] based
on changes in hematologic parameters in the 90-day subchronic dog study.

Short-, Intermediate- and Long-Term Dermal (1-30 days, 30 days -six
months, and six months to lifetime)	dermal NOAEL = 80 mg/kg/day	LOC for
MOE ( 100

(residential and occupational)	LOAEL = 400 mg/kg/day based on decreased
body weight and food consumption, hematologic effects, increased spleen
weight and extramedullary hemapoiesis in the spleen in the 21-day dermal
toxicity study in rats.

Short-Term

Inhalation (1-30 days)	oral NOAEL= 10 mg/kg/day inhalation absorption
rate = 100%	LOC for MOE ( 100

(residential and occupational) 	maternal LOAEL = 100 mg/kg/day based on
clinical signs, decreased body weight and food consumption during the
dosing period in the rat developmental study.

Intermediate-Term Inhalation (30 days-six months)	oral NOAEL= 0.9
mg/kg/day

inhalation absorption rate = 100%	LOC for MOE ( 100

(residential and occupational)	LOAEL = 10.4/10.7 mg/kg/day based on
changes in hematologic parameters in the 90-day dog feeding study.

Long-Term Inhalation (six months-lifetime)	Oral study NOAEL= 1.0
mg/kg/day

(inhalation absorption rate = 100%)	LOC for MOE ( 100

(residential and occupational)	LOAEL = 8.9/10.4 mg/kg/day [M/F] based on
changes in hematological and clinical chemistry parameters, and
histopathology in bone marrow, liver, and kidney in the one-year dog
feeding study.

Cancer (oral, dermal, inhalation)	Bifenazate is classified as "not
likely" to be a human carcinogen.

1	UF = uncertainty factor; NOAEL = no-observed-adverse-effect-level;
LOAEL = lowest-observed-adverse-effect level; RfD = reference-dose
(NOAEL ( 100); PAD = population-adjusted dose (NOAEL ( FQPA SF); LOC =
level-of-concern; MOE = margin-of-exposure.

3.1  Endocrine Disruption

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

In a 90-day oral toxicity study (MRID 44464941), bifenazate caused
vacuolation of the zona fasicula in the adrenal cortex of male rats. 
When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, bifenazate may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

3.2  Residues of Concern for Dietary Risk Assessment  

Table 5 (below) is a summary of the MARC decisions concerning the
residues of concern in plants, livestock, rotational crops, and drinking
water (D276801, T. Bloem, 16-Aug-2001; D290053, T. Bloem, 29-May-2003). 

The nature of the residue in plants is adequately understood based on
acceptable studies with radish, apple, orange, and cotton.  The
metabolic routes in all crops were found to be similar and proceeded via
oxidation of the hydrazine moiety of bifenazate to form the metabolite
D3598 which is further degraded to D1989, D9963, D4642, and/or A1530 and
to bound residues by reaction with natural products.  For purposes of
tolerance expression and risk assessment, the HED MARC has previously
determined that the residues of concern in plants are bifenazate and its
metabolite D3598.  The analytical enforcement method does not
distinguish between D3598 and bifenazate.  

The nature of the residue in livestock is adequately understood based on
studies with lactating goats and laying hens.  The HED MARC has
determined that for tolerance expression and risk assessment purposes,
the residues of concern in livestock tissue (excluding fat), eggs, and
milk are bifenazate and the metabolites D3598 (expressed as bifenazate),
A1530, and A1530-sulfate (expressed as A1530).  The residues of concern
for tolerance expression and risk assessment purposes in fat are
bifenazate and D3598 (expressed as bifenazate).  The HED MARC also
determined that for tolerance expression and risk assessment purposes
the residues of concern in milk are bifenazate, D3598 (expressed as
bifenazate), A1530, and A1530-sulfate (expressed as A1530; D276801, T.
Bloem, 16-Aug-2001).  The analytical enforcement method does not
distinguish between D3598 and bifenazate nor A1530 and A1530-sulfate.  

Subsequent to the MARC decision, the petitioner submitted a
radiovalidation study for the livestock enforcement method.  In order to
generate samples for this study, a goat was dosed with radiolabeled
bifenazate (20 ppm dietary burden; 46691301.der.wpd).  Milk, fat, and
liver samples were collected and analyzed.  Contrary to the ruminant
metabolism study which indicated that A1530-sulfate was the major
residue in milk (41% TRR; D9569 was a minor residue), the
radiovalidation study indicated that D9569 was the major residue (24%
TRR; A1530-sulfate was a minor residue); no differences in the fat and
liver metabolic profile were indicated.  The petitioner has submitted
data confirming the identify of A1530-sulfate in the ruminant metabolism
study (isolated peak degraded to A1530 upon treatment with
glucuronidase/sulfatase) and confirming the identify of D9569 in the
radiovalidation study (D9569 identified using two methods; MRID
47058901).  Therefore, the milk samples from the metabolism and
radiovalidation studies resulted in different major residues.  The
petitioner proposed that this difference arose from the difference in
the dosing levels.  

Based on the currently available information, the dairy cow feeding
study should have monitored for bifenazate, D3598, A1530, A1530-sulfate,
and D9569 in milk (monitoring for bifenazate, D3598, A1530, and
A1530-sulfate in tissues is acceptable).  For risk assessment purposes,
potential A1530-sulfate and/or D9569 residues in milk will be estimated
using the combined bifenazate/D3598 residues from the feeding study and
the 4.6x A1530-sulfate to bifenazate/D3598 residue ratio from the
metabolism study.  HED notes that this procedure was performed for the
most recent bifenazate dietary exposure analysis conducted in
conjunction with the review of this petition (Memo, pending, W.D.
Wassell, DP# 347496) (D330587, T. Bloem, 19-Jul-2006).  

The metabolic routes in goats and hens were similar and proceeded via
oxidation of the hydrazine moiety of bifenazate to form D3598 which is
further degraded to D1989, D9569, A1530, and/or A1530-sulfate and to
bound residues by reaction with natural products.

Table 5.  Residues for Tolerance Expression and Risk Assessment.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	Bifenazate, D3598 (expressed as parent)	Bifenazate, D3598
(expressed as parent)

Livestock (excluding fat)	Bifenazate, D3598 (expressed as parent),
A1530, A1530-sulfate (expressed as A1530)	Bifenazate, D3598 (expressed
as parent), A1530, A1530-sulfate (expressed as A1530)

and D9569 (milk only)

Livestock – fat	Bifenazate, D3598 (expressed as parent)	Bifenazate,
D3598 (expressed as parent)

Rotational Crops	Could not be determined1	Could not be determined1

Drinking Water	D1989	Not applicable

1	Based on the results of the confined rotational crop study conducted
0.5 lb ai/acre and the application rate for the registered and proposed
crops which are likely to be rotated, HED concluded that residues in
rotated crops were unlikely and that tolerances were unnecessary.

4.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION

Residue Chemistry Memo, pending, W.D. Wassell, DP# 33730

Dietary Exposure Memo, pending, W.D. Wassell, DP# 347496

Memo (drinking water), 10/9/2003, T. Nguyen, D286171

Memo (residential exposure assessment), 3/13/2003, M. Dow, D285897

Memo (occupational exposure assessment), 10/1/07, K.M. Lowe, D337535

4.1  Summary of Registered Uses

Bifenazate is currently registered for application to pome fruit,
fruiting vegetables, cucurbit vegetables, tree nut, nectarine, peach,
plum, grape, strawberry, cotton, hops, okra, peppermint, and spearmint
with tolerances ranging from 0.1 - 35 ppm (40 CFR 180.572(a)(1)). 
Section 18 registrations have also been established for application of
bifenazate to cherry, soybean, tomato, potato, and timothy with
tolerances ranging from 0.05-150 ppm (40 CFR 180.572(b)).  Tolerances,
as a result of secondary residues, are established in milk, ruminant
meat, ruminant fat, and ruminant meat byproducts at 0.02-0.10 ppm (40
CFR 180.572(a)(1) and (a)(2)).  

4.2  Summary of Proposed Uses

The petitioner has submitted undated draft labels for the 50%
wettable-powder (WP) formulation (Acramite®-50 WS; EPA Reg. No.
400-503) and the 4 lb/gal FlC formulation (Acramite®-4SC; EPA Reg. No.
400-514).  Information pertaining to the proposed end-use products are
listed in Table 6.  A summary of the proposed use patterns is detailed
in Table 7.

Table 6.  Summary of Proposed End-Use Products.

Trade Name	Reg. No.	ai (% of formulation)	Formulation Type	Target Crops
Target Pests	Label Date

Acramite®-50WS	400-503	50%	Wettable powder (WP)	Caneberry Subgroup 13A,
Wild Raspberry;

Tropical fruit:  Papaya, Star Apple, Black Sapote, Mango, Sapodilla,
Canistel, Mamey Sapote, Lychee, Longan, Spanish Lime, Rambutan, Pulasan,
Guava, Feijo, Jaboticaba, Wax Jambu, Starfruit, Passionfruit, Acerola
Mites controlled:  Bankgrass, Brown almond, Clover, European red,
McDaniel, Pacific spider, Pecan leaf scorch, Strawberry spider,
Willamette, and Two-spotted spider	Undated draft label 

Acramite®-4SC	400-514	43.2% (equivalent to 4 lb ai/gal)	Flowable
concentrate (FlC)	Legume Vegetables Subgroup 6A, succulent;

Beans, Subgroup 6B; Succulent-shelled soybean;

Succulent pea including succulent-shelled, edible-podded, and pigeon
Mites controlled:  Bankgrass, Brown almond, Clover, European red,
McDaniel, Pacific spider, Pecan leaf scorch, Strawberry spider,
Willamette, and Two-spotted spider	Undated draft label

Table 7.  Summary of Proposed Directions for Use of Bifenazate.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Max. Single Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)

Caneberry Subgroup 13A including:  Blackberry, Loganberry, Red and Black
Raspberry, and cultivars and/or hybrids of these

Wild Raspberry

Foliar spray

Ground	50% WP

[400-503]	0.38-0.50	1	0.50

(implied)	1

	Use Directions and Restrictions:  Application is to be made in a
minimum of 50 gal/A using ground equipment.  Application through any
type of irrigation system is prohibited.  

Tropical fruit including:  Papaya, Star Apple, Black Sapote, Mango,
Sapodilla, Canistel, Mamey Sapote, Lychee, Longan, Spanish Lime,
Rambutan, Pulasan, Guava, Feijo, Jaboticaba, Wax Jambu, Starfruit,
Passionfruit, and Acerola

Foliar spray

Ground	50% WP

[400-503]	0.38-0.50	1	0.50

(implied)	1

	Use Directions and Restrictions:  Application is to be made in a
minimum of 50 gal/A using ground equipment.  Application through any
type of irrigation system is prohibited.  

Legume Vegetables Subgroup 6A (succulent)

Beans Subgroup 6B

Succulent-shelled soybean

Including Bean (Lupinous) (includes grain lupin, sweet lupin, white
lupin, and white sweet lupin), Bean (Phaseolus) (includes field bean,
kidney bean, lima bean, navy bean, pinto bean, runner bean, snap bean,
tepary bean, wax bean); Bean (Vigna) (includes adzuki bean, asparagus
bean, blackeyed pea, catjang, Chinese longbean, cowpea, Crowder pea,
moth bean, mung bean, rice bean, southern pea, urd bean, yardlong bean);
Broad bean (fava); Chickpea (garbanzo bean); Guar; Jackbean; Lablab
bean; Lentil; Pea (Pisum) (includes dwarf pea, edible-podded pea,
English pea, field pea, garden pea, green pea, snow pea, sugar snap
pea); Pigeon pea; Soybean; Soybean (immature seed); Sword bean

Foliar spray

Ground and aerial	4 lb/gal FlC

[400-514]	0.38-0.50	1	0.50

(implied)	3

	Use Directions and Restrictions:  Application is to be made in a
minimum of 20 gal/A using ground equipment and 5 gal/A using aerial
equipment.  Application through any type of irrigation system is
prohibited.

Succulent Pea (Pea, Succulent-shelled; Pea, Edible-podded; and Pea,
Pigeon)

Including Sugar pea, Chinese pea, Pois mange tout, Snap pea, Ming pea,
Podded pea, Snow pea, China pea, Chicharo, Shi Hia wandou, Saya-endo,
Sugar snap pea, Congo pea, No-eye pea, Red gram, Arher, Grandul,
Gandules, Dhal, Toor, Gunds pea, Porto Rico pea, Urher Gandul, Guandu,
Pois-d’angole, Gungo pea

Foliar spray

Ground and aerial	4 lb/gal FlC

[400-514]	0.38-0.50	1	0.50

(implied)	3

	Use Directions and Restrictions:  Application is to be made in a
minimum of 20 gal/A using ground equipment and 5 gal/A using aerial
equipment.  Application through any type of irrigation system is
prohibited.

The following rotational crop restriction is specified for the 50% WP
formulation:  Do not plant another crop within 30 days after last
Acramite®-50WS application due to chances of bifenazate residues
showing up in rotational crops.  Rotational crop restrictions do not
appear on the 4 lb/gal FlC formulation (Acramite®-4SC).  

HED concludes the proposed use directions are adequate pending label
revisions to remove members of Legume Vegetables and to list only
members of Subgroups 6A and 6B on the proposed end-use products. 
Additionally, the product label for the 4 lb/gal FlC formulation
(Acramite®-4SC) does not specify any rotational crop restrictions and
must be revised to specify a 30-day PBI.  Thus, a revised Section B
(proposed label) is required.

4.3  Dietary Exposure/Risk Pathway

Nature of the Residue - Plants:  Based on apple, orange, and cotton
metabolism studies, the MARC determined that for tolerance expression
and risk assessment purposes, the residues of concern in these crops are
bifenazate and D3598 (D276801, T. Bloem, 16-Aug-2001).  The metabolic
route in apple, orange, and cotton were similar and proceeded via
oxidation of the hydrazine moiety of bifenazate to form D3598 which is
further degraded to D1989, D9963, D4642, and/or A1530 and to bound
residues by reaction with natural products. 

Subsequent to this decision, the petitioner submitted a radish
metabolism study.  The metabolic route in radish was similar to that of
apple, orange, and cotton with the major identified residues being
bifenazate and D3598.  HED concludes that the nature of the residue in
plants is adequately understood and the residues of concern for
tolerance expression and risk assessment purposes in plant commodities
are bifenazate and D3598.

Nature of the Residue - Livestock:  

The nature of the residue in livestock is adequately understood based on
studies with lactating goats and laying hens.  The HED MARC has
determined that for tolerance expression and risk assessment purposes,
the residues of concern in livestock tissue (excluding fat), eggs, and
milk are bifenazate and the metabolites D3598 (expressed as bifenazate),
A1530, and A1530-sulfate (expressed as A1530).  The residues of concern
for tolerance expression and risk assessment purposes in fat are
bifenazate and D3598 (expressed as bifenazate).  The HED MARC also
determined that for tolerance expression and risk assessment purposes
the residues of concern in milk are bifenazate, D3598 (expressed as
bifenazate), A1530, and A1530-sulfate (expressed as A1530; D276801, T.
Bloem, 16-Aug-2001).  The analytical enforcement method does not
distinguish between D3598 and bifenazate nor A1530 and A1530-sulfate.  

Subsequent to the MARC decision, the petitioner submitted a
radiovalidation study for the livestock enforcement method.  In order to
generate samples for this study, a goat was dosed with radiolabeled
bifenazate (20 ppm dietary burden; 46691301.der.wpd).  Milk, fat, and
liver samples were collected and analyzed.  Contrary to the ruminant
metabolism study which indicated that A1530-sulfate was the major
residue in milk (41% TRR; D9569 was a minor residue), the
radiovalidation study indicated that D9569 was the major residue (24%
TRR; A1530-sulfate was a minor residue); no differences in the fat and
liver metabolic profile were indicated.  The petitioner has submitted
data confirming the identify of A1530-sulfate in the ruminant metabolism
study (isolated peak degraded to A1530 upon treatment with
glucuronidase/sulfatase) and confirming the identify of D9569 in the
radiovalidation study (D9569 identified using two methods; MRID
47058901).  Therefore, the milk samples from the metabolism and
radiovalidation studies resulted in different major residues.  The
petitioner proposed that this difference arose from the difference in
the dosing levels.  

Based on the currently available information, the dairy cow feeding
study should have monitored for bifenazate, D3598, A1530, A1530-sulfate,
and D9569 in milk (monitoring for bifenazate, D3598, A1530, and
A1530-sulfate in tissues is acceptable).  For risk assessment purposes,
potential A1530-sulfate and/or D9569 residues in milk will be estimated
using the combined bifenazate/D3598 residues from the feeding study and
the 4.6x A1530-sulfate to bifenazate/D3598 residue ratio from the
metabolism study.  HED notes that this procedure was performed for the
previous and current bifenazate dietary exposure analysis (D330587, T.
Bloem, 19-Jul-2006).  

The metabolic routes in goats and hens were similar and proceeded via
oxidation of the hydrazine moiety of bifenazate to form D3598 which is
further degraded to D1989, D9569, A1530, and/or A1530-sulfate and to
bound residues by reaction with natural products.

Magnitude of the Residue - Plants:  The following are summaries of the
crop field trial data for edible-podded beans, a representative of crop
subgroup 6A (edible-podded legume vegetables); succulent-shelled beans,
a representative of crop subgroup 6B (succulent, shelled pea and bean);
lima beans, a representative of crop subgroup 6B (succulent, shelled pea
and bean); raspberry and blackberry, the representatives of the
caneberry subgroup 13A; guava; lychee; and papaya. 

Edible-podded Legume Vegetables (Subgroup 6A) and Succulent-shelled Pea
and Bean (Subgroup 6B):  IR-4 submitted field trial data for bifenazate
on edible-podded beans, a representative of crop subgroup 6A
(edible-podded legume vegetables) and succulent-shelled beans, a
representative of crop subgroup 6B (succulent, shelled pea and bean). 
Eleven bean field trials were conducted in the U.S. during the 2002
growing season.  

Each field trial consisted of one untreated plot and one treated plot. 
Two foliar directed or broadcast applications of the 4 lb/gal SC
formulation [equivalent to a FlC formulation] of bifenazate was made to
beans at ~0.75 lb ai/A/application, with 13- to 15-day RTIs, for a total
rate of ~1.5 lb ai/A (3x the maximum proposed seasonal rate of 0.5 lb
ai/A).  All applications were made using ground equipment in 20-42
gal/A.  An adjuvant was not added to the spray mixture for any
applications.  Mature beans were harvested 2-4 days after the second
application.

A summary of residue data from the edible-podded bean and
succulent-shelled bean field trials is presented in Table 8.    SEQ
CHAPTER \h \r 1 The maximum combined residue of bifenazate and D3598 was
0.178 ppm in/on succulent-shelled beans and 1.989 ppm in/on
edible-podded beans harvested 2-4 days after the second application. 
Residue decline data were not generated with the study.

Succulent-Shelled Bean (Lima Bean):  IR-4 submitted field trial data for
bifenazate on lima beans, a representative of crop subgroup 6B
(succulent, shelled pea and bean).  Two field trials were conducted on
lima beans in Zone 2 (GA and MD) in the U.S. during the 2003 growing
season.  

Each field trial consisted of one untreated plot and one treated plot. 
Two foliar directed applications of the 4 lb ai/gal SC formulation
[equivalent to a flowable concentrate (FlC) formulation] of bifenazate
was made to lima beans at ~0.75 lb ai/A/application, with 8- to 16-day
RTIs, for a total rate of ~1.5 lb ai/A (3x the maximum proposed seasonal
rate of 0.5 lb ai/A).  All applications were made using ground equipment
in 34-49 gal/A.  An adjuvant was not added to the spray mixture for any
applications.  Mature lima beans were harvested 2-3 days after the
second application.

A summary of residue data from the succulent-shelled bean (lima bean)
field trials is presented in Table 8.    SEQ CHAPTER \h \r 1 The maximum
combined residue of bifenazate and D3598 was 0.262 ppm in/on lima beans
harvested 2-3 days after the second application.  Residue decline data
were not generated with the study.

Table 8.   Summary of Residue Data from Edible-Podded and
Succulent-Shelled Bean and Pea Field Trials with Bifenazate.

Commodity

(MRID)	Total Applic. Rate

lb ai/A	PHI (days)	Combined Bifenazate/D3598 Residue Levels (ppm) 1

	n	Min.	Max.	HAFT2	Mean	Std. Dev.

Proposed Use Pattern:  Single foliar spray of the 4 lb/gal FlC
formulation at 0.38-0.50 lb ai/A, 3-day PHI.

Edible-Podded Bean and Pea

Edible-podded bean (47016705)	1.483-1.537	2-4	12	0.152	1.989	1.789	1.010
0.632

Edible-podded pea (46651703) 3	2 x 0.75	2-4	10	0.91	3.74	3.08	1.99	0.99

Succulent-Shelled Bean and Pea

Succulent-shelled bean

(47016705)	1.480-1.513	2-4	9	0.017	0.178	0.145	0.088	0.059

Succulent-shelled lima bean

(47016706)	1.508-1.518	2-3	4	0.046	0.262	0.222	0.141	0.10

Succulent-shelled pea

(46651703) 3	2 x 0.75	2-4	12	0.028	0.173	0.132	0.060	0.043

1  Residues were quantitated/reported as bifenazate equivalents.

2  HAFT = Highest-Average Field Trial.

3  Edible-podded and succulent-shelled pea data reviewed in conjunction
with PP#5E6992 (refer to DP# 324430, 7/19/06, T. Bloem).

Conclusions.  The submitted residue data for succulent-shelled bean and
pea and edible-podded bean and pea are inadequate because the field
trials do not reflect the proposed use pattern (trials were conducted at
an exaggerated rate, 3x the maximum proposed seasonal rate). 
Additionally, residue decline data were not submitted.  IR-4 has
previously submitted residue data for bifenazate on edible-podded pea
and succulent-shelled pea in PP#5E6992 (Memo, 7/19/2006, T. Bloem, DP#
324430).  These studies were also conducted with application rates 1.5x
the single application rate and 3x the seasonal application rate. 
Therefore, these data are not indicative of the magnitude of the residue
following application at the proposed rate.  It is noted that the
previous petition (PP#5E6992) required a full set of succulent-shelled
pea and edible-podded pea field trial data conducted at the proposed 1x
rate (Memo, 7/19/06, T. Bloem, DP#324430).  

HED will use the submitted data to establish tolerances in conjunction
with a conditional registration while additional residue data are
generated.  HED concludes that there are no residue chemistry issues
that would preclude the establishment of tolerances for combined
residues of bifenazate and D3598 in/on succulent garden-pea and
edible-podded pea at 0.20 ppm and 4.0 ppm, respectively, in conjunction
with a conditional registration while additional residue chemistry data
are generated.  The residue data for edible-podded bean and
succulent-shelled bean were entered into the Agency’s tolerance
spreadsheet as specified by the Guidance for Setting Pesticide
Tolerances Based on Field Trial Data SOP to determine an appropriate
tolerance level.

Currently, the established tolerance is 4.0 ppm for residues in/on
edible-podded succulent pea; the tolerance spreadsheet recommends a
tolerance for residues at 6.0 ppm in/on edible-podded bean.  The
bifenazate residues do not vary by a factor of 5x between edible-podded
bean and edible-podded pea.  HED concludes there are no residue
chemistry issues that preclude the establishment of tolerances for
combined residues of bifenazate and D3598 in/on edible-podded beans,
subgroup 6A, in conjunction with a conditional registration while
additional residue data at the proposed 1x rate are generated.  This
tolerance level recommendation is higher than the level (4.0 ppm)
proposed by the petitioner.  Thus, a revised Section F is required.  

Currently, the established tolerance is 0.20 ppm for combined residues
in/on succulent garden pea; the tolerance spreadsheet recommends a
tolerance of 0.70 ppm for residues in/on succulent-shelled bean.  The
bifenazate residues do not vary by a factor of 5x between
succulent-shelled bean and pea.  HED concludes there are no residue
chemistry data requirements that would preclude the establishment of a
tolerance for residues of bifenazate and D3598 in/on subgroup 6B at 0.70
ppm based on the residue data from succulent-shelled bean, in
conjunction with a conditional registration while additional residue
data at the proposed 1x rate are generated.  This tolerance level
recommendation is higher than the level (0.3 ppm) proposed by the
petitioner.  Thus, a revised Section F is required.  

The issue of using exaggerated rate data for bifenazate was taken to the
HED Chemistry Advisory Council (ChemSAC).  The following are the
ChemSAC’s conclusions (Minutes of 31-Oct-2007 meeting, dated: 
14-Nov-2007)

From the above data, the SAC concluded that residues in the crops at
harvest from the earlier application can not be dismissed as negligible.
 While the submitted data represent an overestimate of the residues
expected from the proposed single application, the degree of
exaggeration can not be determined.  The use of the proportionality
concept to adjust residues downward is not considered appropriate since
the data include more applications than the desired use.  The SAC
recommends that the data as generated be used to determine the tolerance
levels in spite of that data exaggerating the expected residues.  The
team should provide characterization of the exaggeration in their
assessment.  Provided that a safety finding can be made to establish the
tolerances, the SAC further recommends that the registration of these
uses be conditioned upon submission of field trials reflecting the
proposed single application.  Such data are likely to show that the
tolerances will need to be lowered.  A major factor in the
recommendation for the additional data is the risk situation for
bifenazate.  The last risk assessment showed 94% of the chronic PAD with
a fair degree of refinement (average % crop treated for many crops;
average field trial residues for high consumption commodities such as
peaches, tomatoes, and soybeans). 

As a condition of registration the petitioner should be required to
submit crop field trial data for the representative commodities of
edible-podded legume vegetables, subgroup 6a, (9 trials) and
succulent-shelled pea and bean, subgroup 6b, (12 trials).  The field
trials should be conducted according to the proposed use directions of
this petition (not at an exaggerated rate) and residue decline data
should be generated. 

The current chronic dietary exposure analysis (Memo, pending, W.D.
Wassell) shows that (47% of the cPAD is utilized for children 1 to 2
years of age (the most highly exposed population).  This analysis is
partially refined with anticipated residue estimates (ARs) utilized for
squash (winter and summer), peach, tomato and milk.  Based upon a
critical-commodity analysis conducted in DEEM-FCID(, ver. 2.03, the
major contributors to the risk for children 1 to 2 years old were
succulent-shelled peas and beans, succulent or dried-legume vegetables,
milk, and edible pod legume vegetables.

Soybean, Succulent-Shelled:  Residue data were not submitted to support
the proposed use on succulent-shelled soybean.  The available data from
succulent pea and bean subgroup 6B may be translated to
succulent-shelled soybean.  According to an HED memorandum from B.
Schneider, dated 11/4/04 until the Crop Group Regulations are revised, a
tolerance for residues in/on succulent-shelled soybean will be listed
separately at the same tolerance level of subgroup 6B.  HED is
recommending a tolerance of 0.70 ppm for residues of bifenazate in/on
subgroup 6B based on the residue data from succulent-shelled bean.  This
tolerance level recommendation is higher than the level (0.3 ppm)
proposed by the petitioner.  Thus, a revised Section F is required.

Caneberry (Subgroup 13A):  IR-4 has submitted field trial data for
bifenazate on raspberry and blackberry, the representatives of caneberry
(crop subgroup 13A).  Eight field trials were conducted on caneberry in
the U.S. and Canada during the 2004-2005 growing season.  

Each field trial consisted of one untreated plot and one treated plot. 
Two foliar-directed applications of a 50% WP formulation of bifenazate
were made to caneberry at ~0.5 lb ai/A/application, with 29- to 35-day
RTIs, for a total rate of ~1.0 lb ai/A (2x the maximum proposed seasonal
rate of 0.5 lb ai/A).  All applications were made using ground equipment
in ~21-84 gal/A.  A crop oil concentrate was added to the spray mixture
with the exception of one trial.  Mature raspberry and blackberry were
harvested on the day of the second application, after the test substance
had dried.

A summary of residue data from the caneberry field trials is presented
in Table 9.    SEQ CHAPTER \h \r 1 The maximum combined residues of
bifenazate and D3598 were 4.625 ppm in/on caneberry harvested on the day
of the second application, after the test substance had dried.  Residue
decline data were not generated with the study.

Table 9.  Summary of Residue Data from Caneberry Field Trials with
Bifenazate.

Crop matrix	Total Applic. Rate

(lb ai/A)	PHI (days)	Combined Bifenazate/D3598 Residue Levels (ppm)1

	N	Min.	Max.	HAFT2	Mean	Std. Dev.

Proposed Use Pattern:  Single foliar spray of the 50% WP formulation at
0.38-0.50 lb ai/A, 1-day PHI

Caneberry	0.99-1.06	0	16	1.248	4.625	3.553	2.165	0.918

1  Residues were quantitated/reported as bifenazate equivalents.

2  HAFT = Highest-Average field trial result.

Conclusions.  The submitted residue data for caneberry are adequate even
though the trials were conducted at an exaggerated rate.  While the
submitted data for caneberries represent an overestimate of the residues
expected from the proposed single application, the degree of
exaggeration is less than that of the bean and peas field trials.  In
the caneberry trials, the application just prior to harvest was at the
proposed 1x rate and for the beans and peas trials the application just
prior to harvest was 1.5x the proposed rate.  Since caneberries do not
contribute significantly to the dietary risk, the submitted data will be
used to support the proposed tolerance and additional field trial data
will not be required for caneberries.  Although the locations of the
field trials conducted for caneberries (blackberry and raspberry) are
not in strict accordance with OPPTS Guideline 860.1500, the total number
of field trials is in accordance with the guideline.

The field trial data for caneberries were entered into the Agency’s
tolerance spreadsheet as specified by the Guidance for Setting Pesticide
Tolerances Based on Field Trial Data SOP to determine an appropriate
tolerance level.  The tolerance spreadsheet recommends an individual
tolerance of 5.0 ppm for residues in/on caneberry.  HED concludes there
are no residue chemistry data requirements that would preclude the
establishment of a tolerance for residues of bifenazate and D3598 in/on
caneberries, subgroup 13A at 5.0 ppm.  The recommended tolerance level
is lower than the level (6.0 ppm) proposed by the petitioner.  Thus, a
revised Section F is required that reflects this determination.

Wild Raspberry:  Residue data were not submitted to support the proposed
use on wild raspberry.  Wild raspberry was listed by the petitioner in
its proposed label with the caneberry subgroup 13A.  According to the
Reviewer’s Guide and Summary of HED ChemSAC Approvals for Amending
Crop Group/Subgroups [40 CFR 180.41] and Commodity Definitions [40 CFR
180.1(h)], dated 6/14/06, a separate tolerance for wild raspberry should
be listed in the appropriate section of the CFR entry until the new crop
group regulation for the caneberry subgroup 13A is published.

The available field trial data for the caneberry subgroup 13A will be
translated to wild raspberry. HED is recommending a tolerance of 5.0 ppm
for combined residues of bifenazate and D3598 in/on subgroup 13A based
on residue data from blackberry and raspberry.  This recommendation is
lower than the level (6.0 ppm) proposed by the petitioner.  Thus, the
petitioner is required to submit a revised Section F to reflect this
determination.

Guava:  IR-4 submitted field trial data for bifenazate on guava.  Three
field trials were conducted on guava in Zone 3 (FL) in the U.S. during
the 2004 growing season.

Each field trial consisted of one untreated plot and one treated plot. 
Two foliar directed applications of a 50% WP formulation of bifenazate
were made to guava at ~0.5 lb ai/A/application, with 21- to 27-day RTIs,
for a total rate of ~1.0 lb ai/A (2x the maximum proposed seasonal rate
of 0.5 lb ai/A).  All applications were made using ground equipment in
~142 gal/A.  An adjuvant was added to the spray mixture for all
applications.  Mature guava samples were harvested 1 day after the
second application.

A summary of residue data from the guava field trials is presented in
Table 10.    SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 The maximum
combined residue of bifenazate and D3598 was 0.299 ppm in/on guava
harvested 1 day after the second application.

Table 10.  Summary of Residue Data from Guava Field Trials with
Bifenazate.

Crop matrix	Total Applic. Rate

(lb ai/A)	PHI (days)	Combined Bifenazate/D3598 Residue Levels (ppm)1

	n	Min.	Max.	HAFT2	Mean	Std. Dev.

Proposed Use Pattern:  Single foliar spray of the 50% WP formulation at
0.38-0.50 lb ai/A, 1-day PHI

Guava	1.04	1	6	0.039	0.299	0.279	0.188	0.092

1  Residues were quantitated/reported as bifenazate equivalents.

2  HAFT = Highest-Average field trial result.

Conclusions.  The submitted residue data for guava are adequate even
though the trials were conducted at an exaggerated rate (2x).  While the
submitted data for guava represent an overestimate of the residues
expected from the proposed single application, the degree of
exaggeration is less than that of the bean and peas field trials.  In
the guava trials, the application just prior to harvest was at the
proposed rate (1x) and for the beans and peas trials the application
just prior to harvest was 1.5x the proposed rate.  Since guava and
feijoa, jaboticaba, wax jambu, starfruit, passionfruit, and acerola do
not contribute significantly to the dietary risk, the submitted data
will be used to support the proposed tolerance and additional field
trial data will not be required for guava.  Although the locations of
the field trials conducted for guava are not in strict accordance with
OPPTS Guideline 860.1500, the total number of field trials is in
accordance with the guideline.

The field trial data for guava were entered into the Agency’s
tolerance spreadsheet as specified by the Guidance for Setting Pesticide
Tolerances Based on Field Trial Data SOP to determine an appropriate
tolerance level.  The tolerance spreadsheet recommends an individual
tolerance of 0.90 ppm for residues in/on guava which is identical to
that proposed by the petitioner.

According to the Reviewer’s Guide and Summary of HED ChemSAC Approvals
for Amending Crop Group/Subgroups [40 CFR 180.41] and Commodity
Definitions [40 CFR 180.1(h)], dated 6/14/06, the available data for
guava may be translated to support the proposed uses on feijoa,
jaboticaba, wax jambu, starfruit, passionfruit, and acerola.

Lychee:  IR-4 submitted field trial data for bifenazate on lychee. 
Three field trials were conducted on lychee fruit in the U.S. during the
2004 growing season in Zone 3 (FL).

Each field trial consisted of one untreated plot and one treated plot. 
Two foliar directed applications of a 50% WP formulation of bifenazate
were made to lychee fruit at ~0.5 lb ai/A/application, with 20- to
21-day RTIs, for a total rate of ~1.0 lb ai/A (2x the maximum proposed
seasonal rate of 0.5 lb ai/A).  All applications were made using ground
equipment in 126-129 gal/A.  An adjuvant was added to the spray mixture
for all applications.  Mature lychee fruit samples were harvested 1 day
after the last application.

A summary of residue data from the lychee field trials is presented in
Table 11.    SEQ CHAPTER \h \r 1 The maximum uncorrected combined
residues of bifenazate and D3598 were 2.594 ppm in/on lychee fruit
harvested 1 day following the last application.  After correcting for
approximately 30% decline during storage, maximum corrected combined
residues of bifenazate and D3598 were 3.706 ppm. Residue decline data
were not included with the submitted field trial data; however, none are
required since the required number of lychee field trials is <3 trials. 

Table 11.  Summary of Residue Data from Lychee Field Trials with
Bifenazate.

Commodity	Total Applic. Rate

 (lb ai/A)	PHI (days)	Combined Bifenazate/D3598 Residue Levels (ppm)1

	N	Min.	Max.	HAFT2	Mean	Std. Dev.

Proposed Use Pattern:  Single foliar spray of the 50% WP formulation at
0.38-0.50 lb ai/A, 1-day PHI

Bifenazate (uncorrected for decline)

Lychee 	1.01-1.02	1	6	1.545	2.594	2.574	2.155	0.403

Bifenazate (corrected for decline)

Lychee 	1.01-1.02	1	6	2.207	3.706	3.677	3.078	0.575

1  Residues were quantitated/reported as bifenazate equivalents.

2  HAFT = Highest-Average Field Trial.

Conclusions.  The submitted residue data for lychee are adequate even
though the trials were conducted at an exaggerated rate (2x).  While the
submitted data for lychee represent an overestimate of the residues
expected from the proposed single application, the degree of
exaggeration is less than that of the bean and peas field trials.  In
the lychee trials, the application just prior to harvest was at the
proposed rate (1x) and for the beans and peas trials the application
just prior to harvest was 1.5x the proposed rate.  Since lychee, longan,
Spanish lime, rambutan, and pulasan do not contribute significantly to
the dietary risk, the submitted data will be used to support the
proposed tolerance and additional field trial data will not be required
for lychee.  Although the locations of the field trials conducted for
guava are not in strict accordance with OPPTS Guideline 860.1500, the
total number of field trials is in accordance with the guideline.  

The field trial data (corrected for decline) for lychee were entered
into the Agency’s tolerance spreadsheet as specified by the Guidance
for Setting Pesticide Tolerances Based on Field Trial Data SOP to
determine an appropriate tolerance level.  The tolerance spreadsheet
recommends an individual tolerance of 5.0 ppm for residues in/on lychee.
 This tolerance level recommendation is higher than the level (4.0 ppm)
proposed by the petitioner.  Thus, the petitioner is required to submit
a revised Section F to reflect this determination.

According to the Reviewer’s Guide and Summary of HED ChemSAC Approvals
for Amending Crop Group/Subgroups [40 CFR 180.41] and Commodity
Definitions [40 CFR 180.1(h)], dated s/14/06, the available data for
lychee may be translated to support the proposed uses on longan, Spanish
lime, rambutan, and pulasan.

Papaya:  IR-4 submitted field trial data for bifenazate on papaya. 
Three field trials were conducted on papaya in Zone 13 (FL and HI; 3
trials) in the U.S. during the 2004 growing season.

Each field trial consisted of one untreated plot and one treated plot. 
Two foliar directed applications of a 50% WP formulation of bifenazate
were made to papaya at ~0.5 lb ai/A/application, with 21- to 22-day
RTIs, for a total rate of ~1.0 lb ai/A (2x the maximum proposed seasonal
rate of 0.5 lb ai/A).  All applications were made using ground equipment
in 50-150 gal/A.  An adjuvant was added to the spray mixture for all
applications.  Mature to half ripe papaya samples were harvested 1 day
after the second application.

A summary of residue data from the papaya field trials is presented in
Table 12.    SEQ CHAPTER \h \r 1 The maximum combined residue of
bifenazate and D3598 was 1.887 ppm in/on papaya harvested 1 day after
the second application.

Table 12.  Summary of Residue Data from Papaya Field Trials with
Bifenazate.

Crop matrix	Total Applic. Rate

(lb ai/A)	PHI (days)	Combined Bifenazate/D3598 Residue Levels (ppm)1

	n	Min.	Max.	HAFT2	Mean	Std. Dev.

Proposed Use Pattern:  Single foliar spray of the 50% WP formulation at
0.38-0.50 lb ai/A, 1-day PHI

Papaya	1.02-1.04	1	6	0.108	1.887	1.253	0.720	0.647

1  Residues were quantitated/reported as bifenazate equivalents.

2  HAFT = Highest-Average field trial result.

Conclusions.  The submitted residue data for papaya are adequate even
though the trials were conducted at an exaggerated rate (2x).  While the
submitted data for papaya represent an overestimate of the residues
expected from the proposed single application, the degree of
exaggeration is less than that of the bean and peas field trials.  In
the papaya trials, the application just prior to harvest was at the
proposed rate (1x) and for the beans and peas trials, the application
just prior to harvest was 1.5x the proposed rate.  Since papaya black
sapote, canistel, mamey sapote, mango, sapodilla, and star apple do not
contribute significantly to the dietary risk, the submitted data will be
used to support the proposed tolerance and additional field trial data
will not be required for papaya.  The number and locations of field
trials are in accordance with OPPTS Guideline 860.1500 for papaya.

The field trial data for papaya were entered into the Agency’s
tolerance spreadsheet as specified by the Guidance for Setting Pesticide
Tolerances Based on Field Trial Data SOP to determine an appropriate
tolerance level.  The tolerance spreadsheet recommends an individual
tolerance of 7.0 ppm for residues in/on papaya.  This tolerance level
recommendation is higher than the level (6.0 ppm) proposed by the
petitioner.  Thus, the petitioner is required to submit a revised
Section F to reflect this determination.

According to the Reviewer’s Guide and Summary of HED ChemSAC Approvals
for Amending Crop Group/Subgroups [40 CFR 180.41] and Commodity
Definitions [40 CFR 180.1(h)], dated 6/14/06, the available data for
papaya may be translated to support the proposed uses on black sapote,
canistel, mamey sapote, mango, sapodilla, and star apple.

Magnitude of the Residue - Livestock 

Residue Chemistry Memo, DP#337530, pending, W.D. Wassell, (PP#6E7167)

Residue Chemistry Memo; DP# 277089, 8/16/01, T. Bloem, (PP#0F06108)

Residue Chemistry Memo, DP# 324430, 7/19/06, T. Bloem, (PP#5E6992)

A tolerance of 0.1 ppm has been established for the combined residues of
bifenazate and D3598 (expressed as bifenazate) in the fat of cattle,
goat, hog, horse, and sheep [40 CFR §180.572(a)(1)].  A tolerance of
0.02 ppm has been established for the combined residues of bifenazate,
D3598 (expressed as bifenazate), A1530, and A1530-sulfate (expressed as
A1530) in the milk, and meat and meat byproducts of cattle, goat, hog,
horse, and sheep [40 CFR §180.572(a)(2)].

There are livestock feedstuffs associated with the proposed uses in this
petition.  These feedstuffs include soybean commodities derived from the
proposed use on succulent-shelled soybean.  In addition, feedstuffs are
associated with previously approved uses of bifenazate on cotton, apple,
and potato.  The maximum theoretical dietary burdens of bifenazate to
livestock were determined to be2.8 ppm for beef cattle, 1.9 ppm for
dairy cattle, 0.30 ppm for swine, and 0.38 ppm for poultry.  This
determination is based upon the most recent guidance from HED concerning
revisions of feedstuff percentages in Table 1 of the residue chemistry
guidelines. 

Conclusions:  Based on the dietary exposure levels and the residue data
from an available ruminant feeding study, the existing bifenazate
tolerances for milk, fat, meat, and meat byproducts of ruminants are
adequate to support the proposed uses.  Based on a dietary burden of
0.38 ppm for poultry and the residues identified in the poultry
metabolism study, HED concludes that the proposed uses of bifenazate on
the crops addressed in this document are not expected to alter the
Agency’s previous conclusion that there is no reasonable expectation
of finite residues in poultry commodities.  Thus, tolerances are not
required for residues in/on poultry and eggs. 

Residues in Rotational Crops:  A confined rotational crop study has been
previously submitted and reviewed (D277089, T. Bloem, 16-Aug-2001; field
rotational crop study has not been submitted).  The MARC concluded that
residues of concern in/on rotational crops could not be determined from
the available data (D276801, T. Bloem, 16-Aug-2001).  On the basis of
the confined rotational crop study and the proposed maximum seasonal
application rates, HED concludes that a 30-day PBI for the currently
requested/proposed crops is appropriate.  

The product label for the 4 lb/gal FlC formulation (Acramite®-4SC) does
not specify any rotational crop restrictions and must be revised to
specify a 30-day PBI.

Analytical Enforcement Method - Plants:  A method is available for
enforcement of the currently-established plant tolerances (D281973, T.
Bloem, 29-Aug-2002; D281979, T. Bloem, 29-Aug-2002). The methods used in
the field trial and processing studies were similar to the current
enforcement method (Memo, pending, W.D. Wassell, DP# 337530).  Since the
procedures are similar and adequate method validation and concurrent
recoveries were attained in the residue studies, HED concludes that the
current enforcement method is appropriate for enforcement of the
tolerances associated with this petition. 

Multiresidue Methods:  HED reviewed the petitioner submitted Food and
Drug Administration (FDA) Multiresidue Method studies for bifenazate,
D3598, A1530, and A1530-sulfate.   These data indicate that bifenazate,
D3598, A1530, and A1530-sulfate are not quantitatively recovered through
the FDA Multiresidue Methods. 

International Harmonization of Tolerances:  Canada, Codex, and Mexico do
not have maximum residue limits (MRLs) for residues of bifenazate in/on
the commodities associated with the subject petition.  Thus,
international harmonization of tolerances are not required.  

 

Tolerance Summary:  

In the subject petition, the proposed tolerance expression is in terms
of the combined residues of 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).  The proposed tolerance
expression is consistent with the bifenazate tolerances established in
40 CFR §180.572(a)(1) and reflect the residues of concern as determined
by the HED MARC and the bifenazate review team.

Pending submission of revised Sections B and F, the available crop field
trial data support the proposed tolerances on edible-podded legume
vegetable, subgroup 6A and succulent-shelled pea and bean, subgroup 6B
in conjunction with a conditional registration while additional data are
submitted.  Pending submission of a revised Section F, the submitted
crop field trial data for caneberry, guava, lychee, papaya are adequate
to set tolerances.

HED has recently concluded that succulent-shelled soybean will be added
to the pea and bean, succulent-shelled, subgroup 6B.  Until the
regulations have been finalized in the Federal Register, a separate
tolerance is needed for this commodity, at the same level as the pea and
bean, succulent-shelled, subgroup 6B tolerance, 0.70 ppm; the proposed
tolerance for soybean, succulent-shelled must be increased. A revised
Section F to reflect these changes is required.

HED has recently concluded that wild raspberry will be added to the
caneberry subgroup 13A.  Until the regulations have been finalized in
the Federal Register, a separate tolerance is needed for residues in/on
this commodity, at the same level as the caneberry tolerance, 5.0 ppm;
the proposed tolerance for wild raspberry must be decreased.  A revised
Section F to reflect this change is required.

HED is in the process of revising the Commodity Definitions listed under
40 CFR §180.1(h) to include the tropical and subtropical fruit papaya,
guava, and lychee as general commodities.  The specific commodities
included in the definition are as follows:  (i) Papaya; black sapote;
canistel; mamey sapote; mango; sapodilla; and star apple; (ii) Guava;
feijoa; jaboticaba; wax jambu; starfruit; passionfruit; and acerola; and
(iii) Lychee; longan; Spanish lime; rambutan; and pulasan.  Until the
regulations have been finalized in the Federal Register, separate
tolerances are needed for each specific commodity, at the same level as
the respective general commodity tolerance.  The proposed tolerance for
guava is adequate, but increased tolerances are needed for residues
in/on papaya at 7.0 ppm and lychee at 5.0 ppm.  Therefore, proposed
tolerances for:  guava; feijoa; jaboticaba; wax jambu; starfruit;
passionfruit; and acerola will stay at the same level; and proposed
tolerances for:  papaya; black sapote; canistel; mamey sapote; mango;
sapodilla; and star apple and lychee; longan; Spanish lime; rambutan;
and pulasan will increase.

A summary of tolerance assessments, following HED review of submitted
field studies, is presented in Table 13.  The Agency’s Guidance for
Setting Pesticide Tolerances Based on Field Trial Data was utilized for
determining appropriate tolerance levels for edible-podded legume
vegetables (subgroup 6A), succulent-shelled pea and bean (subgroup 6B),
caneberry (subgroup 13A), guava, lychee, and papaya; see Appendix I for
tolerance calculations.  The combined residue levels of bifenazate/D3598
(in bifenazate equivalents) in/on these commodities were readily
quantifiable; no values were below the LOQ.  The available field trial
data indicate that the proposed tolerance for residues in/on guava is
adequate, but that increased tolerances are needed in/on papaya at 7.0
ppm; lychee at 5.0 ppm; edible-podded legume vegetables (subgroup 6A) at
6.0 ppm; and succulent-shelled pea and bean (subgroup 6B) at 0.7 ppm. 
The proposed tolerance for caneberry subgroup 13A is too high; the
available data indicate that a tolerance of 5.0 ppm is appropriate

Table 13.  Tolerance Summary for Bifenazate (PP#6E7167).

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

Papaya	6.0	7.0

	Star apple	6.0	7.0	Data translated from papaya.

Black sapote	6.0	7.0

	Mango	6.0	7.0

	Sapodilla	6.0	7.0

	Canistel	6.0	7.0

	Mamey sapote	6.0	7.0

	Lychee	4.0	5.0

	Longan	4.0	5.0	Data translated from lychee

Spanish lime	4.0	5.0

	Rambutan	4.0	5.0

	Pulasan	4.0	5.0

	Guava	0.9	0.90

	Feijoa	0.9	0.90	Data translated from guava

Jaboticaba	0.9	0.90

	Wax jambu	0.9	0.90

	Starfruit	0.9	0.90

	Passionfruit	0.9	0.90

	Acerola	0.9	0.90

	Caneberry subgroup 13A	6.0	5.0

	Wild raspberry	6.0	5.0	Data translated from Caneberry subgroup 13A

Vegetable, legume, edible-podded, subgroup 6A	4.0 1	6.0	Concomitantly,
the established tolerance for pea, edible-podded, succulent should be
removed. 

Pea and bean, succulent-shelled, subgroup 6B	0.3 1	0.70	Concomitantly,
the established tolerance for pea, garden, succulent should be removed.

Soybean, succulent-shelled	0.3 2	0.70	Data translated from
succulent-shelled pea and bean, subgroup 6B

1  IR-4 had previously submitted a petition for bifenazate on garden pea
(succulent-shelled pea) and edible-podded pea (PP#5E6992; MRID
46651703).

2  A separate tolerance for succulent-shelled soybean is requested based
on the recommendations made by B. Schneider in an HED memorandum, dated
11/4/04 that a succulent-shelled soybean tolerance be established at the
same level as succulent-shelled beans.

4.4  Water Exposure/Risk Pathway

For a complete summary of the drinking water assessment for bifenazate
see the EFED Memo; D286171, T. Nguyen, 10-Oct-2003.  Surface and ground
water estimated drinking water concentrations (EDWCs) were generated
using the FIRST (87% cropped area) and screening concentration in ground
water (SCI-GROW) models, respectively.  Both models were run using the
strawberry application scenario (2 x 0.50 lb ai/acre; 21-day RTI;
highest registered/proposed rate).  The resulting chronic EDWCs in
ground and surface water were <0.001 ppb and 6.38 ppb, respectively.
Since the surface water concentration was the highest, the chronic
dietary run was conducted assuming a residue of 0.00638 ppm for all
water sources (direct and indirect). 

4.5  Dietary Exposure Analysis

Chronic dietary risk assessments were conducted using the DEEM-FCID(,
ver. 2.03.  DEEM- FCID( incorporates the food consumption data from the
USDA’s CSFII (1994-1996 and 1998).  The chronic analyses incorporated
tolerance-level residues for all commodities excluding squash, peach,
and tomato (average field-trial residues were assumed) and milk (the
tolerance level was adjusted upward to account for all of the residues
of concern for risk assessment).  The chronic analyses incorporated
average percent crop-treated information provided by the Biological
Economic Analysis Division (BEAD Memo; J. Carter, 13-Jul-2006).  The
average percent crop-treated estimates are summarized in Appendix 3. 
DEEM( (ver. 7.81) default processing factors were assumed for all
commodities excluding apple juice, grape juice, wine/sherry, tomato
paste, and tomato puree.  The processing factors for these commodities
were reduced to 0.23, 0.17, 0.17, 1, and 1, respectively, based on data
from processing studies.  The analyses also included the chronic surface
water point estimate generated using the FIRST and the strawberry
application scenario (2 x 0.50 lb ai/acre; 21-day RTI; highest
registered/proposed rate).  The chronic exposure estimates are (47% cPAD
and are, therefore, not of concern to HED.   The most highly-exposed
population subgroup was children 1 to 2 years old.  Based on a
critical-commodity analysis conducted in DEEM-FCID(, the major
contributors to the risk for children 1 to 2 years old were
succulent-shelled peas and beans, succulent or dried-legume vegetables,
milk, and edible pod legume vegetables.  Table 14 is a summary of the
chronic dietary exposure estimates.

Table 14.  Summary of Chronic Dietary Exposure and Risk for Bifenazate
(Drinking Water Exposure Included).

Population Subgroup	cPAD (mg/kg/day)	Chronic

Exposure (mg/kg/day)	

%cPAD

General U.S. Population	0.01	0.0019	19%

All Infants (< 1 year old)

0.0041	41%

Children 1-2 years old

0.0047	47%

Children 3-5 years old

0.0040	40%

Children 6-12 years old

0.0026	26%

Youth 13-19 years old

0.0016	16%

Adults 20-49 years old

0.0013	13%

Adults 50+ years old

0.0016	16%

Females 13-49 years old

0.0015	15%

4.6  Residential Exposure and Risk Assessment

Memo, M. Dow and D. Vogel, 15-Aug-2002, D284802

HED previously reviewed a petition for homeowner application of
bifenazate to “all ornamental plants, including bedding plants,
flowering plants, foliage plants, bulb crops, perennials, trees, and
shrubs.”  In conjunction with this petition, labeling for FloramiteTM
SC (2lb ai/gal) was submitted and the assessment was conducted using the
instructions on this label.  HED noted that the petition indicated that
Florimite, Floramite LS, Floramite GN, and Floramite SC/LS may also be
applied to ornamentals.  Copies of those product labels were not
forwarded for review; therefore, HED is not aware of any differences in
labels that might exist.  

HED anticipated only short-term dermal and inhalation exposure for
residential handlers.  The proposed formulation was appropriate for
application via pump up sprayers, garden hose-end sprayers, or similar
“homeowner” pesticide devices.  HED policy indicates a larger area
per day may be treated with a hose-end sprayer than with a “pump-up”
compressed-air sprayer, which in turn results in possibly greater
contact with the active ingredient per day.  Therefore, exposure from a
hose-end sprayer was assessed rather than that of a compressed-air
sprayer.  The resulting dermal and inhalation MOEs were 4200 and 430000,
respectively, and yielded a combined MOE of 4200; therefore, residential
exposure to bifenazate is not of concern.  With respect to
post-application residential exposures, current HED policy (see minutes
to ExpoSAC meeting, 26-Jul-2001) specifies that no significant
post-application exposure is anticipated from landscape ornamentals,
either by residents or professional applicators; therefore, no
residential post-application assessment was conducted. 

4.7  Non-occupational Off-Target Exposure

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from ground application.  The Agency has been working with
the Spray Drift Task Force, EPA Regional Offices, State Lead Agencies
for pesticide regulation, and other parties to develop the best spray
drift management practices.  On a chemical by chemical basis, the Agency
is now requiring interim mitigation measures for aerial applications
that must be placed on product labels/labeling.  The Agency has
completed its evaluation of the new data base submitted by the Spray
Drift Task Force, a membership of U.S. pesticide registrants, and is
developing a policy on how to appropriately apply the data and the
AgDRIFT computer model to its risk assessments for pesticides applied by
air, orchard airblast and ground hydraulic methods.  After the policy is
in place, the Agency may impose further refinements in spray drift
management practices to reduce off-target drift with specific products
with significant risks associated with drift. 

5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In general, HED conducts aggregate risk assessments by summing dietary
(food and water) and residential exposures (residential or other
non-occupational exposures).  Based on the registered/proposed
agricultural and residential uses and since a common toxicological
endpoint has been identified for assessment of oral, dermal, and
inhalation exposures (all durations; changes in body weights and body
weight gains, and hematological effects), HED conducted short-term
(food, water, residential dermal, and residential inhalation) and
chronic (food and water) aggregate risk assessments.  The HIARC did not
select an acute dietary endpoint for the general U.S. population,
infants, children, and females 13-50 years old and bifenazate has been
classified as “not likely” to be a human carcinogen.  Therefore,
acute and cancer aggregate exposure analyses are not required for
bifenazate.  

Short-Term Aggregate Risk Assessment:  Since a common endpoint has been
identified for assessment of short-term oral, dermal, and inhalation
exposures (changes in body weights and body-weight gains, and
hematological effects) the short-term aggregate risk assessment
considered exposure from food, water, and residential sources.  Since
the doses corresponding to the identified oral, dermal, and inhalation
endpoints were different but the level of concern for all three routes
of exposure are identical, the short-term aggregate exposures were
calculated using the 1 ( MOE approach.  HED combines chronic dietary
(food and water) exposure estimates with residential exposure estimates
when conducting short-term aggregate risk assessments.  Short-term
exposure has been defined as from 1- 30 days and HED has concluded that
chronic dietary exposure estimates will more accurately reflect actual
dietary exposure over these time periods than will high-end
acute-dietary exposures.  The residential scenarios result in exposure
to only adults.  Therefore, short-term aggregate assessments were not
conducted for infants and children. Table 15 is a summary of the
short-term aggregate exposures and risk estimates.  Since the aggregate
MOEs are equal to 3900 for all population subgroups, short-term
aggregate exposure to bifenazate is not of concern. 

Table 15.  Short-Term Aggregate Exposure.

Population	Target Aggregate

MOE1	dietary 

MOE2	dermal 

MOE3	inhalation 

MOE4	agg. MOE

(dietary and residential)5

General U.S. pop.	100	53000	4200	430000	3900

Youth 13-19 years old

63000	4200	430000	3900

Adults 20-49 years old

77000	4200	430000	3900

Adults 50+ years old

62500	4200	430000	3900

Females 13-49 years old

67000	4200	430000	3900

1	Total uncertainty factor for all routes of exposure is 100x;
therefore, the target MOE is 100.

2	Dietary MOE = short-term incidental oral NOAEL ( chronic dietary
exposure.

3	Dermal MOE = short-term dermal NOAEL ( dermal residential exposure
(see Section 4.5).

4	Inhalation MOE = short-term inhalation NOAEL ( inhalation residential
exposure (see Section 4.5).

5 	Aggregate MOE (dietary and residential) = 1(((1(MOEdietary)+
(1(MOEdermal) + (1(MOEinhalation)).

Chronic Aggregate Risk Assessment:  Since there are no
registered/proposed uses which result in chronic residential exposures,
the chronic aggregate exposure assessment is concerned only with
exposure from food and water.  Since the dietary exposure analysis
included drinking water, the discussion and exposure estimates presented
in Section 4.5 represent aggregate chronic exposure. 

6.0  CUMULATIVE RISK

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding for bifenazate and any other
substances, and bifenazate does not appear to produce a toxic metabolite
produced by other substances.  For the purposes of this tolerance
action, therefore, EPA assumed that bifenazate does not have a common
mechanism of toxicity with other substances.  For information regarding
EPA’s efforts to determine which chemicals have a common mechanism of
toxicity and to evaluate the cumulative effects of such chemicals, see
the policy statements released by EPA’s OPP concerning common
mechanism determinations and procedures for cumulating effects from
substances found to have a common mechanism on EPA’s website at    
HYPERLINK "http://www.epa.gov/pesticides/cumulative/." 
http://www.epa.gov/pesticides/cumulative/. 

7.0  OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT

Memo, 10/1/2007, K.M. Lowe, DP# 337535 (on caneberries and tropical
fruits)

It is anticipated that the following scenarios could result in handler
exposure:  mixer/loaders for groundboom applications of water soluble
bags and applicators using airblast equipment. 

7.1  Handler Exposure and Risk Assessment

HED notes that the Acramite®-4SC (4 lb ai/gal; EPA Reg. No. - 400-514)
and Acramite®-50WS (50% ai; EPA Reg. No. - 400-503) labels indicate
that applicators and other handlers should wear a long-sleeved shirt,
long pants, shoes, and socks.  The Acramite®-4SC label also indicates
that when not using a closed system, an apron and chemical-resistant
gloves should be worn for mixing/loading activities (this statement is
not included on the Acramite®-50WS label).  HED notes that the
Acramite®-50WS is a WP formulation in water soluble bags and is
therefore considered a closed system by HED.  

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED
(August, 1998).   For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for “baseline”; that is, for
workers wearing a single layer of work clothing consisting of a
long-sleeved shirt, long pants, shoes plus socks and no protective
gloves, as well as for “baseline” and the use of protective gloves
or other personal protective equipment (PPE) as might be necessary.  The
proposed product label involved in this assessment directs applicators
and other handlers to wear a long-sleeved shirt and long pants, and
shoes plus socks. 

HED believes most exposure durations will be short-term (1-30 days).  
However, the Science Policy Council for Exposure maintains it is
possible for commercial applicators to be exposed to intermediate-term
exposure durations (1-6 months).  In addition, the short- and
intermediate-term toxicological endpoints are the same, therefore, the
estimates of risk for short-term duration exposures are protective of
those for intermediate-term duration exposures.  Long-term exposures are
not expected, therefore, a long-term assessment was not conducted. 

Daily dermal or inhalation handler exposures are estimated for each
applicable handler task with the application rate, the area treated in a
day, and the applicable dermal or inhalation unit exposure using the
following formula:

Daily Exposure (mg ai/day) = UE (mg ai/lb ai handled) x AR (lbs ai/area)
x AT (area/day)

Where:  

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

UE			=	Unit exposure value (mg ai/lb ai) derived from August 1998 PHED
data;

AR			=	Application rate (lb ai/A or lb ai/gal); and

	AT		 	=	Application area (A/day or gal/day). 

The daily dermal or inhalation dose is calculated by normalizing the
daily exposure by body weight and adjusting, if necessary, with an
appropriate dermal or inhalation absorption factor using the following
formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100) / Body Weight (kg)

Where:

Average Daily Dose 		= 	Absorbed dose received from exposure to a
pesticide in a given scenario (mg ai/kg bw/day);

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

Absorption Factor 		= 	A measure of the amount of chemical that crosses
a biological boundary such as the skin or lungs (% of the total
available absorbed); and

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

Non-cancer dermal and inhalation risks for each applicable handler
scenario are calculated using a MOE, which is a ratio of the NOAEL to
the daily dose.  All MOE values were calculated using the formula below:

MOE= NOAEL or LOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

		

Table 10 presents the exposure/risks for short-term dermal and
inhalation exposures for water soluble bag formulations.  HED has
determined that there are no risks of concern for all exposure scenarios
(i.e., MOEs>100).  

Table 16.  Bifenazate Occupational Noncancer Dermal and Inhalation
Exposures and Risks from                                   Applications
of Water Soluble Bag Formulations to Caneberry and Tropical Fruits.

Application Rate (lb ai/acre)a	Area Treated Daily (acres)b	Dermal  and
Inhalation Unit Exposures (mg/lb ai)	Doses (mg/kg/day)d	MOEse

Mixer/Loader for Groundboom Applications

0.5	80	Dermal

Engineering controlc: 0.0098	Dermal

Engineering control: 0.0056	Dermal

Engineering control: 14,000

Inhalation

Engineering controlc:  0.00024	Inhalation

Engineering control: 0.00014	Inhalation

Engineering control: 73,000

Applicator for Airblast Applications

0.5	40	Dermal

Engineering control: 0.019	Dermal

Engineering control: 0.0054	Dermal

Engineering control: 15,000

Inhalation

Engineering control:  0.00045	Inhalation

Engineering control: 0.00013	Inhalation

Engineering control: 78,000

a	Application rates are the maximum application rates determined from
proposed labels for bifenazate.

b	Amount handled per day values are HED estimates of acres treated per
day based on Exposure SAC SOP #9 “Standard Values for Daily Acres
Treated in Agriculture,” industry sources, and HED estimates.	

c	Eng Con Dermal and Inhalation: In this case, the water soluble bag
formulation is considered an engineering control for wettable powders.

d	Dose (mg/kg/day) = Unit exposure(mg/lb ai or ug/lb ai) x App Rate (lb
ai/acre) x Area Treated (acres/day) x  %Absorption (100% dermal and
inhalation) / Body weight (kg).  

e	MOE = NOAEL/Dose; where the short-term dermal NOAEL = 80 mg/kg/day and
the short-term inhalation NOAEL = 10 mg/kg/day.

7.2  Post-Application Exposure and Risk Assessment

It is possible for agricultural workers to have post-application
exposure to pesticide residues during the course of typical agricultural
activities.  Since no postapplication data was submitted in support of
this registration action, exposures during postapplication activities
were estimated using dermal transfer coefficients (TCs) from HED’s
Science Advisory Council (SAC) for Exposure (ExpoSAC) Policy Number 3.1:
Agricultural Transfer Coefficients, August 2000, summarized in Table 17
below and the following assumptions:

					

Assumptions:

Application Rate	= 	0.5 lb ai/A 

Exposure Duration	=	8 hours per day

Body Weight		=	70 kg			

Dermal Absorption	= 	100% 

Fraction of ai  retained on foliage is assumed to be 20% (0.2) on day
zero (= % dislodgeable foliar residue, DFR, after initial treatment). 
This fraction is assumed to further dissipate at the rate of 10% (0.1)
per day on following days.  These are default values established by
HED’s ExpoSAC.



Table 17.  Anticipated Postapplication Activities and Dermal Transfer
Coefficients1

Proposed Crops	Policy Crop Group Category	Transfer Coefficients (cm2/hr)
Activities

Caneberry (subgroup 13a)	Vine / Trellis	1,100 	Irrigation; Hand-weeding;
Scouting; Training; Hand-pruning; Tying1

Tropical fruits	Tree, fruit	1,000	Irrigation; Scouting; Hand-weeding

1,500	Hand-harvest; Propping; Hand-pruning; Training3

3,000 	Thinning4

1  The information in the table is based on proprietary and
non-proprietary data.

2  Revised transfer coefficient (ExpoSAC minutes, 8/7/03)

3  The tree fruit harvester TCs used in this assessment (1,500 cm2/hr)
was reduced from a value of 3,000 cm2/hr.  This modification has been
permanently incorporated into Policy 003 for agricultural TCs and was
made by considering the results of six different tree harvester studies
conducted/owned by the ARTF.  (ExpoSAC minutes 1/16/03)

4  The TC in Policy 003 for tree fruit thinning has been reduced since
the issuance of the policy from 8,000 cm2/hour to 3,000 cm2/hour based
on a re-evaluation of the data (i.e., the change is based on an altered
analytical recovery correction factor that was erroneously used by Bayer
in the initial study report).  This modification has been made in the
tree fruit group and any other scenarios which have used this value. 
Additionally, preliminary data from a biomonitoring study of tree fruit
thinning presented at the International Society of Exposure Analysis
meeting in August 2002, sponsored by Bayer and conducted by Krieger et
al from the University of California Riverside, also supports use of a
TCs of 3,000 cm2/hr for tree fruit thinners (ExpoSAC minutes 1/16/03).	

Daily dermal exposures were calculated on each postapplication day after
application using the following equation:

DE(t) (mg/day) = (TR(t) (µg/cm2) x TC (cm2/hr) x Hr/Day)/1000 (µg/mg)

Where:

DE(t)	=	Daily exposure or amount deposited on the surface of the skin at
time (t) attributable for activity in a previously treated area, also
referred to as potential dose (mg ai/day);

	TR(t)	=	Transferable residues that can be dislodgeable foliar residue
at time “t” (µg/cm2);

	TC	=	Transfer Coefficient (cm2/hour); and

	Hr/day	=	Exposure duration meant to represent a typical workday
(hours).

Note that the (TR(t)) input may represent levels on the day of
application in the case of short-term risk calculations.  Once daily
exposures are calculated, the calculation of daily absorbed dose and the
resulting MOEs use the same algorithms that are described above for the
handler exposures.  These calculations are completed for each day or
appropriate block of time after application.

Table 18 presents a summary of occupational postapplication risks
associated with use of bifenazate.  For caneberry and tropical fruit
applications, HED has determined that risks are not of concern on day 0
(REI=12 hours) for all exposure activities (i.e., MOEs>100).  

Table 18.  Summary of Occupational Postapplication Risks for Bifenazate.

Crop Grouping	Application rate

(lb ai/acre)	Transfer Coefficient (µg/cm2)	Day after Application	MOE at
Day 0

(Level of Concern = 100)

Caneberries (subgroup 13A)	0.5	1,100 (Irrigation; Hand-weeding;
Scouting; Training; Hand-pruning; Tying)	0 (12 hours)	570

Tropical fruits

1,000 (Irrigation; Scouting; Hand-weeding)	0 (12 hours)	620

1,500 (Hand-harvest; Propping; Hand-pruning; Training)

420

3,000 (Thinning)

210

7.3 RESTRICTED ENTRY INTERVAL

Bifenazate is classified in Toxicity Category IV for acute dermal, oral
and inhalation, as well as for primary eye irritation and primary skin
irritation.  It is not a dermal sensitizer.  Therefore, the Worker
Protection Standard (WPS) interim restricted entry interval, 12 hours,
is adequate to protect agricultural workers from postapplication
exposures to bifenazate.  

  SEQ CHAPTER \h \r 1 8.0  DEFICIENCIES

8.1  Toxicology

None.

8.2  Residue Chemistry

Label revisions are required to remove members of Legume Vegetables and
to list only members of Subgroups 6A and 6B on the proposed end-use
products.

The product label for the 4 lb/gal FlC formulation (Acramite®-4SC) does
not specify any rotational crop restrictions and must be revised to
specify a 30-day PBI.

Edible-podded Legume Vegetables (Subgroup 6A) and Succulent-shelled Pea
and Bean (Subgroup 6B):  As a condition of registration the petitioner
should be required to submit crop field trial data for the
representative commodities of edible-podded legume vegetables, subgroup
6a, (9 trials) and succulent-shelled pea and bean, subgroup 6b, (12
trials).  The field trials should be conducted according to the proposed
use directions of this petition (not at an exaggerated rate) and residue
decline data should be generated. 

The petitioner should submit a revised Section F reflecting the
recommended tolerances presented in Table 3.

8.3  Occupational/Residential

None

Attachment 1:  Structures

Attachment 2:  Toxicology Profile Table.

Attachment 3:  Percent Crop-Treated Data used for Bifenazate.

RDI:  RAB1 Chemists:  12/12/2007

Petition Number:  PP#6E7167

DP Number:  347497

PC Code:  000586



Attachment 1: chemical structures

Chemical name	chemical structure

bifenazate (D2341)

hydrazinecarboxylic acid, 2-(4-methoxy-[1,1’-biphenyl]-3-yl),
1-methylethyl ester	

D3598

diazinecarboxylic acid, 2-(4-methoxy-[1,1’-biphenyl]-3-yl),
1-methylethyl ester	

D4642

 

D9963

 

D1989

 

D9569

 

A1530

 

D23-14; 

biphenyl hydrazine;

 

Attachment II:  Toxicity Profile of Bifenazate Technical

Guideline No.	

Study Type 

(All Studies Acceptable)	

Results

870.3100	

90-Day oral toxicity rodents-rat	

NOAEL = 13.8 mg/kg/day in males, 3.2 mg/kg/day in females.

LOAEL = 27.7 mg/kg/day in males, 16.3 mg/kg/day in females based on
decreased body weight gain in both sexes, decreased liver weight in
males, increased spleen weight in females, and histopathology in liver
in both sexes, and histopathological changes in the spleen and adrenal
cortex in males.

870.3150	

90-Day oral toxicity non-rodents-dog	

NOAEL = 0.9 mg/kg/day in males, 1.3 mg/kg/day in females.

LOAEL = 10.4 mg/kg/day in males, 10.7 mg/kg/day in females based on
changes in hematological parameters in both sexes, increased bilirubin
in the urine in males, increased absolute and relative liver weight in
females and liver histopathologic effects in both sexes. 

870.3200	

21-Day dermal toxicity- rat	

NOAEL = 80 mg/kg/day in males and females.

LOAEL = 400 mg/kg/day in males and females based on decreased body
weight in females, decreased food consumption in both sexes, increased
urinary ketones, increased urinary protein, increased urinary specific
gravity, and decreased urinary volume in both sexes, and increased
incidence of extramedullary hematopoiesis in the spleen in both sexes.

870.3700a	

Prenatal developmental in rodents- rat	

Maternal NOAEL = 10 mg/kg/day.

LOAEL = 100 mg/kg/day based on increased clinical signs, and decreased
body weight, body weight gain, and food consumption.

Developmental NOAEL = 500 mg/kg/day.

LOAEL = not established

870.3700b	

Prenatal developmental in non-rodents- rabbit	

Maternal NOAEL = 200 mg/kg/day

LOAEL = not established; Doses for the main study were selected based on
a range-finding study in which groups of 5 rabbits each received 0, 125,
250, 500, 750, or 1,000 mg/kg/day during gestation days 6-19 by gavage.
Maternal toxicity was seen as increased deaths and decreased body weight
at 750 mg/kg/day and above.  A treatment-related increase in the number
of does aborting was seen at 250 mg/kg/day and above.  

Developmental NOAEL =200 mg/kg/day

LOAEL = not established; Due to only one or two litters available in
each of the treated groups in the range finding study, a clear
assessment of developmental toxicity was not possible.  Based on these
results, doses of 10, 50, and 200 mg/kg/day were selected for the main
study. 

870.3800	

Reproduction and fertility effects- rat	

Parental/Systemic NOAEL = 1.6 mg/kg/day in males, 1.8 mg/kg/day in
females.

LOAEL = 6.5 mg/kg/day in males and 7.4 mg/kg/day in females based on
decreased body weight, body weight gain, and food consumption in both
sexes.

Reproductive NOAEL = 16.4 mg/kg/day in males, 18.3 mg/kg/day in females.

LOAEL = not established.

Offspring NOAEL = 16.4 mg/kg/day in males, 18.3 mg/kg/day in females.

LOAEL = not established

870.4100b	

Chronic toxicity dogs	

NOAEL = 1.01 mg/kg/day in males, 1.05 mg/kg/day in females

LOAEL = 8.95 mg/kg/day in males, 10.42 mg/kg/day in females based on
changes in hematological and clinical chemistry parameters in both sexes
and histopathological effects in bone marrow, liver, and kidney in both
sexes.

870.4300	

Chronic/Carcino-genicity rats	

NOAEL = 3.9 mg/kg/day in males, 4.8 mg/kg/day in females. 

LOAEL = 9.7 mg/kg/day in males and 9.7 mg/kg/day in females based on
decreased body weight, body weight gain, and food consumption in both
sexes.

No evidence of carcinogenicity

870.4300	

Carcinogenicity mice	

NOAEL = 1.5 mg/kg/day in males, 19.7 mg/kg/day in females.

LOAEL = 15.4 mg/kg/day in males, 35.7 mg/kg/day in females based on
decreased body weight and body weight gain in females and hematological
effects and decreased kidney weight in males. 

No evidence of carcinogenicity

870.5265	

Gene Mutation	

Non-mutagenic when tested up to 5000 ug/plate, in presence and absence
of activation, in S. typhimurium strains TA98, TA100, TA1535 and TA1537
and E. coli strain WP2uvra.

870.5300	

Gene Mutation	

Non-mutagenic at the TK locus in L5178Y mouse lymphoma cells tested up
to cytotoxic concentrations or limit of solubility, in presence and
absence of S-9 activation.

870.5375	

Chromosome aberration	

Did not induce structural chromosome aberration in CHO-K1 cell cultures
in the presence and absence of activation up to cytotoxic
concentrations.

870.5385 	

Chromosomal aberration	

Non-mutagenic in ICR mouse bone marrow micronucleus chromosomal
aberrations assay up to cytotoxic concentrations.

870.7485	

Metabolism and pharmacokinetics - rat	

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groups.  Fecal excretion was the major route of elimination (66-83% of
the dose), with eight primary metabolites detected. These metabolites,
as well as those identified in the urine and bile, were the result of
metabolic reactions including hydrazine oxidation, demethylation, ring
hydroxylation, and molecular scission with the loss of
hydrazinecarboxylic acid portion with subsequent conjugation.

Attachment 3:  Percent Crop-Treated Data used for Bifenazate.

Commodities	Percent Crop-treated

Almond Commodities	1.0%

Apple Commodities	1.0%

Apricot Commodities	1.0%

Cucumber	1.0%

Grape Commodities	5.0%

Nectarine	5.0%

Peach Commodities	5.0%

Pear Commodities	10%

Pecans	1.0%

Peppers (bell and non-bell)	1.0%

Plum and Prune Commodities	5.0%

Strawberry Commodities	25%

Tomato Commodities	5.0%

Walnuts	1.0%

Watermelon Commodities	1.0%

Reference:  BEAD Memorandum, 7/13/2006, J. Carter.

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