UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 		07/25/2007

MEMORANDUM

SUBJECT:	Bifenthrin: PP#6E7125, PP#6E7126, PP#6E7127, PP#6E7128;
Human-Health Risk Assessment for Proposed Uses on Mayhaw, Root
Vegetables, (Except Sugar Beets, Crop Subgroup 1B), Peanut, Pistachio,
Soybean, and Fruiting Vegetables (Crop Group 8).

Regulatory Action:  Section 3 Registration Action

Risk Assessment Type:  Single Chemical Aggregate

Petition Nos.	6E7125, 6E7126, 6E7127, 6E7128	Decision Nos:	371449,
371450, 371452

DP Numbers:	334154, 334165, 334168	40 CFR:	§180.442

Chemical No.:	128825	Class:	Synthetic Pyrethroid

Trade Name:	Capture 2EC, Capture 1.15G, Brigade WSB	EPA Reg. No.:
279-3069; 279-3244; 279-3108

MRIDs:	None

From:		William D. Wassell, Chemist

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

		Mark I. Dow, Ph.D., Biologist

		Registration Action Branch 1 (RAB1)

		Health Effects Division (HED, 7509P)

Through:	PV Shah, Ph.D., Acting Branch Chief

		RAB1/HED (7509P)

To:		Daniel Rosenblatt/Shaja Brothers (RM 05)

	Registration Division (7505P)

The Interregional Research Project Number 4 (IR-4) has submitted
requests for Section 3 registrations for the application of bifenthrin
to mayhaw, root vegetables, (except sugar beets, crop subgroup 1b),
peanut, pistachio, soybean, and fruiting vegetables (crop group 8).  In
conjunction with this request, the petitioner has proposed the
establishment of tolerances for bifenthrin
(2-methyl[1,1′-biphenyl]-3-yl)methyl
(1R,3R)-rel-3-[(1Z)-2-chloro-3,3,3-trifluoro-1-propenyl]-2,2-dimethylcyc
lopropanecarboxylate] per se in/on:

Mayhaw	1.4 ppm

Vegetable, root, except sugar beet and garden beet, subgroup 1B	0.07 ppm

Beet, garden, root	0.45 ppm

Beet, garden, top	15 ppm

Radish, top	4.5 ppm

Soybean	0.2 ppm

Soybean, hulls	0.7 ppm

Soybean, refined oil	0.4 ppm

Vegetable, fruiting, group 8	0.5 ppm

Peanut	0.05 ppm

Pistachio	0.05 ppm

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human-health from exposure to pesticides.  The RD
of OPP has 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 the proposed uses of bifenthrin.

A summary of the findings and an assessment of human-health risk
resulting from the proposed and registered uses of bifenthrin are
provided in this document.  The hazard characterization was provided by
PV Shah, Ph.D., (RAB1); the residue chemistry review was provided by
William Wassell (RAB1); the dietary exposure assessment was provided by
Sheila Piper (CEB) and William Wassell; the occupational/residential
exposure assessment was provided by Mark Dow (RD); the drinking water
assessment was provided by Jose Melendez of the Environmental Fate and
Effects Division (EFED); and the aggregate exposure and risk assessment
were provided by William Wassell (RAB1).

1.0	Executive Summary

References:

Revised Preliminary HED Chapter for the Bifenthrin Tolerance
Reassessment Eligibility Decision (TRED). DP Barcode: D283796.  J.
Liccione. 12/04/2002.

Bifenthrin: Human-health Risk Assessment for Proposed Uses on Cilantro,
Leafy Brassica Greens (subgroup 5b), Tuberous and Corm Vegetables
(Subgroup 1c), Dried Shelled Peas and Beans (except Soybean) (Subgroup
6c) and Tobacco. DP Barcode: D310088. M. Rust-Clock, et. al. 4/6/2006.

Background

Bifenthrin is a neurotoxic insecticide acting through direct contact and
ingestion, having a slight repellent effect.  The primary biological
effects of bifenthrin and other pyrethroids on insects and vertebrates
are inhibition of the voltage-gated Ca 2+ channels coupled with a
stimulatory effect on the voltage-gated Na+ channels.  All pyrethroids
act as axonic poisons, affecting both the peripheral and central nervous
systems, and share similar modes of action.  Pyrethroids, including
bifenthrin, stimulate repetitive action in the nervous system by binding
to voltage-gated sodium channels, prolonging the sodium ion permeability
during the excitatory phase of the action potential.  This action leads
to spontaneous depolarizations, augmented neurotransmitter secretion
rate and neuromuscular block, which ultimately results in paralysis of
the insect.

Bifenthrin is formulated as an emulsifiable concentrate (EC), wettable
powder (WP), or granular (G) product and has registered uses on a
variety of commodities .  Current tolerances (ranging from 0.05 to 10
ppm) are established in 40 CFR §180.442 for residues of bifenthrin
in/on various plant and livestock commodities.   Time-limited tolerances
for orchard grass and sweet potato roots (0.05 ppm) have been
established in conjunction with Section 18 Emergency Exemptions [40 CFR
§180.442(2b)].  A tolerance of 0.05 ppm is established for residues of
bifenthrin in food and feeds as a result of uses in food/feed handling
establishments [40 CFR §180.442(2)].  Residential uses are registered
for bifenthrin; however, no new residential uses are proposed in the
subject actions.

A Tolerance Reassessment Eligibility Decision (TRED) was issued for
bifenthrin in 2002 (reference above) and a human-heath risk assessment
was completed on 4/6/2006.  The TRED examined all registered uses of
bifenthrin.  The background information and conclusions reported in the
2002 TRED (including exposure from dietary, occupational and residential
uses) and previous risk assessment have been summarized and incorporated
into this risk assessment.  For more details, see the 2002 TRED or the
2006 risk assessment.

Hazard Characterization

Bifenthrin has a moderate order of acute toxicity via the oral route
(Category II) and a low order of acute toxicity via the dermal route
(Category III) of exposure.  There are no acute inhalation studies on
bifenthrin technical; however, acceptable studies on the end-use
products are available.  Bifenthrin has a low vapor pressure.  It is
neither an eye nor skin irritant, nor is it a dermal sensitizer.

Bifenthrin produces characteristic pyrethroid neurotoxicity.  Tremors
have been observed in developmental toxicity studies in the rat and
rabbit, a 2-generation rat reproduction toxicity study, subchronic
toxicity studies in the rat and dog, acute and subchronic neurotoxicity
rat studies, a 21-day toxicity dermal rat study, chronic oral toxicity
studies in the rat and dog, and a mouse oncogenicity study.  The
subchronic and chronic oral toxicity studies in dogs and rats
demonstrate neurotoxicological responses of similar magnitude.
Staggered gait and exaggerated hindlimb flexion were noted in a 21-day
dermal toxicity study in the rat.  The neurotoxicity of bifenthrin has
been supported by the results of acute and subchronic neurotoxicity
studies in the rat.  Functional observation battery (FOB) findings were
observed in these neurotoxicity studies.  FOB findings consisted of
tremors, abnormal posture, splayed hindlimbs, staggered gait, altered
activity, altered landing foot-splay, twitching, uncoordinated
movement/ataxia, and convulsions.

Bifenthrin is neither a developmental nor a reproductive toxicant.
Bifenthrin has been evaluated for potential developmental effects in the
rat (following gavage or dietary administration) and in the rabbit
(gavage administration).  Maternal toxicity included neurological
effects (tremors in rats and rabbits; head and forelimb twitching in
rabbits).  There were no developmental effects of biological
significance in either species.

The potential reproductive toxicity of bifenthrin was examined in a
two-generation reproduction study in the rat.  Tremors were noted only
in females of both generations with one parental generation rat observed
to have clonic convulsions.  Administration of bifenthrin did not result
in reproductive or offspring toxicity.

A developmental neurotoxicity (DNT) study on bifenthrin with rats has
been submitted. In this study, maternal and offspring toxicity was
observed at the same dose levels.  The maternal toxicity was primarily
manifested as tremors, clonic convulsions, and increased grooming
counts.  The offspring toxicity was manifested as increased grooming
counts.   This study does not show any evidence of increased
susceptibility of offspring following exposure to bifenthrin.

Bifenthrin was negative in most tests for mutagenicity.  It was
marginally mutagenic with and without S9 activation in the mouse
lymphoma forward gene mutation assay.  This finding has not been
confirmed in a repeat test.  There is also inconclusive, but
presumptive, evidence that bifenthrin was mutagenic in the S9-activated
phase of the Chinese hamster ovary (CHO) cell gene mutation assay;
however, this study was classified as unacceptable.

There was no conclusive evidence of carcinogenic potential of
bifenthrin in the rat.  A mouse oncogenicity study provided some
evidence for carcinogenic potential in this species.  In the mouse
oncogenicity study, high-dose (81.3 mg/kg/day) males showed a highly
significant increased incidence of urinary bladder tumors.  Other
findings in the mouse study included a dose-related trend of increased
combined incidences of adenoma and adenocarcinoma of the liver (males
only), and increased incidences of bronchioalveolar adenomas and
adenocarcinomas of the lung in females at some, but not all dose levels
relative to their controls.  HED’s Carcinogenicity Peer Review
Committee (CPRC) has characterized bifenthrin as Category C (possible
human carcinogen) primarily on the basis of a mouse study in which the
Cancer Assessment Review Committee (CARC) (1992) recommended that, for
the purpose of risk characterization, the reference-dose (RfD) approach
should be used for quantification of human cancer risk.

Several dermal-absorption studies on bifenthrin are available; each
study was considered acceptable for regulatory purposes when taken in
conjunction with the other studies.  The Hazard Identification and
Review Committee (HIARC) recommended a dermal absorption rate of 25%
based on the weight-of the-evidence available for structurally related
pyrethroids.

Dose Response Assessment and Food Quality Protection Act (FQPA) Decision

The HED HIARC met on June 25, 2002 to select endpoints for risk
assessment and to evaluate the potential for increased susceptibility of
infants and children from exposure to bifenthrin.  Since the last HIARC
meeting, the registrant submitted the DNT study in rats. This study is
classified as Acceptable/Non-guideline and may be used for regulatory
purposes.  This study did not impact endpoints selected by the HIARC for
various exposure scenarios.  The database uncertainty factor due to lack
of a DNT study is now removed.  No appropriate acute dietary endpoints
were available to quantify risk to females 13-50 years of age from a
single-dose administration of bifenthrin.  However, an acute reference
dose (aRFD) of 0.33 mg/kg/day, relevant to the general population
including infants and children, and based on observation of mortality
(females only), clinical and FOB findings, and differences in motor
activity, was selected from an acute neurotoxicity study in rats for
acute risk assessment.  The aRfD is based on the no observed
adverse-effect level (NOAEL) of 32.8 mg/kg/day divided by an uncertainty
factor (UF) of 100 (10x for inter-species extrapolation and 10x for
intra-species variations).

The short- and intermediate-term incidental oral and inhalation
endpoints are based on observations of an increased incidence of tremors
in male and female dogs in a 90-day oral toxicity study.  A cRfD of
0.013 mg/kg/day was determined from the 1-year oral dog study that
demonstrated increased incidence of tremors in both sexes.  The cRfD is
based on the NOAEL of 1.3 mg/kg/day divided by an UF of 100 (10x for
inter-species extrapolation and 10x for intra-species variations).  The
results of the 1-year dog toxicity study were also the basis for the
determination of the short-, intermediate-, and long-term inhalation
endpoint. An inhalation-absorption default factor of 100% was used for
risk assessment purposes, since the endpoint was derived from an oral
study.  The 21-day rat dermal toxicity study was used to select short-,
intermediate- and long-term dermal endpoints; clinical signs included
staggered gait and exaggerated hindlimb flexion.

The FQPA requires the Agency to consider potential special sensitivity
to infants and children from exposure to bifenthrin.  The HED FQPA
Safety Factor Committee (SFC) met on July 15 and 22, 2002 to evaluate
the hazard and exposure data for bifenthrin with regard to making a
decision on the additional safety factor for the protection of infants
and children.  Acceptable developmental studies in the rat and rabbit
revealed no increased susceptibility of rat or rabbit fetuses following
in utero exposure to bifenthrin.  In addition, there was no evidence of
increased susceptibility of young rats in the reproduction study with
bifenthrin.  Since the last HIARC meeting, a developmental toxicity
study in rats has been submitted.  There was no evidence of increased
susceptibility of offspring in the DNT study in rats conducted with
bifenthrin.

The 1x FQPA safety factor has been applied to all dietary and
residential non-dietary exposure scenarios.  The acute and chronic RfD
modified by the FQPA Safety Factor is referred to as a
population-adjusted dose (PAD).  Therefore, the acute PAD (aPAD) for
bifenthrin is 0.33 mg/kg/day, and the chronic PAD (cPAD) for bifenthrin
is 0.013 mg/kg/day.

The FQPA Committee noted that there were no residual uncertainties in
the exposure databases.  The dietary food exposure assessment was
refined using percent crop treated (CT) information, and anticipated
residue (AR) values calculated from the available monitoring data and
field trial results.  Dietary drinking water exposure is based on
conservative modeling estimates, and the HED residential standard
operating procedures (SOPs), in conjunction with some chemical specific
data, were used to assess residential handler and post-application
exposure to adults and children.  These assessments will not
underestimate the exposure and risks posed by bifenthrin.

Dietary Exposure Assessment

 (DEEM-FCID™, Version 2.03) which uses food consumption data from the
U.S. Department of Agriculture’s (USDA) Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998.    SEQ CHAPTER
\h \r 1

Acute Dietary Exposure and Risk

A Tier 3, acute probabilistic dietary exposure and risk assessment was
conducted for all registered (and pending) food uses and drinking water.
 Anticipated residues (ARs) were developed based on the latest U.S.
Department of Agriculture’s Pesticide Data Program (PDP) monitoring
data 1998-2005, Food and Drug Administration (FDA) data, or field trial
data for bifenthrin.  Anticipated residues were further refined using
the latest percent crop treated (%CT) data and processing factors where
appropriate.

EFED calculated the ground and surface drinking water Tier 1 estimated
drinking water concentrations (EDWCs) for bifenthrin using the screening
concentration in ground water (SCI-GROW) and FQPA Index Reservoir
Screening Tool (FIRST) models.  EDWCs in ground water were estimated as
0.003 ppb and 0.014 ppb in surface water.  The acute drinking water
concentration of bifenthrin in surface water (0.014 ppb) is based on the
application of bifenthrin to lettuce at the highest application rate
(0.5 lb ai/A/season).

The acute dietary exposure estimates for food and drinking water are
below HED’s level of concern (<100% aPAD) at the 99.9th percentile of
exposure.  Bifenthrin dietary exposure at the 99.9th percentile for food
and drinking water for the U.S. population is 10% of the aPAD and 25% of
the aPAD for all infants, the most highly exposed population subgroup.
These estimates include drinking water.

Chronic Dietary Exposure and Risk

An   SEQ CHAPTER \h \r 1 chronic population-adjusted-dose (cPAD) is
established based upon the one-year oral toxicity study in dogs.  In
this study, the lowest observed adverse-effect level (LOAEL) of 2.7 mg
/kg/day is based on observations of increased incidence of tremors in
both sexes.  A UF of 100x was used to calculate the cPAD.

A refined chronic dietary exposure assessment was also conducted for the
supported food uses of bifenthrin and drinking water using single point
estimates of anticipated bifenthrin residues for food and drinking
water.  The estimated surface water concentration of 0.014 ppb, based on
application to lettuce at the highest application rate, was also used
for the chronic dietary assessment.

The chronic dietary exposure estimates for food and drinking water are
below HED’s level of concern (<100% cPAD) for the U.S. population and
all population subgroups.  Bifenthrin dietary exposure for food and
drinking water is 20% of the cPAD for the U.S. population and 53% of the
cPAD for children 3-5 years old, the most highly exposed population
subgroup.

Cancer Dietary Risk

The CARC (1992) recommended that for the purpose of risk
characterization, the RfD approach should be used for quantification of
human risk.  The chronic exposure analysis exhibited exposures that were
less than 100% RfD, and it is assumed that the chronic dietary endpoint
is protective for cancer dietary exposure.

Residential Exposure and Risk

Bifenthrin has both indoor and outdoor residential uses.  Adults are
potentially exposed to bifenthrin residues during residential
application of bifenthrin.  Adults and children are potentially exposed
to bifenthrin residues after application (post-application) of
bifenthrin products in residential settings.  Risk estimates were
generated for residential handler exposures, and potential
post-application contact with lawn, soil, and treated indoor surfaces
using HED’s Draft SOPs for Residential Exposure Assessment, and
dissipation data from a turf transferable residue (TTR) study.  These
estimates are considered conservative, but appropriate, since the study
data were generated at maximum application rates.

Residential Handler Risk Estimates

Short- to intermediate-term dermal and inhalation exposures may occur
for residential handlers of bifenthrin products.  Residential handler
risks from inhalation exposures to bifenthrin gas/vapor are considered
unlikely, since the vapor pressure of bifenthrin is low. Inhalation
exposure was assessed for aerosols/particulates during residential
mixing, loading, and application of granular products.  Short- and
intermediate-term handler MOEs estimated for combined dermal and
inhalation exposures were > 100, and therefore, are not of concern to
HED.

Residential Post-Application Risk Estimates

Adults and children may be potentially exposed to bifenthrin residues
after application of bifenthrin products in residential settings.
Short- and intermediate-term post-application dermal exposures for
adults, and short- and intermediate-term post-application dermal and
incidental oral exposures for children are anticipated.  Risk estimates
were generated for potential contact with lawn, soil, and treated indoor
surfaces. Short- and intermediate-term risks estimated for
post-application exposure for adults and children are not of concern to
HED.  Combined oral and dermal short-term exposures  for children are
not of concern to HED.  Combined adult handler and post-application risk
estimates (inhalation and dermal) associated with homeowner applied
formulations are not of concern to HED.

Aggregate Risk

≤100).  Chronic (>6 months) non-dietary post-application exposure to
bifenthrin as a residential treatment is considered unlikely; therefore,
chronic aggregate risk assessments were not performed.

Occupational Handler Risk

Based upon the proposed use pattern, HED expects the most highly exposed
occupational pesticide handlers (mixers, loaders, applicators) to be 1)
mixer/loader using open pour loading of liquids; 2) mixer/loader using
open pour loading of granules; 3) an aerial applicator and 4) an
applicator using open-cab, ground-boom spray equipment.  Estimates for
short- and intermediate-term occupational risks were calculated.
Provided that mixer/loaders wear protective gloves, all MOEs are above
100, and, therefore, are not of concern to HED.

Occupational Post-Application Risk

Based on the proposed use pattern, HED has calculated post-application
exposure and risk for workers exposed to bifenthrin residues following
treatment.  Workers engaging in activities such as hand harvesting,
topping, stripping and irrigation activities were assessed.  Standard
assumptions were incorporated into the assessment to reflect
conservative risk estimates.  The MOE for the theoretically most highly
exposed post-application agricultural activity is 410, and is not of
concern to HED.  All other identified post-application activities are
expected to have lower exposures and greater MOEs.

Based on the acute toxicity category classification for bifenthrin, the
interim worker protection standard (WPS) restricted-entry interval (REI)
of 12 hours is adequate to protect agricultural workers from
post-application exposures.  The proposed end-use product labels list an
REI of 12 hours.

HED Recommendations

The tolerances proposed by the registrants in the current petitions are
listed below, along with HED’s recommended tolerance levels.   SEQ
CHAPTER \h \r 1

Provided revised Sections B and F are submitted, the residue chemistry
and toxicology databases support conditional registration and permanent
tolerances for the following:

Tolerance Summary for Bifenthrin.

Proposed	Recommended

Commodity Definition	Tolerance (ppm)	Commodity Definition	Tolerance
(ppm)

Mayhaw	1.4	Same	Same

Vegetable, root, except sugar beet and garden beet, subgroup 1B	0.07
Same	0.10

beet, garden, root	0.45	Same	Same

beet, garden, top	15	Same	Same

Radish, top	4.5	Same	Same

Soybean	0.2	Same	Same

Soybean, hulls	0.7	Same	0.50

Soybean, refined oil	0.4	Same	0.30

Vegetable, fruiting, group 8	0.5	Delete request for fruiting vegetables

Groundcherry	0.5

Pepino	0.5

Peanut	0.05	Same	Same

Pistachio	0.05	Same	Same

None	None	Aspirated Grain Fractions 	70

The registration may be made permanent once additional data concerning
aspirated grain fractions are submitted.  Revised Sections F with the
correct tolerance levels and commodity definitions should be submitted
where appropriate.

2.0	Ingredient Profile

Summary of Proposed Uses

The petitioner has proposed the use of Brigade WSB, Capture 2EC, and/or
Capture 1.15G (EPA Reg. Nos.  279-3069, 279-3244, and 279-3108,
respectively) for use on mayhaw, root vegetables, (except sugar beets,
crop subgroup 1B), peanut, pistachio, soybean, and fruiting vegetables
(crop group 8).  Table 2.1 is a summary of the proposed application
scenarios.

The submitted labels adequately describe the proposed application
scenarios.  As the petitioner has not requested the establishment of
tolerances for residues in/on peanut hay, the following restriction must
be added to the label:  Do not feed green immature plants and peanut hay
to livestock.  Based on the current rotational crop data, HED concludes
that a 30-day rotational crop restriction is appropriate for all
non-labeled crops (labeled crops may be planted at anytime; see section
OPPTS 860.1850).  A revised Section B is requested.

Table 2.1.  Proposed Application Scenarios.

Formulation

Crop

App. Rate

(lb ai/acre)1

PHI2 (days)

Comments3

Brigade WSB

Capture 2EC	Mayhaw	0.08 to 0.10 	30	Apply in at least 28 gallons per
acre.  Apply no more than once every 7 days.  Do not apply more than 0.2
lb ai/A per season.

Brigade WSB

Capture 2EC

Capture 1.15G	Root Crops (edible burdock, carrot, celeriac, chevil,
chicory, ginseng, horseradish, parsley, parsnip, radish, oriental
radish, rutabaga, salsify, black salsify, Spanish salsify, skirret,
turnip)	0.08 to 0.10

(0.006 lb ai per 1000 linear ft)3	21	Apply in at least 25 gallons per
acre.  Apply no more than once every 7 days.  Do not apply more than 0.5
lb ai/A per season (including soil application).  (Make one in-furrow
application of Capture 1.15G at planting.)

Brigade WSB

Capture 2EC

Capture 1.15G	Garden beet	0.08 to 0.10

(0.006 lb ai per 1000 linear ft)	1	Apply in at least 25 gallons per
acre.  Apply no more than once every 7 days.  Do not apply more than 0.4
lb ai/A per season (including soil application).  (Make one in-furrow
application of Capture 1.15G at planting.)

Brigade WSB

Capture 2EC	Peanut	0.033 to 0.10	14	Apply in at least 10 gallons per
acre.  Apply no more than once every 14 days.  Do not apply more than
0.5 lb ai/A per season.

Brigade WSB

Capture 2EC	Pistachio	0.05 to 0.20	21	Apply in at least 50 gallons per
acre by ground and at least 10 gallons per acre by air.  Apply no more
than once every 15 days.  Do not apply more than 0.2 lb ai/A per
application and do not exceed 0.50 lb ai/A per season.

Brigade WSB

Capture 2EC	Soybean	0.033 to 0.10	18	Apply in at least 10 gallons per
acre.  Apply no more than once every 30 days.  Do not apply more than
0.3 lb ai/A per season.

Brigade WSB

Capture 2EC

Capture 1.15G	Eggplant, bell and non-bell pepper, groundcherry, pepino
0.033 to 0.08

(0.04 to 0.10)	7	Apply in at least 2 gallons per acre by air or 10
gallons per acre by ground.  Apply no more than once every 7 days.  Do
not apply more than 0.2 lb ai/A per season. (Make application of Capture
1.15G as soon as pest are present.)

Brigade WSB

Capture 2EC

Capture 1.15G	Tomato, tomatillo	0.033 to 0.08

(0.04 to 0.10)	1	Apply in at least 15 gallons per acre.  Apply no more
than once every 10 days.  A maximum of 4 applications may be applied per
season.  (Make application of Capture 1.15G as soon as pest are
present.)

1  The rates list in parentheses are for Capture 1.156 G; ai = active
ingredient.

2  PHI = pre-harvest interval.

3  The comments in parentheses and application rates are specific to
Capture 1.15 G.

2.2	Structure and Nomenclature

Table 2.2.  Nomenclature of Bifenthrin.

Compound

Common name	Bifenthrin

Company experimental names	Capture® Insecticide/Miticide

IUPAC name	2-methylbiphenyl-3-ylmethyl
(1RS,3RS)-3-[(Z)-2-chloro-3,3,3-trifluoroprop-1-enyl]-2,2-dimethylcyclop
ropanecarboxylate

or

-methyl[1,1′-biphenyl]-3-yl)methyl
(1R,3R)-rel-3-[(1Z)-2-chloro-3,3,3-trifluoro-1-propenyl]-2,2-dimethylcyc
lopropanecarboxylate

CAS #	82657-04-03

End-use products/EPs	2.0 lb ai/gal emulsifiable concentrate formulation
(Capture 2EC; EPA Reg. No. 279-3069)

1.15% granular formulation (Capture 1.15G; EPA Reg. No. 279-3244)

10% wettable-powder formulation  (Brigade WSB, EPA Reg. No. 279-3108)

2.3	Physical and Chemical Properties

Table 2.3.  Physicochemical Properties of the Technical Grade
Bifenthrin.

Parameter	Value	Reference

Melting range	68-70.6°C	Product Chemistry Chapter of the TRED

<0.1 μg/L

	Solvent solubility (g/100 mL)	8.9 in heptane and methanol

125 in acetone, chloroform, ether, methylene chloride, and toluene

	Vapor pressure (Pa) at 25°C	2.41 x 10-5

	Dissociation constant (pKa)	Not applicable

	Octanol/water partition coefficient (Kow)	>1 x 10 6

	UV/visible absorption spectrum	NA

	1 NA = information not available.

Hazard Characterization/Assessment

References:

BIFENTHRIN - 3rd Report of the Hazard Identification Assessment Review
Committee. TXR No. 0051570. B. Tarplee. 2/19/2003.

Revised Preliminary HED Chapter for the Bifenthrin Tolerance
Reassessment Eligibility Decision (TRED). PC Code: 128825 DP Barcode:
D283796. J. Liccione. 12/04/2002.

Bifenthrin is a non-systemic insecticide/miticide in the class of
synthetic pyrethroids.  It is registered for use on a variety of crops
for the control of insect pests.

Bifenthrin is classified as Category II for acute oral toxicity, and
Category III for acute dermal toxicity.  There are no acute inhalation
studies on bifenthrin technical.  It is not an eye or skin irritant, or
a dermal sensitizer.

Bifenthrin produces characteristic pyrethroid neurotoxicity.  Tremors
have been observed in developmental toxicity studies in the rat and
rabbit, a 2-generation rat reproduction study, subchronic toxicity
studies in the rat and dog, acute and subchronic neurotoxicity rat
studies, a 21-day dermal rat study, chronic oral studies in the rat and
dog, and oncogenicity rat and mouse studies.  FOB findings were observed
in the acute and subchronic neurotoxicity studies in the rat.

There is no evidence of increased susceptibility of rats or rabbits to
in utero and/or post-natal exposure to bifenthrin.  A DNT study on
bifenthrin was conducted in rats. In this study maternal and offspring
toxicity was observed at the same dose levels.  The maternal toxicity
was primarily manifested as tremors, clonic convulsions, and increased
grooming counts.  The offspring toxicity was manifested as increased
grooming counts.   This study does not show any evidence of increased
susceptibility of offspring following exposure to bifenthrin.

Bifenthrin was negative in most tests for mutagenicity.  It was
marginally mutagenic with and without S9 activation in the mouse
lymphoma forward gene mutation assay.  This finding has not been
confirmed in a repeat test.  There is also inconclusive, but presumptive
evidence that bifenthrin was mutagenic in the S9-activated phase of the
CHO gene mutation assay (unacceptable study).

The CPRC (1992) has characterized bifenthrin as Category C (possible
human carcinogen) and recommended that for the purpose of risk
characterization, the RfD approach should be used for quantification of
human cancer risk.  This decision was based in part on the statistically
significant increased trend for hemangiopericytomas in the urinary
bladders’ of Swiss Webster mice.  The incidence of these lesions was
double at the highest dose tested (HDT; 600 ppm) as compared to
controls.  The male mice also had significant dose-related trends with
respect to hepatocellular carcinomas and combined hepatocellular
adenomas and carcinomas, and increased incidences of bronchioalveolar
adenomas and adenocarcinomas of the lung in females at 50, 200 and 600
ppm (but not 500 ppm) relative to their controls.  No compound related
tumors were noted in rats.  The mutagenicity evidence presents low
concern for bifenthrin.

3.1	 	Hazard and Dose-Response Characterization

The acute toxicity profile for bifenthrin is presented below in Table
3.1.  The full toxicological profile is presented in Attachment 1 to
this memo.  A summary of the toxicology of bifenthrin is discussed
below.

Subchronic Toxicity

	The database for subchronic toxicity is considered complete.  The
available subchronic oral toxicity studies in rats and dogs demonstrated
the neurotoxicity of bifenthrin.  Tremors were observed in rats fed
doses equal to or greater than 100 ppm (7.5 mg/kg/day for males; 8.5
mg/kg/day for females) bifenthrin for 90 days.  Male and female dogs
were administered (via gelatin capsule) bifenthrin at doses equal to or
greater than 4.42 mg/kg/day for up to 13 weeks exhibited tremors. Ataxia
was noted in male dogs at 8.84 and 17.7 mg/kg/day, and in female dogs at
4.42 mg/kg/day.  Languidness occurred primarily at 17.7 mg/kg/day in
both sexes, but also occasionally at 8.84 mg/kg/day.  All of these
symptoms occurred more frequently during the last 3 weeks of the study.
Other dose-related clinical signs included blinking, mydriasis,
nystagmus, lacrimation, and polypnea (increased rate of respiration) in
the two highest dose groups.  One high-dose female appeared thin and/or
dehydrated during the final weeks of the study.  A non-statistically
significant, but possibly treatment-related, reduction in mean
body-weight gain was noted in females at 17.7 mg /kg/day (0.6 kg)
relative to the controls (1.3 kg).

	Neurotoxicity

	Bifenthrin produces characteristic pyrethroid neurotoxicity.  Tremors
have been observed in developmental toxicity studies in the rat and
rabbit, a 2-generation rat reproduction study, subchronic toxicity
studies in the rat and dog, acute and subchronic neurotoxicity rat
studies, a 21-day dermal rat study, chronic oral studies in the rat and
dog, and oncogenicity rat and mouse studies.  Staggered gait and
exaggerated hindlimb flexion were noted in a 21-day dermal toxicity
study in the rat.  The neurotoxicity of bifenthrin has been supported by
the results of acute and subchronic neurotoxicity studies in the rat.
FOB findings were observed in these neurotoxicity studies.  FOB findings
consisted of tremors, abnormal posture, splayed hindlimbs, staggered
gait, altered activity, altered landing foot-splay, twitching,
uncoordinated movement/ataxia, and convulsions.

	Chronic Toxicity

	The database for chronic toxicity is considered complete.  No
additional data are required at this time. The results of chronic
toxicity studies support the finding of neurotoxicity for bifenthrin.
Tremors were observed in both a 1-year feeding study in the dog (LOAEL =
2.7 mg/kg/day for both sexes; NOAEL = 1.3 mg/kg/day for both sexes), in
a combined chronic toxicity/oncogenicity dietary study in the rat (LOAEL
= 6.1 mg/kg/day for females; NOAEL = 3.0 mg/kg/day for males), and in a
combined chronic toxicity/oncogenicity dietary study in the mouse (LOAEL
= 25.6 mg/kg/day in males; NOAEL = 6.7 mg/kg/day in males).

	Developmental Toxicity

	A complete developmental toxicity database exists for bifenthrin.  The
available data provided no indication of increased susceptibility
(quantitative or qualitative) of rats or rabbits to in utero and/or
post-natal exposure to bifenthrin.  In the prenatal developmental
(gavage) toxicity study in rats, a slight increase in the incidence of
“hydroureter without hydronephrosis” was observed in fetuses at the
highest dose tested (2 mg/kg/day); maternal toxicity (tremors) was also
observed at this dose level, and the maternal and developmental NOAELs
were equivalent at 1 mg/kg/day.  This effect was not observed in the
prenatal developmental (dietary) toxicity study in rats; maternal
toxicity was evident at 15.5 mg/kg/day as tremors and decreased food
consumption, body-weight gains, and adjusted (for gravid uterine weight)
body-weight gains. In the prenatal developmental toxicity study in
rabbits, there was no evidence of developmental toxicity at the highest
dose tested (8 mg/kg/day).  Head and forelimb twitching was observed at
the maternal LOAEL of 4 mg/kg/day; the maternal NOAEL was established at
2.67 mg/kg/day.

A DNT study on bifenthrin was conducted in rats. In this study maternal
and offspring toxicity was observed at the same dose levels.  The
maternal toxicity was primarily manifested as tremors, clonic
convulsions, and increased grooming counts.  The offspring toxicity was
manifested as increased grooming counts.   This study does not show any
evidence of increased susceptibility of offspring following exposure to
bifenthrin.

	Reproductive Toxicity

	Bifenthrin is not a reproductive toxicant and there is no evidence of
increased susceptibility of offspring.  In an acceptable two-generation
reproduction study in rats, no evidence of toxicity was noted in the
offspring at dietary levels up to 100 ppm (5 mg/kg/day).  Parental
toxicity (tremors and decreased body-weights) was observed at 100 ppm (5
mg/kg/day), with a NOAEL of 60 ppm (3.0 mg/kg/day).

	Carcinogenicity

	The CPRC (1992) has characterized bifenthrin as Category C (possible
human carcinogen) and recommended that for the purpose of risk
characterization, the RfD approach should be used for quantification of
human cancer risk.  This decision was based in part on the statistically
significant increased trend for hemangiopericytomas in the urinary
bladders of Swiss Webster mice.  The incidence of these lesions was
double at the highest dose tested (HDT; 600 ppm) as compared to
controls.  The male mice also had significant dose-related trends with
respect to hepatocellular carcinomas and combined hepatocellular
adenomas and carcinomas, and increased incidences of bronchioalveolar
adenomas and adenocarcinomas of the lung in females at 50, 200 and 600
ppm (but not 500 ppm) relative to their controls.  No compound related
tumors were noted in rats.  The mutagenicity evidence presents low
concern for bifenthrin.

	Mutagenicity

	Bifenthrin was negative in most tests for mutagenicity.  It was
marginally mutagenic with and without S9 activation in the mouse
lymphoma forward gene mutation assay.  This finding has not been
confirmed in a repeat test.  There is also inconclusive, but
presumptive, evidence that bifenthrin was mutagenic in the S9-activated
phase of the CHO gene mutation assay; however, this was an unacceptable
study.

	Metabolism

	Bifenthrin is absorbed by the oral route and eliminated primarily in
the feces (about 70% within 48 hours).  Approximately 10% of the
administered doses were excreted in the urine.  Nearly all the
administered dose was eliminated in urine and feces within 7 days
indicating no retention in the body.  Very little of the administered
radioactive dose is expired as 14C-CO2.  The major metabolic route of
radiolabeled bifenthrin is hydrolysis of the ester linkage with
oxidation of the resulting alcohol to the acid.  Protein binding of
radioactive components or metabolites increases with time.

	Dermal Absorption

	Several dermal-absorption studies on bifenthrin are available; each
study is considered acceptable for regulatory purposes when taken in
conjunction with the other studies.  The HIARC recommended a dermal
absorption rate of 25% based on the weight-of the-evidence available for
structurally related pyrethroids.

Table 3.1. Acute Toxicity Profile – Bifenthrin

Guideline No./Study Type

MRID No.

 (♂); 53.8 mg/kg (♀) 	II

870.1200/Acute dermal toxicity	00132520	LD50 > 2,000 mg/kg 	III

870.1300/Acute inhalation toxicity	46029703	Data waived. Acceptable
atmosphere could not be generated with product.	IV

870.2400/Primary eye irritation	00132522	Non-irritant	IV

870.2500/Primary dermal irritation	00132521	Non-irritant	IV

870.2600/Dermal sensitization	00132523	Not a sensitizer	N/A

3.2		FQPA Considerations

3.2.1	 	Adequacy of the Toxicity Database

The HIARC concluded that the toxicology database for bifenthrin is
complete.

3.2.2		Evidence of Neurotoxicity

The HIARC concluded that there is a concern for neurotoxicity resulting
from exposure to bifenthrin.  This is based on the observation of
neurotoxicity (clinical signs) in the acute neurotoxicity, subchronic
neurotoxicity, 2-generation reproduction, developmental toxicity, dermal
toxicity, subchronic toxicity and chronic toxicity studies.   In
addition, FOB findings were observed in the acute and subchronic
neurotoxicity studies.

<IP_ADDRESS>        Acute Neurotoxicity Study

In an acute oral neurotoxicity study (MRID 44862102), bifenthrin (FMC
54800 technical, 93.7% ai; FMC Ref. No. PL97-592) was administered by a
single gavage dose to 10 Sprague-Dawley rats/sex/dose at doses of 0, 10,
35 or 75 mg/kg, or 0, 9.4, 32.8, or 70.3 mg/kg/day (2 control males and
2 control females were removed from the study due to an unspecified
dosing error, leaving 8/sex).  The FOB assessment and motor activity
testing were performed during the pretest interval, and on days 0, 7 and
14.  Five animals/sex/group were perfused in situ for neurohistological
examination at day 14 and brain, central and peripheral nervous system
tissues from control and high dose animals were examined
microscopically.

At 75 mg/kg, two females died on day 0, shortly after dosing.  The
following clinical signs were observed in males after dosing (#
incidences):  decreased feces (1 vs. 0 control); staggered gait (1 vs. 0
control); tremors (1 vs. 0 control); and twitching (3 vs. 0 control).
Females displayed the following clinical signs following dosing (#
incidences):  abdominogenital staining (2 /2 died vs. 0 control); clonic
convulsions (1 treated/died vs. 0 control); chromorhinorrhea (2 /2 died
vs. 0 control); and tremors (3 [2 died] vs. 0 control).  All clinical
signs of toxicity were resolved in survivors by study day 2.

The following FOB home cage observations were noted on day 0 at 6-8 hrs
postdosing:  whole body tremors (1 male, 1 female/died vs. 0 control);
abnormal mobile posture (1 male vs. 1 control); uncoordinated
movement/ataxia (1 male vs. 0 control); splayed hindlimbs (1 male vs. 0
control); convulsions (2 females/2 died vs. 0 control); tense/rigid
during handling (1 male, 4 females/2 died vs. 0 controls); and unusual
posture (immobile; 1 female/died vs. 0 control).  Day 0 FOB open field
observations included the following:  localized spasms/twitching (2
males vs. 0 control); whole body tremors (2 males, 2 females/ 1 died
treated vs. 0 control); staggered gait (1 male vs. 0 control); abnormal
posture (mobile; 1 male vs. 0 control); uncoordinated movement/ataxia (1
male vs. 0 control); splayed hindlimbs (1 male vs. 0 control); increased
activity (1 female vs. 0 control); decreased activity (1 female/died vs.
0 control); convulsions (2 females/1 died vs. 0 control); walking on
toes (1 female vs. 0 controls); and unusual immobile posture (1
female/died vs. 0 control).  Landing foot-splay values were decreased in
males during the day 0 FOB (↓15%, p≤0.05).  No treatment-related
differences from controls were observed in the FOB assessment in
survivors on study days 7 and 14.  Mean motor activity was decreased in
males on day 0 (↓36%, not statistically significant), while motor
activity in the females was increased on days 0 and 14 (↑23% and
↑18%, respectively; not statistically significant), although the day
14 increase was not considered biologically significant.  No
treatment-related differences were observed in body-weights, body-weight
gains, gross observations or neuropathological examinations in any
treated group (the latter only examined in control and high dose
groups).  No treatment-related findings were observed at 10 or 35 mg/kg.

The LOAEL for this study is 75 mg/kg (70.3 mg/kg/day) based on mortality
(females only), clinical and FOB findings and differences in motor
activity.  The NOAEL for this study is 35 mg/kg (32.8 mg/kg/day).

<IP_ADDRESS>		Subchronic Neurotoxicity Study

In this subchronic oral neurotoxicity study (MRID 44862103), FMC 54800
technical (Bifenthrin, 93.7% ai, batch PL97-592) was administered
continuously in the diet for 13 weeks to 10 Sprague-Dawley rats/sex/dose
at doses of 50, 100 or 200 ppm (equivalent to [M/F] 0/0, 2.9/3.7,
6.0/7.2 or 11.8/14.6 mg/kg).

At 100 ppm, tremors were observed during clinical examinations in 8 (28
incidences) males and 10 (119 incidences) females.  Twitching was
observed in 4 (4 incidences) males and 2 (5 incidences) females.  During
the open field portion of the FOB, tremors were observed in all females
following 4 weeks of treatment.  In addition, females displayed
decreased (p≤0.05) hindlimb grip strength during weeks 8 and 13
(↓22-25%).  One female died on day 52 as a result of kidney
inflammation; however, this death was not considered treatment related.

layed decreased (p≤0.05 or 0.01) forelimb grip strength (↓20-31%)
and hindlimb grip strength (↓18-36%), and increased landing foot-splay
values (↑21-28%) during weeks 4, 8 and 13.  In addition, decreased
forelimb grip strength was observed in males at week 4 (↓27%, not
statistically significant), but not at later times.

No treatment-related differences were observed at any dose level in
body-weights, body-weight gains, food consumption, home cage FOB
examination, motor activity measurements, or gross or neuropathological
examinations.

The LOAEL for this study is 100 ppm (equivalent to 6.0 mg/kg/day in
males and 7.2 mg/kg/day in females) based on neuromuscular findings
(tremors, changes in grip strength and landing foot-splay).   The NOAEL
is 50 ppm (equivalent to 2.9 mg/kg/day in males and 3.7 mg/kg/day in
females).

3.2.3		Developmental Toxicity Studies

<IP_ADDRESS>		Rat

Developmental Rat Studies

In a pilot developmental study (MRID 00154482), bifenthrin (88.35% ai)
in corn oil was administered via gavage to mated female Sprague-Dawley
rats (10/sex/dose) at dose levels of 0, 0.5, 1.0, 2.0, or 2.5 mg/kg/day
FMC 54800 during days 6-15 of gestation.  These doses are equivalent to
0, 0.44, 0.88, 1.77, and 2.2 mg/kg/day.  Three of 10 rats at 2.5
mg/kg/day died on days 14-15.  Tremors were noted in all 10 rats at 2.5
mg/kg/day (days 6-15) and in 9/10 at 2.0 mg/kg/day (days 7 through 18).
Two of the rats administered 2.5 mg/kg/day also exhibited clonic
convulsions.  Mean body-weight gains were depressed at 2.5 mg/kg/day
throughout the study, and food consumption was lower (↓20%) at this
dose level during days 6-13.  There were no differences in mean
body-weight gains or food consumption in the lower dose groups with
respect to the controls. There were no treatment-related differences
from controls in the number of implantations or litter size.  The mean
number of resorptions was similar in the lower dose groups; at 2.5
mg/kg/day it was somewhat higher, but this was attributable to an
excessive number of resorptions in a single rat.

The maternal LOAEL is 1.77 mg/kg/day (2.0 mg/kg/day) based on sporadic
tremors (gestation days 7-18) and 30% mortality at 2.2 mg/kg/day (2.5
mg/kg/day).  The maternal NOAEL is 0.88 mg/kg/day (1.0 mg/kg/day).  The
developmental LOAEL and NOAEL were not determined; fetuses were not
examined.

In a second developmental study in rats (MRID 00141201), bifenthrin
(88.35% ai) (as FMC 54800 technical) in corn oil was administered via
gavage to pregnant female Sprague-Dawley rats (25/dose) at dose levels
of 0, 0.5, 1.0, or 2.0 mg/kg/day, which is equivalent to 0, 0.44, 0.88,
and 1.77 mg/kg/day, or with 250 mg/kg/day aspirin (positive control) in
2% carboxymethylcellulose during days 6-15 of gestation.

Maternal toxicity was characterized as tremors in 18/25 dams at 1.77
mg/kg/day (2.0 mg/kg/day) during days 10-19.  There were no deaths
during the study, and no significant differences between groups or
dose-related trends with respect to mean maternal body-weight gains or
food consumption were noted.

The maternal LOAEL is 1.77 mg/kg/day (2.0 mg/kg/day) based on the
incidence of tremors.  The maternal NOAEL is 0.88 mg/kg/day (1.0
mg/kg/day).

Slight developmental toxicity was noted at 1.77 mg/kg/day (2.0
mg/kg/day) and was characterized as an increased fetal and litter
incidence of “hydroureter without hydronephrosis.” Although not
statistically significant, the incidence of hydroureter was double that
of the vehicle control and the lower dose groups (3.55% versus 0% in
controls and low dose groups).  Also, 5 fetuses from dams at 1.77
mg/kg/day (2.0 mg/kg/day) (from five different litters) had
“hydroureter without hydronephrosis,” a finding that was not present
in controls or any of the other exposure groups.  There were no other
treatment-related malformations or variations noted at any dose level.
There were no group differences or dose-related trends with respect to
pregnancy rates, numbers of corpora lutea, implantation sites and
resorptions, litter sizes, sex ratios, fetal body-weights, or viability.
 The positive control gave the appropriate responses of increased early
resorptions, depressed fetal body-weights, external, visceral, and
skeletal malformations and variations.

The developmental LOAEL is 1.77 mg/kg/day (2.0 mg/kg/day) based on the
increased fetal and litter incidence of hydroureter without
hydronephrosis.  The developmental NOAEL is 0.88 mg/kg/day (1.0
mg/kg/day).

This developmental toxicity study in the rat is classified as
acceptable-guideline and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700) in the rat.

Comments: The original DER presented fetal incidence data for
hydroureter (with hydronephrosis and without hydronephrosis separated).
Litter incidence data were not provided.  The reviewer notes that litter
incidence of “hydroureter without hydronephrosis” is 0/23, 0/24,
0/25, and 5/23; the litter incidence of “hydroureter with
hydronephrosis” is 3/23, 2/24, 2/24 and 2/23.  The original DER
concluded based on fetal incidence data, “the increased incidence of
hydroureter without associated hydronephrosis is equivocal, but without
further information it is being interpreted as indicating a slight
fetotoxic effect at 2 mg/kg/day.”  The reviewer notes that the litter
incidence of hydroureter without hydronephrosis was also slightly
increased.  A pilot rat developmental study (MRID 00154482) did not
include gross necropsies, soft tissue or skeletal examination on
fetuses.  Hydroureter was not reported in the rabbit developmental
study, or in the prenatal developmental toxicity (dietary) study in rats
(MRID 45352301).  No historical control data were presented.

In another developmental toxicity study (MRID 45352301), bifenthrin
(95.3% ai; Lot/Batch #PL99-0108) was administered orally in the diet to
25 female Sprague-Dawley CD rats/group at dose levels of 0, 30, 60, 90,
or 200 ppm (equivalent to 0, 2.5, 5.0, 7.4, and 16.3 mg/kg/day or 0,
2.4, 4.8, 7.1 or 15.5 mg/kg/day when adjusted for purity) on gestation
days (GD) 6 through 20.  All dams were sacrificed on GD 20 and their
fetuses were removed by cesarean and examined.

No animals died during the study.  When compared to concurrent controls,
no treatment-related changes were observed in gross pathology, the
number of corpora lutea, number of implantations, number of live and
dead fetuses, number of resorptions, fetal weights, sex ratios, or
post-implantation losses.

animal.  A negative trend (p≤0.05) in body-weight gains was observed
during GDs 6-9, 15-18, and 18-20 with a decrease of 44, 17, and 14%,
respectively, at 200 ppm relative to controls.  In addition, a negative
trend (p≤0.001) was observed in adjusted (for gravid uterine weight)
body-weight gain with a 22% decrease at 200 ppm when compared to
controls.  Food consumption was decreased at 200 ppm at the beginning
(GD 6-9) and end (GD 18-20) of treatment (↓11-12%, relative to
controls).  In addition, a negative trend (p≤0.05) was observed during
GDs 6-9, 9-12, 18-20, and for the overall treatment interval (GD 6-20).

Dose-dependent (p≤0.05 for negative trend) decreases in food
consumption were observed; however, the decreases that were noted at
doses below 200 ppm did not result in decreased body-weight gains and
were considered not to be toxicologically important.

The maternal LOAEL is 200 ppm (equivalent to 16.3 mg/kg/day or 15.5
mg/kg/day) based on clinical signs and decreased food consumption,
body-weight gains, and adjusted (for gravid uterine weight) body-weight
gains.  The maternal NOAEL is 90 ppm (equivalent to 7.4 mg/kg/day or 7.1
mg/kg/day).

No treatment-related developmental findings were noted at any dose
tested.

The developmental toxicity LOAEL was not observed.  The developmental
toxicity NOAEL is 200 ppm.

<IP_ADDRESS>		Rabbit

Developmental Rabbit Study

In a developmental study (MRID 00145997), bifenthrin (88.35% ai) in corn
oil was administered via gavage to pregnant female New Zealand White
rabbits (20/dose) at dose levels of 0, 2.67, 4.0, or 8.0 mg/kg/day FMC
54800 technical (equivalent to 0, 2.36, 3.5, and 7.1 mg/kg/day) or with
3.0 g/kg/day 6-aminonicotinamide (positive control) in 2%
carboxymethylcellulose via IP injection during days 7-19 of gestation.
Maternal toxicity was characterized at 7.1 mg/kg/day (8.0 mg/kg/day) as
tremors in 17/20 rabbits (observed during days 12-23) and twitching of
the head and forelimb in 14/20 rabbits (observed during days 13-20).  In
addition, one rabbit in the 7.1 mg/kg/day group displayed clonic
convulsions and loss of muscle control during days 17 and 18.  At 3.5
mg/kg/day (4.0 mg/kg/day) head and forelimb twitching was noted in 4/20
rabbits (observed during days 8-16).  There were no treatment-related
deaths in the does; however, 10 rabbits died during the study and 9 of
these deaths (including 3 vehicle control animals) were attributed to
Pasteurella multocida.  There were no apparent treatment-related
differences in mean body-weight gains in the does or pregnancy rates;
data excluded those with infection.  There were no gross or microscopic
findings attributable to exposure to the test material.

The maternal LOAEL is 3.5 mg/kg/day (4.0 mg/kg/day) based on the
treatment-related incidence of head and forelimb twitching.  The
maternal NOAEL is 2.36 mg/kg/day (2.67 mg/kg/day).  There was no
developmental toxicity demonstrated at any dose level.

There were no treatment-related effects on the number of live fetuses,
fetal weights, implantations, resorptions, external, visceral or
skeletal malformations and variations.  The positive control gave the
appropriate responses of increased early resorptions, reduced number of
live fetuses, increased external, visceral, and skeletal malformations
and variations.

A developmental LOAEL was not observed.  The developmental NOAEL is
≥7.1 mg/kg/day (8.0 mg/kg/day).

<IP_ADDRESS>		Developmental Neurotoxicity Study (Rat)

In a DNT study (MRID 46750501) Bifenthrin (94.8% ai, lot PL02-0477) was
administered in the diet to 25 female Crl:CD®(SD) rats per dose at dose
levels of 0, 50, 100 and 125 ppm (0, 3.6, 7.2 and 9.0 mg/kg/day,
respectively, during gestation; 0, 8.3, 16.2 and 20.7 mg/kg/day,
respectively, during lactation) from gestation day (GD) 6 through
lactation day (LD) 21.  Dietary concentrations were selected on the
basis of a range-finding study (MRID 46750502).  A FOB was performed on
all dams on GDs 10 and 15 and on LDs 10 and 21.  On post-natal day (PND)
4, litters were culled to yield four males and four females (as closely
as possible).  Offspring were allocated for detailed clinical
observations (FOB) and assessment of motor activity, auditory startle
reflex habituation, learning and memory (water maze testing) and
neuropathology at termination (PND 72).  On PND 21, the whole brain was
collected from 10 pups/sex/group for micropathologic examination and
morphometric analysis.  Pup physical development was evaluated by
body-weight.  The age of sexual maturation (vaginal opening in females
and preputial separation in males) was assessed.

No dams died during the study.  Maternal body-weight, body-weight gain
and food consumption were unaffected by treatment.  Tremors were
observed during the daily examinations in 8/23 females at 100 ppm
beginning on LD 14 and in 23/25 females in the 125 ppm group beginning
on LD 4.  In the 100 ppm group, the tremors were graded as slight and
resolved in 4/8 females after one occurrence; slight tremors were
observed in the remaining 4/8 females 3-7 times. In the 125 ppm group,
the tremors were graded slight to moderate and continued on multiple
occasions (2-18 consecutive days) during lactation.  Piloerection was
observed once or twice in 6/25 females at 125 ppm, primarily during LDs
14-17.  During the FOB, the mean number of grooming counts was
significantly increased in females at 100 and 125 ppm during gestation
and lactation.  At 125 ppm, slight piloerection was observed in 4/25
females on GD 15 and in 1/25 or

2/25 females on LDs 10 and 21.  Clonic convulsions (limb tremors) and
tremors were noted in 2/25 and 7/25 females, respectively, in the 125
ppm group on LD 10. On LD 21, the number of females with these findings
was 10/25 and 13/25, respectively.  Clonic convulsions (limb tremors)
and tremors were noted in 2/23 and 3/23 females in the 100 ppm group,
respectively, on LD 21.  Reproductive performance was unaffected by
treatment.

The maternal LOAEL for bifenthrin in rats was 100 ppm (7.2 mg/kg/day
during gestation and 16.2 mg/kg/day during lactation) based on clinical
signs of neurotoxicity (tremors, clonic convulsions, and increased
grooming counts).  The maternal NOAEL is 50 ppm (3.6 mg/kg/day during
gestation and 8.3 mg/kg/day during lactation).

The mean number of delivered pups per dam, percentage of liveborn and
stillborn pups and sex ratio on the day of birth were not affected by
treatment.  There was no treatment-related effect on offspring
body-weight or body-weight gain. The mean day for reaching sexual
maturation (vaginal opening in females and balanopreputial separation in
males) was not affected by treatment. Two of 20 females in the 125 ppm
group had tremors during the detailed physical examinations on PND 28.
During the FOB, an increase in the incidence of tremors and clonic
convulsions (limb tremors) was observed in males at 125 ppm on PND 21. A
significant increase in mean grooming counts was noted in females at 100
and 125 ppm on PND 21.  No treatment-related effects on motor activity,
acoustic startle response, or learning and memory testing were observed.
 Brain weight, length, and width and macroscopic findings were not
affected by treatment.  Historical control data were not provided for
several microscopic findings and are therefore requested.  In brain
morphometry, a slight increase (3.5%) in the height of the hemisphere
(Level 1) that was observed at 125 ppm was not considered
toxicologically significant.

The offspring LOAEL for bifenthrin in rats is 100 ppm (7.2 mg/kg/day
during gestation and 16.2 mg/kg/day during lactation; maternal dose)
based on clinical signs of neurotoxicity (increased grooming counts).
The offspring NOAEL is 50 ppm (3.6 mg/kg/day during gestation and 8.3
mg/kg/day during lactation).  Direct dosing to pups was not performed.

3.2.4		Reproductive Toxicity Study (Rat)

e ovary weights were slightly decreased (↓9%, p<0.05 or ↓12%,
p<0.01) at 60 and 100 ppm, respectively, in the F1 parental generation;
however, ovary-to-body-weight ratios were unaffected.  In the 100 ppm
group F1b female progeny, absolute adrenal and heart weights were
statistically elevated compared to control values.  Significantly
elevated absolute ovary and ovary/brain weights were also observed in
these animals.  There were no treatment-related gross or microscopic
findings in either adults or progeny.  In either the P or F1
generations, there were no treatment-related effects on reproductive
parameters (mating, male fertility, female fertility and gestation
indices), and there were no treatment-related gross or microscopic
findings in either sex.

The parental LOAEL is 100 ppm (5.0 mg/kg/day) based on the incidence of
tremors and marginally lower body-weights in P and F1 generation females
during gestation and lactation. The parental NOAEL is 60 ppm (3.0
mg/kg/day).  A reproductive and offspring LOAEL was not observed.  The
reproductive and offspring NOAEL is 100 ppm (5.0 mg/kg/day).

Comments:  The original DER identified the 60 ppm dose as a LOAEL based
on decreased absolute ovarian weight; however, the DER also indicated
that the decreased F1 absolute ovarian weight is “equivocal as it was
only observed in F1 adult females and not in F1b or F2b weanlings),”
and “when ovary-to-body-weight ratios for F1 females are examined,
none of the FMC 54800 exposed groups are statistically different from
controls for this parameter.”  The reviewer agrees, and notes the lack
of histopathology effects.  The reviewer considers the 60 ppm dose level
as a NOAEL.

	A range-finding study summarized in the DER indicates that excessive
fetotoxicity occurred at 10 mg/kg/day (all pups from 2 of the 4 litters
at 10 mg/kg/day died within 14 days of birth) and body-weight gains were
decreased during lactation at 2.5, 5, and 10 mg/kg/day.

3.2.5 		Additional Information from Literature Sources

None.

3.2.6	 	Pre-and/or Post-natal Toxicity

The HIARC concluded that there is not a concern for pre- and/or
post-natal toxicity resulting from exposure to bifenthrin.

<IP_ADDRESS>		Determination of Susceptibility

Based on the results in a developmental toxicity studies in rats and
rabbits, there is no quantitative or qualitative evidence of increased
susceptibility of rat or rabbit fetuses to in utero exposure to
bifenthrin.  In the prenatal developmental (gavage) toxicity study in
rats, a slight increase in the incidence of “hydroureter without
hydronephrosis” was observed in fetuses at the highest dose tested (2
mg/kg/day); maternal toxicity (tremors) was also observed at this dose
level, and the maternal and developmental NOAELs were equivalent at 1
mg/kg/day.  This effect was not observed in the prenatal developmental
(dietary) toxicity study in rats.  In the prenatal developmental
toxicity study in rabbits, there was no evidence of developmental
toxicity at the highest dose tested.

Based on the results in a 2-generation reproduction study in rats, there
was no quantitative or qualitative evidence of increased susceptibility
of neonates (as compared to adults) to bifenthrin.

Based on the results of the DNT study in rats, there was no quantitative
or qualitative evidence of increased susceptibility of neonates (as
compared to adults) to bifenthrin.  In this study the maternal and
offspring toxicity NOAEL is 50 ppm (3.6 mg/kg/day during gestation and
8.3 mg/kg/day during lactation) based on clinical signs of
neurotoxicity.

<IP_ADDRESS> 		Degree-of-Concern Analysis

There are no concerns or residual uncertainties for pre- and/or
post-natal toxicity following exposure to bifenthrin.

3.2.7		Recommendation for a DNT Study

A DNT study with bifenthrin is available.

3.2.8		FQPA Safety Factor (SF) for Infants and Children

	The bifenthrin risk assessment team recommends that the 10X FQPA SF for
increased susceptibility be reduced to 1X for all exposure scenarios.
This recommendation is based on the following considerations:

The toxicology database is complete.

There are no residual uncertainties concerning pre- and postnatal
toxicity.

The dietary food exposure assessment utilizes field trial data and 100%
crop treated (CT) information for all proposed commodities.  Anticipated
residue values and percent crop treated were used for some commodities.
By using these assumptions, the acute and chronic exposures/risks will
not be underestimated.

The dietary drinking water assessment (Tier 1 estimates) utilizes values
generated by model and associated modeling parameters which are designed
to provide conservative, health protective, high-end estimates of water
concentrations.

The FQPA Safety Factor recommended by the bifenthrin review team assumes
that the exposure databases (dietary food, drinking water, and
residential) are complete and that the risk assessment for each
potential exposure scenario includes all metabolites and/or degradates
of concern and does not underestimate the potential risk for infants and
children.

Based upon the above-described data, no FQPA safety factor is needed
(i.e. 1X) since there are no residual uncertainties for pre and/or
post-natal toxicity.

3.3	 	Hazard Identification and Toxicity Endpoint Selection

The strengths and weaknesses of the bifenthrin toxicology database were
considered during the process of toxicity endpoint and dose selection.
The selected toxicity endpoints are summarized in Table 3.

Table 3.3.  Summary of Toxicological Doses and Endpoints for
Bifenthrin.

Exposure Scenario

Dose Used in Risk Assessment, UF

FQPA SF1 and Level of Concern for Risk Assessment

Study and Toxicological Effects

Acute Dietary-

general population, including infants and children	NOAEL = 32.8 mg/kg

UF = 100

Acute RfD = 0.33 mg/kg/day	FQPA SF = 1X

aPAD = acute RfD

               FQPA SF

= 0.33 mg/kg/day	Acute neurotoxicity study in rats. LOAEL = 70.3
mg/kg/day based on observations of mortality (females only), clinical
and FOB findings and differences in motor activity.

Chronic Dietary-

general population, including infants and children	NOAEL = 1.3 mg/kg/day

UF = 100

Chronic RfD = 0.013 mg/kg/day	FQPA SF = 1X

cPAD = cRfD

               FQPA SF

= 0.013 mg/kg/day	1-year oral toxicity in dogs. LOAEL = 2.7 mg/kg/day
based on observations of increased incidence of tremors in both sexes.

Short-Term

(1-30 days)

Incidental Oral

	NOAEL= 2.21 mg/kg/day

UF = 100

MOE= 100	Residential MOE = 100	90-day oral toxicity study in dogs. LOAEL
= 4.42 mg/kg/day based on observations of increased incidence of tremors
in both sexes.

Intermediate-Term (1-6 months) Incidental Oral 	NOAEL= 2.21 mg/kg/day

UF = 100

MOE= 100	Residential MOE = 100	90-day oral toxicity study in dogs. LOAEL
= 4.42 mg/kg/day based on observations of increased incidence of tremors
in both sexes.

Short-Term

(1-30 days)

Dermal	Dermal NOAEL = 47 mg/kg/day	Residential MOE = 100

Occupational MOE = 100	21-day dermal study in rats.

LOAEL = 93 mg/kg/day based on observations of clinical signs (staggered
gait and exaggerated hindlimb reflex).

Intermediate-Term (1-6 months) Dermal	Dermal NOAEL = 47 mg/kg/day
Residential MOE = 100

Occupational MOE = 100	21-day dermal study in rats.

LOAEL = 93 mg/kg/day based on observations of clinical signs (staggered
gait and exaggerated hindlimb reflex).

Long-Term

(>6 months)

Dermal	Dermal NOAEL = 47 mg/kg/day	Residential MOE = 100

Occupational MOE = 100	21-day dermal study in rats.

LOAEL = 93 mg/kg/day based on observations of clinical signs (staggered
gait and exaggerated hindlimb reflex).

Short-Term

(1-30 days)

Inhalation	NOAEL= 2.21 mg/kg/day

UF = 100

MOE= 100	Residential MOE = 100

Occupational MOE = 100	1-year oral toxicity in dogs. LOAEL = 2.7
mg/kg/day based on observations of increased incidence of tremors in
both sexes.

Intermediate-Term (1-6 months) Inhalation	NOAEL= 2.21 mg/kg/day

UF = 100

MOE= 100	Residential MOE = 100

Occupational MOE = 100	1-year oral toxicity in dogs. LOAEL = 2.7
mg/kg/day based on observations of increased incidence of tremors in
both sexes.

Long-Term

(>6 months)

Inhalation	NOAEL= 2.21 mg/kg/day

UF = 100

MOE= 100	Residential MOE = 100

Occupational MOE = 100	1-year oral toxicity in dogs. LOAEL = 2.7
mg/kg/day based on observations of increased incidence of tremors in
both sexes.

Cancer (oral, dermal, inhalation)	Classification:  Category C (possible
human carcinogen).  No Q1* has been derived. RfD approach recommended
for cancer assessment.

UF = uncertainty factor, FQPA SF = Special FQPA Safety Factor, NOAEL =
no observed adverse effect level, LOAEL = lowest observed adverse effect
level, RfD = reference dose (a = acute, c = chronic), PAD = population
adjusted dose, MOE = margin of exposure, LOC = level of concern, N/A =
Not Applicable.

1Refer to Section 3.4

3.3.1 		Acute Reference Dose (aRfD) - Females age 13-49

HIARC determined that no appropriate acute dietary endpoint was
available to quantify risk to females 13-50 years of age from a
single-dose administration of bifenthrin.

A developmental toxicity study in rats (gavage) with a developmental
NOAEL of 0.88 mg/kg/day (1.0 mg/kg/day) based on the increased fetal and
litter incidence of hydroureter without hydronephrosis seen at the LOAEL
of 1.77 mg/kg/day (2.0 mg/kg/day) was considered as an endpoint for aRfD
for females age 13-49.  However, this evidence was considered as
equivocal since the litter incidence of “hydroureter without
hydronephrosis” is 0/23, 0/24, 0/25, and 5/23; the litter incidence of
“hydroureter with hydronephrosis” is 3/23, 2/24, 2/24 and 2/23.  In
addition, this effect was not observed in a dietary developmental
toxicity study in rats using the same strain of rats.  Therefore, HIARC
concluded that the endpoint (hydroureter/hydronephrosis) is not
appropriate for this risk assessment.

3.3.2		Acute Reference Dose (aRfD) - General Population

Acute dietary endpoints were available to quantify risk to the general
population, including infants and children.  For this scenario, an aRFD
of 0.33 mg/kg/day was determined on the basis of an acute neurotoxicity
study in rats and the application of an UF of 100 (10x for inter-species
extrapolation and 10x for intra-species variation).  The NOAEL in this
study was 32.8 mg/kg/day and the LOAEL was 70.3 mg/kg/day based on
mortality (females), clinical and FOB findings and differences in motor
activity.  Although a lower NOAEL for an effect (i.e., tremors in dams)
associated with a single dose exposure was observed in a developmental
gavage study, the vehicle (corn oil) used in this study enhanced the
toxicity of bifenthrin.  There is evidence that, in the case for
bifenthrin, corn oil can enhance its toxicity.  This evidence is based
on the results of comparative studies of the acute oral LD50 of
bifenthrin following oral gavage as either a corn oil vehicle or as an
undiluted technical material to rats.  These comparative studies
demonstrate increased lethality from bifenthrin exposure in a corn oil
vehicle.  In the acute neurotoxicity study in rats, bifenthrin was
administered undiluted by gavage, making this study more suitable than
the developmental gavage study (with corn oil as vehicle) for risk
assessment purposes.  Clinical signs of neurotoxicity (tremors, clonic
convulsions, and increased grooming counts) were seen in maternal
animals during gestation and lactation and increased grooming counts in
offspring during lactation in the DNT study.  The DNT NOAEL for maternal
and offspring toxicity was NOAEL is 50 ppm (3.6 mg/kg/day during
gestation and 8.3 mg/kg/day during lactation).  Since the clinical signs
were seen during gestations, it was not considered as a single dose
effect. Therefore, the acute neurotoxicity study was selected for the
acute reference dose, and the aRfD is 0.33 mg/kg/day.

3.3.3	 	Chronic Reference Dose (cRfD)

A cRfD of 0.013 mg/kg/day was determined on the basis of the one-year
oral study in dogs and the application of an UF of 100 (10x for
inter-species extrapolation and 10x for intra-species variation).  The
NOAEL in this study was 1.3 mg/kg/day and the LOAEL was 2.7 mg/kg/day
based on observations of increased incidence of tremors in both sexes.

3.3.4	 	Incidental Oral Exposure (Short- and Intermediate-Term)

A NOAEL of 2.21 mg/kg/day was selected from the 90-day oral study in
dogs, and used for short- and intermediate-term incidental oral and
inhalation risk assessments.  This NOAEL was based on observations of
increased incidence of tremors in males and females at the LOAEL of 4.42
mg/kg/day.  The HIARC concluded that the selected dose/endpoint is
appropriate for the population and durations of concern.

3.3.5	 	Dermal Absorption

Several dermal-absorption studies on bifenthrin were available; each
study was considered acceptable for regulatory purposes when taken in
conjunction with the other studies.  The HIARC recommended a
dermal-absorption rate of 25% based on the weight-of-the-evidence
available for structurally related pyrethroids.  However, since a dermal
toxicity study was used for the assessment of short- and
intermediate-term dermal risk, the dermal-absorption factor was not
used.

3.3.6 		Dermal Exposure (Short- and Intermediate-Term)

A NOAEL of 47 mg/kg/day was selected from the 21-day dermal study in
rats.  The LOAEL of 93 mg/kg/day was based on observations of clinical
signs (staggered gait and exaggerated hindlimb flexion).  The HIARC
determined that the dermal toxicity study is appropriate for short-,
intermediate- and long-term dermal exposures and durations because,
besides route specificity, the subchronic and chronic oral toxicity
studies in dogs and rats demonstrate neurotoxicity of similar magnitude.
 Since a dermal toxicity study is selected for dermal risk assessment, a
dermal-absorption factor is not required.

3.3.7 		Inhalation Exposure (Short- and Intermediate-Term)

A NOAEL of 2.21 mg/kg/day was selected from the 90-day oral study in
dogs, and used for short- and intermediate-term inhalation risk
assessments.  This NOAEL was based on observations of increased
incidence of tremors in males and females at the LOAEL of 4.42
mg/kg/day.  The HIARC concluded that the selected dose/endpoint is
appropriate for the population and durations of concern.  An
inhalation-absorption factor of 100% (default value assuming equivalent
inhalation and oral absorption) was used for route-to-route
extrapolation.

The results of the one-year oral dog study were selected for the
long-term inhalation risk assessment.  The NOAEL in this study was 1.3
mg/kg/day and the LOAEL was 2.7 mg/kg/day based on observations of
increased incidence of tremors in both sexes.  An inhalation absorption
factor of 100% (default value assuming equivalent inhalation and oral
absorption) was used for route-to-route extrapolation.

3.3.8	 	Levels of Concern for Margin of Exposure

The target MOEs for occupational and residential exposure risk
assessments are as follows:

Route

	Duration

	Short-Term

(1-30 days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100a	100	100

Inhalation	100	100	100

Residential (Non-Dietary) Exposure

Oral	100	100	100

Dermal	100	100	100

Inhalation	100	100	100

a Based on the conventional UF of 100X (10X for inter-species
extrapolation and 10X for intra-species variation).

Recommendation for Aggregate Exposure Risk Assessments

The toxicity endpoints selected for these routes of exposure may be
aggregated as follows: for short-, intermediate- and long-term aggregate
exposure risk assessments, the oral, dermal and inhalation (oral
equivalent) routes can be combined because of the common toxicity
endpoints (clinical signs of neurotoxicity) via these routes.

Classification of Carcinogenic Potential

The CPRC (1992) has characterized bifenthrin as Category C (possible
human carcinogen) and recommended that for the purpose of risk
characterization, the RfD approach should be used for quantification of
human cancer risk.  This decision was based in part on the statistically
significant increased trend for hemangiopericytomas in the urinary
bladders of Swiss Webster mice.  The incidence of these lesions was
double at the highest dose tested (HDT; 600 ppm) as compared to
controls.  The male mice also had significant dose-related trends with
respect to hepatocellular carcinomas and combined hepatocellular
adenomas and carcinomas, and increased incidences of bronchioalveolar
adenomas and adenocarcinomas of the lung in females at 50, 200 and 600
ppm (but not 500 ppm) relative to their controls.  No compound related
tumors were noted in rats.  The mutagenicity evidence presents low
concern for bifenthrin.

3.4	 	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
recommendations of its Endocrine Disruptor and Testing Advisory
Committee (EDSTAC), EPA determined that there was a scientific basis 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 the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and, to the
extent that effects in wildlife may help determine whether a substance
may have an effect in humans, FFDCA 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).  Bifenthrin database did not indicate any
endocrine mediated effects.  When additional appropriate screening
and/or testing protocols being considered under the Agency’s EDSP have
been developed, bifenthrin may be subjected to further screening and/or
testing to better characterize effects related to endocrine disruption.

4.0		Dietary Exposure/Risk Characterization

4.1		Pesticide Metabolism and Environmental Degradation

4.1.1		Metabolism in Primary Crops and Livestock

<IP_ADDRESS>		Metabolism in Primary Crops

References:

Bifenthrin TRED,   SEQ CHAPTER \h \r 1 S. Levy, 21-AUG-2002; DP# 283808

Bifenthrin: Human-health Risk Assessment for Proposed Uses on Cilantro,
Leafy Brassica Greens (subgroup 5b), Tuberous and Corm Vegetables
(Subgroup 1c), Dried Shelled Peas and Beans (except Soybean) (Subgroup
6c) and Tobacco. M. Rust-Clock, et. al. 4/6/2006

45794202.der

Bifenthrin;  PP#6E7125, PP#6E7126, PP#6E7127, PP#6E7128; Section 3
Registration for Application of Bifenthrin to Mayhaw, Root Vegetables,
(Except Sugar Beets, Crop Subgroup 1B), Peanut, Pistachio, Soybean, and
Fruiting Vegetables (Crop Group 8).  Summary of Residue Chemistry Data.
Pending, W. Wassell, DP#:  334164

  SEQ CHAPTER \h \r 1 Memo, M. Flood, 07/30/93,   SEQ CHAPTER \h \r 1
PP#7F3456

  SEQ CHAPTER \h \r 1 The nature of bifenthrin residues in plants is
adequately understood based on the available metabolism studies with
corn, cotton, and apple.  HED previously determined that for purposes of
tolerance expression and risk assessment, the residue of concern in
cotton and apple commodities is bifenthrin per se (Memoranda, M. Flood,
12/24/87 and N. Dodd, 7/02/87).  After re-examining the cotton and apple
metabolism data and additional corn metabolism data, the HED Metabolism
Committee (Memo, M. Flood, 7/23/93) reaffirmed that the residue of
concern in plant commodities is bifenthrin per se.

In conjunction with the previous risk assessment for use on tuberous and
corm vegetables, IR-4 submitted a metabolism study on potatoes
reflecting both soil and foliar applications of [14C] bifenthrin.  The
potato study is adequate and the results from the metabolism study
support HED’s previous determination that the residue of concern is
bifenthrin per se.  The bifenthrin review team agrees with these
decisions.

  SEQ CHAPTER \h \r 1

<IP_ADDRESS>	   Metabolism in Livestock

Adequate studies are available depicting the metabolism of
[14C]bifenthrin in ruminants and poultry.  The nature of the residue in
livestock is adequately understood based on goat and hen metabolism
studies.  The HED Metabolism Committee determined that for purposes of
tolerance expression and risk assessment, the residue of concern in
livestock is bifenthrin per se (Memo, M. Flood, 7/23/93).  The
bifenthrin review team agrees with this decision.

4.1.2	Metabolism in Rotational Crops

Adequate confined and field rotational crop studies are available.
Based on the confined study, HED has concluded that the residue of
concern in rotational crops is the parent compound only.  The bifenthrin
review team agrees with this decision.

4.1.3  Analytical Methodology

Adequate gas chromatography (GC)/electron-capture detection (ECD)
methods are available for enforcing tolerances of bifenthrin in plant
and livestock commodities.  The available methods for plant commodities
generally involve extraction of the sample with acetone, partitioning
with hexane, purification using a Florisil column, and analysis of
residues by GC/ECD.  The limit of quantitation (LOQ) for these methods
is 0.05 ppm.  Samples from the current field trials and the potato
processing study were analyzed using methods that are modifications to
one of the current enforcement methods (P-2550 M), with variations in
extraction solvents and detection methods.  Residues of bifenthrin in/on
mustard greens and cilantro (leaves and seeds) were determined using a
GC/ECD method (FMC Report P-2132).  For this method, residues are
extracted with hexane, concentrated, and cleaned up using a Florisil
column, then analyzed by GC/ECD.  Residues in/on potato fractions and
dried beans and peas were determined using a GC/mass-selective detection
(MSD) method (FMC Report P-3426).  For this method, residues are
extracted with acetone, concentrated, and purified by silica-gel
solid-phase extraction (SPE). The residues are then analyzed by GC/MSD,
using the m/z 181 ion for quantitation.  Residues in/on green tobacco
were determined using a related GC/MSD method (FMC Report P-3457).  For
this method, residues are extracted with acetone/water, partitioned into
hexane, and cleaned up with a SPE column, and analyzed by GC/MSD.  For
each of the above methods, the LOQ for bifenthrin is 0.05 ppm, and the
reported limit of detection (LOD) is 0.01 ppm.  Each of these methods
was adequately validated in conjunction with analysis of samples from
the field trials or processing study.

Environmental Degradation

References:

Tier I Estimated Environmental Concentrations of Bifenthrin for the Use
in the Human-Health Risk Assessment. 02/07/2006. J. Melendez

Memo, 6/21/2002, S. Knizer, TXR# 0050887

  SEQ CHAPTER \h \r 1 The environmental fate database for bifenthrin is
complete enough to characterize drinking water exposure.  The submitted
data indicate that bifenthrin is relatively persistent under both
laboratory and field conditions.  Bifenthrin is relatively immobile in
four soils tested.  Due to its low mobility, bifenthrin is not likely to
reach subsurface soil environments (lower microbial activity) or ground
waters.  Various terrestrial field dissipation studies confirm that
bifenthrin remains mostly in the upper soil level.  Due to its low
solubility and high level of binding it appears that bifenthrin would
remain bound to the soils during run-off events and it may reach surface
waters if the run-off event is accompanied by erosion.

The HED Metabolism Assessment Review Committee (MARC) concluded that the
parent compound, bifenthrin per se, should be the residue of concern for
drinking water risk assessment based on its persistence and the absence
of major degradates in laboratory studies (Memo, 6/21/2002, S. Knizer,
TXR# 0050887).  The bifenthrin review team agrees with this decision.

4.1.5		Food Residue Profile

The field trials with bifenthrin on mayhaw, radish, garden beet, carrot,
peanut, and soybeans are   SEQ CHAPTER \h \r 1 adequate.  An adequate
number of trials were conducted reflecting the proposed use patterns in
the appropriate geographic regions, and the appropriate commodities were
collected at the proposed pre-harvest intervals (PHIs).  Samples were
analyzed using adequate analytical methods, and the sample storage
intervals are supported by the available storage stability data.
Tolerance levels for residues in/on mayhaw, root vegetables (subgroup
1B), radish tops, and garden beets were determined using the NAFTA
MRL/Tolerance Harmonization Spreadsheet.

Although tolerances are proposed for bifenthrin per se in/on pistachios
at 0.05 ppm and the fruiting vegetables crop group (group 14) at 0.5
ppm, residue data for these crops were not included in the current
submissions.  A tolerance is established for residues of bifenthrin per
se in/on the tree nut crop group (group 14) at 0.05 ppm.  For
pistachios, HED policy is to translate data and tolerances from almonds
to pistachios (Reviewer’s Guide & Summary of HED ChemSAC Approvals for
Amending Crop Group/Subgroups [40 CFR §180.41] & Commodity Definitions
[40 CFR 180.1(h)], 6/14/2006, B Schneider).  Thus, a tolerance for
residues of bifenthrin per se should be established in/on pistachios at
0.05 ppm.  For fruiting vegetables, tolerances are established for
residues of bifenthrin per se at 0.05 ppm in/on eggplant, at 0.15 ppm
in/on tomato, and at 0.5 ppm in/on bell and non-bell pepper.  HED has
determined that a fruiting vegetables crop group tolerance for residues
of bifenthrin per se is not appropriate for the following reasons:
maximum residues in eggplant are more than a factor of five lower than
the tolerance for tomatoes and the use pattern for tomato and tomatillo
are different from the other members of the crop group in terms of the
PHI, maximum seasonal use rate, number of applications, and interval
between applications.  However, HED could recommend for tolerances for
residues in/on groundcherry and pepino at 0.50 ppm.  A revised Section F
would be required.  As 40 CFR §180.1 indicates that a tolerance for
residues in/on tomato applies to tomatillo, a tolerance for residues
in/on tomatillo is not required.

Mayhaw:  Residues of bifenthrin ranged from 0.24 to 0.78 ppm in/on
mayhaw harvested 28 to 29 days following two broadcast foliar
applications of Capture 2EC for a total rate of approximately 0.2 pounds
active ingredient per acre (lb ai/A).  HED concludes a tolerance for
residues of bifenthrin per se in/on mayhaw at 1.4 ppm is appropriate.

Radish:  Residues of bifenthrin ranged from <0.05 to 0.07 ppm in radish
roots and ranged from 0.56 to 2.26 ppm in radish tops harvested 6 to 8
days following an in-furrow application of Capture 1.15G at planting and
two broadcast foliar applications of Capture 2EC for a total foliar rate
of approximately 0.20 lb ai/A.  Based upon the submitted data, HED
concludes a tolerance for residues of bifenthrin per se in/on radish
tops at 4.5 ppm is appropriate.  For radish roots, see the discussion
below concerning the tolerances for residues in/on subgroup 1B.

Garden Beet:  Residues of bifenthrin ranged from <0.05 ppm to 0.28 ppm
in garden beet roots and ranged from 4.8 ppm to 12.2 ppm in garden beet
tops harvested 1 day following four broadcast foliar applications of
Capture 2EC for a total rate of approximately 0.40 lb ai/A.  Based upon
the submitted data, HED concludes tolerances for residues of bifenthrin
per se in/on garden beet tops and roots at 15 ppm and 0.45 ppm,
respectively, are appropriate.

Carrot:  Residues of bifenthrin were less than the method LOQ (<0.05
ppm) in/on carrots harvested 7, 14, and 20 to 22 days following a three
broadcast foliar applications of Capture 2EC for a total rate of 0.49 to
0.51 lb ai/A.

Carrot and radish are the representative commodities of the root
vegetables, except sugar beet, crop subgroup (1B).  The petitioner has
proposed tolerances for residues of bifenthrin in/on root vegetables,
except sugar beet, crop subgroup (1B) at 0.07 ppm.  Residues of
bifenthrin ranged from <0.05 to 0.07 ppm in radish roots with 4 of 6
trials showing residues levels less than the LOQ (<0.05 ppm).  Residues
of bifenthrin were less than the LOQ (<0.05 ppm) in/on carrots from all
of the submitted trials (10 trials).  Based upon the submitted data, HED
concludes a tolerance for residues of bifenthrin per se in/on root
vegetables, except sugar beet and garden beet, crop subgroup (1B) at
0.10 ppm is appropriate.

Peanut:  For the treated peanut nutmeat samples, residues of bifenthrin
were not detected (<LOD, <0.01 ppm) in all samples except one which had
apparent residue levels estimated at 0.01 ppm.  Apparent residues of
bifenthrin were not detected (<LOD, <0.01 ppm) in/on 9 samples of
untreated peanut nutmeats.  HED concludes a tolerance for residues of
bifenthrin per se in/on peanut at 0.05 ppm is appropriate.

Soybean:  Residues of bifenthrin ranged from <0.05 to 0.18 ppm in
soybean seed harvested 17 to 21 days following the last of three
broadcast foliar applications of Capture 2EC for a total foliar rate of
approximately 0.30 lb ai/A.  In 12 of 15 trials, residues of bifenthrin
were less than the LOQ (<0.05 ppm).  HED concludes a tolerance for
residues of bifenthrin per se in/on soybean at 0.20 ppm is appropriate.

Processed Food and Feed:

Peanut:  The petitioner has submitted processing data for the use of
bifenthrin on peanuts and subsequent processing of the peanuts to peanut
meal and refined oil.  The total foliar application rate was 0.9 lb ai/A
per season (9.0x exaggerated rate).  The harvested peanuts were dried,
shelled, and processed into meal and refined oil using simulated
commercial practices.

The results show that residues of bifenthrin were below the method LOQs
(<0.05 ppm) but above the method limit of detection (LOD, 0.01 ppm)
in/on peanut nutmeat treated at a seasonal rate of 0.9 lb ai/A.
Apparent residue levels of bifenthrin were estimated at 0.02 ppm in/on
treated peanut nutmeats.  Following processing of the treated nutmeat,
the residues were not detected (<0.01 ppm) in peanut meal and were below
the method LOQ but above the method LOD in/on all treated peanut refined
oil samples except one which had bifenthrin residues at the LOQ (0.05
ppm).  Apparent residue levels of bifenthrin in peanut refined oil were
estimated at 0.04 ppm.  As residues decreased when peanut nutmeats are
processed to meal, a processing factor for this process was not
calculated and tolerances for residues in/on peanut meal are not
required.  The processing factors for the processing of peanut nutmeats
to refined oil were estimated to be 2.2x.  The highest-average field
trial (HAFT) value for residues of bifenthrin in/on peanut nutmeats is
0.01 ppm (residues were non-detectable).  The processing factor for
nutmeats to oil multiplied by the HAFT is 0.022ppm (2.2 x 0.01 ppm).  As
this value is below the LOQ (0.05 ppm) and recommended tolerance level
for bifenthrin in/on peanuts, a tolerance for residues in/on peanut oil
is not required.

Soybean:  The petitioner has submitted  SEQ CHAPTER \h \r 1  a
processing study with bifenthrin on soybeans.  In one trial conducted in
Iowa during the 2001 growing season, soybean seed was harvested 18 days
following the last of three foliar broadcast applications of Capture 2EC
for a total rate of 0.7 lb ai/A (7.0x).  Soybean seed samples were
processed into meal, hulls, and refined oil.  Additionally, aspirated
grain fractions (AFGs) were generated.

The average total residues of bifenthrin were the LOQ of 0.05 ppm (0.025
ppm) in/on the raw agricultural commodity (RAC) soybean seed treated at
a total rate of 0.7 lb ai/A.  Following processing of the treated RAC,
total residues did not concentrate in meal, but concentrated slightly in
hulls (2.6x) and refined oil (1.6x).  Additionally, residues
significantly concentrated in AFGs (9.51 ppm, 380x).  The observed
processing factors are less than the theoretical concentration factors
for soybean commodities.

The AGF samples were collected and classified via sieve.  After
classification, the fractions were recombined to produce the AGF
samples.  The study report indicates that the AFGs were recombined as
per the specifications of the Study Director; however, the report does
not indicate the final makeup of the AGF samples in terms of percent
composition based upon particle size.  This information should be
submitted prior to granting of a permanent registration for soybeans.
Once these data are submitted, HED will make a determination as to
whether additional data or an altered tolerance level are needed.

The HAFT value for residues of bifenthrin in/on soybean is 0.18 ppm.
The processing factors for soybeans to hulls, meal, refined oil, and AGF
is as follows:

Soybean hulls:  0.18 ppm x 2.6 = 0.47 ppm.

Soybean meal:  no concentration of residues.

Soybean refined oil:  0.18 ppm x 1.6 = 0.29 ppm

Soybean aspirated grain fractions:  0.18 ppm x 380 = 68.4 ppm

HED concludes tolerances for residues of bifenthrin in/on soybean hulls
at 0.50 ppm, soybean refined oil at 0.30 ppm and aspirated grain
fractions at 70 ppm are appropriate.

  SEQ CHAPTER \h \r 1 <IP_ADDRESS>		Tolerance Summary

The tolerances proposed by the registrants in the current vegetable
petitions are listed below in Table <IP_ADDRESS>, along with HED’s
recommended tolerance levels.   SEQ CHAPTER \h \r 1  Tolerance levels
for residues in/on mayhaw, root vegetables (subgroup 1B), radish tops,
garden beets were determined using the NAFTA MRL/Tolerance Harmonization
Spreadsheet. Tolerances for residues in other commodities were
determined by rounding up the appropriate field trial residue value.

Table <IP_ADDRESS>.  Tolerance Summary for Bifenthrin.

Proposed	Recommended

Commodity Definition	Tolerance (ppm)	Commodity Definition	Tolerance
(ppm)

Mayhaw	1.4	Same	Same

Vegetable, root, except sugar beet and garden beet, subgroup 1B	0.07
Same	0.10

beet, garden, root	0.45	Same	Same

beet, garden, top	15	Same	Same

Radish, top	4.5	Same	Same

Soybean	0.2	Same	Same

Soybean, hulls	0.7	Same	0.50

Soybean, refined oil	0.4	Same	0.30

Vegetable, fruiting, group 8	0.5	Delete request for fruiting vegetables

Groundcherry	0.5

Pepino	0.5

Peanut	0.05	Same	Same

Pistachio	0.05	Same	Same

None	None	Aspirated Grain Fractions 	70

4.1.6		International Residue Limits

  SEQ CHAPTER \h \r 1 The Codex Alimentarius Commission has established
maximum residue limits (MRLs) for residues of bifenthrin in/on various
commodities.  Codex MRLs are expressed in terms of bifenthrin per se, as
are U.S. tolerances.  There are no equivalent Canadian or Mexican MRLs
for the tolerances being requested in the current petition.

4.1.7		Drinking Water Residue Profile

Residues of Concern in Drinking Water

The HED MARC concluded that the parent compound, bifenthrin per se,
should be the residue of concern for drinking water risk assessment
based on its persistence and the absence of major degradates in
laboratory studies (HED Doc. No. 0050887).

Drinking Water Estimates

The EDWCs for bifenthrin were calculated based on a maximum application
rate of 0.5 lb ai/A/season to lettuce.  The acute drinking water
concentration in surface water is 0.0140 ppb of bifenthrin, based on
aerial applications to lettuce.  The cancer/chronic drinking water
concentration is 0.0140 ppb (based on applications of lettuce, highest
application rate).  The SCI-GROW generated EDWC is 0.003 ppb of
bifenthrin, which is recommended for use, both for acute and chronic
exposures.  Because of the very low solubility of bifenthrin, the EDWCs
did not exceed 0.0140 ppb (the solubility of bifenthrin).

Table 4.1.7.  Tier 1 Estimated Drinking Water Concentrations for
Bifenthrin

DRINKING WATER SOURCE (MODEL USED) 	USE (rate modeled)	MAXIMUM ESTIMATED
DRINKING WATER CONCENTRATION  (EDWC)  ( ppb)

Groundwater (SCI-GROW)	Lettuce (0.5 lb. ai/A/season)	Acute and Chronic
0.00300

Surface water  (FIRST)	Lettuce (0.5 lb. ai/A/season)	Acute	0.0140

	Lettuce (0.5 lb. ai/A/season)	Chronic	           0.0140

4.2 		Dietary Exposure and Risk

Acute and chronic dietary exposure and risk assessments were conducted
using the DEEM-FCID™, Version 2.03, which uses food consumption data
from the U.S. Department of Agriculture’s Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998.    SEQ CHAPTER
\h \r 1 The analyses were performed as part of a registration action;
(1) to support a Section 3 Registration on root vegetables (except sugar
beets, Crop Group 1B), peanuts, pistachio, soybean, and fruiting
vegetables (Crop Group 8); (2) to include drinking water estimates
reflecting the new uses; and (3) to support a new evaluation of the
acute and chronic toxicological endpoints.

Acute Dietary Exposure and Risk

A Tier 3, acute probabilistic dietary exposure and risk assessment was
conducted for all supported (and pending) food uses and drinking water.
AR were developed based on the latest U.S. Department of Agriculture’s
Pesticide Data Program (PDP) monitoring data 1998-2005, Food and Drug
Administration (FDA) data, or field trial data for bifenthrin.
Anticipated residues were further refined using the latest percent crop
treated (%CT) data and processing factors where appropriate.

EFED calculated the ground and surface drinking water Tier 1 EDWCs for
bifenthrin new uses using the screening concentration in ground water
(SCI-GROW) and FQPA Index Reservoir Screening Tool (FIRST) models.  It
was found that lettuce is still the use with the major exposure and the
highest PCA, and, therefore, the drinking water assessment results do
not change from the previous ones.  The EDWCs for bifenthrin were
calculated based on a maximum application rate of 0.5 lb ai/A/season and
the EDWCs in ground water were estimated as 0.003 ppb and 0.014 ppb in
surface water.

The acute dietary exposure estimates for food and drinking water are
below HED’s level of concern (<100% aPAD) at the 99.9th percentile of
exposure.  Bifenthrin dietary exposure at the 99.9th percentile for food
and drinking water is 10% of the aPAD for the U.S. population and 25% of
the aPAD for all infants(<1 year old), the most highly exposed
population subgroup.

Table 4.2.1.  Results of Bifenthrin Acute Dietary (Food + Drinking
Water)

Exposure Analysis Using DEEM FCID.

Population Subgroup	aPAD (mg/kg/day)	99.9th Percentile

Exposure (mg/kg/day)	% aPAD

General U.S. Population	0.328	0.033389	10

All Infants (< 1 year old)	0.328	0.083293	25

Children 1-2 years old	0.328	0.058377	18

Children 3-5 years old	0.328	0.051553	16

Children 6-12 years old	0.328	0.043915	13

Youth 13-19 years old	0.328	0.026013	8

Adults 20-49 years old	0.328	0.018021	5

Adults 50+ years old	0.328	0.014262	4

Females 13-49 years old	0.328	0.017374	5

Chronic Dietary Exposure and Risk

A refined chronic dietary exposure assessment was also conducted for the
supported food uses of bifenthrin and drinking water using single point
estimates of anticipated bifenthrin residues for food and drinking
water.  The EDWC of 0.014 ppb, based on application to lettuce at the
highest application rate, was also used for the chronic dietary
assessment.

The chronic dietary exposure estimates for food and drinking water are
below HED’s level of concern (<100% cPAD) for the U.S. population and
all population subgroups.  Bifenthrin dietary exposure for food and
drinking water is 20% of the cPAD for the U.S. population and 53% of the
cPAD for children 3-5 years old, the most highly exposed population
subgroup.

Table 4.2.2. Results of Chronic Dietary (Food + Drinking Water)
Exposure and Risk for Bifenthrin.

Population Subgroup	Chronic Dietary

	Dietary Exposure

(mg/kg/day)	% cPAD

General U.S. Population	0.002620	20

All Infants (< 1 year old)	0.002748	21

Children 1-2 years old	0.006366	49

Children 3-5 years old	0.006912	53

Children 6-12 years old	0.005109	39

Youth 13-19 years old	0.002621	20

Adults 20-49 years old	0.001882	15

Adults 50+ years old	0.001650	13

Females 13-49 years old	0.001914	15

5.0 		Residential (Non-Occupational) Exposure/Risk Characterization

Bifenthrin: REVISED Residential Exposure Assessment and Recommendations
for the Tolerance Reassessment Eligibility Decision (TRED) Document. S.
Weiss. D286358. 10/25/2002.

Bifenthrin products are available to homeowners for indoor and outdoor
application to residential premises.  Adults and children may be
potentially exposed to bifenthrin residues resulting from application.

Potential exposure and risk to residents (or “homeowners”) have been
assessed previously by HED.  Information for this section was adapted
from previous residential assessment for bifenthrin performed in 2002
(see reference above).  Since completion of the last residential
assessment, no product cancellations have occurred that would alter the
conclusions.  A summary of the exposure and risk resulting from
residential uses of bifenthrin is provided below.  These exposure
estimates were used in the aggregate risk assessment which appears in
Section 7.0 of this document.

5.1		Residential Handler Exposure

End-use products containing bifenthrin are formulated as
ready-to-use-sprays, emulsified concentrates, wettable powders,
granulars, pelletized tablets, and pressurized liquids.

The current maximum application rates of granulars and liquids by lawn
care operators (LCOs) are 0.4 and 0.3 lb ai/acre, respectively.   For
liquid and granular formulations applied by homeowners, the maximum rate
is 0.2 lb ai/acre.  In a letter to the Agency dated September 16, 2002,
FMC agreed to lower the maximum rate for all turf uses to 0.2 lb
ai/acre.  Bifenthrin products may be applied by pest control operators
(PCOs) and homeowners in and around homes as a spray in concentrations
of up to 0.06%.  The majority of residential labels do not specify
frequency of application.

On October 25, 2002, HED performed a residential exposure and risk
assessment for the use of bifenthrin (see reference above).  A summary
of the uses and the results of the assessment are summarized below.  For
more details and for the results of all exposure scenarios, please see
the original residential exposure assessment.

Short- and intermediate-term exposures may occur for residents applying
bifenthrin products.  Chronic exposures are not anticipated for
residential handlers.  The exposure and risk for residential handlers
were assessed using the revised draft SOPs for Residential Exposure
Assessment, and includes surrogate data from the Pesticide Handlers
Exposure Database (PHED) Outdoor Residential Exposure Task Force
(ORETF).  Since PHED and ORETF do not include data for ready-to-use
spray bottle application, data from a proprietary study were used to
estimate exposure (MRID 447393-01).

The major exposure scenarios for non-occupational (residential) handler
exposures are as follows:

	*  Mixing/loading/applying Liquids for Low-Pressure Handwand
Application

	*  Mixing/loading/applying Liquids for Hose-end Sprayer Application

	*  Mixing/loading/applying Liquids for Backpack Sprayer Application

	*  Paintbrush Application

	*  Loading/applying Granulars for Belly-Grinder Application

	*  Loading/applying Granulars for Push-type Spreader Application

	*  Applying Granulars with Bare Hands

	*  RTU Spray Bottle Application

The most likely residential handler exposure scenario resulting in the
highest exposure and risk is for loading/applying granular formulation
by belly-grinder application.  The short- and intermediate-term MOEs are
300 for dermal and 25,000 for inhalation, resulting in a combined MOE of
300. The exposure for this use is not of concern to HED.  5.2
Residential Post-application Exposure

Adults and children may be potentially exposed to bifenthrin residues
after application of bifenthrin products in residential settings.
Short- and intermediate-term post-application dermal exposures for
adults, and short- and intermediate-term post-application dermal and
incidental oral exposures for children are anticipated.  Long-term
exposure is not expected.  Risk estimates were generated for potential
contact with lawn, soil, and treated indoor surfaces using HED’s Draft
SOPs for Residential Exposure Assessment, and for the lawn scenarios,
dissipation data from a chemical specific TTR study.  Indoor surface
residues in homes were based on crack and crevice data collected for
bifenthrin and malathion.  These estimates are considered conservative
screening level estimates, but appropriate, since the study data were
adjusted to reflect maximum application rates.  Only the scenarios that
result in the highest exposure are summarized in Table 5.2.

Table 5.2. Summary of Residential Post-Application Risk for Bifenthrin.

Exposure Scenario	Population	Route of Exposure	Short-Term MOE
Intermediate-Term MOE

Indoor: High- Contact Activity	Adults	Dermal	3100	3100

	Toddlers	Derma

Orall	1800

2600	1800

5500

Outdoor:

High-Contact Activity on Turfgrass	Adults	Dermal	2300	4500

	Toddler	Oral and Dermal	740 Oral

1400 Dermal	1600 Oral

2700 Dermal

5.3		Other (Spray Drift)

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 the ground application method employed for bifenthrin.
The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices and 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 database 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.

6.0		Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide
exposures and risks from three major sources:  food, drinking water, and
residential exposures.  In an aggregate assessment, exposures from
dietary and residential sources are added together and compared to
quantitative estimates of hazard (e.g., a NOAEL), or the risks
themselves can be aggregated.  When aggregating exposures and risks from
various sources, HED considers both the route and duration of exposure.

Short-term aggregate risk assessment is required for bifenthrin due to
the potential for residential exposure.  The common toxicological effect
observed across the oral and dermal routes of exposure is clinical signs
of neurotoxicity.  An aggregate MOE was calculated by taking the inverse
of the sum of inverse MOEs for dietary and non-dietary (incidental oral
and dermal) exposure pathways.

6.1		Acute Aggregate Risk

No acute residential/recreational exposures are expected.  Since the
dietary assessment included food and water, the exposures in Table 5.2.1
represent aggregate exposures.  The acute aggregate risk levels are not
of concern to HED.

6.2		Short- and Intermediate-term Aggregate Risk

Because there is the potential for short- and intermediate-term,
non-dietary exposure of children and adults to bifenthrin as a
residential treatment (indoors and outdoors), it is appropriate to
aggregate these exposures with dietary (food and water) exposure.
Adults can be exposed through the residential application of bifenthrin
via dermal and inhalation routes and through post-application exposure
via the dermal route (treated turf).  Children might be exposed
following application in residential settings via dermal and oral
routes.  HED believes that if a toddler were to be exposed to bifenthrin
granules, it would most likely be episodic, that is, a one-time
occurrence and not likely to be repeated.  Therefore, this episodic
scenario was not aggregated with dietary exposure.

Residential exposure and risk have been summarized based on HED
residential risk assessments for the existing uses of bifenthrin.  Those
scenarios resulting in the highest exposure and risk for adults and
children have been summarized in Table 6.2.1.  These exposures were used
to calculated short- and intermediate-term aggregate risk by combining
residential exposure with that from dietary sources.

Table 6.2.1.  Summary of Residential Risk Resulting in Highest Exposure
and Risk for Bifenthrin.

Population	Exposure Scenario	Route of Exposure	Short-Term MOE

Adults	Loading/applying granulars with a belly-grinder	Handler	Dermal
and Inhalation	300 Dermal

25,000 Inhalation

	Hose-end Sprayer Application	Handler	Dermal and Inhalation	97,000
Inhalation

3000 Dermal

Post-Application	Dermal	2300

	Liquid Structural Wood Treatment with Paintbrush	Handler	Dermal and
Inhalation	23,000 Inhalation

600 Dermal

Post-Application	No exposure expected due to low accessibility to
treated areas (termite control).

	Indoor:

Liquid Crack and Crevice Spray	Handler	Dermal and Inhalation	210,000
Inhalation

14,000 Dermal

Post-Application	Dermal	3100

Toddler	Outdoor:

High Contact Activity on Turfgrass	Post-Application	Hand-to- Mouth/Oral
740

	Mouthing Treated Turf	3000

	Soil Ingestion	220,000

	Dermal	1400

1 Combined MOE for handlers since dermal and inhalation endpoints
(clinical signs of same [1/(1/MOE-dermal)+(1/MOE-inhalation)].

The short- and intermediate-term NOAEL for non-dietary oral exposure is
based on the 90-day oral toxicity study in dogs (NOAEL = 2.21
mg/kg/day).  The short- and intermediate-term NOAEL dermal exposure is
based on the 21-day dermal toxicity study in the rat (NOAEL = 47
mg/kg/day).  The common toxicological effect observed across the oral
and dermal routes of exposure is clinical signs of neurotoxicity.  The
aggregate LOC (MOE) is 100.

The results of the short- and intermediate-term aggregate risk
assessment for various subpopulations based on age are reported in Table
6.2.2.  Short- and intermediate-term aggregate (dietary + residential)
MOEs for the general U.S. population and any subpopulation of the
general U.S. population are greater than 150 and therefore are not of
concern to HED.

Table 6.2.2.  Short- and Intermediate-Term Aggregate Risk for
Bifenthrin.

Population	Dietary MOE1	Non-dietary Oral MOE2	Dermal MOE3	Inhalation
MOE4	Aggregate MOE5

General U.S. population	850	N/A	300	25,000	220

All infants

(<1 yr old)

800	590	1400	N/A6	270

Children 1-2 yrs. Old

350	590	1400

190

Children 3-5 yrs. Old

320	590	1400

150

Children 6-12 yrs. Old

430

N/A	1400

330

Youth 13-19 yrs. Old

760

1400

490

Adults 20-49 yrs. Old

1200

300	25,000	240

Adults 50+ yrs. Old

1300

300	25,000	240

Females 13-49 yrs. Old

1200

260	25,000	210

1 Dietary MOE = [(short- or intermediate-term oral NOAEL)÷(chronic
dietary exposure)]; NOAEL = 2.21 mg/kg/day; chronic dietary (food +
water) exposures (see Table 5.2.2) were utilized as surrogates for
short- and intermediate-term exposures.

2 Non-dietary oral MOE = [(short- or intermediate-term oral NOAEL)÷(sum
of all high-end incidental oral residential exposure)]; NOAEL=2.21
mg/kg/day; chronic dietary (food + water) exposures (see Table 4.2.2)
were utilized as surrogates for short- and intermediate-term exposures.

3 Dermal MOE = [(short- or intermediate-term dermal NOAEL)÷(high-end
dermal residential exposure)]; NOAEL=47 mg/kg/day; structural wood
treatment (paintbrush application) used for adult estimates

4 Inhalation MOE = [(short- or intermediate-term inhalation
NOAEL)÷(high-end dermal residential exposure)]; NOAEL=2.21 mg/kg/day.

5 Aggregate MOE (dietary and residential) = 1÷[(1÷dietary MOE) +
(1÷non-dietary oral MOE) + (1÷dermal MOE) + (1÷inhalation MOE)];
values expressed to 2 significant figures; Inhalation MOE based on adult
residential handler exposure.

6 N/A = not applicable.

6.3		Long-term (Chronic) Aggregate Risk

A chronic (non-cancer) aggregate risk assessment was not performed,
because chronic residential exposure to bifenthrin (i.e., >6 months) is
not considered likely to occur.

6.4		Cancer Risk

The CARC (1992) recommended that for the purpose of risk
characterization, the RfD approach should be used for quantification of
human risk.  The chronic exposure analysis revealed <100% RfD, and it is
assumed that the chronic dietary endpoint is protective for cancer
dietary exposure.

7.0		Cumulative Risk Characterization/Assessment

Bifenthrin is a member of the pyrethroid class of pesticides.  EPA is
not currently following a cumulative risk approach based on a common
mechanism of toxicity for the pyrethroids.  Although all pyrethroids
alter nerve function by modifying the normal biochemistry and physiology
of nerve membrane sodium channels, available data show that there are
multiple types of sodium channels and it is currently unknown whether
the pyrethroids as a class have similar effects on all channels or
whether modifications of different types of sodium channels would have a
cumulative effect.  Nor do we have a clear understanding of effects on
key downstream neuronal function, e.g., nerve excitability, or how these
key events interact to produce their compound specific patterns of
neurotoxicity.  Without such understanding, there is no basis to make a
common mechanism of toxicity finding.  There is ongoing research by the
EPA’s Office of Research and Development and pyrethroid registrants to
evaluate the differential biochemical and physiological actions of
pyrethroids in mammals.  This research is expected to be completed by
2007.  When available, the Agency will consider this research and make a
determination of common mechanism as a basis for assessing cumulative
risk.  For information regarding EPA’s 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/ .

8.0	              Occupational Exposure/Risk Pathway

8.1	Short-/Intermediate-Term Handler Risk

Based upon the proposed use pattern, HED expects the most highly exposed
occupational pesticide handlers (mixers, loaders, applicators) to be 1)
mixer/loader using open pour loading of liquids; 2) mixer/loader using
open pour loading of granules; 3) an aerial applicator and 4) an
applicator using open-cab, ground-boom spray equipment.  HED believes
most exposure durations will be short-term (1 - 30 days).  However, the
Science Policy Council for Exposure (ExpoSAC) maintains that it is
possible for commercial applicators to be exposed to intermediate-term
exposure durations (1 - 6 months).   Therefore estimates for short- and
intermediate-term risks are presented.

It is expected that some private applicators may perform all tasks, that
is, mix, load and apply the material.  However, HED ExpoSAC draft SOP
(29 March 2000) directs that although the same individual may perform
all tasks, in some cases they shall be assessed separately.

The available exposure data for combined mixer/loader/applicator
scenarios are limited in comparison to the monitoring of these two
activities separately.  These exposure scenarios are outlined in the
PHED Surrogate Exposure Guide (August 1998).  HED has adopted a
methodology to present the exposure and risk estimates separately for
the job functions in some scenarios and to present them as combined in
other cases.  Most exposure scenarios for hand-held equipment (such as
hand wands, backpack sprayers, and push-type granular spreaders) are
assessed as a combined job function.  With these types of hand held
operations, all handling activities are assumed to be conducted by the
same individual.  The available monitoring data support this and HED
presents them in this way.  Conversely, for equipment types such as
fixed-wing aircraft, groundboom tractors, air-blast sprayers, or
high-pressure handwand sprayers, the applicator exposures are assessed
and presented separately from those of the mixers and loaders.  By
separating the two job functions, HED determines the most appropriate
levels of PPE for each aspect of the job without requiring an applicator
to wear unnecessary PPE that might be required for a mixer/loader (e.g.,
chemical resistant gloves may only be necessary during the pouring of a
liquid formulation).

No chemical-specific data were available with which to assess potential
exposure to occupational pesticide handlers.  The estimates of exposure
to pesticide handlers are based upon surrogate study data available in
the PHED (v. 1.1, 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 PPE as might be necessary.  The proposed product label involved in
this assessment directs applicators and other handlers who may be
exposed to the dilute through application or other tasks must wear:
long-sleeved shirt and long pants, chemical resistant gloves, such as
barrier laminate, nitrile, neoprene or viton rubber and shoes plus
socks.  Handlers who may be exposed to the concentrate through mixing,
loading, application or other tasks must wear; long-sleeved shirt and
long pants, chemical resistant gloves such as barrier laminate, nitrile,
neoprene or viton rubber, shoes plus socks and protective eye wear.

Since single application rates for the proposed uses range from 0.1 lb
ai/acre to 0.3 lb ai/acre, those uses with the higher application rate
were assessed in the table below (potatoes).  Since the dermal effects
are derived from a 21-day dermal study, there are no adjustments made
for dermal absorption.  HED asssumes 100% inhalation absorption.

See Table 9.1 for a summary of estimated exposures and risks.   In this
case, the toxicological effects are similar (i.e., neurological) for the
dermal and inhalation routes although they were identified from
different studies.  Therefore, MOEs are expressed as Combined MOEs.

Table 8.1 Occupational Exposure and Risk Estimates for Proposed Uses of
Bifenthrin

Unit Exposure1

(mg/lb ai handled)	Application rate and Acres Treated2	Average Daily
Dose3

(mg/kg bw/day)	MOE4	Combined MOE5

Mixer/Loader – Liquids – Open Pour – Supporting Aerial
Applications

Dermal:

SLNG: 2.9 HC

SLWG: 0.023 HC	0.3 lb ai/A

350 Acres/Day

	Dermal:

NG: 4.35

WG: 0.0345

NG: 11

WG: 1400

NG: 11

WG: 650

Inhal: 0.0012

Inhal: 0.0018	Inhal: 1200

	Mixer/Loader – Granules – Open Pour

Dermal:

SLNG: 0.0084 LC

SLWG: 0.0069 MC	0.3 lb ai/A

350 Acres/Day

	Dermal:

NG: 0.0126

WG: 0.0104

NG: 3700

WG:4500

NG: 700

WG: 730

Inhal: 0.0017

Inhal: 0.00255	Inhal: 870

	Aerial Applicator6

Dermal:

SLNG: 0.0050	0.3 lb ai/A

350 Acres/Day

	Dermal:

NG: 0.0075

NG: 6300

NG: 4900

Inhal: 0.000068

Inhal: 0.00010	Inhal: 22,000

	Applicator – Open Cab – Ground Boom

Dermal:

SLNG: 0.014

SLWG: 0.014	0.3 lb ai/A

200 Acres/Day

	Dermal:

SLNG: 0.012

SLWG: 0.012

NG: 3900

WG: 3900

NG: 1800

WG: 1800

Inhal: 0.00074

Inhal: 0.00063	Inhal: 3500

	1. Unit exposure = mg/lb ai handled; taken from PHED Surrogate Exposure
Guide (v. 1.1, 8/1998) SLNG=single layer PPE, no gloves; SLWG=single
layer PPE with gloves. HC=high confidence data; MC=medium confidence
data; LC=low confidence data.

2. Application rates are the maximum recommended rates from the product
labels and acres treated are derived from ExpoSAC Policy No. 9.1,
revised 9/25/2001.

3. Average Daily Dose (ADD) = Unit Exposure*Application Rate*Acres
Treated ÷ 70 kg body-weight.

4. MOE=Margin of Exposure (MOE) = NOAEL ÷ ADD.

5. Margins of Exposure may be combined when the dermal and inhalation
toxicological effect is the same but derived from different studies.
The convention used to combine is: 1 ÷ [(1/MOE-DERMAL ) +
(1/MOE-INHALATION)]

6.  Pilots are not required to wear protective gloves.

A MOE of 100 is adequate to protect occupational pesticide handlers.
Provided that mixer/loaders wear protective gloves, all MOEs are > 100
and are not of concern to HED.

8.3	Short-/Intermediate-Term Post-application Risk

There is typically the possibility for agricultural workers to
experience post-application exposure to dislodgeable pesticide residues.
 In conjunction with the Agricultural Re-Entry Task Force (ARTF), HED
has identified a number of agricultural work activities that may result
in post-application, re-entry exposure to pesticides.   In addition, HED
has identified surrogate Transfer Coefficients (TCs) in units of cm²/hr
derived from exposure studies relative to “standard” agricultural
work activities but which were conducted to assess exposure to other
compounds.

Not all of the identified post-application work activities are listed
here.  However, the activities associated with the highest TCs are
summarized in Table 9.2.

Table 8.2. Transfer Coefficients Associated With Proposed Uses of
Bifenthrin.

Crop	Activity	Transfer Coefficient (cm2/hr)

Leafy green vegetables (cilantro)

Hand Harvesting	2500

Brassica leafy greens

2500

Beans, Peas - dried, shelled

2500

Tobacco	Hand Harvesting, Topping, Stripping	2000

Roots and tuber (potatoes)	Irrigation activities, Scouting	1500

Since there are no chemical-specific data with which to assess
post-application exposures to agricultural workers, HED uses TCs
identified from surrogate studies in conjunction with the assumption
that 20% of the rate of application is available as dislodgeable foliar
residue (DFR) on day zero after application.  Although hand harvesting
(cilantro, leafy greens and peas and beans) has a TC of 2,500, the rate
of application is 0.1 lb ai/A.  The rate of application for potato is
0.3 lb ai/A which results in a higher exposure despite a slightly lower
TC.  Therefore, as a “worse case” screening-level assessment, a TC
of 1500 cm²/hr is used in conjunction with an application rate of 0.3
lb ai/A.

The TCs used in this assessment are from an interim TC policy developed
by HED’s ExpoSAC  using proprietary data from the ARTF database
(policy # 3.1 Revised 7 AUG 2000).  It is the intention of HED’s
ExpoSAC that this policy will be periodically updated to incorporate
additional information about agricultural practices in crops and new
data on TCs.  Much of this information will originate from exposure
studies currently being conducted by the ARTF, from further analysis of
studies already submitted to the Agency, and from studies in the
published scientific literature.  The following convention may be used
to estimate post-application exposure to agricultural workers.

Surrogate DFR:

DFR = application rate * 20% available as dislodgeable residue * 4.54 x
108µg/lb * 2.47 x 10-8 A/cm2 or 1.08 x 10-3 ft2/cm²

and the Average Daily Dose

ADD = DFR (µg/cm2) * TC (cm2/hr) * hr/day * 0.001 mg/µg * 1/70 kg bw

∴  0.3 b ai/A * 0.20 * 4.548 µg/lb *  2.47-8 A/cm² = 0.673 g/cm2 and

0.673 µg/cm2 * 1500 cm2/hr * 8 hr/day * 0.001 mg/µg * 1/70 kg bw =
0.12 mg/kg bw/day

Since MOE = NOAEL ÷ ADD then 47 mg/kg bw/day ÷ 0.12 mg/kg bw/day = 410

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y most highly exposed post-application agricultural activity is

410 (>100), and is not of concern.  All other identified
post-application activities are expected to have lower exposures
therefore greater MOEs.

RESTRICTED ENTRY INTERVAL (REI)

Bifenthrin is classified in Acute Toxicity Category II for acute oral
toxicity; Category III for acute dermal toxicity; and Category IV for
acute inhalation, primary eye irritation, and dermal irritation.  It is
not a dermal sensitizer.  Therefore, the interim WPS REI of 12 hours is
adequate to protect agricultural workers from post-application
exposures.  The proposed end-use product labels list a REI of 12 hours.

9.0		Data Needs and Label Requirements

9.1		Toxicology

None.

9.2		Residue Chemistry

Revised Section F – see Table <IP_ADDRESS>

Revised Section B – see Section 2.1

Additional information concerning aspirated grain fractions.

Occupational and Residential Exposure

None.

RDI: RAB1: 07/18/2007

PP#6E7125, PP#6E7126, PP#6E7127, PP#6E7128

EPA Registration Numbers:  279-3069; 279-3244; 279-310808

DP Numbers:  334154, 334165, 334168

PC Code:  128825

WDWassell:S10316:Potomac Yard:703-305-6135:7509P:RAB1

Appendix 1:  Subchronic, Chronic and Other Toxicity Profile

Guideline No. 	Study Type	MRID No. (year)/ Classification /Doses	Results

870.3100

	90-Day oral toxicity (rat)	00141199 (1984)

Acceptable/guideline

M:  0, 0.88, 3.8, 7.5, 15 mg/kg/day

F:  0, 1.04, 4.3, 8.5, 17.2 mg/kg/day	NOAEL=M/F: 3.8/4.3 mg/kg/day

LOAEL=M/F: 7.5/8.5 mg/kg/day based on increased incidence of tremors.

870.3150

	90-Day oral toxicity (dog)	00141200 (1984)

Acceptable/guideline

0, 2.21, 4.42, 8.84, 17.7 mg/kg/day	NOAEL =M/F: 2.21 mg/kg/day

LOAEL = M/F: 4.42 mg/kg/day based on based on increased incidence of
tremors.

870.3200

	21/28-Day dermal toxicity (rat)	45280501 (2000)

Acceptable/guideline

0, 23, 47, 93, 932 mg/kg/day	NOAEL = 47

LOAEL = 93 mg/kg/day based on staggered gait and exaggerated hindlimb
flexion.

870.3200

	21/28-Day dermal toxicity (rabbit)	00141198 (1984)

Acceptable/guideline

0, 22, 44, 88 442 mg/kg/day	NOAEL = 88 mg/kg/day

LOAEL = 442 mg/kg/day based on loss of muscle coordination and increased
incidence of tremors.

870.3700a

	Prenatal developmental in rat (gavage)	00154482 (1983)

Acceptable/non-guideline

0, 0.44, 0.88, 1.77, 2.2 mg/kg/day	Maternal NOAEL = 0.88 mg/kg/day

LOAEL = 1.77 mg/kg/day based on tremors during gestation.

Developmental NOAEL and LOAEL were not established (fetuses were not
examined).

870.3700a

	Prenatal developmental in rat (gavage)	00141201 (1984)

Acceptable/guideline

0, 0.44, 0.88, 1.77 mg/kg/day	Maternal NOAEL = 0.88 mg/kg/day

LOAEL = 1.77 mg/kg/day based on tremors.

Developmental NOAEL = 0.88 mg/kg/day

LOAEL = 1.77 mg/kg/day based on increased fetal and litter incidence of
hydroureter without nephrosis.

870.3700a

	Prenatal developmental in rat (diet)	45352301 (2001)

Acceptable/guideline

0, 2.4, 4.8, 7.1, 15.5 mg/kg/day	Maternal NOAEL = 7.1 mg/kg/day

LOAEL = 15.5 mg/kg/day based on clinical signs and decreased food
consumption, body weight gains, and body weight gains (adjusted for
gravid uterine weight).

Developmental NOAEL = 15.5 mg/kg/day

LOAEL was not established.

870.3700b

	Prenatal developmental in rabbit (gavage)	00145997 (1984)

Acceptable/guideline

0, 2.36, 3.5, 7 mg/kg/day	Maternal NOAEL = 2.36 mg/kg/day,

LOAEL = 3.5 mg/kg/day based on treatment-related head and forelimb
twitching.

Developmental NOAEL =7 mg/kg/day,

LOAEL was not established.

870.3800

	Reproduction and fertility effects

(rat)	00157225 (1986)

Acceptable/guideline

0, 1.5, 3.0, 5.0 mg/kg/day

	Parental/Systemic NOAEL = M/F: 5.0/3.0 mg/kg/day,

LOAEL was not established in males.  In females, LOAEL= 5.0 mg/kg/day
based on tremors and decreased body weights.

Reproductive/ Offspring NOAEL = 5.0 mg/kg/day,

Reproductive/ Offspring LOAEL was not established.

870.4100b

	Chronic toxicity

(dog)	00163065 (1985)

Acceptable/guideline

0, 0.66, 1.3, 2.7, 4.4 mg/kg/day	NOAEL = 1.3 mg/kg/day,

LOAEL= 2.7 mg/kg/day based on increased incidence of tremors.

870.4300

	Chronic/ Carcinogenicity (rat)	00157226 (1986)

Acceptable/guideline

M: 0, 0.6, 2.3, 4.7, 9.7 mg/kg/day

F: 0, 0.7, 3.0, 6.1, 12.7 mg/kg/day 	NOAEL = M/F: 4.7/3.0 mg/kg/day,

LOAEL =M/F: 9.7/6.1 mg/kg/day based on increased incidence of tremors.

No conclusive evidence of carcinogenicity

870.4300

	Chronic/ Carcinogenicity (mouse)	00157227 (1986)

Acceptable/guideline

M: 0, 6.7, 25.6, 65.4, 81.3 mg/kg/day

F: 0, 8.8, 32.7, 82.2, 97.2 mg/kg/day 	NOAEL =M/F: 6.7/8.8 mg/kg/day,

LOAEL = M/F: 25.6/32.7 mg/kg/day based on based on increased incidence
of tremors.

Carcinogenic potential was evidenced by a dose-related increase in the
incidence of leiomyosarcomas in the urinary bladder, a significant
dose-related trend for combined hepatocellular adenomas and carcinomas
in males, and a significantly higher incidence of combined lung adenomas
and carcinomas in females.

870.6200a

	Acute neurotoxicity-rat (gavage)	44862102(1998)

Acceptable/Guideline

0, 9.4, 32.8, 70.3 mg/kg/day	NOAEL = 32.8 mg/kg/day,

LOAEL=70.3 mg/kg/day based on clinical signs of toxicity, FOB findings,
altered motor activity, and mortality (females only).

870.6200b

	Subchronic neurotoxicity screening battery (rat)	44862103 (1998)

Acceptable/Guideline

M:  0, 2.7, 5.6, 11.1 mg/kg/day