Document ID: EPA-HQ-OPP-2006-0875-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-03-25T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:  11/26/2008

SUBJECT:  Fenpropathrin.  Human Health Risk Assessment for the Proposed
Uses on Barley, Stone Fruit (Crop Group 12), Tree Nuts (Crop Group 14),
Pistachio, Caneberries (Crop Subgroup 13-07A), Olive, Avocado, Black
Sapote, Canistel, Mamey Sapote, Mango, Papaya, Sapodilla, and Star Apple
 

 

PC Code:  127901 	DP Barcode:  D313330

Decision No.:  351279	Registration No.:  59639-35 

Petition Nos.:  4E6867, 6E7066, 7E7298	Regulatory Action:  Section 3 

Risk Assess Type:  Single Chemical Aggregate	Case No.:  None 

TXR No.:  None	CAS No.:  39515-41-8

MRID No.:   None 	40 CFR:  180.466

      	

FROM:  	Douglas Dotson, Ph.D., Chemist

		Edward Scollon, Ph.D., Toxicologist

		Margarita Collantes, Biologist

		Anant Parmar, Biologist

		Registration Action Branch 2

	Health Effects Division (7509P)  SEQ CHAPTER \h \r 1 		

		

THROUGH:	Michael Doherty, Ph.D., Chemist

		Linnea Hansen, Ph.D., Biologist

		Suku Oonnithan, Biologist

		Christina Swartz, Branch Chief

	Registration Action Branch 2

Health Effects Division (7509P)

	and

William Donovan, Ph.D., Chemist

Reregistration Branch 3

Health Effects Division (7509P)  SEQ CHAPTER \h \r 1 	

		

TO:		Sidney Jackson/Barbara Madden, RIMUERB

			and

		Olga Odiott, Insecticide Branch

		Registration Division (7505P)



Table of Contents

  TOC \o "1-6" \f  1.0	Executive Summary	4

2.0	Ingredient Profile	8

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc131319175 \h  9 

2.2	Structure and Nomenclature	12

2.3	Physical and Chemical Properties	13

3.0	Hazard Characterization/Assessment	13

3.1 	Hazard and Dose-Response Characterization	13

3.1.1	Database Summary	15

3.1.1.1	Studies Available and Considered	15

3.1.1.2	Mode of Action	15

3.1.2	Dose Response	15

3.1.3	FQPA	16

3.2	Adsorption, Distribution, Metabolism, Excretion (ADME)	16

3.3 	FQPA Considerations	17

3.3.1	Adequacy of the Toxicity Database	17

3.3.2	Evidence of Neurotoxicity	17

3.3.3	Developmental Toxicity Studies	17

3.3.4	Reproductive Toxicity Study	18

3.3.5	Additional Information from Literature Sources	18

3.3.6	Pre- and/or Postnatal Toxicity	18

3.3.6.1	Determination of Susceptibility	18

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre
and/or Post-natal Susceptibility	19

3.3.7	Recommendation for a Developmental Neurotoxicity Study	19

3.4	FQPA Safety Factor for Infants and Children	19

3.5 	Hazard Identification and Toxicity Endpoint Selection	19

3.5.1	Acute Reference Dose (aRfD) - All Populations	19

3.5.2	Chronic Reference Dose (cRfD)	20

3.5.3	Dermal Absorption	20

3.5.4	Dermal Exposure (All Durations)	21

3.5.5	Inhalation Exposure (All Durations)	21

3.5.6	Level of Concern for Margin of Exposure	22

3.5.7	Classification of Carcinogenic Potential	22

3.5.8	Summary of Toxological Doses and Endpoints	22

3.6	Endocrine disruption	23

4.0	Public Health and Pesticide Epidemiology Data	24

4.1	Incident Reports	24

5.0  Dietary Exposure/Risk Characterization	24

5.1	Pesticide Metabolism and Environmental Degradation	24

5.1.1 	Metabolism in Primary Crops	24

5.1.2	Metabolism in Rotational Crops	24

5.1.3 	Metabolism in Livestock	24

5.1.4	Analytical Methodology	25

5.1.5 	Environmental Degradation	25

5.1.6	Comparative Metabolic Profile	25

5.1.7	Toxicity Profile of Major Metabolites and Degradates	26

5.1.8 	Pesticide Metabolites and Degradates of Concern	26

5.1.9	Drinking Water Residue Profile	26

5.1.10	Food Residue Profile	27

5.1.11 	International Residue Limits	29

5.2	Dietary Exposure and Risk	29

5.2.1	Acute Dietary Exposure/Risk	30

5.2.2	Chronic Dietary Exposure/Risk	30

5.2.3	Cancer Dietary Exposure/Risk	31

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information	31

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	31

6.1	Other (Spray Drift, etc.)	31

7.0	Aggregate Risk Assessments and Risk Characterization	32

7.1	Acute Aggregate Risk	32

7.2	Short- and Intermediate-Term Aggregate Risk	32

7.3	Long-Term Aggregate Risk	33

7.4	Cancer Risk	33

8.0	Cumulative Risk Characterization/Assessment	33

9.0	Occupational Exposure/Risk Assessment Pathway	33

9.1	Handler Exposure	34

9.2	Postapplication	36

9.2.1	Exposure and Risk	37

9.2.2	Restricted Entry Interval	37

10.0	Data Needs and Label Recommendations	38

10.1	Toxicology	38

10.2	Residue Chemistry	38

10.3	Occupational and Residential Exposure	39

References:	39

Appendix A:  Fenpropathrin Toxicology	40

Appendix B:  Tolerance Summary for Fenpropathrin	64

 

EXECUTIVE SUMMARY

A human health risk assessment has been conducted to support the
proposed new uses of fenpropathrin [cyano(3-phenoxyphenyl)methyl
2,2,3,3-tetramethylcyclopropanecarboxylate] on barley, stone fruits
(Crop Group 12), tree nuts, (Crop Group 14), pistachio, caneberries
(Crop Subgroup 13-07A), olive, avocado, black sapote, canistel, mamey
sapote, mango, papaya, sapodilla, and star apple.  Fenpropathrin is an
ingestion and contact pyrethroid insecticide and acaricide currently
registered for use on fruit trees, small fruits, vegetables, field
crops, and ornamental plants for the control of various insect pests and
mites.  The Agency received three separate tolerance petitions to
establish permanent tolerances for residues of fenpropathrin in/on the
various raw agricultural commodities, crop groups, and subgroups listed
above.

The formulation proposed for use on the requested crops is Danitol 2.4
EC Spray (EPA Registration Number 59639-35).  The solution is 30.9%
fenpropathrin by weight, or 2.4 pounds of fenpropathrin per gallon of
solution.  Danitol is proposed for multiple foliar spray treatments at
maximum seasonal rates of 0.2 lb ai/A for barley, 0.6 lb ai/A for
caneberries, and 0.8 lb ai/A for stone fruits, tree nuts, and olives as
well as for both tropical and subtropical fruits.  The proposed
preharvest intervals (PHI) range from 1 to 14 days.  For caneberries,
applications may be made using either ground or aerial equipment.  For
all other proposed commodities, applications may be made using ground
equipment only.  The most recent risk assessment performed for
fenpropathrin was completed in September, 2005, when HED recommended in
favor of tolerances for the Fruiting Vegetables Crop Group (Group 8),
succulent peas, and the Bushberry Subgroup (13-B)(Memo, D285421, D.
Dotson, 9/20/2005).

Toxicology

The toxicology database for fenpropathrin is not complete, but it does
provide adequate information to characterize toxicity.  Acute
neurotoxicity, subchronic neurotoxicity, and developmental neurotoxicity
studies, as well as a 21-day dermal study in rats, have been submitted
and reviewed since the most recent risk assessment for fenpropathrin
which was written in 2005.  These studies were classified
acceptable/guideline and were considered during endpoint selection. 
Fenpropathrin database gaps include a 90-day inhalation toxicity study
in rats and an immunotoxicity study.  The 90-day inhalation study was
listed as a data gap in the 2005 risk assessment based on potential
exposure of greenhouse workers.  In response, a justification to waive
the study was submitted to the EPA (MRID 47345610).  The waiver is
currently being considered by HED.  As part of the revised EPA Part 158
Guidelines, an immunotoxicology study in rats must be submitted to the
Agency for review.

The acute toxicity data indicate that fenpropathrin can exhibit high to
low toxicity in rats depending on the route of exposure.  Fenpropathrin
exhibits high toxicity through the oral and dermal routes of exposure
(Categories I and II, respectively).  Acute inhalation toxicity has not
been determined for fenpropathrin.  Because of the chemical’s low
vapor pressure, sufficient test material could not be generated to
elicit a toxic response during the inhalation studies.  Fenpropathrin is
a mild eye irritant (Category III), but does not cause dermal irritation
in rabbits or skin sensitization in guinea pigs.

As with other pyrethroids, fenpropathrin is neurotoxic.  Clinical signs
of toxicity observed in rats and dogs following subchronic exposure
included tremors, ataxia, salivation, and hypersensitivity.  Indications
of neurotoxicity were typically observed within the first few hours to
days following exposure which is characteristic of the short-term,
rather than subchronic, nature of pyrethroids.  Observed decreases in
body weight and food consumption were considered to be more of a general
response to dietary consumption.  Pregnant rats and rabbits exposed to
fenpropathrin during developmental studies also exhibited neurotoxic
signs including tremors, shakiness, unsteadiness, and flicking limbs.

Following chronic dietary exposure to fenpropathrin, no
treatment-related effects were observed in mice.  However, rats and dogs
showed neurotoxic effects that were consistent with the effects that
were seen after subchronic exposures.  There was no evidence of
carcinogenicity in either the rat or mouse long-term dietary studies. 
Fenpropathrin is not mutagenic in bacteria or cultured mammalian cells. 
The chemical is neither clastogenic nor damaging to DNA.  Fenpropathrin
is classified as “not likely to be carcinogenic to humans.”

Rat and rabbit developmental studies, a rat 2-generation study, and a
developmental neurotoxicity study showed no evidence of increased
susceptibility in fetuses following in utero exposure as compared to
maternal animals.  In the absence of quantitative or qualitative
concerns for enhanced sensitivity, the FQPA Safety Factor has been
reduced to 1x.

In an oral metabolism study in rats, greater than 99% of the
administered dose of fenpropathrin was eliminated within 168 hours (7
days) of exposure.  As much as one third of the compound was eliminated
in the urine, with the remaining compound being excreted in the feces. 
After 72 hours, less than 0.5 % remained in other tissue, predominantly
in the fat.  Major metabolic reactions included oxidation,
hydroxylation, cleavage of the ester linkage, and conjugation with
sulfuric or glucuronic acids.  The parent compound was excreted
exclusively through the feces, while major metabolites were excreted in
both the urine and feces.  In the dermal absorption study, elimination
was primarily through the urine and secondarily through the feces.  The
absorption:elimination equilibrium was reached in approximately four
hours in the low-dose group, and in less than 10 hours in the high-dose
group.  In a rat dermal penetration study, mean dermal absorption was
33%, 20%, or 18% at 0.0013, 0.0663, or 1.26 mg/cm2, respectively. 

Metabolic Profile

 

Adequate studies are available depicting the metabolism of
[14C]fenpropathrin in rats, primary crops, rotational crops, and
livestock.  Parent fenpropathrin was the primary residue found in all of
the metabolism studies.  The same metabolites were seen in the confined
rotational crop study as in the primary plant and livestock metabolism
studies as well as in the rat metabolism studies.  The livestock
metabolites were also found in the rat metabolism studies and their
contributions to the overall toxicity of fenpropathrin have been
considered.  In the rat metabolism studies, greater than 99% of the
administered dose was eliminated within 168 hours of exposure.  Major
biotransformations included oxidation at the methyl group of the acid
moiety, hydroxylation at the 4'-position of the alcohol moiety, cleavage
of the ester linkage, and conjugation with sulfuric acid or glucuronic
acid.  Sufficient metabolism data have been submitted.

Parent fenpropathrin is the major metabolite in rats, plant commodities,
and animal commodities, as well as the major degradate in drinking
water.

HED has determined that the residue of concern in plant and animal
commodities for risk assessment is parent fenpropathrin.  Parent
compound is also the residue of concern for risk assessment in drinking
water.  For tolerance expression, parent compound is the residue of
concern in plant and animal commodities.

Residue Chemistry and Dietary Risk Estimates

 

HED evaluated the residue chemistry database for fenpropathrin.  The
residue chemistry data are sufficient to evaluate the nature of residues
in crops and livestock commodities.  With the exception of barley, the
residue chemistry data are sufficient to evaluate the magnitude of the
residues in crops and livestock commodities.  Because the registrant has
not submitted an acceptable barley processing study, HED cannot
recommend in favor of tolerances for barley commodities at the present
time.    

To evaluate acute and chronic dietary risks, HED used information in the
residue chemistry database along with modeled estimates of fenpropathrin
in drinking water to conduct dietary (food + water) exposure
assessments.  Acute and chronic dietary risk assessments were conducted
using the Dietary Exposure Evaluation Model (DEEM-FCID, Version 2.03),
which uses food consumption data from the USDA’s Continuing Surveys of
Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.  The acute
and chronic dietary exposure analyses are both based on the assumption
of 100% crop treated and incorporate conservative estimated drinking
water concentrations (EDWCs) based on the grape use.  The acute dietary
exposure analysis is based on tolerance-level residues for most
commodities and distributions of field trial data for a small number of
commodities (apples, apricots, cherries, grapes, nectarines, peaches,
pears, and plums).  As such, it is conservative with respect to
evaluating potential impacts of acute dietary exposure to fenpropathrin
on human health.  The acute risk estimates for the general U.S.
population and all population subgroups are below HED’s level of
concern (100% of the aPAD).  The chronic dietary analysis is based on
tolerance level residues for most commodities and average field trial
values for a small number of commodities (apples, apricots, cherries,
grapes, nectarines, peaches, pears, and plums).  As with the acute
assessment, the risk estimates are all below HED’s level of concern
(100% of the cPAD).  

Tolerance Harmonization

There are no tolerance harmonization issues associated with these
tolerance petitions.  Codex and Mexican MRLs are established for
residues of fenpropathrin (expressed as fenpropathrin per se for Codex
and fenpropathrin for Mexico), but no MRLs have been established for any
of the crop commodities addressed in this risk assessment.  No Canadian
MRLs are established for fenpropathrin.  

Residential Exposure

Currently there are no residential uses associated with fenpropathrin,
and no new residential uses are proposed. 

Aggregate Exposure

As there are no residential uses associated with fenpropathrin, dietary
sources are the only sources of exposure to the chemical.  The exposure
and risk estimates are equivalent to those determined in the dietary
exposure analysis.  Acute and chronic risk estimates are all below
HED’s level of concern.

Occupational Exposure

	

MOEs ≥ 100) if chemical-resistant gloves are worn in addition to
baseline attire (i.e., long-sleeve shirt, long pants, shoes, and socks).
 Postapplication exposures resulting from use of fenpropathrin on all
the proposed crops resulted in MOEs greater than 100 on Day 0
(immediately after application) and, therefore, are not of concern to
HED.  When postapplication risks are not a concern on day 0 (12 hours
following application), the restricted entry interval (REI) is based on
the acute toxicity of the active ingredient.  Fenpropathrin exhibits
high acute toxicity through the dermal route of exposure and is,
therefore, classified as being in Category II.  It does not cause dermal
irritation in rabbits or skin sensitization in guinea pigs and
therefore, is not a dermal sensitizer.  Under the Worker Protection
Standard for Agricultural Pesticides, active ingredients classified as
being in acute toxicity category II for dermal toxicity are assigned a
24-hour REI.  HED concurs with the proposed label for Danitol 2.4 EC
Spray, which specifies a REI of 24 hours.

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, “Federal Actions to
Address Environmental Justice in Minority Populations and Low-Income
Populations,”
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups, and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, nondietary exposures based on home-use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, and have received that review.  The studies in PHED
were considered appropriate (or ethically conducted) for use in risk
assessments.

Conclusions

HED concludes that the registrant has submitted adequate data for the
Agency to make the safety finding with respect to the use of
fenpropathrin on the proposed commodities with the exception of barley. 
With the exception of the deficiencies listed in Section 10, Data Needs
and Label Recommendations, the toxicology, residue chemistry, and
occupational databases are adequate for the purposes of the current
tolerance petitions.  HED recommends that RD grant conditional
registrations for fenpropathrin, and that permanent tolerances be
established for the residues of fenpropathrin,
cyano(3-phenoxyphenyl)methyl 2,2,3,3-tetramethylcyclopropanecarboxylate,
in or on the proposed commodities except barley.  The recommended
tolerances are given in Table B.1 of Appendix B, Tolerance Summary for
Fenpropathrin.

2.0	INGREDIENT PROFILE  TC \l1 "2.0	Ingredient Profile 

Fenpropathrin is an ingestion and contact pyrethroid insecticide and
acaricide currently registered for use on fruit trees, vegetables, field
crops, and ornamental plants for the control of various insect pests and
mites.  The formulation proposed for use on the requested crops is
Danitol 2.4 EC Spray.  The solution is 30.9% fenpropathrin by weight, or
2.4 pounds of fenpropathrin per gallon of solution.  Danitol is proposed
for multiple foliar spray treatments at maximum seasonal rates of:  0.2
lb ai/A for barley; 0.6 lb ai/A for caneberrries; and 0.8 lb ai/A for
stone fruits, tree nuts, olives, and tropical and subtropical fruits. 
The proposed preharvest intervals (PHI) range from 1 to 14 days. The
requested uses for fenpropathrin are summarized in Table 2.1.

2.1	Summary of Registered/Proposed Uses  TC \l2 "2.1	Summary of
Registered/Proposed Uses 

Tolerances for residues of fenpropathrin are established in 40 CFR
§180.466.  The tolerance expression is in terms of fenpropathrin per
se.  Tolerances have been established on a wide range of plant and
animal commodities.  The tolerances for plant commodities range from
0.01 ppm in peanut to 75 ppm in citrus oil.  Of note is a tolerance of
3.0 ppm for the Bushberry Subgroup (13-B).  IR-4 is currently proposing
a tolerance of 12 ppm for the Caneberry Subgroup (13-A).  Tolerances for
animal commodities range from 0.05 ppm (egg, and the fat, meat, and meat
byproducts of poultry) to 2.0 ppm (milk fat, reflecting 0.08 ppm in
whole milk).  A time-limited tolerance with an expiration date of
12/31/08 is established under 40 CFR §180.466(b) for currant at 15 ppm.

Table 2.1.   Summary of Directions for Use of Fenpropathrin.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

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

(lb ai/A)	PHI

(days)	Use Directions and Limitations

PP#4E6867

Stone Fruits:  apricots, cherries, nectarines, peaches, plums, and
prunes

Foliar spray

Ground	2.4 lb/gal EC

[59639-35]	0.2-0.4	2	0.8	3	Ground applications are to be made in 100-400
gal/A using airblast equipment with a minimum retreatment interval (RTI)
of 10 days.  The feeding or grazing of livestock on cover crops from
treated orchards is prohibited.  For resistance management, it is
generally recommended that no more than two applications of the 2.4
lb/gal EC formulation be made per season.  Use non-pyrethroid products
at other timings to control pests.

Tree Nuts:  almonds, beechnuts, Brazil nuts, butternuts, cashews,
chestnuts, chinquapin, filberts (hazelnuts), hickory nuts, macadamia
nuts, pecans, pistachios, and walnuts

Foliar spray

Ground	2.4 lb/gal EC

[59639-35]	0.2-0.4	2	0.8	3	Ground applications are to be made in 50-400
gal/A using airblast equipment with a minimum RTI of 10 days.  The
feeding or grazing of livestock on cover crops from treated orchards is
prohibited.  For resistance management, it is generally recommended that
no more than two applications of the 2.4 lb/gal EC formulation be made
per season.  Use non-pyrethroid products at other timings to control
pests.

PP#6E7066

Barley

Foliar spray

Ground	2.4 lb/gal EC

[59639-35]	0.2	1	0.2	14	Make a single ground application in the pre-boot
stage in a minimum of 5 gal/A.  For resistance management, it is
generally recommended that no more than one application of the 2.4
lb/gal EC formulation be made per season.  Use non-pyrethroid products
at other timings to control pests.

Tropical and sub tropical fruits (inedible peel) including but not
limited to avocado, canistel, mango, papaya, sapodilla, black sapote,
mamey sapote, star apple

Foliar spray

Ground	2.4 lb/gal EC

[59639-35]	0.3-0.4	2

(implied)	0.8	1	Ground applications are to be made in 100 gal/A with a
minimum RTI of 14 days.  For resistance management, it is generally
recommended that no more than one application (avocado) or two
applications (other crops) of the 2.4 lb/gal EC formulation be made per
season.  Use non-pyrethroid products at other timings to control pests.

PP#7E7298

Caneberries:  blackberry (including bingleberries, boysenberries,
dewberries, lowberries, marionberries, olallieberries, youngberries);
loganberries; and raspberries (black and red)

Foliar spray

Ground or aerial	2.4 lb/gal EC

[59639-35]	0.2-0.3	2	0.6	3	Applications are to be made in ≥20 gal/A
using ground equipment or 3-10 gal/A using aerial equipment with a
minimum RTI of 14 days.  For resistance management, it is generally
recommended that no more than two applications of the 2.4 lb/gal EC
formulation be made per season.  Use non-pyrethroid products at other
timings to control pests.  

Olive

Foliar spray

Ground	2.4 lb/gal EC

nd applications are to be made in ≥100 gal/A with a minimum RTI of 14
days.  

The following general use directions are listed on the draft labels for
Danitol® 2.4 EC Spray:  Application as an ultra low volume (ULV) spray
or through any type of irrigation system is prohibited.  There are no
restrictions on rotational crops listed on the proposed labels.  A
24-hour REI is specified.

The submitted use directions are sufficient to allow evaluation of the
submitted residue data relative to the proposed use.  However, label
revisions are needed to reflect the appropriate preharvest intervals for
barley commodities.  Based on the submitted field trial data, the label
for Danitol® should be amended to specify PHIs of 15 days for barley
hay and 45 days for barley grain and straw.

The proposed label for tropical fruits states the following with respect
to the proposed commodities:  “Tropical and Subtropical Fruit
(Inedible Peel) – including but not limited to:  Avocado, Canistel,
Mango, Papaya, Sapodilla, Black Sapote, Mamey Sapote, Star Apple.” 
The words “including but not limited to” must be removed from the
label.  The Agency anticipates that, at some point in the future, a crop
group or subgroup will be established for the tropical and subtropical
fruits with inedible peels.  Until such time as that crop group/subgroup
is established, however, registrants will be required to submit separate
requests for each individual fruit.

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature 

)-α-cyano-3-phenoxybenzyl 2,2,3,3-tetramethylcyclopropanecarboxylate

CAS name	Cyano(3-phenoxyphenyl) methyl
2,2,3,3-tetramethylcyclopropanecarboxylate

CAS registry number	39515-41-8

End-use product (EP)	2.4 lb/gal EC formulation (Danitol® 2.4 EC Spray;
EPA Reg. No. 59639-35)

2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties 

Table 2.3.	   Physicochemical Properties of Fenpropathrin.

Parameter	Value	Reference

Melting point/range	45-50ºC (113-122ºF)	DP# 315918, W. Cutchin,
9/20/05

pH	4-5 (1% emulsion)

	Density g/cm3	1.103

	Water solubility (25ºC)	0.33 ppm

	Solvent solubility (mg/L at 25ºC)	Xylene, cyclohexanone:  1000

Methanol:  337

	Vapor pressure at 25ºC	0.730 mPa

	Dissociation constant, pKa	NA

	Octanol/water partition coefficient, Log(KOW)	5.1

	UV/visible absorption spectrum	NA

	

3.0	HAZARD CHARACTERIZATION/ASSESSMENT

Hazard and Dose-Response Characterization

 an α-cyano-phenoxy-benzyl substituent.  Pyrethroids are known
neurotoxins.  They have been shown to act on the sodium channel,
inhibiting the proper flow of sodium ions to the axon, thus causing the
nerve cells to repetitively discharge, eventually leading to paralysis. 
In insects, these effects are produced in the nerve chord and giant
nerve fiber axons.  This phenomenon shows a negative temperature
differential which may contribute to the differential toxicity seen in
insects versus mammals.

  SEQ CHAPTER \h \r 1 The acute toxicity data indicate that, in rats,
fenpropathrin can exhibit high to low toxicity depending on the route of
exposure.  Fenpropathrin exhibits high toxicity through the oral and
dermal routes of exposure (Categories I and II, respectively).  In
contrast, the dermal LD50 in rabbits was more than twice as high as it
was in rats, suggesting that rabbits are less sensitive to fenpropathrin
than are rats.  Acute inhalation toxicity has not been determined for
fenpropathrin.  Because of the chemical’s low vapor pressure,
sufficient test material could not be generated to elicit a toxic
response during the inhalation studies.  Fenpropathrin is a mild eye
irritant (Category III), but does not cause dermal irritation in rabbits
or skin sensitization in guinea pigs.  

As with other pyrethroids, fenpropathrin is neurotoxic.  Clinical signs
of toxicity observed in rats and dogs following subchronic exposure
included tremors, ataxia, salivation, and hypersensitivity.  Decreased
body weights and food consumption are more general responses to dietary
consumption in rats and dogs.  Pregnant rabbits exposed to fenpropathrin
during a developmental study also exhibited neurotoxic signs including
tremors, shakiness, unsteadiness, and flicking limbs.

Following chronic dietary exposure to fenpropathrin, no
treatment-related effects were observed in mice.  Following chronic
exposure, rats and dogs showed evidence of neurotoxicity that was
consistent with the effects that were seen after subchronic exposures. 
There was no evidence of carcinogenicity in either the rat or mouse
long-term dietary studies.  Fenpropathrin is not mutagenic in bacteria
or cultured mammalian cells.  This chemical is neither clastogenic nor
damaging to DNA.  Fenpropathrin is classified as “not likely to be
carcinogenic to humans.”

Developmental studies in rats and rabbits showed no evidence of
increased susceptibility in fetuses as compared to maternal animals
following exposure to fenpropathrin in utero.  Maternal animals of both
species exhibited clinical signs of neurotoxicity.  In rats, reduced
body weight gains were also present.  In neither study did dose-related
changes in fecundity, fertility, implantations, number of abortions, or
early or late resorptions occur.  The only anomaly noted for either
species was an increased incidence of asymmetrical or incomplete
ossification of the fifth or sixth sternebrae in rat fetuses.  A
two-generation reproduction study in rats, likewise, did not show an
increased sensitivity to fenpropathrin in pups as compared to adults. 
There are no residual uncertainties for pre- and/or post-natal toxicity.
 In the absence of quantitative or qualitative concerns for enhanced
sensitivity after exposure to fenpropathrin, the FQPA Safety Factor was
reduced to 1x.

Fenpropathrin did not produce systemic or dermal toxicity following
repeated exposure in rats and rabbits.

In an oral metabolism study in rats, greater than 99% of the
administered dose of fenpropathrin was eliminated within 168 hours (7
days) of exposure.  As much as one third of the compound was eliminated
in the urine, with the remaining compound being excreted in the feces. 
After 72 hours, more than 99% of the urinary and fecal elimination had
occurred.  Less than 0.5% of the radiolabel was found in the tissues,
predominately in the fat.  No radiolabel was found in the heart, lung,
spleen, gonads, and brain, and only traces were found in the blood,
kidney, liver, muscle, bone, and carcass.  Major biotransformations
included oxidation at the methyl group of the acid moiety, hydroxylation
at the 4'-position of the alcohol moiety, cleavage of the ester linkage,
and conjugation with sulfuric acid or glucuronic acid.  The parent
compound was excreted exclusively through the feces, while major
metabolites were excreted in both the urine and feces.  In the dermal
absorption study, elimination was primarily through the urine and
secondarily through the feces.  The absorption:elimination equilibrium
was reached in approximately four hours in the low dose group, and in
under 10 hours in the high dose group.  In a rat dermal penetration
study, mean dermal absorption was 33.3%, 20.1%, or 17.6% at 0.0013,
0.0663, or 1.26 mg/cm2, respectively.  The body burden of this chemical
could be expected to decrease rapidly upon cessation of treatment.

There is no evidence that fenpropathrin induces endocrine disruption.

3.1.1	Database Summary

The database for fenpropathrin is not complete, but it does provide
adequate information to characterize toxicity.  Acute neurotoxicity,
subchronic neurotoxicity, and developmental neurotoxicity studies have
been submitted and reviewed since the previous risk assessment (Memo,
D285421, D. Dotson, 9/20/2005).  These studies were classified
acceptable/guideline and were considered during endpoint selection. 
Fenpropathrin database gaps include a 90-day inhalation toxicity study
in rats and an immunotoxicity study.  The 90-day inhalation study was
listed as a data gap in the 2005 risk assessment based on potential
exposure to greenhouse workers (HIARC, 12/22/2003).  In response, a
justification to waive the study was submitted to the EPA (MRID
47345610).  The waiver is currently being considered by HED.  As part of
the revised EPA Part 158 Guidelines, an immunotoxicology study in rats
must be submitted to the Agency for review.  However, because there was
no indication of immunotoxicity in the toxicity database, an additional
10x database uncertainty factor is not considered necessary in order to
be protective of potential immunotoxic effects.

3.1.1.1 Studies Available and Considered (Animal, Human, General
Literature)

The acceptable/guideline studies available for risk assessment included:
1) 90-day subchronic oral toxicity studies in rats and dogs; 2) 21-day
dermal studies in rats and rabbits; 3) developmental studies in rats and
rabbits, as well as a 2-generation reproduction study in rats; 4)
chronic and/or carcinogenicity studies in rats, mice, and dogs; and 5)
neurotoxicity studies in rats (acute, subchronic, and developmental); 6)
single and repeated-dose rat metabolism studies; 7) mutagenic battery. 
A dermal penetration study was available to determine a dermal
absorption factor for risk assessment.

3.1.1.2	Mode of Action

  SEQ CHAPTER \h \r 1 Fenpropathrin is a member of the pyrethroid class
of insecticides.  It contains an α-cyano-phenoxy-benzyl substituent. 
It is more effective in biological systems at lower temperatures, which
may account for the differential toxicity seen in insects versus
mammals.  While the exact location and mode of action of pyrethroids is
not clear, pyrethroids are known neurotoxins.  It is likely that
pyrethroids act by blocking the nerve axons, as this phenomenon shows a
negative temperature differential.  Pyrethroids are also known to act on
the sodium channel, inhibiting the proper flow of sodium ions to the
axon, thus causing the nerve cells to repetitively discharge, eventually
leading to paralysis.  In insects, these effects are produced in the
nerve chord and giant nerve fiber axons.

3.1.2.	Dose Response

Fenpropathrin targeted the nervous system in acute, subchronic, and
chronic oral toxicity studies in rats (LOAEL range 6-50 mg/kg/day) and
in the subchronic and chronic studies in dogs (LOAEL approximately 6.25
mg/kg/day).  Neurotoxic effects were absent in mice in the
carcinogenicity study up to the highest dose tested of 65 mg/kg/day. 
Clinical signs in rats included tremor and ataxia (both observed in dogs
as well), sensitivity to external stimuli, spastic jumping, and flicking
of extremities.  Clinical signs were evident within several hours
post-dosing.  Mortality was observed in females in the developmental and
2-generation rat studies as well as in the chronic/carcinogenicity rat
study either at the LOAEL or at slightly higher doses in the presence of
signs of neurotoxicity (dose range 10-19.45 mg/kg/day), indicating a
tight dose-response curve.  Mortality occurred as early as the first
week of treatment in the developmental rat study.

Fenpropathrin toxicity and severity did not increase greatly with
duration.  In the acute neurotoxicity screening battery in rats, the
LOAEL was 30 mg/kg/day, based on slight tremors and convulsions in both
sexes.  Subchronic LOAELs ranged from 6 to 50 mg/kg/day, with a mean of
25 mg/kg/day.  These LOAELs were based on neurotoxicity tremors, ataxia,
convulsions, sensitivity to stimuli, spastic jumping, and mortality. 
The chronic/carcinogenicity study in rats produced a LOAEL of 19.45
mg/kg/day, based on tremors and mortality.  In the subchronic and
chronic studies in dogs, the LOAELs were comparable at 6.2 and 6.25
mg/kg/day, respectively, based on ataxia and tremors.

3.1.4	FQPA

There is no concern for pre-and/or post-natal toxicity resulting from
exposure to fenpropathrin.  There is no evidence (qualitative or
quantitative) of increased susceptibility following in utero and/or
pre-/post-natal exposure in adequate developmental toxicity studies in
rats or rabbits, a two-generation reproduction study in rats, and a
developmental neurotoxicity study in rats.  

There are no concerns or residual uncertainties for pre- and post-natal
toxicity, based on the submitted guideline study results.  Therefore,
the FQPA Safety Factor was reduced to 1x.

Absorption, Distribution, Metabolism, Excretion (ADME)

In an oral metabolism study in rats, greater than 99% of the
administered dose of fenpropathrin was eliminated within 168 hours (7
days) of exposure.  As much as one third of the compound was eliminated
in the urine, with the remaining compound being excreted in the feces. 
Major biotransformations included oxidation at the methyl group of the
acid moiety, hydroxylation at the 4'-position of the alcohol moiety,
cleavage of the ester linkage, and conjugation with sulfuric acid or
glucuronic acid.  The parent compound was excreted exclusively through
the feces, while major metabolites were excreted in both the urine and
feces.  In the dermal absorption study, elimination was primarily
through the urine and secondarily through the feces.  The
absorption:elimination equilibrium was reached in approximately four
hours in the low dose group, and in under 10 hours in the high dose
group.  In a rat dermal penetration study, mean dermal absorption was
33.3%, 20.1%, or 17.6% at 0.0013, 0.0663, or 1.26 mg/cm2, respectively. 
The body burden of this chemical could be expected to decrease rapidly
upon cessation of exposure.

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database

  SEQ CHAPTER \h \r 1 The toxicology database for fenpropathrin is
adequate for an FQPA assessment based on the following considerations:
(1) developmental toxicity studies in rats and rabbits were
acceptable/guideline,  (2) a two-generation reproduction toxicity study
in rats was acceptable/guideline, and (3) a developmental neurotoxicity
study in rats was acceptable/guideline.

3.3.2	Evidence of Neurotoxicity

Neurotoxicity was observed throughout the entire toxicology database in
rats, dogs, and rabbits.  In the subchronic and chronic exposure studies
in rats, neurotoxicity was present in the form of tremors, ataxia,
sensitivity to external stimuli, and spastic jumping.  Clinical signs
were more predominant in females than males in the 2-generation
reproduction study, subchronic oral toxicity study, developmental
toxicity study, and chronic/carcinogenicity study in rats.  In the
subchronic dog study, tremors were observed in both sexes.  In the
chronic dog study, ataxia was also observed in both sexes.  Female
rabbits in the developmental study showed signs of neurotoxicity with
repeated flicking of the forepaws.

Since the previous risk assessment, acceptable/guideline acute,
subchronic, and developmental neurotoxicity studies have been submitted
to the Agency and reviewed by HED.  In the acute neurotoxicity study in
rats, a single dose of 30 mg/kg produced slight tremors and whole body
tremors in both males and females approximately 3 hours post-dosing.  A
repeat functional observational battery on day 7 post-exposure showed no
evidence of prolonged neurotoxic effects.  In the subchronic
neurotoxicity screening battery, tremors, convulsions, impaired gait,
and FOB findings were observed in both sexes, predominantly the females.
 In the developmental neurotoxicity study in rats, maternal animals
exhibited tremors during lactation at a dose of 40 mg/kg/day.  No
neurotoxicity was observed in the same females during gestation at an
average dose of 19 mg/kg/day.  Pups were born with small body size and
decreased body weight and showed slower body weight gains than controls
during lactation.  Average body weights and body weight gains returned
to control values shortly after weaning.  Neurotoxicity was evident in
the pups as an increased mean overall maximum startle response amplitude
and average response amplitude in females (post-natal day (PND) 60), and
decreased absolute brain weights in males.  

3.3.3	Developmental Toxicity Studies

In the rat developmental toxicity study, developmental effects occurred
at a dose that was higher than the dose that caused maternal toxicity. 
Increased incidence of asymmetrical ossification of sternebrae and
incomplete ossification of the 5th and 6th sternebrae were observed in
the fetuses at 10 mg/kg/day.  The maternal LOAEL was 6 mg/kg/day, based
on decreased food consumption and body weight gains.  At 10 mg/kg/day,
the dose at which fetal effects were observed, maternal animals also
exhibited neurotoxic clinical signs including ataxia, sensitivity to
external stimuli, spastic jumping, tremors, and mortality.  These signs
were most severe 2 hours post-dosing and during the first few days of
exposure.  Mortality occurred primarily on gestation days 7-13 and in
the presence of neurotoxicity.  There was no evidence of increased
susceptibility in this study.

In the study in rabbits, no developmental effects were seen at the
highest dose tested.  Neurotoxicity was observed in the maternal animals
at the high dose in the form of repeated flicking of the forepaws. 
There was no evidence of increased susceptibility.

In the developmental neurotoxicity study in rats, effects on the
offspring (small size, decreased body weights, and body weight gains
pre-weaning) were noted in the presence of maternal toxicity.  Evidence
of neurotoxicity in pups at 19/40 mg/kg/day (gestation/lactation,
respectively) included increased mean overall maximum startle response
amplitude and average response time in the females and decreased
absolute brain weights in the males.  Maternal animals at this dose
level showed signs of neurotoxicity in the form of tremors,
predominantly during lactation when the average daily dose was higher. 
There were no signs of increased susceptibility.

3.3.4	Reproductive Toxicity Study

Maternal effects in the 2-generation reproduction study in rats included
body tremors, spasmodic muscle twitches, sensitivity to external
stimuli, and mortality, predominately in females, at 8.9/10.1 mg/kg/day
(M/F, respectively).  At the high dose group, clinical signs and
mortality occurred mostly during lactation in the F0 and F1B maternal
animals.  There was no evidence of neurotoxicity or mortality in males
at the high dose level.  Offspring effects at the 8.9/10.1 mg/kg/day
included body tremors and mortality.  The deaths in two pups of the F2
generation were not considered to be evidence of qualitative increased
susceptibility as (1) the deaths occurred at the same dose that caused
severe maternal toxicity (i.e., maternal deaths and neurotoxic clinical
signs) and, (2) the deaths occurred during lactation (days 19 and 21)
when these pups were exposed to the compound via the milk and the diet. 

3.3.5	Additional Information from Literature Sources

No outside literature has been used at this time to characterize
potential risks.

3.3.6	Pre-and/or Postnatal Toxicity

3.3.6.1	Determination of Susceptibility

There is no evidence of increased qualitative or quantitative
susceptibility in fetuses exposed in utero and/or post-natally to
fenpropathrin.

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility

There is no evidence of increased susceptibility of fetuses exposed in
utero and/or post-natally; there are no residual concerns or
uncertainties for pre- and post-natal toxicity.

3.3.7	Recommendation for a Developmental Neurotoxicity Study

An acceptable/guideline DNT study has been submitted to the Agency and
reviewed by HED.  This study was available for endpoint selection.

3.4	FQPA Safety Factor for Infants and Children

After evaluating the toxicological and exposure data, the fenpropathrin
risk assessment team 

recommends that the FQPA Safety Factor be reduced to 1x based on the
following:

The toxicological database for fenpropathrin is adequate for FQPA
determination.

  

The toxicity data, including a developmental neurotoxicity study, showed
no increase in qualitative or quantitative susceptibility in fetuses and
pups with in utero and/or post-natal exposure.

The dietary drinking water assessment is based on values generated by a
model and associated modeling parameters that are designed to provide
conservative, health protective, upper bound estimates of water
concentrations.

The dietary exposure analysis is based on conservative assumptions
concerning fenpropathrin residues in food and drinking water and, as a
result, does not underestimate dietary exposure to fenpropathrin. 

No residential uses are proposed at this time.

3.5	Hazard Identification and Toxicity Endpoint Selection

Acute Reference Dose (aRfD) – All Populations

Study Selected:    SEQ CHAPTER \h \r 1 Developmental Toxicity Study in
Rats

	MRID No.:	  SEQ CHAPTER \h \r 1 41525903

Dose and Endpoint for Risk Assessment:  Maternal NOAEL = 6 mg/kg/day,

LOAEL = 10 mg/kg/day, based on clinical signs including ataxia,
sensitivity to external stimuli, spastic jumping, and tremors.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors:

  SEQ CHAPTER \h \r 1 The maternal NOAEL for the developmental rat study
was 3.0 mg/kg/day based on decreased food consumption and body weight
gains.  However, these effects are not characteristic of an acute
exposure and are not a suitable option for this exposure scenario.  One
of the factors to consider in selecting an acute dietary endpoint is the
point at which the toxic effects occur.  For an acute effect, a relevant
endpoint would occur as the result of a single dose.  As the neurotoxic
signs observed in the dams in the high dose group of the developmental
rat study were most severe within two hours of dosing, the clinical
effects are resultant from a single dose and, therefore, are appropriate
endpoints for acute exposure scenarios. 

3.5.2	Chronic Reference Dose (cRfD)

	

            Study Selected:    SEQ CHAPTER \h \r 1 52-Week Chronic Oral
Toxicity Dog Study

	MRID No.:    SEQ CHAPTER \h \r 1 00143130

Dose and Endpoint for Risk Assessment:  NOAEL = 2.5 mg/kg/day, LOAEL =
6.25 mg/kg/day, based on tremors and ataxia in both sexes.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Chronic RfD = 2.5 mg/kg/day = 0.025mg/kg/day

100 (UF)

Comments about Study/Endpoint/Uncertainty Factors:

  SEQ CHAPTER \h \r 1 It was determined by the risk assessment team that
this study has the lowest LOAEL of the chronic studies, and that the
NOAEL (3 mg/kg/day) of the two-generation reproduction study (MRID No.
00163817) is comparable to the NOAEL of this 52-week dog study. 
Consistent with other type II pyrethroids, neurotoxic effects occurred
early and throughout the study.

3.5.3	Dermal Absorption

A dermal penetration study (MRID 43433801) showed that dermal absorption
increased with dose.  However, the percentage of the dose absorbed
decreased with increasing dose administered, i.e., mean dermal
absorption for the 10-hour interval was 33.3%, 20.1%, and 17.6% in the
low, mid, and high dose groups, respectively.  The total body burden of
fenpropathrin could be expected to decrease rapidly because of excretion
via the urine and feces.  

The risk assessment team decided that a dermal absorption factor of
33.3% should be used for all dermal risk scenarios.

Two 21-day dermal toxicity studies were submitted for fenpropathrin. 
One of these was in rats (MRID 47325602) and the other was in rabbits
(MRID 00127366).  Neither study showed evidence of systemic or dermal
toxicity up to the limit dose of 1000 mg/kg/day.  However, as dermal
studies are not designed to look at developmental effects in pups
exposed in utero, and because developmental effects are of concern for
this chemical, the risk assessment team has decided to select an
endpoint for risk assessment from the oral studies and use the dermal
absorption factor.

3.5.4	Dermal Exposure (All Durations)

Study Selected:  2-generation reproduction study in rats	

	MRID No.:	00163817

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 3.0 mg/kg/day,

LOAEL = 8.9/10.1 mg/kg/day (M/F, respectively) based on increased
mortality and body tremors in the offspring

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors:

The offspring NOAEL was selected for dermal risk assessment to be
protective of potential developmental effects that, because of the
limitations in scope, were not assessed in the dermal toxicity studies
in rats or rabbits.  Because the clinical signs and mortality occurred
on PND 19-21, the duration of exposure was considered to be comparable
to the short-term (1-30 day) exposure scenario.  This dose is similar to
the NOAEL from the chronic dog study of 2.5 mg/kg/day, which was based
on ataxia and tremors seen at 6.25 mg/kg/day.  Therefore, as the
selected endpoint is protective of the developmental effects of concern,
and because the NOAEL and LOAEL from the chronic dog study are similar
to the NOAEL and LOAEL from the 2-generation study, this dose and
endpoint are acceptable for use in intermediate- and long-term risk
assessment scenarios.  A 33.3% dermal absorption factor should be used
in all dermal risk assessment scenarios.

Inhalation Exposure (All Durations)

No inhalation toxicity study was submitted.  

Study Selected:  2-generation reproduction study in rats	

	MRID No.:	00163817

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 3.0 mg/kg/day,
LOAEL = 8.9/10.1 mg/kg/day (M/F, respectively) based on increased
mortality and body tremors in the offspring

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

     

Comments about Study/Endpoint/Uncertainty Factors:

The offspring NOAEL was selected for inhalation risk assessment to be
protective of potential developmental effects.  No inhalation studies
were available.  Because the clinical signs and mortality occurred on
PND 19-21, the duration of exposure was considered to be comparable to
the short-term (1-30 day) exposure scenario.  This dose (3.0 mg/kg/day)
is similar to the NOAEL from the chronic dog study (2.5 mg/kg/day),
which was based on ataxia and tremors seen at 6.25 mg/kg/day. 
Therefore, as the selected endpoint is protective of the developmental
effects of concern, and because the NOAEL and LOAEL from the chronic dog
study are similar to the NOAEL and LOAEL from the 2-generation study,
this dose and endpoint are acceptable for use in intermediate- and
long-term risk assessment scenarios.  A 100% default inhalation
absorption factor should be used in all inhalation risk assessment
scenarios.

3.5.6	Level of Concern for Margin of Exposure

Table 3.5.6 summarizes the level of concern (LOC) for margin of exposure
(MOE) for fenpropathrin risk assessment.  For occupational assessment
for fenpropathrin, MOEs below 100 represent a risk concern for HED.

Table 3.5.6.  Summary of Levels of Concern for Risk Assessment

Route	Short-Term

(1-30 Days)	Intermediate-Term

(1-6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	100

Inhalation	100	100	100

Residential Exposure

There are no proposed or registered residential uses for fenpropathrin.

3.5.7	Classification of Carcinogenic Potential

  SEQ CHAPTER \h \r 1 There was no evidence of carcinogenicity in either
the rat or mouse long-term dietary studies.  Fenpropathrin is not
mutagenic in bacteria or cultured mammalian cells.  This chemical is
neither clastogenic nor damaging to DNA.  Fenpropathrin is classified as
“not likely to be carcinogenic to humans,” in accordance with the
EPA Final Guidance for Carcinogen Risk Assessment (3/29/2005).

3.5.8	Summary of Toxicological Doses and Endpoints for Fenpropathrin for
Use in Human Risk Assessments

Table 3.5.8.a. Toxicological Doses and Endpoints for Fenpropathrin for
Use in Dietary and

Non-Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (All populations)	NOAEL = 6.0 mg/kg/day

	UFA = 10x

UFH = 10x

FQPA SF = 1x 	Acute RfD = 6.0mg/kg/day

aPAD = 0.06 mg/kg/day

	Study: Rat Developmental Study

LOAEL = 10 mg/kg/day, based on clinical signs in maternal animals
including ataxia, sensitivity to stimuli, spastic jumping, and tremors
two hours post-dosing

Chronic Dietary (All Populations)	NOAEL = 2.5 mg/kg/day	UFA = 10x

UFH = 10x

FQPA SF = 1x	Chronic RfD = 2.5 mg/kg/day

cPAD = 0.025 mg/kg/day	Study: Chronic Dog Study

LOAEL =  6.25 mg/kg/day, based on tremors and ataxia beginning during
week 6 of testing

Cancer (oral, dermal, inhalation)	

  SEQ CHAPTER \h \r 1 Classification: Not likely to be carcinogenic to
humans

  TC \l3 "3.5.10	Classification of Carcinogenic Potential NOAEL = no
observed adverse effect level.  LOAEL = lowest observed adverse effect
level.  UF = uncertainty factor.  UFA = extrapolation from animal to
human (interspecies).  UFH = potential variation in sensitivity among
members of the human population (intraspecies).  FQPA SF = FQPA Safety
Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD =
reference dose.   

Table 3.5.b.  Summary of Toxicological Doses and Endpoints for
Fenpropathrin for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal

All Durations 	NOAEL =  3.0 mg/kg/day

DAF = 33.3%	UFA = 10x

UFH = 10x

FQPA SF = 1x	MOE = 100	Study: 2-gen Reproduction Study 

LOAEL = 8.9/10.1 mg/kg/day (M/F), based on clinical signs and mortality
in offspring

Inhalation 

All Durations	NOAEL =  3.0 mg/kg/day

IAF=100%	UFA = 10x

UFH = 10x

FQPA SF = 1x	MOE = 100	Study: 2-gen Reproduction Study 

LOAEL = 8.9/10.1 mg/kg/day (M/F), based on clinical signs and mortality
in offspring

Cancer (oral, dermal, inhalation)	  SEQ CHAPTER \h \r 1 Classification: 
Not likely to be carcinogenic to humans

Dermal Absorption	Mean dermal absorption was 33.3% at 10 hours
post-dosing (MRID 43433801)

NOAEL = no observed adverse effect level.  LOAEL = lowest observed
adverse effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (interspecies).  UFH = potential variation in
sensitivity among members of the human population (intraspecies).  MOE =
margin of exposure.  DAF=dermal absorption factor, IAF=inhalation
absorption factor.

3.6	Endocrine Disruption

EPA is required under the 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 Screening 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 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).

4  TC \l2 "4.1	Hazard Characterization   TC \l3 "4.4.1   Acute
Reference Dose (aRfD) - Females age 13-49 .0	PUBLIC HEALTH and PESTICIDE
EPIDEMIOLOGY DATA  TC \l1 "5.0	Public Health Data 

4.1	Incident Reports

For fenpropathrin, 43 incidents were reported to the American
Association of Poison Control Centers from 1993-2005.  Of those 43, 3
were classified as having a moderate severity, the rest were either of
minor or no severity (there were no incidents classified as major
severity or death).  About half of the incidents occurred in a
residential environment (21 in a residence, 2 in a public area) and the
rest at the workplace (18).  Two incidents were not classified with
respect to exposure site.  The fenpropathrin risk assessment team
interprets this information to indicate that the registered uses for
this chemical are safe, and that the risk assessment is protective.

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

5.1	Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops

The nature of the residue in plants is adequately understood.  Adequate
metabolism studies were conducted on at least three dissimilar crops: 
apple, cotton, pinto beans, and tomatoes.  These studies have been
reviewed (Memo, D222174, L. Cheng, 10/23/97).  The residue of concern is
the parent compound fenpropathrin.

5.1.2.	Metabolism in Rotational Crops  TC \l3 "3.2.3	Description of
Rotational Crop Metabolism  

The nature of the residue in rotational crops is adequately understood. 
In its review of a confined rotational crop study, HED determined that,
with the exception of a soil metabolite which may have occurred in
rotated lettuce and carrots from soil contamination, the same
metabolites were seen in the confined rotational crop study as in the
primary plant and livestock metabolism studies and rat metabolism
studies.  In a limited field rotational crop study, no detectable
residues of fenpropathrin were found in any rotated carrot, lettuce, or
wheat samples at any of the plantback intervals (~30, 120, and 365
days).  Based on these studies, HED has determined that no fenpropathrin
rotational crop tolerances or restrictions are required for the crops
that are presently registered.  This conclusion applies as well to the
rotatable crops addressed herein.

5.1.3.	Metabolism in Livestock  TC \l3 "3.2.2	Description of Livestock
Metabolism 

Metabolism studies with goats and poultry dosed with radiolabeled
fenpropathrin were previously submitted and reviewed.  The majority of
the residue in muscle, fat, milk, and eggs was found to be the parent
compound, fenpropathrin.  The residues in kidney and liver consisted
mainly of various metabolites.  HED previously stated that the livestock
metabolites, with the possible exception of TMPA lactone, have also been
identified in rat metabolism studies and their contributions to the
overall toxicity of fenpropathrin have been considered (memo, J. Whalen,
9/16/89).  The levels of the metabolites in livestock are low enough
that they do not need to be included in the tolerance expression.

Analytical Methodology

There are adequate enforcement methods, gas chromatography using an
electron capture detector (GC/ECD), for the determination of
fenpropathrin residues in/on plants (RM-22-4, revised 5/3/93) and
animals (RM-22A-1).  The limit of detection (LOD) for Method RM-22-4 is
0.01 ppm.  The lowest limits of method validation (LLMV) for Method
RM-22A-1 were 0.05 ppm in milk and 0.5 ppm in fat and meat.  In
addition, the   SEQ CHAPTER \h \r 1 recovery of fenpropathrin was tested
through FDA multiresidue methods, and fenpropathrin was found to be
completely recovered by the PAM I Section 302 Method (Luke Method).  The
data collection method used to analyze samples from the submitted field
trials and processing study was Method RM-22-4 or its modification.  The
adequacy of Method RM-22-4 (and/or its modifications) for data
collection was verified and demonstrated by fortifying control samples
with fenpropathrin at levels approximating field-incurred residues.

Environmental Degradation

Reference:  Review of Hydrolysis, Photolysis in Water, Photolysis on
Soil, Anaerobic Soil Metabolism, Mobility and Adsorption/ Desorption,
and Terrestrial Field Dissipation Studies; Proposed New Uses on Tomatoes
and Strawberries; Label Ammendment, D180582, M. Shamim, 7/6/1993

Fenpropathrin appears to be resistant to degradation in biotic processes
and is relatively stable to abiotic processes.  The chemical is expected
to have little mobility in soil surfaces, and leaching into groundwater
is not expected to be an important transport process.  Volatilization is
not expected to be an important transport process, as fenpropathrin has
a relatively low vapor pressure and Henry’s Law Constant.  In
addition, bioaccumulation is likely, based on the octanol/water
partition coefficient (Log Kow = 5.1).  Fenpropathrin is stable to
hydrolysis at both pH 5 and 7, and shows moderate hydrolysis at pH 9
(half-lives on the order of 15 days).  The chemical is light-stable
under aqueous photolysis and soil photodegradation.  Under both aerobic
and anaerobic soil metabolism conditions, fenpropathrin degrades slowly,
with half-lives of 152 and 186 days, respectively.  If released to
water, it appears that fenpropathrin will partition with the sediment
(and organic matter) where it might persist.  In the field,
fenpropathrin shows a wide range of half-lives (8-144 days).  This
variability might be due to the wide range of conditions observed in
different parts of the U.S.  Except for COOH-fenpropathrin (observed in
the anaerobic soil metabolism study), other degradates observed in the
laboratory result from the cleavage of the ester moiety of
fenpropathrin.  TMPA and 3-phenoxybenzoic acid were among the observed
degradates in the hydrolysis study.  CONH2-fenpropathrin, monitored in
the field, was observed only in the upper layers of soil and appeared to
be immobile.

5.1.6 	Comparative Metabolic Profile  TC \l2 "3.1 	Comparative Metabolic
Profile 

Adequate studies are available depicting the metabolism of
[14C]fenpropathrin in rats, primary crops (apples, cotton, pinto beans,
tomatoes), rotational crops (carrots, lettuce, wheat), and livestock
(lactating goats, laying hens).  Parent fenpropathrin was the primary
residue found in all of the metabolism studies.  The same metabolites
were seen in the confined rotational crop study as in the primary plant
and livestock metabolism studies as well as in the rat metabolism
studies.  The livestock metabolites were also found in the rat
metabolism studies and their contributions to the overall toxicity of
fenpropathrin have been considered.  In the rat metabolism studies,
greater than 99% of the administered dose was eliminated within 168
hours of exposure.  Major biotransformations included oxidation at the
methyl group of the acid moiety, hydroxylation at the 4'-position of the
alcohol moiety, cleavage of the ester linkage, and conjugation with
sulfuric acid or glucuronic acid.  Sufficient metabolism data have been
submitted for the purposes of the current tolerance petitions.

5.1.7	Toxicity Profile of Major Metabolites and Degradates   TC \l2 "3.5
Toxicity Profile of Major Metabolites and Degradates  

Parent fenpropathrin is the major metabolite in rats, plant commodities,
and animal commodities, as well as the major degradate in drinking
water.  Any other metabolites or degradates in these matrices are minor
metabolites or degradates.

5.1.8	Pesticide Metabolites and Degradates of Concern  TC \l2 "3.6
Summary of Residues for Tolerance Expression and Risk Assessment 

Table 5.1.8  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	Primary Crop	Fenpropathrin	Fenpropathrin

	Rotational Crop	Fenpropathrin	Fenpropathrin

Livestock	Ruminant	Fenpropathrin	Fenpropathrin

	Poultry	Fenpropathrin	Fenpropathrin

Drinking Water	Fenpropathrin	Not Applicable

HED has determined that the residue of concern in plant and animal
commodities for risk assessment is parent fenpropathrin.  Parent
compound is also the residue of concern for risk assessment in drinking
water.  For tolerance expression, parent compound is the residue of
concern in plant and animal commodities.

Drinking Water Residue Profile

Reference:  Tier 1 Estimated Drinking Water Concentrations of
Fenpropathrin, D313331, J. Melendez, 9/3/2008

EFED performed a Tier 1 screening-level drinking water analysis (DWA)
for the registered and proposed agricultural uses of fenpropathrin.  The
Tier 1 models utilized were FIRST and SCI-GROW for surface and
groundwater, respectively.  There are no major degradates for
fenpropathrin; therefore, no degradates were modeled in this assessment.
 Only the parent compound was included in the drinking water expression.
 Table 5.1.9 provides a summary of the EDWCs obtained in the assessment.
 In preparing the current DWA, EFED relied on the previous DWA because
the previous DWA included grapes, which was the scenario that resulted
in the highest exposure.

Table 5.1.9.  Maximum Tier I Estimated Drinking Water Concentrations
based on aerial application of fenpropathrin to grapes

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

Groundwater (SCI-GROW)	Grapes (0.8 lb a.i./A/season)	Acute and Chronic
0.00480

Surface water  (FIRST)	Grapes (0.8 lb a.i./A/season)	Acute	10.3

Chronic	            1.81

5.1.10	Food Residue Profile  TC \l3 "6.1.1	Residue Profile 

Reference:  Fenpropathrin.  Request for Tolerances for Barley, Stone
Fruits (Crop Group 12), Tree Nuts (Crop Group 14), Pistachio,
Caneberries (Crop Subgroup 13-07A), Olives, Avocado, Black Sapote,
Canistel, Mamey Sapote, Mango, Papaya, Sapodilla, and Star Apple,
Summary of Analytical Chemistry and Residue Data, A. Parmar, 11/26/2008.

There are adequate enforcement methods (gas chromatography using an
electron capture detector (GC/ECD)), for the determination of
fenpropathrin residues in/on plants (RM-22-4, revised 5/3/93) and
animals (RM-22A-1).  The limit of detection (LOD) for Method RM-22-4 is
0.01 ppm.  The lowest limits of method validation (LLMV) for Method
RM-22A-1 were 0.05 ppm in milk and 0.5 ppm in fat and meat.  In
addition, the   SEQ CHAPTER \h \r 1 recovery of fenpropathrin was tested
through FDA multiresidue methods, and fenpropathrin was found to be
completely recovered by the PAM I Section 302 Method (Luke Method).  The
data collection method used to analyze samples from the submitted field
trials and processing study was Method RM-22-4 or its modification.  The
adequacy of Method RM-22-4 (and its modifications) for data collection
was verified and demonstrated by fortifying control samples with
fenpropathrin at levels approximating field-incurred residues.

There are adequate storage stability data to support the integrity of
samples collected from the field and processing studies.  Fenpropathrin
residues were found to be relatively stable in a wide range of
commodities under frozen storage conditions.

The proposed uses include livestock feedstuffs such as almond hulls and
barley grain, hay, and straw.  The available ruminant and poultry
feeding data are adequate to cover secondary residues resulting from the
livestock feedstuffs cited above as well as from feedstuffs with
registered uses.  The dietary burdens of fenpropathrin to livestock were
recalculated using the most recent guidance from HED concerning
revisions of feedstuff percentages in Table 1 of the OPPTS Series 860
Guidelines (Table 1 Feedstuffs, June 2008) and constructing maximum
reasonably balanced livestock diets (MRBDs).  Based on the dietary
exposure levels and the residue data from an available ruminant feeding
study, the existing fenpropathrin tolerances on cattle, goat, hog,
horse, and sheep commodities should be lowered or removed (see Appendix
B).  Based on the dietary exposure levels and the residue data from an
available poultry feeding study, the existing fenpropathrin tolerances
of 0.05 ppm for egg, fat, meat, and meat byproducts of poultry are
adequate to support the proposed uses on barley.

The submitted residue data for cherries, peaches, and plums are adequate
to support the establishment of a fenpropathrin tolerance for Stone
Fruits (Crop Group 12).  The field trials were conducted according to
the proposed use rate and PHI.  The maximum residues of fenpropathrin
in/on treated samples were 0.58 ppm in plums, 1.11 ppm in peaches, and
3.53 ppm in cherries.  HED recommends in favor of the proposed tolerance
of 1.4 ppm for residues of fenpropathrin per se in/on Stone Fruits
except cherry (Crop Group 12).  The recommended tolerance for both sweet
cherry and tart cherry is 5.0 ppm.

The submitted residue data for almonds and pecans are adequate to
support the establishment of fenpropathrin tolerances for Tree Nuts
(Crop Group 14) as well as for almond hulls.  The field trials were
conducted according to the proposed use rate and PHI.  The maximum
residues of fenpropathrin in/on treated samples were 0.05 ppm for pecan
nutmeat, 0.03 ppm for almond nutmeat, and 4.3 ppm for almond hulls.  HED
recommends in favor of the proposed tolerance of 0.10 ppm for residues
of fenpropathrin per se in/on Tree Nuts (Crop Group 14).  The almond and
pecan data will be translated to pistachio, so the recommended tolerance
for pistachio is also 0.10 ppm.  The recommended tolerance for almond
hulls is 4.5 ppm.

The submitted residue data for avocado are adequate.  The avocado trials
were conducted according to the proposed use rate and PHI.  The maximum
fenpropathrin residue was 0.58 ppm in/on treated avocado samples.  HED
recommends in favor of the proposed tolerance of 1.0 ppm for residues of
fenpropathrin per se in/on avocado.  The avocado data will be translated
to support the proposed uses on black sapote, canistel, mamey sapote,
mango, sapodilla, and star apple.  No residue decline data were
submitted for avocado.  The proposed label for tropical fruits states
the following with respect to the proposed commodities:  “Tropical and
Subtropical Fruit (Inedible Peel) – including but not limited to: 
Avocado, Canistel, Mango, Papaya, Sapodilla, Black Sapote, Mamey Sapote,
Star Apple.”  The words “including but not limited to” must be
removed from the label.  The Agency anticipates that, at some point in
the future, a crop group or subgroup will be established for the
tropical and subtropical fruits with inedible peels.  Until such time as
that crop group/subgroup is established, however, registrants will be
required to submit separate requests for each individual fruit. 

The submitted residue data are not adequate to support the establishment
of fenpropathrin tolerances on barley processed commodities.  A barley
processing study is required in order for HED to complete its review of
the proposed use on barley.  The proposed label should be revised to
specify appropriate preharvest intervals.  The barley field trials were
conducted according to the proposed use rate and PHIs of 15-60 days for
hay and 45-96 days for straw and grain.  The registrant proposed a
14-day PHI for uses on barley.  The maximum residues of fenpropathrin
were 0.038 ppm for barley grain, 1.27 ppm for barley straw, and 2.05 ppm
for barley hay.  HED’s tolerance generator for NAFTA-harmonized
tolerances recommends tolerances of 0.04 ppm, 2.5 ppm, and 4.0 ppm for
residues of fenpropathrin per se in/on barley grain, hay, and straw,
respectively.  As stated above, however, because of the lack of a
processing study, tolerances cannot be established at the present time. 
HED will complete its assessment of the barley tolerance petition when
the processing study is submitted.

The submitted residue data for raspberry and blackberry are adequate to
support the establishment of a fenpropathrin tolerance for the Caneberry
Subgroup (13-07A).  The field trials were conducted at a slightly
exaggerated rate (1.3x the maximum proposed seasonal rate of 0.6 lb
a.i./A) and reflect the proposed 3-day PHI.  The maximum residues of
fenpropathrin in/on treated samples were 7.1 ppm.  HED recommends in
favor of the proposed tolerance of 12 ppm for residues of fenpropathrin
per se in/on the Caneberry Subgroup.  The registrant needs to submit a
revised Section F in which tolerances are proposed for the updated Crop
Subgroup 13-07A, as opposed to Subgroup 13-A.  No residue decline data
were submitted for raspberries or blackberries.

A time-limited tolerance established in conjunction with a Section 18
registration is currently in effect for currant at 15 ppm.  The
tolerance is due to expire on 12/31/2008.  A permanent tolerance for the
Bushberry Subgroup (13-B) is in effect at 3.0 ppm.  The results of
currant field trials have been submitted and were reviewed by HED
(45317201.DER, W. Cutchin, 9/20/2005 and Memo, D315918, W. Cutchin,
9/20/2008).  Residues ranged up to 1.51 ppm.  As a result, the bushberry
tolerance of 3.0 ppm will be adequate to cover residues in currants when
the 15-ppm tolerance expires on 12/31/2008.

The submitted residue data for olives are adequate.  The olive trials
were conducted according to the proposed use rate and PHI.  The maximum
fenpropathrin residue was 3.7 ppm in/on treated olive samples collected
at a 7- to 8-day PHI.  HED recommends in favor of the proposed tolerance
of 5.0 ppm for residues of fenpropathrin per se in/on olives.

There are adequate processing data for olives and plums.  Residues of
fenpropathrin marginally concentrated in olive oil (processing factor of
1.07x) whereas residues concentrated more noticeably in dry prunes
(2.6x) following processing of respective raw agricultural commodities
(RACs) bearing quantifiable residues.  Based on these data, tolerances
are not needed for residues of fenpropathrin in olive oil or dried
prunes.  Barley processing data were not submitted.  These data are
needed to support the proposed use of fenpropathrin on barley.

5.1.11	International Residue Limits 

Codex and Mexican MRLs are established for residues of fenpropathrin
(expressed as fenpropathrin per se for Codex and fenpropathrin for
Mexico) but no limits are listed for the crop commodities addressed in
this risk assessment.  No Canadian MRLs are established for
fenpropathrin.

Dietary Exposure and Risk

Reference:  Fenpropathrin Acute Probabilistic and Chronic Aggregate
Dietary (Food and Drinking Water) Exposure and Risk Assessment for the
Section 3 Registration Action, D356137, A. Parmar, 11/26/2008

Acute and chronic dietary exposure assessments were conducted using the
Dietary Exposure Evaluation Model (DEEM-FCID, Version 2.03), which uses
food consumption data from the USDA’s Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998.  The analyses
were performed to estimate the dietary exposures and risks associated
with the uses of fenpropathrin on all registered and proposed
commodities.  Both analyses include estimates for residues of
fenpropathrin in water.  Because of the lack of a processing study to
support the proposed use on barley, HED is not currently recommending in
favor of the establishment of tolerances on barley commodities.  These
commodities are included in the dietary exposure analyses, however,
because HED anticipates that the data deficiencies will be resolved in a
timely manner.  Conservative estimates were used for processed barley
commodities.  When the results of the processing study are submitted, if
the empirical processing factors do not result in increases in the
dietary exposure estimates, the current dietary exposure analysis will
be sufficient to cover the proposed uses.  It will not be necessary for
HED to prepare a revised dietary exposure analysis or human health risk
assessment to address the requested use on barley once the deficiency is
resolved.

5.2.1	Acute Dietary Exposure/Risk

The acute analysis is based on the assumption of 100% crop treated for
all commodities.  It is also based on tolerance-level residues for most
commodities and distributions of field trial data for a small number of
commodities (apples, apricots, cherries, grapes, nectarines, peaches,
pears, and plums).  In addition, it incorporates conservative EDWCs
based on the grape use.  For these reasons, it is conservative with
respect to evaluating potential impacts of acute dietary exposure to
fenpropathrin on human health.  The 95th percentile of exposure is used
for regulation.  The acute risk estimates for the general U.S.
population and all population subgroups are below HED’s level of
concern (100% of the aPAD).  The most highly exposed population subgroup
is Children 1-2, which utilizes 53% of the aPAD at the 95th percentile
of exposure.  The dietary risk estimate for the general U.S. population
is 21% of the aPAD.  The dietary exposure and risk estimates for the
general U.S. population and all population subgroups are given in Table
5.2.

5.2.2	Chronic Dietary Exposure/Risk

The chronic analysis is based on the assumption of 100% crop treated for
all commodities.  The analysis is also based on tolerance-level residues
for most commodities and average field trial values for a small number
of commodities (apples, apricots, cherries, grapes, nectarines, peaches,
pears, and plums).  In addition, it incorporates conservative EDWCs
based on the grape use.  For these reasons, it is conservative with
respect to evaluating potential impacts of chronic dietary exposure to
fenpropathrin on human health.  The chronic risk estimates for the
general U.S. population and all population subgroups are below HED’s
level of concern (100% of the cPAD).  The most highly exposed population
subgroup is Children 1-2, which utilizes 41% of the cPAD.  The dietary
risk estimate for the general U.S. population is 14% of the cPAD.  The
dietary exposure and risk estimates for the general U.S. population and
all population subgroups are given in Table 5.2.

5.2.3	Cancer Dietary Exposure/Risk

Fenpropathrin is classified as “not likely to be carcinogenic to
humans,” in accordance with the EPA Final Guidance for Carcinogen Risk
Assessment (3/29/2005).

Table 5.2.  Summary of Dietary Exposure and Risk Estimates for
Fenpropathrin

Population Subgroup	Acute Dietary

(95th Percentile)	

Chronic Dietary	

Cancer

	Exposure (mg/kg/day)	% aPAD	Exposure

(mg/kg/day)	% cPAD	Exposure

(mg/kg/day)	Risk

General U.S. Pop.	0.012843	21	0.003622	14	Not Applicable

All Infants (< 1 year)	0.025763	43	0.005819	23

	Children (1-2 years)	0.031700	53	0.010325	41

	Children (3-5 years)	0.027571	46	0.008644	35

	Children (6-12 years)	0.017509	29	0.005130	21

	Youth (13-19 years)	0.008862	15	0.002572	10

	Adults (20-49 years)	0.009329	16	0.002644	11

	Adults (50+ years)	0.010777	18	0.003265	13

	Females (13-49 years)	0.009325	16	0.002678	11

	

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information

The acute and chronic analyses are both based on the assumption of 100%
crop treated for all commodities.  The acute dietary exposure analysis
is based on tolerance-level residues for most commodities and
distributions of field trial data for a small number of commodities
(apples, apricots, cherries, grapes, nectarines, peaches, pears, and
plums).  The chronic analysis is based on tolerance-level residues for
most commodities and average field trial values for a small number of
commodities (apples, apricots, cherries, grapes, nectarines, peaches,
pears, and plums).    

6.0	RESIDENTIAL (Non-Occupational) EXPOSURE/RISK CHARACTERIZATION  TC
\l2 "6.3	Residential (Non-Occupational) Exposure/Risk Pathway 

Currently there are no residential uses associated with fenpropathrin
and no new uses are proposed.  As a result, an assessment for
non-occupational/residential exposures is not required.

6.1	Other (Spray Drift, etc.)  TC \l3 "6.3.3	Other (Spray Drift, etc.) 

Spray drift is always a potential source of exposure to residents living
in close proximity to spraying operations.  This situation is
particularly the case with aerial application.  However, to a lesser
extent, spray drift resulting from the ground application of
fenpropathrin could also be a potential source of exposure.  The Agency
has been working with the Spray Drift Task Force (a membership of U.S.
pesticide registrants), EPA Regional Offices, State Lead Agencies for
pesticide regulation, and other parties to develop the best spray drift
management practices.  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, and is developing a
policy on how to apply appropriately 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 might impose further refinements in spray drift management
practices to reduce off-target drift risks associated with pesticide
application.

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
relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.  There
are no residential exposure uses associated with fenpropathrin. 
Therefore, for purposes of this assessment, only dietary (food) and
drinking water sources of exposure were combined to obtain an estimate
of potential aggregate risk.

  TC \l1 "7.0	Aggregate Risk Assessments and Risk Characterization 

For most pesticide active ingredients, water monitoring data are
considered inadequate to determine surface and groundwater drinking
water exposure estimates, so model estimates have been used to estimate
residues in drinking water.  EFED and HED have agreed that acute,
chronic, and cancer EDWCs can be used directly in dietary exposure
assessments to calculate aggregate dietary (food + water) risk.  For
fenpropathrin, the relevant FIRST value as a residue for water (all
sources) was used in the dietary exposure assessment.  The principal
advantage of this approach is that the actual individual body weight and
water consumption data from the CSFII are used, rather than assumed
weights and consumption for broad age groups.

7.1	Acute Aggregate Risk

Dietary (food + water) consumption is the only source of exposure to
fenpropathrin that is expected to result in acute exposure.  Therefore,
the acute aggregate exposure and risk estimates are equivalent to the
acute dietary exposure and risk estimates discussed in Section 5.2.1,
above.  See Table 5.2 for the results of the analysis.  Acute aggregate
risk is below HED’s level of concern for the general U.S. population
and all population subgroups.  The most highly exposed population
subgroup is Children 1-2, which utilizes 53% of the aPAD at the 95th
percentile of exposure.  The dietary risk estimate for the general U.S.
population is 21% of the aPAD.  

7.2	Short- and Intermediate-Term Aggregate Risk  TC \l2 "7.2	Short-Term
Aggregate Risk 

There are no residential uses associated with fenpropathrin; therefore,
short- and intermediate-term aggregate risk assessments are not
required.  TC \l2 "7.3	Intermediate-Term Aggregate Risk 

7.3	Long-Term Aggregate Risk

As there are no residential uses associated with fenpropathrin, dietary
(food + water) consumption is the only source of exposure to
fenpropathrin that is expected to be long-term (180-365 days). 
Therefore, the long-term aggregate exposure and risk estimates are
equivalent to the chronic dietary exposure and risk estimates discussed
in Section 5.2.2, above.  The most highly exposed population subgroup is
Children 1-2, which utilizes 41% of the cPAD.  The risk estimate for the
general U.S. population is 14% of the cPAD.  As with the acute
assessment, the risk estimates are all below HED’s level of concern
(100% of the cPAD).

7.4	Cancer Risk  TC \l2 "7.5	Cancer Risk 

Aggregate cancer risk is not a concern because fenpropathrin is
classified as “not likely to be carcinogenic to humans.”

					

8.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT  TC \l1 "8.0	Cumulative
Risk Characterization/Assessment 

Fenpropathrin is a member of the pyrethroid class of pesticides. 
Although all pyrethroids alter nerve function by modifying the normal
biochemistry and physiology of nerve membrane sodium channels, EPA is
not currently following a cumulative risk approach based on a common
mechanism of toxicity for the pyrethroids.  Although all pyrethroids
interact with sodium channels, there are multiple types of sodium
channels and it is currently unknown whether the pyrethroids have
similar effects on all channels.  The Agency does not have a clear
understanding of effects on key downstream neuronal function, e.g.,
nerve excitability, nor does it understand how these key events interact
to produce their compound-specific patterns of neurotoxicity.  There is
ongoing research by EPA’s Office of Research and Development and
pyrethroid registrants to evaluate the differential biochemical and
physiological actions of pyrethroids in mammals.  When the results of
the research are available, the Agency will consider this research and
make a determination of common mechanism as a basis for assessing
cumulative risk.  Information regarding EPA’s procedures for
cumulating effects from substances found to have a common mechanism can
be found on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

OCCUPATIONAL EXPOSURE/RISK ASSESSMENT PATHWAY

Reference:  Fenpropathrin: Occupational/Residential Exposure and Risk
Assessment for Proposed Use on Tropical Fruit (Avocado, Sapote,
Canistel, Mango, Papaya, Sapodilla, Star Apple), Barley, Caneberry
Subgroup (13-07A), Olives, Stone Fruit and Tree Nuts, D351279, M.
Collantes, 11/20/2008

9.1	Handler Exposure

Based on the anticipated application practices for the Danitol ® 2.4EC
Spray Insecticide product, handler exposures are expected to be
short-term in duration.  HED addressed the following exposure scenarios:

•	Mixing/Loading liquid to support groundboom applications to barley,
tropical fruit and 	caneberries

•	Mixing/Loading liquid to support aerial applications to caneberries

•	Mixing/Loading liquid to support airblast applications to tree nuts,
tropical fruit, stone 	fruit and olives

•	Applying liquid formulation to support air equipment for caneberries

•	Applying liquid formulation to support groundboom use on barley,
tropical fruit and 	caneberries

•	Applying liquid formulation to support airblast on to tree nuts,
tropical fruit, stone fruit 	and olives

•	Flagger

No chemical-specific data for assessing handler exposures were submitted
to the Agency in support of the proposed uses; therefore, HED used
surrogate data from the Pesticide Handlers Exposure Data Base (PHED)
Version 1.1, Outdoor Residential Exposure Task Force (ORETF) studies,
and standard assessment variables established by the Health Effects
Division Science Advisory Council for Exposure.

Summaries of the short- and intermediate-term MOEs for handlers at the
baseline and PPE levels (single layer clothing and gloves) are provided
in Table 9.1.  As both dermal and inhalation endpoints were based on the
same toxicological effect, the route-specific exposures were combined to
calculate a total risk (MOE).  

 resulting in MOEs greater than or equal to 100 are not of concern to
HED.  All handler scenarios resulted in total MOEs greater than the
level of concern (MOEs ≥ 100) if chemical-resistant gloves are worn in
addition to baseline attire (i.e., long-sleeve shirt, long pants, shoes,
and socks).



Table 9.1.  Short- and Intermediate-term Handler Exposure and Risk for
Fenpropathrin

Exposure Scenario (Scenario #)	

Mitigation Level	

Dermal Unit Exposure (mg/lb ai)	

Inhalation Unit Exposure  

 (mg/lb ai)	

Crop	

Application Rate 

(lb ai/acre)	

Amount Treated

(acres/day)	

Short- & Intermediate-term

Dermal Dosea  (mg/kg/day)	

Short-& Intermediate term

Inhalation Dose (mg/kg/day)b	

Total Dosec	

Total MOEd

Mixer/Loader

Emusifiable Concentrate Groundboom	Single layer & gloves

	0.023

	0.0012

	Barley	

0.2	200	0.0051	0.0008	0.0059	500

Caneberry	0.3	80	0.003	0.00048	0.0035	850

Emusifiable Concentrate

aerial

350	0.0134	0.0021	0.0155	190

Emusifiable Concentrate Airblast

Tropical fruit; Stone fruit;, Tree Nuts	0.4	40 	0.002	0.00032	0.0023
1300

Olives	0.3

0.0015	0.00024	0.0017	1700

Applicator

Emusifiable Concentrate Groundboom	Single layer & gloves	0.014	0.00074
Barley	

0.2

	

200	0.0031	0.000493	0.0036	830

caneberry	

0.3	80	0.001865	0.000296	0.002161	1400

Emusifiable Concentrate

aerial	Engineer Controls	0.005	0.000068

	350	0.0029	0.000119	0.0030	990

Emusifiable Concentrate

Airblast	Single layer & gloves	0.24	0.0045	Tropical fruit;	0.4	40 
0.021312	0.0012	0.022512	130

Olives	0.3

0.0159	0.0009	0.0168	180

Flagger

Emusifiable Concentrate	Baseline	0.011	0.00035	caneberry	0.3	350	0.00641
0.000613	0.0070	430

a. Short- and Intermediate-term Dermal Dose (mg/kg/day) = [Rate (lb
ai/A) x DAF (0.333) x UE (mg /lb ai )  x  Acres Treated (A/day)] / BW
(60 kg)		

b. Short- and Intermediate-term Inhalation Dose (mg/kg/day) = [ Rate (lb
ai/A) x IAF (100%) x  UE (mg /lb ai ) x  Acres Treated (A/day)] / BW (60
kg)	

c. Total Dose (mg/kg/day) = Dermal Dose (mg/kg/day) + Inhalation Dose
(mg/kg/day)                                                  d. Total
MOE = NOAEL (3 mg/kg/day)/ Total Dose (mg/kg/day) 

9  SEQ CHAPTER \h \r 1 .2 	Postapplication

Postapplication data (i.e, dislodgeable foliar residue (DFR) data) were
submitted in support of a previous action in which fenpropathrin was
proposed for use on citrus and grapes.  DFR data were taken from the
following memo:  “Re-Evaluate Previously Reviewed Studies for Reentry
Data Review on Fenpropathrin, HED Project # 9-0207,” B. Kitchens,
7/30/1991.  These DFR data were used to estimate exposure risk for
caneberries, olives, and tree nuts as well as for tropical and stone
fruits.  Default DFR values were established by HED’s Science Advisory
Council (SAC) for Exposure and were used for assessing postapplication
exposure for barley.  The fraction of a.i. retained on foliage is
assumed to be 20% (0.2) on day zero after initial treatment.  This
fraction is assumed to dissipate further at the rate of 10% (0.1) per
day on subsequent days.

The Occupational and Exposure Branch (OREB) reviewed dislodgeable foliar
residue (DFR) values and field worker exposure rates resulting from use
of fenpropathrin on citrus (0.4 lb ai/A) and grape foliage (0.2 lb
ai/A).  Table 9.2 provides a summary of the DFR values.

Table 9.2.  Dislodgeable Foliar Residues for use of Fenpropathrin on
Citrus and Grapes

# Applications	Sampling Interval  (days)	Total (μg)	DFR (two sides)

(μg/cm2)

Grapes

1

	

1	

44.0	

0.089

Citrus

1

	

1	

29.0	

0.061

Exposures during postapplication activities were estimated using dermal
transfer coefficients from the Science Advisory Council for Exposure SOP
Number 3.1 (Agricultural Transfer Coefficients, August 2000) and the
following assumptions.

Assumptions:

•	Application Rate	= 	maximum application rate according to proposed
label

•	Exposure Duration	=	8 hours per day

•	Body Weight		=	60 kg			

•	Dermal absorption	= 	33.3%

 

9.2.1	Exposure and Risk

HED’s level of concern (LOC) for occupational post application dermal
exposures is 100 (i.e., MOE less than 100 is of concern). 
Postapplication exposure resulting from use of fenprotharin on all the
proposed crops resulted in MOEs greater than 100 on Day 0 (immediately
after application) and, therefore, are not of concern to HED.  A summary
of the risk and exposure during occupational postapplication activities
is given in Table 9.2.1.

Table 9.2.1  Postapplication Risks for Fenpropathrin

Crop	Applica-tion

Rate

(lb ai/A)	Contact Potential	Transfer Coefficient

(cm2/hr)	DFR

	Adjus-ted DFR 1	Days After Treat-ment	Daily Dose2

(mg/kg/ay)	MOE3	PHI

(Days)

Barley	0.2	Low	scouting (100)	0.448	NA	

0

	0.002	1,500	14

High	scouting (1500)

0.030	100

	Caneberry

 (vine & trellis)	0.3	Low	scouting,irrigation, hand weeding (500)	0.089
0.1335

0.003	1000	

21

High	Tying, training, pruning, hand harvest (5,000)

0.03	100

	Olives

 (Tree Nut)

Low	Scouting, thinning, irrigation (500)	0.061	0.04575	0	0.001	3000	

7

High	Hand harvest, pruning and thinning (2500)

0.005	590

	Tree Nut	0.4	Low	Scouting, thinning, irrigation (500)

NA	0

	0.00135	2200	

3

High	Hand harvest, pruning and thinning (2500)

0.0067	440

	Tropical and Stone Fruit

Low	Irrigation, scouting, hand weeding (1,000)

	0

	0.0027	1100	1

High	Thinning (3,000)

0.008125	370	3

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

1.  Adjusted DFR = Application Rate on label / application rate used in
study x DFR value in study

2:  Daily Dose = [DFR (ug/cm2) x Tc (cm2/hr) x 0.001 mg/µg x Dermal
Absorption (0.1) x 8 hrs/day] ÷ Body Weight (60 kg)

3:  NOAEL/Daily Dose (Short- and Intermediate-term NOAEL = 10 mg/kg/day)

Tc = transfer coefficient

9.2.2	Restricted Reentry Interval

When postapplication risks are not a concern on Day 0 (12 hours
following application), the REI is based on the acute toxicity. 
Fenpropathrin exhibits high toxicity through the dermal route of
exposure and is, therefore, classified as being in Category II.  It does
not cause dermal irritation in rabbits or skin sensitization in guinea
pigs and, therefore, is not a dermal sensitizer.  Under the Worker
Protection Standard for Agricultural Pesticides, active ingredients
classified as acute toxicity category II for dermal toxicity are
assigned a 24-hour REI.  Based on results of this review, HED concurs
with the proposed label for Danitol 2.4 EC Spray, which specifies an REI
of 24 hours. 10.	DATA NEEDS AND LABEL RECOMMENDATIONS  TC \l1 "10.0
Data Needs and Label Requirements 

10.1	Toxicology

HED recommends that an immunotoxicology (870.7800) study be requested.

A 90-day inhalation toxicity study in rats (870.3465) was requested
previously, and the registrant submitted a justification to waive the
study.  The waiver request is currently under review by the Agency.

10.2	Residue Chemistry

Pending label revisions (see requirements under 860.1200 Directions for
Use, below), the submission of barley processing data (see requirements
under 860.1520 Processed Food and Feed, below), and the submission of a
revised Section F (see requirements under 860.1550 Proposed Tolerances,
below), there are no residue chemistry issues that would preclude
granting a conditional registration for the requested uses of
fenpropathrin on the crops, subgroups, or crop groups addressed herein,
except for barley.  The proposed barley use requires the submission of a
barley processing study.  HED will complete its review of the residue
data for the proposed use on barley upon receipt of the processing
study.  The remaining registrations should be made conditional pending
resolution of the data gaps detailed below by guideline topic.

860.1200 Directions for Use

As HED is not recommending in favor of tolerances for barley commodities
at this time, barley should be removed from the label.  At such time as
the registrant submits the barley processing study, the registrant
should also submit a proposed label that specifies a PHI of 15 days for
barley hay and 45 days for barley grain and straw.

The proposed label for tropical fruits states the following with respect
to the proposed commodities:  “Tropical and Subtropical Fruit
(Inedible Peel) – including but not limited to:  Avocado, Canistel,
Mango, Papaya, Sapodilla, Black Sapote, Mamey Sapote, Star Apple.” 
The words “including but not limited to” must be removed from the
label.  

860.1520  Processed Food and Feed

A barley processing study needs to be submitted.  Upon completion and
review of an acceptable barley processing study, HED will make
recommendations regarding the requested use on barley and the need for
tolerances on processed barley commodities.

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F that incorporates the
recommended tolerances and correct commodity definitions that are given
in Table B1 of Appendix B.

10.3	Occupational and Residential Exposure

	None  TC \l2 "10.3	Occupational and Residential Exposure 

REFERENCES  TC \l1 "References: 

Fenpropathrin.  Request for Tolerances for Barley, Stone Fruits (Crop
Group 12), Tree Nuts (Crop Group 14), Pistachio, Caneberries (Crop
Subgroup 13-07A), Olives, Avocado, Black Sapote, Canistel, Mamey Sapote,
Mango, Papaya, Sapodilla, and Star Apple.  Summary of Analytical
Chemistry and Residue Data, D333113, A. Parmar, 11/20/2008

Fenpropathrin: Occupational/Residential Exposure and Risk Assessment for
Proposed Use on Tropical Fruit (Avocado, Sapote, Canistel, Mango,
Papaya, Sapodilla, Star Apple), Barley, Caneberry Subgroup (13-07A),
Olives, Stone Fruit and Tree Nuts, D356138, M. Collantes, 11/20/2008

Re-Evaluate Previously Reviewed Studies for Reentry Data Review on
Fenpropathrin, HED Project # 9-0207, HED File R108801, Accession #
412-05-0095, B. Kitchens, 7/30/1991

Fenpropathrin Acute Probabilistic and Chronic Aggregate Dietary (Food
and Drinking Water) Exposure and Risk Assessment for the Section 3
Registration Action, D356137, A. Parmar, 11/20/2008

Review of Hydrolysis, Photolysis in Water, Photolysis on Soil, Anaerobic
Soil Metabolism, Mobility and Adsorption/ Desorption, and Terrestrial
Field Dissipation Studies; Proposed New Uses on Tomatoes and
Strawberries; Label Ammendment, D180582, M. Shamim, 7/6/1993

Tier I Estimated Drinking Water Concentrations of Fenpropathrin: IR-4
Tolerance Petition for the Use of Fenpropathrin on Tree Nuts and
Pistachio, Barley, Tropical and Sub Tropical Fruits, Bushberries,
Fruiting Vegetables, Peas, Caneberries and Olives (PC Code 127901, DP
Barcodes D313331, D333118,  D342501 and D347897), J. Melendez, D313331,
9/3/2008

PP#s 1E6331, 1E6336, and 3E6588:  Human Health Risk Assessment for the
Proposed Section 3 Uses of Fenpropathrin on Fruiting Vegetables (Crop
Group 8), Succulent Peas, and the Bushberry Subgroup (13-B), D285421, D.
Dotson, 9/20/2005

Appendix A:  Fenpropathrin Toxicology

Toxicology Data Requirements TC \l2 "A.1  Toxicology Data Requirements  

The requirements (40 CFR 158.340) for a food use for fenpropathrin are
in Table A.1.  Use of the new guideline numbers does not imply that the
new (1998) guideline protocols were used.

Table A.1.  Toxicology Data Requirements

Test 

	

Technical

	

Required	

Satisfied

870.1100	Acute Oral Toxicity	

870.1200	Acute Dermal Toxicity	

870.1300	Acute Inhalation Toxicity	

870.2400	Primary Eye Irritation	

870.2500	Primary Dermal Irritation	

870.2600	Dermal Sensitization		

yes

yes

yes

yes

yes

yes	

yes

yes

yes

yes

yes

yes

870.3100	Oral Subchronic (rodent)	

870.3150	Oral Subchronic (nonrodent)	

870.3200	21/28-Day Dermal	

870.3250	90-Day Dermal	

870.3465	90-Day Inhalation		

yes

yes

yes

no

yes	

yes

yes

yes

--

no1

870.3700a	Developmental Toxicity (rodent)	

870.3700b	Developmental Toxicity (nonrodent)	

870.3800	Reproduction		

yes

yes

yes	

yes

yes

yes

870.4100a	Chronic Toxicity (rodent)	

870.4100b	Chronic Toxicity (nonrodent)	

870.4200a	Oncogenicity (rat)	

870.4200b	Oncogenicity (mouse)	

870.4300	Chronic/Oncogenicity		

yes

yes

yes

yes

yes	

--2

yes

--2

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial	

870.5300	Mutagenicity—Gene Mutation - mammalian	

870.5375	Mutagenicity—Structural Chromosomal Aberrations	

870.5395	Mutagenicity—Other Genotoxic Effects		

yes

yes

yes

yes	

yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)	

870.6100b	90-Day Neurotoxicity (hen)	

870.6200a	Acute Neurotox. Screening Battery (rat)	

870.6200b	90 Day Neurotox. Screening Battery (rat)	

870.6300	Develop. Neuro		

no

no

yes

yes

yes	

--

--

yes

yes

yes

870.7485	General Metabolism	

870.7600	Dermal Penetration	

870.7800    Immunotoxicity in Rats……………………………….	

yes

no

yes	

yes

yes

no

1Waiver request is currently under review

2Requirement fulfilled by the chronic/carcinogenicity study in rats
870.4300

A.2  Toxicity Profiles

  SEQ CHAPTER \h \r 1 Table A2.  Acute Toxicity of Fenpropathrin

Guideline No./Study Type	     MRID No.	             Results	Toxicity    
      Category

870.1100 Acute oral toxicity (rat)	     00127343	LD50  =M:54 mg/kg

             F:48.5 mg/kg	I

870.1200 Acute dermal toxicity (rat)	     00127352       	LD50 = M:1600
mg/kg

              F:870 mg/kg	II

870.1200b Acute dermal toxicity (rabbit)	     00127355	LD50 = M: >2000
mg/kg bw

              F: >2000 mg/kg bw	III

870.1300 Acute inhalation toxicity (rat)	     00163812	LC50 = Not
Determined	IV

870.2400 Acute eye irritation (rabbit)	     00127357	Mild eye irritant
III

870.2500 Acute dermal irritation (rabbit)	     00127357	Not a dermal
irritant	IV

870.2600 Skin sensitization (guinea pig)	     00127358	Not a dermal
sensitizer	NA

  SEQ CHAPTER \h \r 1 NA = Not applicable

  SEQ CHAPTER \h \r 1 Table A3.  Subchronic, Chronic, and Other Toxicity
Studies for Fenpropathrin  

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

Subchronic Studies

870.3100

90-Day oral toxicity rats

(unreported strain)

	00127363 (1979)

Acceptable/guideline

M&F: 0, 3, 30, 100, 300, 600 ppm

(0, 0.15, 1.5, 5, 15, 30 mg/kg/day), in diet	NOAEL = 15 mg/kg/day

LOAEL = 30 mg/kg/day based on clinical signs of tremors, body weight
reductions, decreased blood clotting time in females, and possibly
increased alkaline phosphatase levels (both sexes).

870.3150

90-Day oral toxicity

(Beagle dog)	00127364 (1980)

Acceptable/guideline

M&F: 0, 250, 500, 750 ppm

(0, 6.25, 12.5, 18.8 mg/kg/day), in diet	NOAEL = <6.2 mg/kg/day

LOAEL = 6.2 mg/kg/day based on effects on the gastrointestinal system,
tremors, and body weight changes.

870.3200

21-Day dermal toxicity (Sprague-Dawley rat)	47325602 (2006)

Acceptable/guideline

0, 20, 200, or 1000 mg/kg/day for 6 hrs/day, 21 days	Systemic NOAEL =
1000 mg/kg/day

Systemic LOAEL = not observed

Dermal NOAEL = 1000 mg/kg/day

Dermal LOAEL = not observed

870.3200

21-Day dermal toxicity

(NZW rabbit)	00127366 (1982)

Acceptable/guideline

M&F: 0, 500, 1200, 3000 mg/kg/day	NOAEL = >3000 mg/kg/day

Only local irritation was seen.  There were no systemic effects, thus
the LOAEL was not determined.



Developmental and Reproduction Studies

870.3700a

Prenatal developmental

[CDF (F-344)/CrLBR rats)	41525903 (1990)

Acceptable/guideline

0, 0.4, 1.5, 2.0, 3.0, 6.0, 10.0 mg/kg/day (gavage)

LOAEL = 10 mg/kg/day based on increased incidence of asymmetrical
ossification of sternebrae and incomplete ossification of the 5th and
6th sternebrae	Maternal NOAEL = 3 mg/kg/day

LOAEL = 6 mg/kg/day based on decreased food consumption and body weight
gains.

At 10 mg/kg/day, 6 dams died between days 7 and 13, and one dam was
sacrificed moribund on day 8.   The remaining 23 dams survived through
the end of gestation.

Also in the high dose group, many clinical signs were observed in the
dams including ataxia, sensitivity to external stimuli, spastic jumping,
and tremors.  These signs were most severe 2 hours post-dosing and
during the first days of dosing. 

Developmental

NOAEL = 6 mg/kg/day  

LOAEL = 10 mg/kg/day based on increased incidence of asymmetrical
ossification of sternebrae and incomplete ossification of the 5th and
6th sternebrae

870.3700b

Prenatal developmental

(NZW rabbit)	00163816 (1985)

Acceptable/guideline

0, 4, 12, 36 mg/kg/day (gavage)	Maternal NOAEL = 4 mg/kg/day

LOAEL = 12 mg/kg/day based on flicking of the forepaws.

Developmental NOAEL = >36 mg/kg/day

No dose related effects were seen, thus the LOAEL was not determined.

870.3800

Reproduction and fertility effects

(Sprague-Dawley rats)	00163817 (1986)

Acceptable/guideline

0, 40, 120, 360 ppm

(M: 0, 3.0, 8.9, 26.9 mg/kg/day

F: 0, 3.4, 10.1, 32.0 mg/kg/day), in diet, premating determinations
Parental/Systemic NOAEL = M:3.0; F: 3.0 mg/kg/day

LOAEL = M: 8.9; F: 10.1 mg/kg/day based on death and clinical signs of
neurotoxicity in females.

Offspring NOAEL = M:3.0; F:3.4 mg/kg/day

LOAEL = M: 8.9; F: 10.1 mg/kg/day based on increased mortality and body
tremors.



Chronic Toxicity Studies		

870.4100b

Chronic toxicity (Beagle dog)	00143130 (1984)

Acceptable/guideline

0, 100, 250, 750 ppm

(0, 2.5, 6.25, 18.75 mg/kg/day) in diet	NOAEL = 2.5 mg/kg/day

LOAEL = 6.25 mg/kg/day based on tremors and ataxia in both sexes.

Chronic/Carcinogenicity Studies

870.4200b

Carcinogenicity (CD-1 mouse)	00163814 (1985)

Acceptable/guideline

0, 40, 150, 600 ppm

(M: 0, 3.9, 13.7, 56.0 mg/kg/day

F: 0, 4.2, 16.2, 65.2 mg/kg/day), in diet	NOAEL = Not established

LOAEL = M: >56.0; F: >65.2 mg/kg/day

There was an overall lack of toxic response.  However the aborted mouse
carcinogenicity study (MRID No. 00163815) demonstrated that at a
slightly higher maximum tolerated dose (MTD) of 1000 ppm, the test
article was lethal to 15% of the mice after only 13 weeks.  Thus the
maximum dose used in this completed study (600 ppm) was very close to
the MTD.  A repeat study is not justified.

There was no evidence of carcinogenicity.

870.4300

Chronic/

Carcinogenicity - (CD rat)	00163813 (1986)

Acceptable/guideline

0, 50, 150, 450, 600 ppm

(M: 0, 1.93, 5.71, 17.06, 22.8 mg/kg/day

F: 0, 2.43, 7.23, 19.45, 23.98 mg/kg/day), in diet	NOAEL = M:17.06; F:
7.23 mg/kg/day

LOAEL = 19.45 mg/kg/day based on increase mortality and body tremors in
the females

g/plate

+/- S9	Negative in Salmonella typhimurium TA 1535, TA1537, TA1538, TA98,
and TA100 and Escerichia coli Wp2 uvrA up to the limit concentration
with evidence of compound insolubility.

Gene Mutation

870.5300

In vitro mammalian cell gene mutation test	00126832 (1982)

Acceptable/guideline

0, 50.3, 84.5 141.9, 238.2, 400 g/mL in the absence of mammalian
metabolic activation

0, 30, 47.5, 75.3, 119.4, 189.2, 300 mg/mL in the presence of mammalian
metabolic activation	There was no clear evidence (or a concentration
related positive response) of induced mutant colonies over background.

870.5375

Cytogenetics 

In vitro mammalian cell chromosomal aberration assay	41281601 (1989)

Acceptable/guideline

10-30 μg/mL -S9 and 250-1000 μg/mL +S9	Negative in Chinese hamster
ovary (CHO) cells (cytotoxicity observed at ≥30 μg/mL -S9 and
compound precipitation at 1000 μg/mL +S9).

870.5500 

Other Genotoxic Effects Bacterial DNA damage or repair test	00126831
(1980)

Acceptable/non-guideline

10-5000 μg/disc -S9 only 	Negative in Bacillus subtilis H17 (DNA repair
proficient) and M45 (DNA repair deficient).

870.5900 

Other Genotoxic Effects

In vitro sister chromatid exchange assay   

	00163821 (1984)

Acceptable/guideline

3x10-6-1x10-4 M (solubility limit) +/-S9	Negative in CHO cells up to the
solubility limit.

Neurotoxicity Studies

870.6200a Neurotoxicity Screening Battery (Sprague-Dawley rats)	47345605
(2006)

Acceptable/guideline

0, 3, 6, 15, or 30 mg/kg	NOAEL = 15 mg/kg 

LOAEL = 30 mg/kg, based on slight tremors and clonic convulsions in both
sexes at the time of peak effect

870.6200b Subchronic Neurotoxicity Study (Sprague-Dawley rats)	47345607
(2007)

Acceptable/guideline

0, 60, 190, or 570 ppm

M: 0, 4, 13, or 38 mg/kg/day

F: 0, 5, 15, or 50 mg/kg/day	NOAEL = 13/15 mg/kg/day (M/F)

LOAEL = 38/50 mg/kg/day, based on tremors, convulsions, impaired gait,
and related findings in the FOB predominantly in the females

870.6300 Developmental Neurotoxicity Study (Sprague-Dawley rats)
47345609 (2008)

Acceptable/guideline

0, 40, 100, or 250 ppm

0/0, 3/7, 8/16, or 19/40 mg/kg/day gestation/lactation, respectively
Maternal NOAEL = 8/16 mg/kg/day (gestation/lactation)

Maternal LOAEL = 19/40 mg/kg/day, based on tremors during lactation

Offspring NOAEL = 8/16 mg/kg/day

Offspring LOAEL = 19/40 mg/kg/day, based on small pup size and decreased
body weights and body weight gains during the pre-weaning period

Neurotoxicity NOAEL = 8/16 mg/kg/day

Neurotoxicity LOAEL = 19/40 mg/kg/day, based on increased mean overall
maximum auditory startle response amplitude and average response
amplitude in the females (PND60) and decreased absolute brain weights in
the males



Other Studies

870.7485

Metabolism and pharmacokinetics (Sprague-Dawley rat)	43476801 (1994)

Acceptable/guideline

0, 2.5, 25 mg/kg/day

radiolabeled S-3206 on either the alcohol or acid portion of the
molecule by gavage.  In experiment I, rats received 14 daily doses of
2.5 mg/kg followed on the 15th day by radiolabeled S-3206.  In
experiments II and III, rats received a single dose of radiolabeled
S-3206 at either 2.5 or 25 mg/kg.	Greater than 99% of the administered
dose was excreted within 168 hours with 28%-56% excreted in the urine
and the remainder in the feces.  Major biotransformations of the
absorbed compound included the oxidation of the methyl group of the acid
moiety, hydroxylation at the 4'-position of the alcohol moiety, cleavage
of the ester linkage, and conjugation with sulfuric acid or glucuronic
acid.

870.7600

Dermal penetration	43433801 (1991)

Acceptable/guideline

0, 0.03, 1.5, 30 mg/rat

(0, 0.0013, 0.0663, 1.26 mg/cm2 - radiolabeled) 

EC Formulation (31.9% a.i.)

Exposure times of 0.5, 1, 2, 4, 10, and 24 hours	Dermal absorption
increased with dose but not proportionally.  The percentage of the dose
absorbed decreased with the increasing administered dose.  The total
body burden could be expected to decrease rapidly because of excretion
via urine and feces.  Mean dermal absorption for the 10-hour interval
was 33.3, 20.1, and 17.6% in the low, mid, and high dose groups,
respectively.  

A.3	Executive Summaries

A.3.1	Subchronic Studies

A.3.1.1	90-Day Oral Toxicity Study in Rats 

  SEQ CHAPTER \h \r 1 In a 90-day oral toxicity study (MRID 00127363)
WL-41706 (97% a.i., Batch No. 24) was administered in the diet to five
groups (12/sex/dose) of 3-week old rats (unreported strain) at dose
levels of 3, 30, 100, 300, or 600 ppm (0.15, 1.5, 5, 15, and 30
mg/kg/day)1.  The control group was made up of 24 male and 24 female
rats.  The 600 ppm treatment level was added to the test design late,
and thus, was handled separately from the other treatments and was not
included in the block randomization.  However, the results for this
treatment level were compared to the controls in the main test. 

The test material had no effect on death or histopathology (including an
examination of the central and peripheral nervous system for lesions). 
Tremors, occurring at week 5 and persisting to week 11 were reported for
9 of 12 high-dose females only.  Significant (p<0.01) decreases in body
weights (8-14%) were seen in females receiving 600 ppm throughout the
study.  High-dose males had significant reductions in body weights from
week 1 to week 5.  Body weights for lower treatment groups were
comparable to the control.  With the exception of a decrease in
kaolin-cephalin blood clotting time (14%) in the high-dose females,
there were no adverse effects on hematological endpoints.  Similarly,
the only biologically relevant finding for clinical chemistry was the
significant increase in plasma alkaline phosphatase at 600 ppm in both
sexes (33%/42% M/F).

Female absolute liver weights were non-significantly elevated in the 300
ppm treatment group (7.2%) but not in the 600 ppm treatment group.  Rats
dosed at 600 ppm had increased kidney weight (males 7.2%) and brain
weights (females 6.9%)

The NOAEL is 300 ppm (~15 mg/kg/day), based on clinical signs of
tremors, body weight reductions, decreased blood clotting time in
females, and possibly increased alkaline phosphatase levels (both sexes)
at the LOAEL of 600 ppm (30 mg/kg/day).

This 90-day oral toxicity study in the rat is acceptable/guideline and
satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3100; OECD 408) in rats.

A.3.1.2	90-Day Oral Toxicity Study in Dogs

  SEQ CHAPTER \h \r 1 In a 90-day oral toxicity study (MRID 00127364)
fenpropathrin as S-3206 (96.2% a.i., lot # 90403) was administered to
four groups of pure-bred beagles, six/sex/dose in their diet at dose
levels of 0, 250, 500, or 750 ppm (equivalent to 0, 6.25, 12.5, 18.8
mg/kg bw/day).  The high dose group started out at 1000 ppm, but after 3
weeks one dog in this group was sacrificed moribund.  The high dose was
then lowered to 750 ppm for the remaining weeks.  

There were no definite dose related effects seen in the clinical
chemistry, urinalysis, gross necropsy, organ weights, histopathology, or
ophthalmologic analyses.  There was one mortality throughout this study
in the high dose male group during week 3.  Clinical signs of toxicity
in all treatment levels included soft and mucoid stools and/or diarrhea,
emesis, tremors, ataxia, and sometimes, lethargy, panting, and
salivation.  Slight decreases in body weight gains were found in the mid
level female group (6%) and in both sexes in the high dose group (6%/7%
M/F), relative to controls.  Hematology analysis showed decreases in
blood hematocrit (9%, females), hemoglobin (11%, male), and RBC count
(13%, female) at the high dose level.  

The LOAEL is 250 ppm (6.25 mg/kg/day), based on effects on the
gastrointestinal system, tremors, and body weight changes.  The NOAEL is
<250 ppm (<6.25 mg/kg/day).

This 90-day oral toxicity study in the dog is acceptable (guideline);
and satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3150; OECD 409) in dog. 

A.3.1.3	21-Day Dermal Toxicity Study in Rats 

In a 21-day dermal toxicity study (MRID 47345602), fenpropathrin as
S-3206 (92.0% a.i., Lot # 050213G) was applied to the shaved intact skin
of 10 Sprague-Dawley rats/sex/dose at dose levels of 0, 50, 200, or 1000
mg/kg/day (limit dose) for 6 hours/day, 7 days/week, for 21 days.

(p≤0.05) at 200 mg/kg/day and by 18% (p≤0.01) at 1000 mg/kg/day. 
However, these decreases were not considered adverse because they were
transient and did not affect body weights or body weight gains.

Triglycerides were increased by 33% over controls in the 200 and 1000
mg/kg/day females.  However, there were no other differences in clinical
chemistry indicating an effect on lipid metabolism.  Similarly, there
were no effects of treatment on liver weights and no treatment-related
macroscopic findings in the liver.  Thus, the increased triglycerides
were considered of equivocal toxicological significance.

At 1000 mg/kg/day, examination of the skin at the treated site revealed:
 (i) squamous cell hyperplasia in 3/10 rats per sex compared to 0
controls; (ii) mononuclear cell infiltration in the dermis in 4/10 rats
per sex compared to 0 controls; and (iii) crust in 2/10 males compared
to 0/10 controls.  The incidences of mononuclear cell infiltration were
significantly (p≤0.05) increased over controls, whereas the increases
in squamous cell hyperplasia and crust were not significant.  It should
be noted that crust was observed at the same incidence in the control
females (2/10), indicating that this finding in the 1000 mg/kg/day males
may be due to the daily shaving of the fur from the skin as opposed to
dermal irritation from the test material.  Furthermore, because all of
these lesions were slight in severity and were not accompanied by other
signs of dermal irritation (e.g., edema, erythema, scabbing, or
necrosis), they were not considered adverse.

The systemic LOAEL was not observed.  The systemic NOAEL is 1000
mg/kg/day (limit dose).

The dermal LOAEL was not observed.  The dermal NOAEL is 1000 mg/kg/day
(limit dose).

This study is classified as acceptable/guideline and satisfies the
guideline requirement for a 21-day dermal toxicity study (OPPTS
870.3200; OECD 410) in rats. 

A.3.1.4	21-Day Dermal Toxicity Study in Rabbits

  SEQ CHAPTER \h \r 1 In a 21-day dermal toxicity study (MRID 00127366),
fenpropathrin as S-3206 ( 91.4%  a.i., lot # 01113) was applied to the
skin of groups of 10 male or 10 female New Zealand white rabbits (5
clipped with intact skin and 5 clipped with upbraded skin per group) at
doses of 0, 500, 1200, or 3000  mg/kg bw/day, 6 hours/day for 5
days/week during a 21-day period.  The test article was premoistened
with normal saline and evenly distributed over the rabbits’ backs. 
Animals receiving 3000 mg/kg/day were dosed over 15-20% of their total
skin surface.  Treatment sites were occluded, and the rabbits were
fitted with collars to prevent ingestion of the test material.  

There were no compound-related effects on mortality, clinical signs,
body weight, food consumption, hematology, clinical chemistry, organ
weights, or gross and microscopic pathology on the liver or kidneys. 
Many high-dose rabbits had “doubtful or barely perceptible erythema
and edema.” Trace or mild “inflammatory cell infiltrate” in the
intact and abraded skin, which was noted in males and females receiving
all doses including the control, was attributed by the study authors to
the test material.  

Since only local irritation and no systemic effects were seen, the NOAEL
was >3000 mg/kg/day.  

This 21-day dermal toxicity study in the (rabbit) is acceptable
(guideline) and satisfies the guideline requirement for a 21-day dermal
toxicity study (OPPTS 870.3200; OECD 410) in the rabbit.

A.3.2	Developmental and Reproduction Studies

A.3.2.1	Developmental Toxicity Study in Rats

  SEQ CHAPTER \h \r 1 In a developmental toxicity study (MRID 41525903),
fenpropathrin as S-3206 (91.9% a.i., batch/lot 70711) was administered
to 30 mated CDF®(F-344)/CrlBR female rats/dose via gavage at levels of
0, 0.4, 1.5, 2.0, 3.0, 6.0 or 10.0 mg/kg/day in corn oil from days 6
through 15 of gestation. 

In the high dose group, 6 dams died between gestation days 7 and 13, and
one was sacrificed moribund on day 8 because of convulsions and
prostration.  The remaining 23 dams survived to gestation 20.  Neither
death nor moribundity were found in the lower treatment groups.

Clinical signs seen in the majority of the high dose dams included signs
of neurotoxicity (ataxia, sensitivity to external stimuli, spastic
jumping, and tremors).  These signs were most severe 2 hours after
dosing and during the first days of dosing, although the sensitivity to
external stimuli persisted throughout the dosing period.  Prostration,
convulsions, hunched posture, and squinted eyes were each seen in one
high-dose dam.  Chromodacryorrhea, which occurred in all groups before
dosing, was more frequently observed (17/23 versus 5/30 in the vehicle)
during treatment at 10.0 mg/kg/day.  Lacrimation was also seen
sporadically throughout the study and was largely confined to the
high-dose animals. 

  

Body weight gain was significantly decreased in the 10-mg/kg/day and the
6-mg/kg/day groups between gestation days 6 -8, 6-11, 6-15, 6-16. 
Decreases ranged from 29 to >97% for the high-dose group and 14-80% for
6 mg/kg/day.  Over the course of the study (gestation days 0-20 or
6-20), however, body weights, gravid uterine weights, corrected body
weights, and food consumption were similar in all groups.  The corrected
body weight (terminal weight-gravid uterine weight) for the high dose
dams was significantly less (4% ) than the controls, and the net weight
change (corrected weight minus day 0 body weight) was also significantly
less (40%)  than controls.  For the 6-mg/kg/day group, there was a
non-significant 16% reduction in the net weight change.  Food
consumption was also significantly decreased (17 or 8%) in the 10- or
6.0-mg/kg/day groups, respectively, between gestation day 6 and 8. 
Between gestation days 8-11, there was a significant reduction (6%) in
food consumption for the 10-mg/kg/day group.  Throughout the remainder
of the study, food consumption was unaffected by treatment.  There were
no dose-related gross lesions in the survivors of any treatment group or
in the seven animals that died after administration of the high dose. 

All treatment groups were comparable to the vehicle control group with
regards to fertility, fecundity, lack of abortions, number of corpora
lutea, implantations, early or late resorptions, dead fetuses, live
fetal body weight or sex ratio.

Based on the above considerations, maternal toxicity was clearly
attained at 10 mg/kg/day as evidenced by the six deaths and one moribund
sacrifice as well as the observed evidence of neurotoxicity.  Food
consumption and body weight gain were also affected at 6 and 10
mg/kg/day.  

In agreement with the study author, therefore, the Maternal NOAEL = 3
mg/kg/day with a LOAEL = 6 mg/kg/day based on decreased food consumption
and body weight gain.  None of the fetuses had any external variations
or malformations.  There were no skeletal malformations.  The
developmental NOAEL is 6 mg/kg/day and the LOAEL is 10 mg/kg/day.

The developmental toxicity study in the rat is classified as
acceptable/guideline and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat.

A.3.2.2	Oral Developmental Toxicity Study in Rabbits

  SEQ CHAPTER \h \r 1 In a developmental toxicity study (MRID 00163816),
fenpropathrin as  S-3206 (92.5% a.i.; Batch # 20514) was administered
orally via gavage to 60 New Zealand White female rabbits at doses of 0,
4, 12 and 36 mg/kg bw/day in corn oil from days 7 through 19 of
gestation. 

Three dams aborted their fetuses after the last day of dosing (day 19),
one at 12 mg/kg/day and two at 36 mg/kg/day.  These incidences did not
appear to be dose related as this effect was not seen in the remaining
dams that carried to term without effects on the offspring.  No adverse
clinical signs were observed at 4 mg/kg/day other than an increased
incidence of grooming.  At 12 mg/kg/day, dams experienced flicking of
the forepaws (6/19) and at 36 mg/kg/day, 12/16 animals were flicking
their forepaws and 4/16 were flicking their hind feet.  Also noted at
the high dose were 2/16 females experiencing shaking movements,
trembling, unsteadiness (one nonpregnant animal) and 1/16 that was
lethargic.  The onset or duration of these neurological signs was not
reported.  Neither body weight gain nor food consumption were
significantly altered at any dose.  There were no gross macroscopic
changes observed which were considered related to treatment.  

The maternal LOAEL is 12 mg/kg bw/day, based on flicking of the
forepaws.  The maternal NOAEL is 4 mg/kg bw/day.

No effects were observed at any dose on implantations, pre- or
post-implantation loss, live fetuses, dead fetuses, early or late
embryonic loss, litter size, sex ratios, or mean fetal weight.
Similarly, there were no dose-related effects on the incidence or types
of malformations or anomalies in the pups.  

A developmental LOAEL cannot be determined based on the study findings. 
The developmental NOAEL is >36 mg/kg bw/day. 

The developmental toxicity study in the rabbit is classified as
acceptable/guideline  and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) in rabbits.

A.3.2.3	Oral 2-Generation Reproduction Study in Rats

  SEQ CHAPTER \h \r 1 In a 2-generation reproduction study (MRID
00163817), Fenpropathrin as S-3206 (92.5%, Batch 20514) was administered
to groups of 28 Sprague Dawley male and female rats [(CrL: COBS CD (SD)
BR] /sex/dose in the diet at 0, 40, 120 or 360 ppm (equivalent to 0,
3.0, 8.9 or 26.9 mg/kg bw/day for males and 0, 3.4, 10.1 or 32.0 mg/kg
bw/day for females).  Animals were continuously fed the experimental
diets for three generations.  Animals in the F0 generation were exposed
to the test material for 13 weeks prior to mating and mated twice to
produce the F1A and the F1B pups.  F1A animals were maintained for 11
weeks (until selection of F1B pups for the second generation) and
discarded.  F1B animals (24 pups/sex/dose) were selected to constitute
the second generation and were mated twice to produce the F2A and F2B. 
All F2A pups were killed at weaning.  F2B pups were selected
(1/sex/litter) and maintained on treatment for 13 weeks and killed; the
remaining F2B pups were killed at weaning.  

There were no clear adverse effects on food consumption, mating
performance, duration of gestation or live births in the parental
animals.  There were no clinical signs reported for males, and no males
receiving 360 ppm died.  At the high dose, a total of 18 females died (2
F0, 1 F1A, 13 F1B and 2F2B).  Deaths (10) generally occurred during
lactation in the F1B dams.  Clinical signs observed in the high-dose
dams of the F0 and F1B generations included: body tremors, spasmodic
muscle twitches and increased sensitivity to external stimuli.  Two
females at 120 ppm died during lactation and one F1B female showed the
clinical signs observed for the high-dose group during the lactation
Week 2.  The deaths and clinical signs noted at 120 ppm were considered
by the study authors to be associated with treatment.  A consistent 10%
reduction in absolute body weight of the F1B generation high-dose males
and females was generally seen starting at Week 4 to termination (males)
or from Week 4 until Week 26 (females); body weight gain was also
generally reduced.  There were no clear effects on absolute body weight
or body weight gain during gestation or lactation for any generation
(1stor 2nd matings).   

Based on death and clinical signs of neurotoxicity in the females, the
parental systemic LOAEL was determined at 120 ppm (8.9 mg/kg/day for
males and 10.1 mg/kg/day for females).  The NOAEL is established at 40
ppm (3.0 mg/kg/day for males and 3.4 mg/kg/day for females).

The high-dose F2A pups had decreased litter sizes from birth to weaning,
which attained statistical significance for lactation days 8, 12 and 21.
 The high-dose F1B and F2B pups had non- significantly decreased litter
sizes for lactation day 21 (8%).  In addition, the high-dose F1B pups
had significantly decreased litter and pup body weight on lactation days
8, 12 and 21.  No other effects were seen in the pups of any generation.
 Body tremors were observed in three F2B pups (one each from separate
litters) at 120 ppm prior to weaning (days 19 or 21); two of these
mid-dose pups died shortly after the onset of tremors.  Tremors were not
observed in the high-dose pups.  Organ weights for the pituitary, liver,
thyroid, kidney and adrenal were affected for F1A, F2A, and F2B
weanlings at 120 ppm and 360 ppm.  There were, however, no corresponding
histopathological lesions.  

Based on body tremors and increased mortality, the offspring LOAEL is
established at 120 ppm (8.9 mg/kg/day for males and 10.1 mg/kg/day for
females).  The NOAEL is 40 ppm (3.0 mg/kg/day for males and 3.4
mg/kg/day for females.)

This study is acceptable/guideline and satisfies the guideline
requirement for a 2-generation reproductive study (OPPTS 870.3800; OECD
416) in rats.

A.3.3.	Chronic and/or Carcinogencity Studies

A.3.3.1	Carcinogenicity Study in Mice

  SEQ CHAPTER \h \r 1 In a chronic toxicity study (MRID 00163814),
fenpropathrin as S-3206 (91.4 and 92.5% Batch Nos. 01113 and 20514,
respectively) was administered to groups of 52 CD-1 mice/sex/dose (main
groups) or 40 mice/sex/dose (satellite groups for interim sacrifices at
26, 52 or 78 weeks) in the diet at levels of 0, 40, 150 or 600 ppm
[equivalent to 0, 3.9, 13.7 or 56.0 mg/kg/day (males) or 0, 4.2, 16.2 or
65.2 mg/kg/day (females) for 104 weeks. 

Mortality was highest during the final quarter of the study but was
comparable in all dosed and control groups (45 % in the control, 52% in
the low-dose group, 54% in the mid-dose group and 50% in the high-dose
group).  There was no sex-specific effect on mortality.  The only
clinical sign reported was marginally increased hyperactivity in the
high-dose females prior to Week 78.   There were no compound-related
effects on body weight, food and water consumption, hematology, clinical
chemistry, organ weights, or gross and histologic (including tumors)
pathology.  No other evidence of toxicity or carcinogenicity was seen.  

Since there was an overall lack of a toxic response at the doses tested,
the LOAEL is >600 ppm (equivalent to 56.0 mg/kg/day); a NOAEL was not
established.  However, the aborted mouse carcinogenicity study (MRID No.
00163815) demonstrated that at a slightly higher maximum tolerated dose
(MTD) of 1000 ppm, the test article was lethal to 15% of the mice after
only 13 weeks.  Thus, the maximum dose used in the completed study (600
ppm) was very close to the MTD.  A repeat study is not justified.  

This chronic study in the mouse is acceptable (guideline) and satisfies
the guideline requirement for a carcinogenicity study (OPPTS 870.4200,
OECD 451) in the mouse.

A.3.3.2 	Chronic/Carcinogenicity Study in Rats 

  SEQ CHAPTER \h \r 1 In a chronic toxicity study (MRID 00163813),
fenpropathrin as S-3206 (91.4 and 92.%, Batch Nos. 01113 and 20514,
respectively) was administered to groups of 50 CD-1 rats/sex/dose (main
groups) or 15 rats/sex/dose (satellite groups for interim sacrifices at
26, 52, 78 and 104 weeks) in the diet at levels of 0, 50, 150, 450 or
600 ppm [equivalent to 0, 1.93, 5.71, 17.06 or 22.80  mg/kg/day (males)
or 0, 2.43, 7.23, 19.45 or 23.98  mg/kg/day (females)] for 108 weeks
(males) or 115 weeks (0, 50, 150 or 450 ppm, females) or 52 weeks (600
ppm, females). 

Mortality was highest among females receiving 450 ppm (2%/16% M/F) and
600 ppm (10%/46% M/F) during the first 26 weeks; no deaths occurred in
the control group.  Consequently, all surviving high-dose females were
terminated at 52 weeks. For the remainder of the study, mortality was
not dose related and generally occurred at a higher rate in the control
than the treated groups.  The only dose-related clinical sign was body
tremors in the 600-ppm group males (less than or equal to 6% affected
between weeks 1 and 10) and females (less than or equal to 65% affected
between weeks 1 and 52).  At 450 ppm, less than or equal to 5% of the
females were affected with body tremors between weeks 1 and 14.  These
tremors occurred primarily in the morning.  Body weight gain, food and
water consumption were similar for all groups but food efficiency was
impaired for the 600 ppm females only.  There were no signs of adverse
effects on ophthalmology or clinical pathology.  Organ weight effects
included: a doubling in the absolute and relative pituitary weights (600
ppm males), significant increases in the absolute and relative kidney
and adrenal weights (600 ppm males) and decreased absolute and relative
ovary weights (600 ppm females).  However, no compound-related gross or
microscopic lesions associated with these organ weight anomalies were
found in either sex.  Minimal axonal degeneration was reported for both
sexes of all groups (including the controls) with a slightly higher
incidence in the high-dose group but there was no correlation between
tremors and axonal degeneration.  Both males and females had an increase
in anterior pituitary adenomas but the incidence rate was not
dose-related and was lower than the control.  Thus, there was no
evidence of a carcinogenic effect at any dose up to and including 600
ppm.  Based on these considerations, the increased mortality at 600 ppm
is evidence that the maximum tolerated dose was administered.  

Accordingly, the LOAEL for males is 600 ppm (equivalent to 22.80
mg/kg/day), based on increased mortality and body tremors; the LOAEL for
females is 450 ppm (equivalent to 19.45 mg/kg/day), based on increased
mortality and body tremors.  The NOAEL for males and females was 450 ppm
(equivalent to 17.06 mg/kg/day) and 150 ppm (equivalent to 7.23
mg/kg/day), respectively.       

This chronic toxicity/carcinogenicity study in the rat is acceptable
(guideline) and satisfies the guideline requirement for a chronic oral
study (OPPTS 870.4300; OECD 453) in the rat.

A.3.3.3		Oral Chronic Toxicity Study in Dogs

  SEQ CHAPTER \h \r 1 In a chronic toxicity study (MRID 00143130),
fenpropathrin as S-3206 (92.5% Lot no. 20514) was administered to groups
of four male and four female Beagle dogs/sex/dose in the diet at levels
of 0, 100, 250 or 750 ppm (equivalent to 0, 2.5, 6.25 or 18.75 mg/kg
bw/day1) ad libitum for 52 weeks. 

One high-dose male was found dead during week 32.  Prior to death, the
animal was languid, thin and exhibited ataxia, tremors and polypnea
(excessive respiration).  There were numerous gross findings (including
soft brain, enlarged and congested liver, enlarged lymph nodes,
ulcerations and erosions of the oral cavity, perforations of the tongue
and  multiple skin sores) and histopathological findings (including
adrenal congestion and hemorrhage, pulmonary edema and congestion,
liver, kidney and stomach congestion, decreased spermatogenesis,
prostate atrophy, thymus atrophy, and multiple lesions of the oral
cavity.  There were, however, no other deaths and no gross or
histopathological lesions in any other treatment group.  Clinical signs
included tremors (750 ppm, during week 1 to termination; 250 ppm
starting at week 6 and sporadically, thereafter); ataxia  (750 ppm,
starting at week 2 and consistently observed from week 8 to32); and
languid appearance (750 ppm, weeks 7 through 48).  Mean body weight of 
high-dose dogs was reduced less than or equal to 11% in males and 20% in
females.  No effect was seen on body weight in the lower treatment
groups. No significant differences in food consumption were observed. 
There were no treatment-related effects on hematology, clinical
chemistry, urinalysis, opthalmoscopy, clinical pathology or organ
weight.  With the exception of the high-dose male that died on study, no
compound-related gross or histopathological effects were noted at any
dose.  

From these findings, the LOAEL is 250 mg/kg/day (~6.25 mg/kg/day), based
on tremors and ataxia in males and females; the NOAEL is 100 ppm (~2.5
mg/kg/day).

This chronic study in the dog is acceptable (guideline) and satisfies
the guideline requirement for a chronic oral study (OPPTS 870.4100; OECD
452) in the dog.

A.3.4	Mutagenicity Studies

A.3.4.1	In Vitro Bacterial Reverse Gene Mutation

	

Gene mutation assays were negative for mutagenicity.   A bacterial
Reverse Mutation Assay Test using Salmonella typhimurium TA 1535,
TA1537, TA1538, TA98 and TA100 and Escerichia coli Wp2 uvrA (MRID
00163818) at 0, 10, 50, 100, 500, or 5000 µg/plate with and without S9
was negative for mutagenicity though there was evidence of insolubility
at higher concentrations.  

A.3.4.2	In Vitro Mammalian Cell Gene Mutation

In an in vitro mammalian cell gene mutation test (MRID 00126832), there
was no clear evidence of induced mutant colonies in mouse lymphoma cells
L51785 over background.  Tests were conducted in the absence of S-9 at
50.3, 84.5, 141.9, 238.2, and 400 µg/ml and in the presence of S9 at 0,
30, 47.5, 75.3, 119.4, 189.2, and 300 µg/mL.

A.3.4.3	In Vitro Mammalian Cytogenetics

≥ 30µg/mL (–S9) and precipitation was observed at 1000 µg/mL
(+S9).

A.3.4.4	In Vitro DNA Damage

 

Bacillus subtilis strains M45 rec- and H17 were exposed to 0, 10, 50,
100, 1000, and 5000 ug/paper disk (MRID 00126831).  The test consisted
of applying the cultured suspension of bacteria (0.1 mL of H17 or 0.2 mL
of M45) to the top of an agar plate, then a paper disk containing the
test substance was placed into the center of the plate.  The diameter of
growth inhibition zone was measured after 24 hours.  No inhibition zone
was noted at any level.

A.3.4.5	In Vitro Sister Chromatid Exchange Assay

Chinese hamster ovary (CHO) cells were cultured for 24 hours in Ham’s
F12 medium containing 3x10-6-1x10-4 M fenpropathrin with and without S9.
 There was no increase in sister chromatid exchange.

A.3.5	Neurotoxicity Studies

A.3.5.1	Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 47345605), fenpropathrin (92.0%
a.i.; Lot No. 050213G) in corn oil was administered once via gavage (5
mL/kg) to 12 Sprague-Dawley rats/sex/group at dose levels of 0, 3, 6,
15, or 30 mg/kg.  Neurobehavioral assessment (functional observational
battery [FOB] and motor activity testing) was performed on 12
rats/sex/group at pre-dosing and Days 0 (approximately 3 hours
post-dosing; time of peak effect), 7, and 14.  At study termination, 6
rats/sex/group were anesthetized and perfused in situ for
histopathological examination.  The tissues from 6 animals in the
control and 30 mg/kg groups were subjected to neuropathological
evaluation of brain and peripheral nervous system tissues.  Acceptable
positive control data were provided.

No compound-related effects were observed in mortality, clinical signs
of toxicity, body weight, body weight gain, motor activity, brain weight
and morphology, or gross and neuropathology in either sex.

At 30 mg/kg, the following FOB effects (# affected/12 vs. 0/12 controls)
were noted at 3 hours post-dosing (time of peak-effect):  (i) slight
tremors in 10 animals of each sex during the open-field observations;
(ii) clonic convulsions (whole body tremors) in one rat of each sex
during the open-field observations, and (iii) slight tremors in 2 males
and 1 female during the home cage observations.  These behavioral
changes were apparently reversible, as all animals appeared normal by
Day 7.

Findings at 15 mg/kg were limited to slight tremors in 2 females at 3
hours post-dosing during the open-field observations.  In the absence of
other neurotoxic effects in this group and the absence of any findings
in the 15 mg/kg males, this finding is considered equivocal for
neurotoxicity.

There was evidence of neurotoxicity observed at 30 mg/kg.

The LOAEL was 30 mg/kg based on slight tremors and clonic convulsions
(whole body tremors) in both sexes at the time of peak-effect.  The
NOAEL is 15 mg/kg.

The study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.6200a; OECD 424) for an acute
neurotoxicity study in rats.

A.3.5.2	Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (MRID 47345607), fenpropathrin
(92.0% a.i.; Lot No. 050213G) was administered daily in the diet to 12
Sprague-Dawley rats/sex/group at dose levels of 0, 60, 190, or 570 ppm
(equivalent to 0/0, 4/5, 13/15, and 38/50 mg/kg/day; M/F) for 90 days. 
Neurobehavioral assessment (functional observational battery [FOB] and
motor activity testing) was performed on all animals at pre-dosing and
Weeks 3, 7, and 12.  At study termination, all animals were anesthetized
and perfused in situ for neuropathological examination, brain weights
and measurements were recorded.  The tissues from 6 animals/sex in the
control and 570 ppm groups were subjected to neuropathological
evaluation of brain and peripheral nervous system tissues.  Acceptable
positive control data were provided.

No compound-related effects were observed in ophthalmoscopic
examinations, motor activity, brain weight and morphology, or gross and
neuropathology in either sex.

At 570 ppm, one female was found dead on Day 7 and displayed tremors and
hypersensitivity to sound during the first 6 days of test article
administration.  The following clinical signs of toxicity were observed
(# affected/12 vs. 0/12 controls): (i) tremors (10 males and 12
females); (ii) hypersensitivity to sound (12 rats of each sex); and
(iii) popcorn seizures (4 females).  The frequency of tremors and
hypersensitivity to sound was greater in the females compared to males. 

Body weights were decreased throughout the study by 11-13% in the males
and by 8-13% in the females.  Cumulative body weight gains were also
decreased throughout the study by 18-40% in the males and by 29-62% in
the females.  Overall (Weeks 0-13) body weight gains were decreased by
19% in the males and by 29% in the females.  These decreases in body
weight and cumulative body weight gain were corresponded with the 10-19%
decrease in mean food consumption throughout the study in the males. 
Mean food efficiency (bw gained as a % of food consumed) was decreased
by 27% in the males during Week 0-1 and by 29-59% in the females during
Weeks 0-1, 1-2, and 4-5 compared to controls.  

Treatment-related FOB effects were predominantly observed in the 570 ppm
females and included the following (# affected/11 females vs. 0/12
controls):  During the home cage observations, slight to markedly coarse
tremors were noted in 3-5 females throughout the treatment period. 
During the handling observations, soft and flabby muscle tone was noted
in 3 females during Week 3.  In the open-field, slight to markedly
coarse tremors were noted in 3-7 females throughout the treatment period
and in 1 male at Week 3; slightly to moderately impaired mobility was
noted in 2-3 females during Weeks 3 and 12 and in 2 males at Week 3;
clonic convulsions (whole body tremors) were observed in 3 females
during Weeks 3 and 7; slight to moderately impaired gait score was noted
in 2-3 females throughout the treatment period, and 1 male displayed
body dragging during Week 3; abnormal gait including walking on tiptoes
was noted in 2 females at Week 12 and hunched body was noted in 3
females at Week 12; and the mean number of rears was increased by 91% in
the males during Week 3 and by 100% in the females during Week 12. 
During the sensory observations, a more energetic startle response was
noted in 3 females during Weeks 3 and 12, and slightly uncoordinated
air-righting reflex was noted in 1-3 females during Weeks 3 and 12. 
Also during the air-righting reflex testing, 1 additional female landed
on its side or back during Weeks 3 and 7, respectively.  During the
neuromuscular observations, mean hindlimb grip strength was decreased by
27% in the females during Week 3; rotarod performance was decreased by
51-68% in the females throughout treatment; and hindlimb footsplay
decreased by 34% in the females during Week 3.  Additional findings
observed at this dose in the home cage or open-field included ataxia in
2 females during Week 3 and in 1 female at Week 7, whole body tremors in
1 female at Weeks 3 and 12, biting the cage or self in 2 females at Week
12, and ‘popcorn’ seizure in 1 female each at Weeks 3 and 7.

The LOAEL for neurotoxicity was 570 ppm (equivalent to 38/50 mg/kg/day,
M/F) based on tremors, convulsions, impaired gait, and related findings
in the FOB predominantly in the females.  The NOAEL is 190 ppm
(equivalent to 13/15 mg/kg/day, M/F).

The study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.6200b; OECD 424) for a subchronic
neurotoxicity study in rats.

A.3.5.3		Developmental Neurotoxicity Study

In a developmental neurotoxicity study (MRID 47345609), fenpropathrin
(92.0% a.i.; Lot No. 050213G) was administered in the diet to 25
presumed pregnant Sprague Dawley (Crl:CD[SD]) rats/dose from gestation
day (GD) 6 through lactation day (LD) 21 at doses of 0, 40, 100, or 250
ppm (equivalent to 0, 3, 8, and 19 mg/kg/day during gestation, and 0, 7,
16, and 40 mg/kg/day during lactation).  The pups were not dosed.  Dams
were allowed to deliver naturally and were killed on LD 21.  On
post-natal day (PND) 4, litters were randomly standardized to 8
pups/litter (4/sex where possible), and the remaining offspring were
sacrificed without further examination.  Subsequently, pups were
allocated to the following subsets.  For Subset A (20 pups/sex/dose
group), the following parameters were examined:  functional
observational battery (FOB) on PND 4, 11, 21, 35, 45, and 60; motor
activity on PND 13, 17, 21, and 61; auditory startle on PND 20 and 60;
and learning and memory beginning on PND 62.  Fifteen animals/sex/dose
group were selected from Subset A for brain weight evaluations on PND
72; of these, 10 animals/sex from the controls and 250 ppm groups were
selected for neuropathological and morphometric evaluations on PND 72. 
All Subset A animals were also examined for balanopreputial separation
or vaginal patency as appropriate.  For Subset B (20 pups/sex/dose
group), learning and memory testing was initiated on PND 25.  For Subset
C, 15 animals/sex/dose group were selected for brain weight evaluations
on PND 21; of these, 10 animals/sex from the controls and 250 ppm groups
were selected for neuropathological and morphometric evaluations on PND
21.

In the dams, there were no effects of treatment observed on mortality,
body weights, body weight gains, food consumption, reproductive
parameters, gestation duration, or macroscopic pathology.

Treatment-related tremors were observed in 24/25 dams at 250 ppm during
lactation.  The onset and duration were somewhat variable among the
group, and one female displayed tremors on GD 13.  The severity of the
tremors generally increased from slight to moderate/severe as lactation
progressed, corresponding to a higher test compound consumption on a
mg/kg basis during lactation compared to gestation.  Similarly, during
the LD 10 modified FOB, a greater number of 250 ppm dams were observed
with slight tremors compared to controls.  One 250 ppm female was
observed with moderately coarse tremors and slightly impaired mobility
on LD 10 and splayed hindlimbs on LD 21.

The LOAEL for maternal toxicity is 250 ppm (equivalent to 19/40
mg/kg/day during gestation/lactation, respectively), based on tremors
during lactation.  The NOAEL is 100 ppm (equivalent to 8/16 mg/kg/day
during gestation/lactation, respectively).

There were no effects of treatment on the number of pups born, sex ratio
at birth, live litter size on PND 0, post-natal survival indices, the
number of pups found dead, killed in extremis, and/or missing, or on the
general physical condition of the pups.

During lactation, increased numbers of pups that were small in size were
observed in the 250 ppm litters.  This finding was often observed on
multiple occasions in the affected pups, and correlated with decreased
pup body weights.  Offspring pre-weaning body weights were decreased by
10-16% in both sexes from PND 7 through 21.  Interval body weight gains
for the corresponding intervals were also decreased by 11-21%.

The LOAEL for offspring toxicity is 250 ppm (equivalent to 19/40
mg/kg/day during gestation/lactation, respectively), based on pups small
in size and decreased body weights and body weight gains during the
pre-weaning period.  The NOAEL is 100 ppm (equivalent to 8/16 mg/kg/day
during gestation/lactation, respectively).

There were no effects of treatment on the FOB, motor activity, learning
and memory, gross or microscopic pathology, or brain morphometric
measurements.

On PND 60, the mean overall maximum response amplitude (VMAX) and
average response amplitude (VAVE) were increased, and the latency to
maximum response was decreased in the 250 ppm females.  The VMAX and
VAVE values exceeded the 75th quartile values of the historical control
data; and the TMAX value was equal to the 25th quartile value of the
historical control data.  On PND 21, absolute brain weights were
decreased by 6% in the 250 ppm males.

The LOAEL for developmental neurotoxicity is 250 ppm (equivalent to
19/40 mg/kg/day during gestation/lactation, respectively), based on
increased mean overall maximum startle response amplitude and average
response amplitude in the females, and decreased absolute brain weights
in the males.  The NOAEL is 100 ppm (equivalent to 8/16 mg/kg/day during
gestation/lactation, respectively).

This study is acceptable/guideline and meets the requirements (OPPTS
870.6300; OECD 426) for a developmental neurotoxicity study in rats.

A.3.6 	Other Studies

A.3.6.1	Metabolism and Pharmokinetics Study

  SEQ CHAPTER \h \r 1 In a metabolism study (MRID 43476801), groups of
five male and five female Crl:CD®BR® VAF/Plus (Sprague-Dawley) rats
were dosed by oral gavage with radiolabeled S-3206 (fenpropathrin) by
three protocols.  They were dosed with S-3206 radiolabeled on either the
alcohol [alcohol-14C]-S-3206 (98.7% a.i.; Lot No. C-91-089)] or acid
[acid-14C]-S-3206 (98.5% a.i.; Lot No. C-90-039) portion of the
molecule.  In Experiment I, rats received 14 daily oral low-doses of 2.5
mg/kg/day of unlabelled S-3206 followed by a 15th dose of either the
alcohol or acid radiolabeled S-3206.  In Experiments II and III, groups
of rats received a single dose of either of the two radiolabeled test
articles at 2.5 mg/kg (II) or 25 mg/kg (III).  No clinical signs were
seen in any rats.

  

Elimination for both sexes was similar in the single low and high-dose
experiments (II and III), with about one-third of the dose being
eliminated in the urine (II - 30-40%; III - 28-35%) and the balance in
the feces (II and III - 65-69%).  In the multiple dose experiment (I),
half of the elimination was in the urine (52-56%) and the remainder in
the feces (46-55%) for both sexes.  The half-life was 11-16 hours in the
urine, and 7-9 hours in the feces.  In all three experiments, >99% of
the administered dose was excreted after 168 hours (7 days).  The small
percentage of radiolabel found in the tissues was mostly in the fat.  

The major biotransformations included oxidation at the methyl group of
the acid moiety, hydroxylation at the 4'- position of the alcohol
moiety, cleavage of the ester linkage, and conjugation with sulfuric
acid or glucuronic acid.   

Four metabolites were found and characterized in the urine of rats dosed
with alcohol-radiolabel.  The major metabolites were the sulfate
conjugate of 3-(4'-hydroxyphenoxy)benzoic acid and 3-phenoxybenzoic acid
(22-44% and 3-9% of the administered dose, respectively).  Eight
metabolites were found in the urine of rats dosed with acid-radiolabel,
but only four were characterized.  The major urinary metabolites of the
acid-labeled fenpropathrin were TMPA-glucuronic acid and TMPA-CH2OH
(11-26% and 6-10% of the administered dose, respectively).  None of the
parent chemical was found in urine.  

The major elimination products in the feces included the parent chemical
(13-34% of the administered dose) and 4 metabolites.  The fecal
metabolites (and the percentage of administered dose) included
CH2OH-fenpropathrin (9-20%), 4'-OH-fenpropathrin (4-11%),
COOH-fenpropathrin (2-7%), and 4'-OH-CH2OH-fenpropathrin (2-7%).  

This study in the rat is acceptable (guideline), and satisfies the
guideline data requirement for a metabolism study (OPPTS 870.7485, OECD
417) in the rat.

A.3.6.2	Dermal Penetration Study

  SEQ CHAPTER \h \r 1 In a dermal penetration study (MRID 43433801),
skin penetration and excretion of radiolabelled fenpropathrin  [99%
radiochemical purity; specific activity of 166 mCi (6.14 Gbq/g; Lot no.
C-89-049] were measured following single applications to the clipped
skin of male Sprague-Dawley (CD/BR) rats.  Groups of thirty rats were
randomly assigned to three dose levels: 0.03% (lowest concentration
encountered by applicators in the field), 1.5% (recommended field
dilution), and 30% (concentration found in Danitol 2.4 EC).  The
corresponding doses were 0.03, 1.5, and 30 mg/rat (calculated doses were
0.0013, 0.0663, and 1.26 mg/cm2).  Within each of the three dose levels
were six termination groups of five rats each which were sequentially
sacrificed at intervals of 0.5, 1, 2, 4, 10, and 24 hours.

Mean dermal absorption for the 10-hour interval was 33.3, 20.1, and 17.6
% in the low, mid, and high-dose groups, respectively.  Elimination was
primarily through the urine, and secondarily through the feces. 
Absorption:elimination equilibrium was reached in as little as 4 hours
at the low dose, and under 10 hours at the mid and high-doses. 
Elimination at the 24-hour interval for the low, mid, and high-doses was
18.2%, 8.2%, and 4.1% in the urine, and 5.8%, 1.8%, and 0.4% in the
feces, respectively.  The rates of elimination for the low, mid, and
high concentrations were 0.88%/hour, 0.38%/hour, and 0.19%/hour in the
urine (between the 4 and 24 hour intervals), and 0.39%/hour, 0.13%/hour,
and 0.029%/hour in the feces (between the 10 and 24 hour intervals),
respectively.  Residual radioactivity in the carcass was 9.0%, 3.7%, and
1.3%, respectively.  Although considerable radioactivity was found in
the application site skin, very little was found in the blood and
non-application site skin.  Group mean radioactivity recovery for any
given dose/interval group ranged from 96.8% to 110.8%.  

Dermal absorption increased with dose concentration, but not at a
proportional rate.  The percentage of dose absorbed decreased as dose
concentration increased.  That is why the percentage of dose found in
the urine, feces, blood, carcass, and application site skin was greatest
in the low-dose group and least in the high-dose group.  If a recovery
phase had been included in the study protocol, the total body burden
could be expected to decrease rapidly upon removal of the dose in the
urine and feces.  

This study is Acceptable (guideline), and satisfies the data requirement
for a dermal absorption study (OPPTS 870.7600) in the rat.

A.4  Immunotoxicity Study Guidance

Guideline Number: 870.7800

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愀Ĥ摧偳؀nt under 40 CFR Part 158 as a part of the data
requirements for registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies assessing functional immunotoxic endpoints are helpful
in fully characterizing a pesticide’s potential immunotoxicity.  These
data will be used in combination with data from hematology, lymphoid
organ weights, and histopathology in routine chronic or subchronic
toxicity studies to characterize potential immunotoxic effects.  

Practical Utility of the Data

How will the data be used?

These animal studies can be used to select endpoints and doses for use
in risk assessment of all exposure scenarios and are considered a
primary data source for reliable reference dose calculation. For
example, animal studies have demonstrated that immunotoxicity in rodents
is one of the more sensitive manifestations of TCDD
(2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive,
and endocrinologic toxicities.  Additionally, the EPA has established an
oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed
immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have these data, a 10X database uncertainty
factor might be applied for conducting a risk assessment from the
available studies.

 

Appendix B:  Tolerance Summary for Fenpropathrin

Table B.1.   Tolerance Summary for Fenpropathrin.

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

Tolerances Proposed Under PP#4E6867

Stone Fruit, Crop Group 12 (except Cherry)	5.0	1.4	Fruit, stone, group
12

Cherry, sweet and tart	--	5.0	Cherry, sweet

Cherry, tart

Tolerance recommendation is based on >5x differences of maximum field
trial residues between cherry and remaining stone fruit representative
crops

Tree Nuts (including Pistachio), Crop Group 14	0.10 (nutmeats)	0.10	Nut,
tree, group 14

	5.0 (almond hulls)	4.5	Almond, hulls

Tolerance That Needs to be Proposed Under PP#4E6867

Pistachio	--	0.10	Tolerance recommendation is based on residue data
translated from the Nut, Tree, Crop Group 14.

Tolerances Proposed Under PP#6E7066

Avocado	1.0	1.0

	Black Sapote	1.0	1.0	Tolerance recommendations are based on residue
data translated from avocado.

Canistel	1.0	1.0

	Mamey sapote	1.0	1.0

	Mango	1.0	1.0

	Papaya	1.0	1.0

	Sapodilla	1.0	1.0

	Star apple	1.0	1.0

	Barley, grain	0.30	Withheld	HED will complete its review of the
proposed barley use upon submission of a barley processing study.

Barley, hay	2.5	Withheld

	Barley, straw	4.5	Withheld

	Tolerances Proposed Under PP#7E7298

Caneberry subgroup 13A	--	12	Caneberry subgroup 13-07A

Olive	--	5.0

	Reassessment of Tolerances for Ruminant Commodities

Cattle, fat	1.0	0.05	The available data indicate that the tolerances may
be decreased.

Cattle, meat byproducts	0.1	0.01

	Cattle, meat	0.1	0.01

	Goat, fat	1.0	0.05	The available data indicate that the tolerances may
be decreased.

Goat, meat byproducts	0.1	0.01

	Goat, meat	0.1	0.01

	Hog, fat	1.0	Remove	The available data indicate that tolerances for hog
commodities are not needed.

Hog, meat byproducts	0.1	Remove

	Hog, meat	0.1	Remove

	Horse, fat	1.0	0.05	The available data indicate that the tolerances may
be decreased.

Horse, meat byproducts	0.1	0.01

	Horse, meat	0.1	0.01

	Milk, fat (reflecting 0.002 ppm in whole milk)	2.0	0.05	Milk, fat

Sheep, fat	1.0	0.05	The available data indicate that the tolerances may
be decreased.

Sheep, meat byproducts	0.1	0.01

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ᔵ഍഍慐敧ጠ倠䝁⁅ㄔ―景ጠ丠䵕䅐䕇⁓㘔ᔵ഍഍഍

഍倍条⁥–䅐䕇ᐠ㈶  of   NUMPAGES  65 

Acute RfD = 6.0 mg/kg/day = 0.06 mg/kg/day

100 (UF)