Document ID: EPA-HQ-OPP-2007-0303-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-04-09T04:00Z

UNITED STAES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:		December 31, 2007 

SUBJECT:	Fenhexamid.  Human Health Risk Assessment for a Proposed
Section 			3 Registration for Use on Asparagus.  

	

Petition #	7E7187	

PC Code:	090209

DP #:	340304	

Class:	Fungicide

Decision #:	375841	40 CFR:	§180.553

FROM:	Breann Hanson, Biologist 

		Alternative Risk Integration and Assessment (ARIA) Team

		Risk Integration Minor Use and Emergency Response Branch 				
(RIMUERB)/Registration Division (RD) (7505P)

THROUGH:	William Cutchin, Acting Branch Senior Scientist 

		ARIA Team

		RIMUERB/RD (7505P)

		AND

		

		Kelly Schumacher, Toxicologist  

		Christina Swartz, Branch Chief

		Registration Action Branch 2 (RAB 2)

		Health Effects Division (HED) (7509P)

TO:		Shaja Brothers, RM Team 05

		RIMUERB/RD (7505P)

ARIA/RIMUERB of RD of the Office of Pesticide Programs (OPP) is charged
with estimating the risk to human health from exposure to pesticides. 
RD of OPP has requested that ARIA evaluate hazard and exposure data and
conduct dietary, occupational, residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from proposed and currently registered uses of the active
ingredient fenhexamid. 

In this document, ARIA has conducted an assessment of the human exposure
and health risks resulting from these proposed uses and all currently
registered uses.  The overall risk assessment and dietary risk
assessment were provided by Breann Hanson, the residue chemistry
assessment by Debra Rate (ARIA), the water exposure assessment by Cheryl
Sutton (Environmental Fate and Effects Division (EFED)) and the
occupational exposure assessment by Mark Dow (ARIA).  

TABLE OF CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc186859490"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc186859490 \h  5  

  HYPERLINK \l "_Toc186859491"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc186859491 \h  9  

  HYPERLINK \l "_Toc186859492"  2.1	Proposed Use	  PAGEREF _Toc186859492
\h  10  

  HYPERLINK \l "_Toc186859493"  2.2	Identification of Active Ingredient	
 PAGEREF _Toc186859493 \h  10  

  HYPERLINK \l "_Toc186859494"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc186859494 \h  11  

  HYPERLINK \l "_Toc186859495"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc186859495 \h  11  

  HYPERLINK \l "_Toc186859496"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc186859496 \h  11  

  HYPERLINK \l "_Toc186859497"  3.1.1	Database Summary	  PAGEREF
_Toc186859497 \h  17  

  HYPERLINK \l "_Toc186859498"  3.1.2	Toxicological Effects	  PAGEREF
_Toc186859498 \h  17  

  HYPERLINK \l "_Toc186859499"  3.1.3	Dose-response	  PAGEREF
_Toc186859499 \h  17  

  HYPERLINK \l "_Toc186859500"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc186859500 \h  18  

  HYPERLINK \l "_Toc186859501"  3.3	FQPA Considerations	  PAGEREF
_Toc186859501 \h  18  

  HYPERLINK \l "_Toc186859502"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc186859502 \h  18  

  HYPERLINK \l "_Toc186859503"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc186859503 \h  18  

  HYPERLINK \l "_Toc186859504"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc186859504 \h  18  

  HYPERLINK \l "_Toc186859505"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc186859505 \h  18  

  HYPERLINK \l "_Toc186859506"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc186859506 \h  20  

  HYPERLINK \l "_Toc186859507"  3.3.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc186859507 \h  20  

  HYPERLINK \l "_Toc186859508"  3.3.7	Recommendation for a Developmental
Neurotoxicity (DNT) Study	  PAGEREF _Toc186859508 \h  21  

  HYPERLINK \l "_Toc186859509"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc186859509 \h  21  

  HYPERLINK \l "_Toc186859510"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc186859510 \h  21  

  HYPERLINK \l "_Toc186859511"  3.5.1	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc186859511 \h  21  

  HYPERLINK \l "_Toc186859512"  3.5.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc186859512 \h  22  

  HYPERLINK \l "_Toc186859513"  3.5.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc186859513 \h  22  

  HYPERLINK \l "_Toc186859514"  3.5.5	Dermal Absorption	  PAGEREF
_Toc186859514 \h  22  

  HYPERLINK \l "_Toc186859515"  3.5.6	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc186859515 \h  23  

  HYPERLINK \l "_Toc186859516"  3.5.7	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc186859516 \h  23  

  HYPERLINK \l "_Toc186859517"  3.5.8	Level of Concern for Margin of
Exposure	  PAGEREF _Toc186859517 \h  24  

  HYPERLINK \l "_Toc186859518"  3.5.9	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc186859518 \h  24  

  HYPERLINK \l "_Toc186859519"  3.5.10	Classification of Carcinogenic
Potential	  PAGEREF _Toc186859519 \h  25  

  HYPERLINK \l "_Toc186859520"  3.5.11	Summary of Toxicological Doses
and Endpoints for Fenhexamid for Use in Human Risk Assessments	  PAGEREF
_Toc186859520 \h  25  

  HYPERLINK \l "_Toc186859521"  3.6	Endocrine Disruption	  PAGEREF
_Toc186859521 \h  26  

  HYPERLINK \l "_Toc186859522"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc186859522 \h  27  

  HYPERLINK \l "_Toc186859523"  4.1	Incident Reports	  PAGEREF
_Toc186859523 \h  27  

  HYPERLINK \l "_Toc186859524"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc186859524 \h  27  

  HYPERLINK \l "_Toc186859525"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc186859525 \h  27  

  HYPERLINK \l "_Toc186859526"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc186859526 \h  27  

  HYPERLINK \l "_Toc186859527"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc186859527 \h  27  

  HYPERLINK \l "_Toc186859528"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc186859528 \h  27  

  HYPERLINK \l "_Toc186859529"  5.1.4	Analytical Methodology	  PAGEREF
_Toc186859529 \h  27  

  HYPERLINK \l "_Toc186859530"  5.1.5	Environmental Degradation	 
PAGEREF _Toc186859530 \h  28  

  HYPERLINK \l "_Toc186859531"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc186859531 \h  28  

  HYPERLINK \l "_Toc186859532"  5.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc186859532 \h  29  

  HYPERLINK \l "_Toc186859533"  5.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc186859533 \h  29  

  HYPERLINK \l "_Toc186859534"  5.1.9	Drinking Water Residue Profile	 
PAGEREF _Toc186859534 \h  29  

  HYPERLINK \l "_Toc186859535"  5.1.10	Food Residue Profile	  PAGEREF
_Toc186859535 \h  30  

  HYPERLINK \l "_Toc186859536"  5.1.11	International Residue Limits	 
PAGEREF _Toc186859536 \h  30  

  HYPERLINK \l "_Toc186859537"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc186859537 \h  31  

  HYPERLINK \l "_Toc186859538"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc186859538 \h  31  

  HYPERLINK \l "_Toc186859539"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc186859539 \h  32  

  HYPERLINK \l "_Toc186859540"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc186859540 \h  32  

  HYPERLINK \l "_Toc186859541"  6.0	RESIDENTIAL (NON-OCCUPATIONAL
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc186859541 \h  32  

  HYPERLINK \l "_Toc186859542"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc186859542 \h  32  

  HYPERLINK \l "_Toc186859543"  7.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc186859543 \h  33  

  HYPERLINK \l "_Toc186859544"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc186859544 \h  33  

  HYPERLINK \l "_Toc186859545"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc186859545 \h  33  

  HYPERLINK \l "_Toc186859546"  9.1	Occupational Pesticide Handler
Exposure and Risk	  PAGEREF _Toc186859546 \h  34  

  HYPERLINK \l "_Toc186859547"  9.2	Occupational Post-Application Worker
Exposure and Risk	  PAGEREF _Toc186859547 \h  36  

  HYPERLINK \l "_Toc186859548"  10.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc186859548 \h  37  

  HYPERLINK \l "_Toc186859549"  REFERENCES	  PAGEREF _Toc186859549 \h 
38  

  HYPERLINK \l "_Toc186859550"  Appendix A:	INTERNATIONAL RESIDUE LIMIT
STATUS	  PAGEREF _Toc186859550 \h  39  

  HYPERLINK \l "_Toc186859551"  Appendix B:	TOXICOLOGY ASSESSMENT	 
PAGEREF _Toc186859551 \h  41  

  HYPERLINK \l "_Toc186859552"  Appendix C:	REFERENCES (in MRID order)	 
PAGEREF _Toc186859552 \h  53  

  HYPERLINK \l "_Toc186859553"  Appendix D:	REVIEW OF HUMAN RESEARCH	 
PAGEREF _Toc186859553 \h  55  

 

1.0	EXECUTIVE SUMMARY

The Interregional Research Project No. 4 (IR-4) has submitted a petition
for use of fenhexamid
[N-(2,3-dichloro-4-hydroxyphenyl)-1-methyl-cyclohexanecarboxamide], a
hydroxyanilide class fungicide, on asparagus (PP# 7E7187).  Fenhexamid
prevents fungi from infecting plants by inhibiting germ tube elongation,
mycelial growth and spore germination.  Fenhexamid is absorbed into the
waxy layer of the cuticle and is protected from being washed off. 
Fenhexamid is effective in controlling Botrytis cinerea, Monolinia
(brown rot /blossom blight /twig blight) and has been shown to suppress
Uncinula necator (powdery mildew).  It also provides post-infection
activity when applied early in the disease life cycle. 

The most recent human health risk assessment for fenhexamid was
conducted in conjunction with a request for the establishment of
tolerances for residues on cilantro, non-bell pepper and pomegranate (DP
#: 329137, J. Redden, 6/14/2006).

Use Profile

Fenhexamid is currently registered to Bayer CropScience and Arvesta
LifeScience North America Corporation for use on a variety of food/feed
crops. IR-4 is proposing a new use for fenhexamid on asparagus.  The
product proposed for use is Elevate® 50 WDG Fungicide (Reg. No.
66330-35), a water dispersible granule which contains 50% by weight,
fenhexamid active ingredient (ai).  The target pest is Botrytis cinerea,
the plant disease organism that causes gray mold. The proposed use is
for multiple broadcast foliar applications to mature ferns late in the
season with a minimum retreatment interval (RTI) of 7 days. Applications
are restricted to the use of ground equipment in a minimum volume of
water.  The minimum preharvest interval (PHI) is 90 days for asparagus
grown in CA and 180 days for all other states.

Current Tolerances

There are existing permanent tolerances (40 CFR §180.553(a)) for
fenhexamid in/on a variety of commodities ranging from 0.02 ppm (almond)
to 30 ppm (cilantro; leafy greens, subgroup 4A, except spinach).  

Proposed Tolerances

Under PP# 7E7187, IR-4 requests the establishment of a tolerance for
fenhexamid in/on asparagus at 0.02 ppm.  

Human Health Risk Assessment

Toxicology/Hazard

In general, the toxicology studies conducted on fenhexamid demonstrated
that it has few or no biologically significant toxic effects at
relatively low dose levels in many animal studies and only mild or no
toxic effects at high dose levels which often approach or exceed the
limit dose.  It was classified as Toxicity Category IV in all acute
studies and was not a dermal sensitizer.  In subchronic and chronic oral
studies, the most toxicologically significant effects were anemia in
dogs, and decreased body weights, increased food consumption and mild
liver and/or kidney effects in rats and mice.  Fenhexamid is not acutely
toxic, neurotoxic, carcinogenic or mutagenic and is not a developmental
or reproductive toxicant.  Although no increased susceptibility of
fetuses was demonstrated in developmental toxicity studies in rats and
rabbits, equivocal results, with respect to evaluating potentially
increased sensitivity of pups, were observed in the reproduction study
in rats.   On the basis of No Observed Adverse Effect Levels
(NOAELs)/Lowest Observed Adverse Effect Levels (LOAELs), no increased
susceptibility of pups to fenhexamid was demonstrated in this study. 
However, the severity of the effects observed in the pups may have been
greater than that observed in the adults at the same dose levels.  In
addition, several other toxicological considerations, including possibly
increased intake of test material in pups resulting from intake in both
milk and diet during the lactation period and possibly decreased levels
of UDP-glucuronyltransferase enzyme in pups resulting in decreased
metabolism or “detoxification” of test material, contributed to the
uncertainty of the determination.  The toxicological and regulatory
significance of the equivocal findings in the reproduction study are
discussed more fully in section 3.3.6.2.  There is low concern for pre-
and/or postnatal toxicity resulting from exposure to fenhexamid.  No
Food Quality Protection Act Safety Factor (FQPA SF) is needed (i.e. 1X)
since there are no residual uncertainties for pre and/or post natal
toxicity.   

Minimal or no toxic effects were observed in studies in which fenhexamid
was administered by the dermal or inhalation routes of exposure.  In an
acute neurotoxicity study in rats, the only possibly treatment-related
effect was a marginally decreased mean body temperature in male rats. 
This effect is not considered to be biologically significant.  

In a battery of five mutagenicity studies (with and without metabolic
activation, as appropriate for the specific study), technical grade
fenhexamid was negative for genotoxicity in all five studies.    

In a dermal absorption study in rats using a 50% wettable powder
formulation as the test material, the potential cumulative dermal
absorption of test material after a 10 hour dermal exposure was
determined to be 20%.   

No acute dietary endpoint was selected since no appropriate
toxicological endpoint attributable to a single exposure was identified
in the available toxicology studies.  The short- and intermediate-term
dermal endpoints are based on decreased body weight gain and food
consumption.  No other short- and intermediate-term endpoints were
selected.  Chronic dietary and long-term endpoints are based on
decreased red blood cell (RBC) hemoglobin and hematocrit and increased
Heinz bodies in males and females; increased adrenal weights and
intracytoplasmic vacuoles in adrenal cortex in females.  

No cancer risk assessment is required.  HED classified fenhexamid as a
“not likely” human carcinogen.  

Dietary Exposure and Risk

Product chemistry data, residue chemistry data relevant to food use, and
environmental fate data relevant to drinking water are adequate to
assess human exposure to fenhexamid.  Adequate residue data are
available to support the proposed use pattern and tolerance.  Residues
of fenhexamid were <0.02 ppm in the submitted field trials.

The nature of fenhexamid residues in plants is understood based on
adequate metabolism studies on grapes, tomatoes, and apples.  Fenhexamid
residues are non-systemic and primarily surface residues.  HED’s
Metabolism Assessment Review Committee (MARC) concluded that only
residues of parent fenhexamid need to be included in the tolerance
expression and considered for risk assessment.

As the crop use being proposed in this petition does not include any
regulated livestock feedstuffs, issues pertaining to livestock
metabolism, analytical methods and storage stability data for livestock
commodities, and residues in livestock commodities are not relevant to
the current petition. 

  SEQ CHAPTER \h \r 1  An adequate high performance liquid
chromatography (HPLC) method using electrochemical detection (ECD) is
available for enforcing tolerances for fenhexamid in/on plant
commodities.  In submitted asparagus field trials, residues of
fenhexamid were determined using an LC mass spectrometry method (LC/MS).

As there are no regulated processed commodities associated with
asparagus, no processing studies are required for this petition.  Data
pertaining to rotational crops are also not required for this petition
as asparagus is not rotated.  

Canadian, Mexican and Codex Maximum Residue Limits (MRLs) are
established for fenhexamid on various fruit and vegetable crops.  As
there are no established or proposed Canadian, Mexican or Codex MRLs for
fenhexamid on asparagus, there are no issues for international
harmonization for the current petition.

Water Exposure and Risk

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) and
incorporated directly into the chronic dietary assessment.  Considering
all currently registered uses as well as the proposed new uses, the
highest chronic estimated drinking water concentration (EDWC) is 1.1
ppb.  

Acute and Chronic Dietary Exposure Results and Characterization

No toxic effects attributable to a single (i.e., acute) exposure to
fenhexamid have been identified; therefore, an acute reference dose
(RfD) has not been established for fenhexamid and an acute dietary
exposure assessment has not been conducted.  

Chronic dietary exposure and risk was calculated assuming tolerance
level residues for all commodities with existing and proposed
tolerances, DEEM( default processing factors (PFs), and assumed 100%
crop treated (CT).  The only exceptions to these assumptions were EPA
processing adjustment factors for grapes destined for wine and sherry
production and for currants, dried.  The highest chronic EDWC of 1.1 ppb
was used in the analysis.

The results of the analysis indicate that chronic risk from dietary
(food + drinking water) exposure to fenhexamid does not exceed ARIA’s
level of concern (i.e. <100% chronic population adjusted doses (cPAD))
for the general U.S. population, and all population subgroups.  For the
U.S. population the exposure for food and water utilized 10% of the
chronic Population Adjusted Dose (cPAD).  The chronic dietary risk
estimate for the highest reported exposed population subgroup, children
1-2 years old, is 27% of the cPAD.

Non-Occupational and Residential Exposure/Risks

Currently, there are no residential or other non-agricultural uses of
fenhexamid.  For these reasons, a non-occupational/residential
assessment has not been conducted.

Aggregate Exposure/Risks

No acute, short/long-term or cancer aggregate exposure is expected.  

Chronic aggregate risk estimates do not exceed ARIA’s level of
concern.  Since the chronic aggregate risk exposure includes only food
and water, and the chronic dietary analysis included both, no further
calculations are necessary.  Since chronic dietary risk does not exceed
ARIA’s level of concern, chronic aggregate risk does not exceed
ARIA’s level of concern.

Occupational Exposure/Risks

An occupational risk assessment was completed for fenhexamid for its use
on asparagus.  Based upon the proposed use patterns ARIA expects the
most highly exposed occupational pesticide handlers to be 1)
mixer/loaders using open pour loading of granules and 2) applicators
using open-cab, ground-boom spray equipment.  Due to the volume of spray
recommended per acre, ARIA believes aerial application is not a
practical option.

A MOE of 100 is adequate to protect occupational pesticide handlers. 
Since all estimated MOEs are >100, the proposed use does not exceed
ARIA’s level of concern.

There typically is the possibility for agricultural workers to
experience post-application exposure to pesticide residues.  A MOE of
100 is adequate to protect agricultural workers from post-application
exposures to fenhexamid.  The estimated MOE is based upon conservative
assumptions and is >100; therefore, risks from estimated
post-application exposures do not exceed ARIA’s level of concern.

A restricted entry interval (REI) of 12 hours is adequate to protect
agricultural workers from post-application exposures (i.e., field
treatment) to fenhexamid under these circumstances.

Environmental Justice Consideration

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,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
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, non-dietary 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
post-application 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 (listed in Appendix D) have been determined to
require a review of their ethical conduct, and have received that
review.

 

Additional Data Needs

No deficiencies were noted in the subject petition that would preclude
establishing a permanent tolerance for fenhexamid residues on asparagus.
 

Recommendations for Tolerances/Registration

ARIA concludes that there is a reasonable certainty that no harm will
result to the U.S. Population, including infants and children, from
chronic aggregate exposure to fenhexamid residues. 

ARIA recommends for a 0.02 ppm tolerance for the residues of fenhexamid
in/on asparagus.

Table 1.0. 	Tolerance Summary for Fenhexamid.

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

Asparagus	0.02	0.02	Adequate field trial data are available on
asparagus.

2.0	INGREDIENT PROFILE

Fenhexamid is a reduced risk, hydroxyanilide fungicide registered in the
U.S. for use on a variety of fruit, nut and vegetable crops for
controlling Botrytis cinerea and Monolinia spp. (brown rot / blossom
blight / twig blight) and suppressing Uncinula necator (powdery mildew).
 Fenhexamid is a locally systemic, protectant fungicide that is absorbed
into the waxy layer of the cuticle.  It prevents fungal infections by
inhibiting germ tube elongation, mycelial growth and spore germination. 
Fenhexamid is currently registered in the U.S. to Bayer and Arysta and
is formulated as 50% WDGs for uses on food/feed crops.

2.1	Proposed Use

Table 2.1.  Summary of Directions for Use of Fenhexamid.

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 1

Asparagus

Broadcast foliar applications to asparagus in fern stage only.  Ground
equipment only	50% WDG

[66330-35]	0.75	4	3.0	180 (except CA)

90 (CA)	Apply only at the fern stage.  Treated ferns must be mowed down
or allowed to senesce prior to harvest of asparagus spears.  

Apply in a minimum of 40 gal/A.

The minimum RTI is 7 days. 

1	Do not apply through any type of irrigation system.  Do not replant
treated fields with food crops other than those with labeled uses within
30 days of the last application.

2.2	Identification of Active Ingredient

Table 2.2.	Fenhexamid  Nomenclature. tc "TABLE A.1.	Test Compound
Nomenclature" 

Compound

	

Common name	Fenhexamid

Company experimental name	KBR 2738

IUPAC name	2,3-dichloro-4-(1-methylcyclohexyl-carbonylamine)-phenol

CAS name	N-(2,3-dichloro-4-hydroxyphenyl)-1-methylcyclohexanecarboxamide

CAS #	126833-17-8

End-use product/EP	50% WDG (ELEVATE® 50 WDG Fungicide, EPA Reg. No.
66330-35)

2.3	Physical and Chemical Properties

Table 2.3.	Physicochemical Properties of the Technical Grade Fenhexamid.

Parameter	Value	Reference

Melting point/range	153oC	Fenhexamid: Pesticide Fact Sheet (May 20,
1999)

Fenhexamid (KBR 2738)-a Botryticide from a New Chemical Class,
Pflanzenschutz-Nachrichten Bayer 52/1999, 2

pH	8.3 in 1% solution of water

	Density (20ºC)	1.34 g/ml

	Water solubility (mg/L at 20°C)	20

	Solvent solubility (g/L at 20°C)	dichloromethane – 31

2-propanol - 91

n-hexane - <0.1

Toluene – 5.7

	Vapor pressure at 25°C	7x10-9  Torr

	Dissociation constant (pKa)	7.3

	Octanol/water partition coefficient Log(KOW)	3.51 (pH 7, 20oC )

	UV/visible absorption spectrum	245 and 290 nm

	

3.0	HAZARD CHARACTERIZATION  TC \l1 "3.0  HAZARD CHARACTERIZATION 

3.1	Hazard and Dose-Response Characterization

Hazard Assessment

In general, the toxicology studies conducted on fenhexamid demonstrated
that it has few or no biologically significant toxic effects at
relatively low dose levels in many animal studies and only mild or no
toxic effects at high dose levels which often approach or exceed the
limit dose.  It was classified as Toxicity Category IV in all acute
studies and was not a dermal sensitizer.  In subchronic and chronic oral
studies, the most toxicologically significant effects were anemia in
dogs, and decreased body weights, increased food consumption and mild
liver and/or kidney effects in rats and mice.  Fenhexamid is not acutely
toxic, neurotoxic, carcinogenic or mutagenic and is not a developmental
or reproductive toxicant.  Although no increased susceptibility of
fetuses was demonstrated in developmental toxicity studies in rats and
rabbits, equivocal results, with respect to evaluating potentially
increased sensitivity of pups, were observed in the reproduction study
in rats.  

Minimal or no toxic effects were observed in studies in which fenhexamid
was administered by the dermal or inhalation routes of exposure.   In an
acute neurotoxicity study in rats, the only possibly treatment-related
effect was a marginally decreased mean body temperature in male rats
following a single high dose of 2000 mg/kg.  This effect is not
considered to be biologically significant.  

In 13-week and 1-year feeding studies in dogs, the most significant
treatment-related effects were decreased erythrocyte counts, hemoglobin
and hematocrit (i.e. anemia) and increased Heinz bodies in erythrocytes.
 In the 13-week study, increased Heinz bodies were first observed at 13
weeks in both males and females at the LOAEL of 239/261 mg/kg/day in
males and females (M/F), respectively.  At the next higher dose of
1748/1866 mg/kg/day (M/F), the highest dose tested (HDT), increased
Heinz bodies were first observed at 6 weeks and marginal signs of anemia
at 2 weeks in males and at 13 weeks in females.  In the 1-year study in
dogs, increased Heinz bodies and signs of anemia were first observed at
13 weeks in both males and females at the LOAEL of 124/133 mg/kg/day
(M/F).  At the same dose level, in females only, minimal effects were
also observed in the adrenal gland (increased adrenal weights and
increased incidence and severity of intracytoplasmic vacuoles in the
adrenal cortex).  At the next higher dose of 918/947 mg/kg/day
(M/F)(HDT), in addition to increased severity of the effects observed at
the LOAEL, decreased body weight gain and decreased food consumption
were also observed.  The NOAEL of 17/19 mg/kg/day (M/F) in this 1-year
dog study was used to establish the RfD for fenhexamid since it was the
lowest NOAEL observed in any of the subchronic or chronic feeding
studies on fenhexamid.  The particular effects on which the RfD is based
(increased Heinz bodies and anemia in males and females and mild effects
in the adrenal gland of females) are toxicologically significant and
were clearly observed in dogs, but were not observed to any appreciable
extent in any other studies in any other species.  There was, however, a
suggestion of possible anemia in the 2-year chronic feeding study in
rats in which enlarged spleens, splenic extramedullary hematopoiesis,
bone marrow hyperplasia and increased reticulocytes were observed in
males and/or females.  Although decreased erythrocytes, hemoglobin, or
hematocrit were not observed in this study, it is possible that these
signs of anemia may have occurred early in the study , been transient,
and fully compensated for later in the study when blood samples were
first taken (at 6 months).  It is most likely that treatment-related
anemia occurs in both dogs and rats, but that dogs are more sensitive
than rats.  The LOAEL for anemia in dogs was 124/133 mg/kg/day (M/F) and
for a suggestion of anemia in rats (splenic extramedullary hematopoiesis
and bone marrow hyperplasia) was 292/415 mg/kg/day (M/F).        

In a 28-day oral (gavage) range-finding study in rats, no
treatment-related effects were observed at 1000 mg/kg/day, the highest
dose level tested.  In a 13-week feeding study in rats, the predominant
treatment-related effects in males were decreased body weights and body
weight gains, increased food consumption, decreased food efficiency and
increased serum levels of alanine amino-transferase enzyme (suggestive
of slight liver toxicity).  The LOAEL for these effects in males was 904
mg/kg/day and the NOAEL was 415 mg/kg/day.  In females, the predominant
treatment-related effects were increased food consumption, decreased
food efficiency, decreased liver weights and mild histopathological
effects in the liver.  The LOAEL for these effects in females was 2824
mg/kg/day and the NOAEL was 1132 mg/kg/day.  In this study, males
appeared to be somewhat more sensitive than females to fenhexamid since
the LOAEL/NOAELs for males was lower than for females.  Since a
biologically meaningful sex difference in sensitivity to fenhexamid was
not observed in any other studies on fenhexamid, however, the
differences in LOAEL/NOAELs in this study were also considered to be not
biologically meaningful.      

In the 2-year chronic feeding/carcinogenicity study in rats, in males at
the LOAEL of 292 mg/kg/day, only mild treatment-related effects were
observed (increased splenic extramedullary hematopoiesis and increased
cecal mucosal hyperplasia).  At the next higher dose level of 1280
mg/kg/day (HDT), additional treatment-related effects included increased
food consumption, decreased food efficiency, enlarged spleens, increased
reticulocytes and mild histopathological changes in the thyroid gland
(decreased follicular volume and blue-gray clumps of colloid).  In
females at the LOAEL of 415 mg/kg/day, treatment-related effects were
also mild and included decreased body weight (only after 60 weeks),
decreased body weight gain (only after 39 weeks), decreased food
efficiency, and bone marrow hyperplasia.  At the next higher dose level
of 2067 mg/kg/day (HDT), additional treatment-related effects included
increased food consumption,  enlarged spleens, increased reticulocytes
and mild histopathological changes in the thyroid gland (decreased
follicle volume and blue-gray clumps of colloid).  As previously noted,
the enlarged spleens, splenic extramedullary hematopoiesis, bone marrow
hyperplasia and increased reticulocytes observed in the animals in this
study may be indicative of an earlier occurring transient anemia that
was subsequently fully compensated for.  In this study, there was no
treatment-related increase in tumor incidence, tumor spectrum or latency
when compared to controls.  The test material was tested at adequate
dose levels for carcinogenicity testing since it was tested at the limit
dose of 20000 ppm (1280 mg/kg/day in males and 2067 mg/kg/day in
females) for rats.  

Of particular interest in the 2-year and 13-week feeding studies in rats
is the regular and consistent observation of decreased body weights,
decreased body weight gains, increased food consumption and decreased
food efficiency at relatively high dose levels (>415 mg/kg/day) in both
male and female rats.  At this time, there is no available biological
explanation for this finding.       

In a 14-week feeding (range-finding) study in mice and a 2-year
carcinogenicity study in mice, the predominant toxic effects were
indicative of kidney damage.  In the 14-week study at the LOAEL of
3284/5151 mg/kg/day (M/F) (HDT), the following treatment-related effects
were observed in both males and females and suggested kidney damage:
increased water consumption, increased serum creatinine levels,
decreased kidney weights and histopathological changes in the kidneys
(increased basophilic cortical tubules and/or increased protein casts
and cellular detritus).  Additional effects at the LOAEL included
increased serum cholesterol and bilirubin levels in males and females;
and increased food consumption, decreased food efficiency and decreased
glycogen in hepatocytes in males only.  The NOAEL in this study was
267/454 mg/kg/day (M/F).  In the 2-year study in mice, in males at the
LOAEL of 807 mg/kg/day, decreased kidney weights and histopathological
changes in the kidney (decreased sex specific vacuolation of the
proximal tubules) was observed.  Additional effects observed at the next
higher dose level of 2355 mg/kg/day (HDT) in males included increased
water consumption, increased serum creatinine level and increased
chronic renal disease (all indicative of kidney damage), increased serum
bilirubin level, decreased body weight, decreased body weight gain, and
increased serum albumin levels.  In females at the LOAEL of 3178
mg/kg/day (HDT), increased water consumption, decreased kidney weights
and increased basophilic cortical tubules in the kidney also suggested
kidney damage.  In this study, there was no treatment-related increase
in tumor incidence, tumor spectrum or latency when compared to controls.
 The test material was tested at adequate dose levels for
carcinogenicity testing since it was tested at the limit dose of 7000
ppm (2355 mg/kg/day in males and 3178 mg/kg/day in females) for mice.   

In a battery of five mutagenicity studies (with and without metabolic
activation, as appropriate for the specific study), technical grade
fenhexamid was negative for genotoxicity in all five studies.    

In a developmental toxicity study in rats, maternal toxicity (marginally
decreased body weight gain and decreased food consumption during the
treatment period only) was observed at the LOAEL of 1044 mg/kg/day (only
dose level tested).  The NOAEL for maternal toxicity was <1044
mg/kg/day.  At the same dose level of 1044 mg/kg/day, no
treatment-related signs of developmental toxicity were observed in the
fetuses.  The NOAEL for developmental toxicity was 1044 mg/kg/day and
the LOAEL was not established (>1044 mg/kg/day).  Although a NOAEL was
not determined for maternal toxicity in this study, the study need not
be repeated because the effects at the LOAEL were only marginal and of
minimal toxicological concern.    

In a developmental toxicity study in rabbits, the NOAEL for maternal
toxicity was 100 mg/kg/day and the LOAEL was 300 mg/kg/day, based on
alterations of excretory products (discolored urine, scant feces, small
scybala), decreased body weight gain and decreased food consumption
(especially during the first week of dosing) and decreased placental
weight.  At the next higher dose level of 1000 mg/kg/day, the maternal
effects were increased in severity.  A decreased gestation index, based
on a slightly increased incidence of abortions and total litter
resorptions, was not considered to be treatment-related because the
incidences of abortions and resorptions fell within the historical
control range submitted with the study.  The NOAEL for developmental
toxicity was 300 mg/kg/day and the LOAEL was 1000 mg/kg/day, based on
slightly decreased fetal body weights (<5%) in males only and increased
delayed ossification in several bones (especially the 5th sternal
segments and the 15th caudal vertebrae).   	

In a 2-generation (1 litter/generation) reproduction study in rats,
there were no treatment-related effects on mortality, clinical signs,
behavior or reproductive parameters for adult (parent) animals.  The
NOAEL for reproductive toxicity was 1814/2043 (M/F) (HDT).  The NOAEL
for parental toxicity was 38/45 mg/kg/day (M/F) and the LOAEL was
406/477 mg/kg/day (M/F).  In males at the LOAEL of 406 mg/kg/day,
increased serum creatinine levels and decreased kidney weights indicated
mild kidney damage and increased serum alkaline phosphatase levels and
decreased liver weights indicated mild liver damage.  In females at the
LOAEL of 477 mg/kg/day, increased serum alkaline phosphatase levels and
very slightly increased serum GGT levels suggested mild liver damage. 
At the next higher dose level of 1814/2043 mg/kg/day (M/F)(HDT), the
effects observed at the LOAEL in both males and females were slightly
increased in severity.  In addition, decreased body weight, increased
food consumption, and increased serum GGT levels were observed in males
and decreased body weights, increased food consumption, increased serum
urea nitrogen levels, increased serum creatinine levels and decreased
kidney weights were observed in females.  The NOAEL for neonatal
toxicity was 38/45 mg/kg/day (M/F) and the LOAEL was 406/477 mg/kg/day
(M/F).  At the LOAEL of 406/477 mg/kg/day, treatment-related decreased
pup body weights were observed in F1 pups on postnatal days 14 and 21
and in F2 pups on postnatal days 7, 14 and 21.  At the next higher dose
level of 1814/2043 mg/kg/day (M/F) (HDT), the decreased pup body weights
were increased in severity.  In addition, an increased mortality was
observed among the post weaning F1 pups selected to be F1 parents
(possibly due to the small size of the pups at weaning, which was 30%
less than controls).  

The results in this reproduction study are equivocal with respect to
evaluating the possibility of increased susceptibility of pups, as
compared to adults, to fenhexamid.  On the basis of NOAELs/LOAELs, no
increased susceptibility of pups to fenhexamid was demonstrated in this
study.  However, the severity of the effects observed in the pups may
have been greater than that observed in the adults at the same dose
levels.  In addition, several other toxicological considerations,
including possibly increased intake of test material in pups resulting
from intake in both milk and diet during the lactation period and
possibly decreased levels of UDP-glucuronyltransferase enzyme in pups (a
normally occurring phenomenon in rat pups) resulting in decreased
metabolism or “detoxification” of test material, contributed to the
uncertainty of the determination.  

In a dermal absorption study in rats using a 50% wettable powder
formulation as the test material, the potential cumulative dermal
absorption of test material after a 10 hour dermal exposure was
determined to be 20%.   

In a 21-day dermal toxicity study in rabbits, no treatment-related
systemic or skin effects were observed at the limit dose of 1000
mg/kg/day.  In a 5-day range-finding inhalation study in rats using
technical grade fenhexamid dust as the test material, marginally
increased lung weights and gray discoloration of the lungs were observed
at the LOAEL of 1.093 mg/L.  The NOAEL was 0.098 mg/L.  The effects
observed in this study were not considered to be systemic, but rather
the result of the physical deposition of fenhexamid dust in the lungs.  

Dose Response

No acute RfD was selected by HED.  No appropriate toxicological endpoint
attributable to a single exposure was identified in the available
toxicology studies, including the developmental toxicity studies in rats
and rabbits and the acute neurotoxicity study in rats.  In the
developmental toxicity study in rabbits, treatment-related decreased
mean fetal body weight in male fetuses (less than 5%) and increased
incidence of delayed ossification in several bones (particularly fifth
sternal segments and fifteenth caudal vertebrae) were observed at the
high dose of 1000 mg/kg/day.  Although possibly occurring after a single
dose, the magnitudes of both of these effects were so small that HED
considered neither of them to be an appropriate toxicological endpoint
for acute dietary risk assessments.   In the acute neurotoxicity study
in rats, a marginally decreased mean body temperature in males was
observed on the first day of treatment at the high dose of 2000 mg/kg. 
Since this equivocal effect occurred only in one sex, only one time,
only at the high dose and no other signs of toxicity were observed in
the rats in this study, HED did not consider this possible effect to be
an appropriate toxicological endpoint for acute dietary risk
assessments.      

HED selected a chronic RfD of 0.17 mg/kg/day (NOAEL = 17 mg/kg/day;
Uncertainty Factor = 100).  This RfD is based on the 1-year chronic oral
toxicity study in dogs, in which decreased RBC counts, hemoglobin and
hematocrit and increased Heinz bodies in RBC were seen at the LOAEL of
124/133 mg/kg/day in males/females.  Also, in females, increased
absolute and relative adrenal weights correlated with histopathological
observations of increases in incidence and severity of intracytoplasmic
vacuoles in the adrenal cortex.  The Uncertainty Factor (UF) accounts
for both interspecies extrapolation (10X) and intraspecies variability
(10X).

Short- and intermediate-term dermal risk assessments are required.  HED
concluded it   would be appropriate to use the dermal dose level of 1000
mg/kg/day (NOAEL), the HDT, from the 21-day dermal toxicity study in
rabbits for short- and intermediate-term dermal risk assessments.  HED
required these dermal risk assessments to be performed because in the
oral developmental toxicity study in rabbits, maternal effects
(decreased body weight gain and decreased feed consumption, particularly
during the first week of dosing) were observed at an oral dose of 300
mg/kg/day (LOAEL).  Using a 20% dermal absorption factor, this oral dose
is equivalent to a dermal dose of 1500 mg/kg/day.  Since
treatment-related effects were observed at a dermal equivalent dose of
1500 mg/kg/day in the developmental toxicity study in rabbits, HED
required that short- and intermediate-term dermal risk assessments be
performed using the NOAEL of 1000 mg/kg/day from the 21-day dermal study
in rabbits as the toxicological endpoint.  No long-term dermal exposure
is expected to occur with the proposed use on asparagus.     

Based on the low acute inhalation toxicity (Toxicity Category IV), the
low 5-day subchronic toxicity (no systemic toxicity at 1.092 mg/L), the
composition of the formulated product (water-dispersible granules), the
application rate, and the application method (ground spray, groundboom
and airblast), there is minimal concern for potential inhalation
exposure/risk.  HED determined that a separate inhalation risk
assessment is not required for short- and intermediate-term inhalation
risk assessments.  Based on the use pattern, no long-term inhalation
exposure is expected to occur with the proposed use on asparagus.

No cancer risk assessment is required.  HED classified fenhexamid as a
“not likely” human carcinogen.  This classification is based on the
lack of evidence of carcinogenicity in male and female rats as well as
in male and female mice and on the lack of genotoxicity in an acceptable
battery of mutagenicity studies.

3.1.1	Database Summary

  TC \l3 "3.1.1	Database Summary 

3.1.1.1	Studies available and considered (animal, human, general
literature)

Acute, sub-chronic, chronic, reproductive and developmental studies were
available and considered when preparing this risk assessment.  

  TC \l4 "3.1.1.1	Studies available and considered (animal, human,
general literature) 

3.1.1.2	Mode of action, metabolism, toxicokinetic data

Fenhexamid prevents penetration of fungi into plants by inhibiting germ
tube and mycelial growth.  Fenhexamid appears to be unique in that it
apparently does not belong to any previously registered class of
compounds.  Its toxicological properties, then, are also unique and not
directly comparable to those of any other registered chemical at this
time.   

  TC \l4 "3.1.1.2	Mode of action, metabolism, toxicokinetic data 

3.1.1.3	Sufficiency of studies/data

The scientific and regulatory quality of the toxicology data base for
fenhexamid is high and is considered sufficient to clearly define the
toxicity of this chemical.  

  TC \l4 "3.1.1.3	Sufficiency of studies/data 

3.1.2	Toxicological Effects

In general, the toxicology studies conducted on fenhexamid demonstrate
that it has few or no biologically significant toxic effects at
relatively low dose levels in many animal studies and only mild or no
toxic effects at high dose levels which often approach or exceed the
limit dose.  In subchronic and chronic oral studies, the most
toxicologically significant effects were anemia in dogs, and decreased
body weights, increased food consumption and mild liver and/or kidney
effects in rats and mice.  Fenhexamid is not acutely toxic, neurotoxic,
carcinogenic or mutagenic and is not a developmental or reproductive
toxicant.  Although no increased susceptibility of fetuses was
demonstrated in developmental toxicity studies in rats and rabbits,
equivocal results, with respect to evaluating potentially increased
sensitivity of pups, were observed in the reproduction study in rats.
Since there is qualitative evidence of increased susceptibility of the
young following exposure to fenhexamid in the rat reproduction study,
HED performed a Degree of Concern Analysis.  For information regarding
the results of this analysis see section 3.3.6.2, below.  Minimal or no
toxic effects were observed in studies in which fenhexamid was
administered by the dermal or inhalation routes of exposure.       

  TC \l3 "3.1.2	Toxicological Effects 

3.1.3	Dose-response

No acute dietary endpoint was selected since no appropriate
toxicological endpoint attributable to a single exposure was identified
in the available toxicology studies.  The short- and intermediate-term
dermal endpoints are based on decreased body weight gain and food
consumption.  No other short- and intermediate-term endpoints were
selected.  Chronic dietary and long-term endpoints are based on
decreased RBC count, hemoglobin and hematocrit and increased Heinz
bodies in males and females; increased adrenal weights and
intracytoplasmic vacuoles in adrenal cortex in females. 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

In a metabolism study in rats, fenhexamid was rapidly and completely
absorbed, distributed, metabolized and almost completely excreted within
48 hours.  The major route of excretion was feces (62-81%) with lesser
amounts in the urine (15-36%).  A pronounced first pass effect and
enterohepatic circulation was observed.  Bile contained mostly the
glucuronide conjugate of fenhexamid, which was subsequently hydrolyzed
in the intestine back to the parent compound and reabsorbed.  The feces
contained almost exclusively unchanged parent compound.  The urine
contained mostly parent compound and the glucuronide conjugate of parent
compound.  In addition, considerably lesser amounts of additional
metabolites (formed by hydroxylation on the cyclohexyl ring) and
glucuronide and sulfate conjugates of these same metabolites were also
identified in the urine.  All the glucuronide and sulfate conjugates of
the parent compound and of the hydroxylated metabolites of the
cyclohexyl ring are considered to be considerably less toxic than the
parent compound because glucuronide and sulfate conjugation is well
known to be a commonly occurring “detoxification” mechanism in
mammalian species as it results in the formation of more polar, more
water-soluble metabolites which are readily and easily excreted from the
body (in this case, in the bile and urine).  

3.3	FQPA Considerations

  TC \l2 "3.3	FQPA Considerations 

3.3.1	Adequacy of the Toxicity Database

HED concluded that the toxicology database for fenhexamid is complete
for FQPA assessment.

  TC \l3 "3.3.1	Adequacy of the Toxicity Database 

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity

HED concluded that there is not a concern for neurotoxicity resulting
from exposure to fenhexamid. 

3.3.3	Developmental Toxicity Studies

In the developmental toxicity studies in rats and, there was no evidence
of increased susceptibility to fetuses from in utero exposure to
fenhexamid.

  TC \l3 "3.3.3	Developmental Toxicity Studies 

3.3.4	Reproductive Toxicity Study

The results in the reproduction study are equivocal with respect to
evaluating the possibility of increased susceptibility of pups, as
compared to adults, to fenhexamid.  At 5000 ppm (neonatal LOAEL),
statistically significant, treatment-related and dose-related decreased
pup body weights were observed.  At the same dose level of 5000 ppm
(parental LOAEL), treatment-related and dose-related effects were also
observed in the adult (parent) animals.  In adult males, increased
creatinine levels and decreased absolute and relative kidney weights
suggested an effect on the kidney and increased alkaline phosphatase
levels and decreased absolute and relative liver weights suggested an
effect on the liver.  In adult females, increased alkaline phosphatase
levels and slightly increased GGT levels (not considered to be
biologically relevant) suggested a possible effect on the liver;
however, histopathological examination of kidney and liver did not
reveal any treatment-related morphological changes in these organs at
this dose level (or at the highest dose level of 20000 ppm).  Since
treatment-related effects were observed in both pups and adults at 5000
ppm, but not at 500 ppm, on the basis of NOAELs and LOAELs, no increased
susceptibility of pups to fenhexamid was demonstrated in this study. 
However, the severity of effects in the pups at 5000 ppm (decreased body
weights) may have been greater than that observed in the adults at the
same dose level (suggestion of mild effects in the kidney and liver
without supporting histopathological changes).  In addition, at the
highest dose level of 20000 ppm, the severity of effects in the pups
(decreased body weights and increased mortality in F1 pups selected to
be F1 parents) was considered to be greater than that observed at the
same dose level in adults (mild effects in the kidney and liver not
supported by histopathological changes; decreased body weights and
increased food consumption).  Interpretation of relative severities of
effects in pups and adults at 5000 and 20000 ppm also consider, however,
that the pups may be consuming significantly greater amounts of test
material than adults (on a mg/kg/day basis) since pups consume
considerably more food per unit body weight than do adults, and pups
receive test material from not one, but two sources viz. mother’s milk
and treated diet (particularly during the late lactation period).  The
body weight decrements in late lactation are supportive of this
argument.    

Regarding the decreased pup body weights observed at 5000 and 20000 ppm,
investigators offered some possible explanations.  However, HED did not
concur with the investigators conclusion that the decreased pup body
weights in the 5000 and 20000 ppm dose groups does not represent a
neonatal toxicity concern.  To the contrary, this explanation supports a
possibly increased sensitivity of the neonates (as compared to adults)
to the test material.  The demonstrated poor glucuronidation capacity of
rat pups, in fact, provides a reasonable and likely pharmacological
explanation for a possibly increased sensitivity of pups and serves to
support a concern for neonatal toxicity, rather than a reason to dismiss
it.  Supporting this explanation are the results in the metabolism study
on fenhexamid in which glucuronidation of fenhexamid was clearly
demonstrated to be the single major route of metabolism, detoxification
and excretion of fenhexamid in adult male and female Wistar rats. 
Further support for a neonatal toxicity concern is also provided by the
observation that for the F1 pups selected post-weaning to be F1 parents
in this study, a treatment-related increased mortality was observed in
the 20000 ppm dose group compared to the control group.  This increase
in the death of pups in the 20000 ppm dose group was attributed by the
investigators “to the small size of pups at weaning”.  Hence the
decreased pup body weights observed on lactation days 7 through 21
(neonatal toxicity) actually resulted in increased mortality at a later
time in the study.

With respect to determining the possible increased susceptibility of
pups to fenhexamid, HED considered the results to be equivocal (i.e.
subject to two interpretations).  On the one hand, on the basis of
NOAELs and LOAELs, no increased susceptibility was observed.  On the
other hand, the greater severity of effects in pups and a likely
pharmacological explanation for this finding suggested an increased
sensitivity of pups, as compared to adults, to fenhexamid.

3.3.5	Additional Information from Literature Sources

None.

3.3.6	Pre-and/or Postnatal Toxicity

HED concluded that there is low concern for pre- and/or postnatal
toxicity resulting from exposure to fenhexamid.

  TC \l3 "3.3.6	Pre-and/or Postnatal Toxicity 

3.3.6.1	Determination of Susceptibility

In the developmental toxicity studies in rats and rabbits, HED
determined that neither quantitative nor qualitative evidence of
increased susceptibility of fetuses to in utero exposure to fenhexamid
was observed in this study.

In the multigeneration reproduction study, qualitative evidence of
increased susceptibility of rat pups is observed.  Although the parental
and offspring NOAELs and LOAELs are at the same doses (38.2 and 406
mg/kg/day), the offspring effects are considered to be more severe than
the parental effects.  Quantitative evidence of increased susceptibility
of rat pups to fenhexamid, however, was not observed in this study.

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties  TC \l4
"3.3.6.2	Degree of Concern Analysis and Residual Uncertainties  for Pre-
and/or Postnatal Susceptibility

Since there is qualitative evidence of increased susceptibility of the
young following exposure to fenhexamid in the rat reproduction study,
HED performed a Degree of Concern Analysis to: 1) determine the level of
concern for the effects observed when considered in the context of all
available toxicity data; and 2) identify any residual uncertainties
after establishing toxicity endpoints and traditional uncertainty
factors to be used in the risk assessment of this chemical.  If residual
uncertainties are identified, HED examines whether these residual
uncertainties can be addressed by a FQPA safety factor and, if so, the
size of the factor needed.  The results of the HED Degree of Concern
analysis for fenhexamid follow. 

In the rat reproduction study, qualitative susceptibility was evidenced
as significantly decreased pup body weights in both generations during
the lactation period (on lactation days 7, 14, and 21 in the F2
generation and lactation days 14 and 21 in the F1 generation offspring)
in the presence of lesser maternal toxicity (alterations in clinical
chemistry parameters and decreased organ weights without collaborative
histopathology).  Considering the overall toxicity profile and the doses
and endpoints selected for risk assessment for fenhexamid, HED
characterized the degree of concern for the effects observed in the rat
reproduction study as low, noting that there is a clear NOAEL and
well-characterized dose response for the offspring effects observed and
that these effects occurred in the presence of parental toxicity.  No
residual uncertainties were identified. 

The does selected for risk assessment purposes are protective of the
susceptibility of the young. 

3.3.7	Recommendation for a Developmental Neurotoxicity (DNT) Study

HED concluded that there is not a concern for developmental
neurotoxicity resulting from exposure to fenhexamid; therefore, a DNT
study conducted with fenhexamid is not required.  This decision was
based on the following weight-of-the-evidence considerations:

lack of evidence of abnormalities in the development of the fetal
nervous system in the pre/post-natal studies;

neither brain weight nor histopathological examination of the nervous
system was affected in the subchronic and chronic studies; and 

decreased body temperatures observed in male rats in the acute
neurotoxicity study were not considered to be toxicologically
significant.

Based on the weight of evidence presented, HED has reaffirmed
(2/13/2003) the previous conclusion that a DNT study conducted with
fenhexamid is not required.

  TC \l3 "3.3.8	Rationale for the UFDB (when a DNT is recommended) 

3.4	FQPA Safety Factor for Infants and Children

Based upon the above-described data, it was concluded that there is low
concern for pre- and/or postnatal toxicity resulting from exposure to
fenhexamid; therefore HED recommended the FQPA Safety Factor (SF) be
reduced to 1X.

  TC \l2 "3.4	Safety Factor for Infants and Children 

3.5	Hazard Identification and Toxicity Endpoint Selection

For more detailed information regarding toxicity endpoint selections,
please refer to the HED memo (B. Tarplee, TXR NO.  0051704, 3/26/2003).

3.5.1	Acute Reference Dose (aRfD) - General Population

Study Selected: 	None

MRID No.:		None

Dose and Endpoint for Establishing RfD:   Not applicable

Uncertainty Factor(s) (UFs): Not applicable

Comments about Study/Endpoint/Uncertainty Factor:  No appropriate
toxicological endpoint attributable to a single exposure was identified
in the available toxicology studies including the developmental toxicity
studies in rats and rabbits and the acute neurotoxicity study in rats.

  TC \l3 "3.5.2	Acute Reference Dose (aRfD) - General Population 

3.5.2	Chronic Reference Dose (cRfD) 

Study Selected: 1-Year Chronic Toxicity Study, Dogs				

MRID No.:  44346804

Dose and Endpoint for establishing the RfD:  NOAEL = 17 mg/kg/day. 
Based on decreased RBC counts, hemoglobin and hematocrit, and increased
Heinz bodies in RBC at the LOAEL of 124/133 mg/kg/day in males/females. 
Also, in  females, increased absolute and relative adrenal weights
correlated with histopathological observations of increases in incidence
and severity of intracytoplasmic vacuoles in the adrenal cortex.        
 

Uncertainty Factor: An uncertainty factor of 100 was applied to account
for both interspecies extrapolation (10X) and intraspecies variability
(10X).

Comments about Study/Endpoint/Uncertainty Factor(s):  The RfD derived
from the use of the NOAEL and endpoint from the 1-year chronic toxicity
study in dogs and an uncertainty factor of 100 is supported by a similar
RfD that could have been derived from the use of the NOAEL from the
combined chronic/carcinogenicity feeding study in rats (MRID 44346806)
and an uncertainty factor of 100.  In the rat study, the NOAEL = 28
mg/kg/day and the LOAEL = 292/415 mg/kg/day in males/females, based in
males on increased cecal mucosal hyperplasia and increased splenic
extramedullary hematopoiesis, and in females on decreased body weight,
decreased body weight gain, decreased food efficiency and increased
hyperplasia in the bone marrow of the femur and sternum.  Had the RfD
been derived from this rat study, the RfD would have been 28
mg/kg/day/100 = 0.28 mg/kg/day.  The NOAEL from the chronic study in
dogs, rather than the NOAEL from the combined chronic/ carcinogenicity
study in rats, was used to calculate the chronic RfD because it is the
lowest NOAEL for this time period.

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

There are no residential exposure scenarios; therefore, endpoints were
not selected.

  TC \l3 "3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

3.5.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 	

Dermal Absorption Factor:  20% (rounded from 21, highest mean dermal
absorption at 120 hours).  This value is considered to represent the
potential cumulative dermal absorption of test material that might occur
after a 10 hour dermal exposure.

Study Selected: Dermal Absorption Study, Rats

MRID No.: 44346815

Comments about Dermal Absorption: At 10 hours post-dose in the low dose
level group, radioactivity (as test material) in the skin test site was
10.1% and in the urine, feces, blood and carcass was 9.75%, whereas by
120 hours, radioactivity in the skin test site decreased to 6.05% and in
the urine, feces, blood and carcass increased to 14.94%.  These data
indicate that radioactivity in the skin test site continued to be
absorbed after 10 hours (at which time the skin was washed) up to 120
hours (at which time the study was terminated).  Since radioactivity in
the skin test site at 10 hours continued to be absorbed in significant
amounts for up to 120 hours, HED concluded that all the radioactivity in
the test skin site might eventually have been absorbed if the study were
continued beyond 120 hours.  Therefore, 21%, the mean total amount of
radioactivity in test skin site, urine, feces, blood and carcass at 120
hours was considered to represent the potential cumulative dermal
absorption of test material that might occur after a 10 hour exposure.

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Short- and Intermediate-Term

Study Selected: 21-Day Dermal Toxicity Study, Rabbits

MRID No.:  44346780

Dose and Endpoint for Risk Assessment: NOAEL = 1000 mg/kg/day (HDT).

Comments about Study/Endpoint: This study is selected because its
duration and route of exposure are appropriate for short- and
intermediate-term dermal exposure.  Results in this study are consistent
with those in the oral developmental toxicity study in rabbits (MRID
44346801) in which maternal effects (decreased body weight gain and
decreased feed consumption) were observed, particularly during the first
week of dosing, at the LOAEL of 300 mg/kg/day.  The NOAEL for maternal
toxicity in this study was 100 mg/kg/day.  Using a 20% dermal absorption
factor, the oral NOAEL in this study (100 mg/kg/day) is equivalent to a
dermal NOAEL of 500 mg//kg/day and the oral LOAEL (300 mg/kg/day) is
equivalent to a dermal LOAEL of 1500 mg/kg/day.  Since treatment-related
effects were observed at an equivalent dermal dose level of 1500
mg/kg/day, HED concluded it would be appropriate to use the dermal dose
level of 1000 mg/kg/day (NOAEL) from the 21-day dermal study for short-
and intermediate-term dermal risk assessments.

Long-Term

Long-term exposure is not expected from the proposed use on asparagus.

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Short- and Intermediate-Term

Study Selected: 	None

MRID No.:		None

Dose and Endpoint for Risk Assessment:   Not applicable

Comments about Study and Endpoint:  The acute inhalation LC50 for
technical grade fenhexamid dust (95.5% purity) is >5.057 mg/L (Toxicity
Category IV) for both male and female rats and for technical grade
fenhexamid aerosolized in PEG 400/ethanol mixture at  0.322 mg/L (the
maximum technically possible concentration) is > 0.322 mg/L for both
male and female rats.  In both of these acute inhalation toxicity
studies (MRID 44366513), there were no mortalities, treatment-related
clinical signs, changes in body weights or necropsy findings.  Further,
in a 5-day range-finding inhalation toxicity study in rats using
technical grade fenhexamid dust as the test material (MRID 44366514),
macroscopic gray colouration of the lungs and marginally increased lung
weights were observed at a concentration of 1.092 mg/L, but not at 0.098
mg/L.  It is likely that the effects observed in this study are due to
the physical deposition of fenhexamid dust in the lungs and not to any
systemic effect of the test material.

Based on the low acute inhalation toxicity (Toxicity Category IV), the
low 5-day subchronic toxicity (no systemic toxicity at 1.092 mg/L), the
composition of the formulated product (water dispersible granules
containing 50% ai) and the application method (ground spray, groundboom
and airblast), there is minimal concern for potential inhalation
exposure/risk.  HED determined that a separate inhalation risk
assessment is not required for short- and intermediate-term inhalation
risk assessments.  

Long-Term

Long-term exposure is not expected from the proposed use on asparagus.

  TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and
Long-Term) 

3.5.8	Level of Concern for Margin of Exposure

For occupational exposure: short- and intermediate-term dermal, a MOE of
100 is required.  This is based on the conventional uncertainty factor
of 100X (10X for intraspecies extrapolation and 10X for interspecies
variation).

For occupational exposure: long-term dermal and all inhalation
durations, MOEs are not applicable (NA) since the use pattern does not
indicate a potential for these exposure scenarios.

For residential exposure:  No residential use.  MOEs are not applicable.

Table 3.5.8.  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	

NA

Inhalation	

NA	

NA	

NA

Residential (Non-Dietary) Exposure

Oral	

NA	

NA	

NA

Dermal	

NA	

NA	

NA

Inhalation	

NA	

NA	

NA

3.5.9	Recommendation for Aggregate Exposure Risk Assessments	

There are no residential uses for fenhexamid; therefore, aggregate
exposure includes only food and water.

3.5.10	Classification of Carcinogenic Potential

Based on the lack of evidence of carcinogenicity in male and female rats
as well as in male and female mice and on the lack of genotoxicity in an
acceptable battery of mutagenicity studies, fenhexamid is classified as
a “not likely” human carcinogen.

  TC \l3 "3.5.10	Classification of Carcinogenic Potential 

3.5.11	Summary of Toxicological Doses and Endpoints for Fenhexamid for
Use in Human Risk Assessments

Table 3.5.11 Summary of Toxicological Doses and Endpoints for Fenhexamid
for Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure

Scenario	

Dose Used in Risk Assessment, UF 	

FQPA SF and Level of Concern for Risk Assessment	

Study and Toxicological Effects

Acute Dietary

(General Population including infants and children)	

None

UF = NA

Acute RfD = None	

FQPA SF = 1X

aPAD = 

acute RfD

 FQPA SF

= None	

Not selected.  No appropriate toxicological endpoint attributable to a
single exposure was identified in the available toxicology studies.

Chronic Dietary

(All populations)	

NOAEL = 17 mg ai/kg/day

UF = 100

Chronic RfD = 0.17 mg/kg/day	

1X

cPAD = 

chronic RfD

 FQPA SF

=0.17 mg/kg/day	

1-Year Feeding-Dog. 

Decreased RBC count, hemoglobin and hematocrit and increased Heinz
bodies in males and females; increased adrenal weights and
intracytoplasmic vacuoles in adrenal cortex in females. at the LOAEL of
124 mg/kg/day.

Short-Term 

(1 - 30 days) and 

Intermediate-Term (1 - 6 months)

Dermal	

NOAEL = 1000 mg ai/kg/day	

Residential MOE = NA

Occupational MOE = 100	

21-Day Dermal-Rabbit.

In the developmental toxicity study in rabbits, decreased body weight
gain and food consumption at LOAEL of 1500 mg/kg/day (dermal equivalent
dose using 20% dermal absorption factor); NOAEL was 500 mg/kg/day
(dermal equivalent dose)

Long-Term Dermal 

(>6 months)

	

None	

Residential MOE = NA

Occupational MOE = NA	

Not selected.    It was determined that no long term exposure would
occur (see TXR NO. 013258).

Short-Term 

(1 - 30 days) and 

Intermediate-Term (1 - 6 months) Inhalation 	

None	

Residential MOE = NA

Occupational MOE = NA	

Not selected.  It was determined that a separate inhalation risk
assessment is not required for short- and intermediate-term inhalation
risk assessments (see TXR NO. 013258).  

Long-Term Inhalation

(>6 months)

	

None	

Residential MOE = NA

Occupational MOE = NA	

Not selected.  It was determined that no long term exposure would occur
(see TXR NO. 013258).

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies.

Dermal absorption factor: 20%

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable

3.6	Endocrine Disruption

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there was scientific
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 has authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, fenhexamid may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

4.1	Incident Reports

There are no known incidents reported for fenhexamid.

  TC \l2 "4.1	Incident Reports 

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

Residue chemistry data were submitted for this petition and reviewed by
ARIA (DP#: 346385, D. Rate, 11/30/2007).

  TC \l1 "5.0	Dietary Exposure/Risk Characterization 

5.1	Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops

Acceptable fenhexamid metabolism studies on grapes, tomatoes, and apples
have previously been submitted and reviewed by HED.  The results from
these studies indicate that most of the terminal residue is
unmetabolized parent.  Fenhexamid residues are non-systemic and
primarily surface residues.  Only residues of parent fenhexamid need to
be included in the tolerance expression (DP#: 253792, G. Herndon,
3/11/1999).  However, additional 14C-fenhexamid metabolism studies (on
dissimilar crops) may be required to support future requests for
tolerances and registrations.  For the purposes of this action, the
nature of fenhexamid residues in plants is adequately understood.    

  TC \l3 "5.1.1	Metabolism in Primary Crops 

5.1.2	Metabolism in Rotational Crops

An acceptable confined accumulation in rotational crop study has
previously been submitted and reviewed by HED.  HED concluded that a
30-day plant back interval should appear on the label and apply to all
crops without a registered use.

Because asparagus is not rotated, no data pertaining to rotational crops
are required to support the proposed use.

  TC \l3 "5.1.2	Metabolism in Rotational Crops 

5.1.3	Metabolism in Livestock

Since there are no asparagus feed items of regulatory interest, a
discussion of the metabolism of fenhexamid in livestock commodities is
not germane to this action.

  TC \l3 "5.1.3	Metabolism in Livestock 

5.1.4	Analytical Methodology

An adequate HPLC method using ELCD is available for enforcing tolerances
for fenhexamid in/on plant commodities.  For this method, residues are
extracted with acetone, filtered and concentrated to an aqueous
remainder.  The aqueous fraction is then loaded onto a Chem Elute
column, and residues are eluted with cyclohexane:ethyl acetate (85:15). 
Residues are concentrated to dryness, redissolved in methanol and
analyzed, using external standards. The method LOQ is 0.02-0.05 ppm
depending on the matrix.

Samples from the current asparagus field trails were analyzed for
residues of fenhexamid using a LC/MS method (Cornel Analytical
Laboratory Method, “Residue Analysis of Fenhexamid on Asparagus Using
LC with MS detection, Version #8”).  This method is similar to the
enforcement method, except that MS detection was used instead of ELCD. 
For the LC/MS method, residues are extracted with acetone, concentrated
and purified using a Chem Elute column.  Residues are then analyzed by
LC/MS using external standards.  The m/z 302 and 304 ions are used for
quantitation and confirmation of residues.  The statistically calculated
LOQ is 0.008 ppm and the LOD is 0.003 ppm.  The method LOQ is 0.02 ppm. 
The LC/MS method was adequately validated prior to and in conjunction
with the analysis of field trial samples.

  TC \l3 "5.1.4	Analytical Methodology 

5.1.5	Environmental Degradation

Fenhexamid is non-persistent in aerobic environments and only slightly
persistent in anaerobic environments.  Although the compound is
hydrolytically stable and has low to moderate mobility in most soils its
transport in the environment will be mitigated by its rapid rate of
degradation in aerobic surface soils.  The potential for surface water
or groundwater contamination associated with fenhexamid use is,
therefore, considered to be low.  In the event that the compound does
reach surface water bodies, the tendency for fenhexamid to bind to
aquatic sediments would reduce the potential for exposure to many
aquatic organisms.  The exception would be benthic organisms that may
ingest sediment (e.g., Hexagenia sp.).  Aqueous photolysis may also
contribute to degradation in the environment in clear, shallow water. 

 TC \l3 "5.1.5	Environmental Degradation 

5.1.6	Comparative Metabolic Profile

In a metabolism study in rats, fenhexamid was rapidly and completely
absorbed, distributed, metabolized and almost completely excreted within
48 hours.  The major route of excretion was feces (62-81%) with lesser
amounts in the urine (15-36%).  A pronounced first pass effect and
enterohepatic circulation was observed.  Bile contained mostly the
glucuronide conjugate of fenhexamid, which was subsequently hydrolyzed
in the intestine back to the parent compound and reabsorbed.  The feces
contained almost exclusively unchanged parent compound.  The urine
contained mostly parent compound and the glucuronide conjugate of parent
compound.  In addition, considerably lesser amounts of additional
metabolites (formed by hydroxylation on the cyclohexyl ring) and
glucuronide and sulfate conjugates of these same metabolites were also
identified in the urine.  All the glucuronide and sulfate conjugates of
the parent compound and of the hydroxylated metabolites of the
cyclohexyl ring are considered to be considerably less toxic than the
parent compound because glucuronide and sulfate conjugation is well
known to be a commonly occurring “detoxification” mechanism in
mammalian species as it results in the formation of more polar, more
water-soluble metabolites which are readily and easily excreted from the
body (in this case, in the bile and urine).  Further, based on
similarities of chemical structure, the non-conjugated hydroxylated
metabolites of the cyclohexyl ring would be expected to be no more toxic
than the parent compound.  None of the metabolites of fenhexamid
identified in rats, then, are likely candidates for regulatory or risk
assessment purposes.  

HED has concluded that only the parent compound needs to be included in
the tolerance expression and used for dietary risk assessment purposed
for both crops and water.  In 3 plant metabolism studies submitted, the
parent compound accounted for greater than an 87% of the TRR from
approximately 1X rates.  The studies also showed very low levels of
dichlorohydroxyaniline (estimated maxima of 2-6 ppb in grapes and
apples).  All identified plant metabolites were found in the rat (with
exception of glucuronide conjugate in rat versus glucosides in plants). 
Rotational crop data suggest that fenhexamid is metabolized in the soil
to a series of intermediates before entering the general carbon pool and
becoming incorporated into lignin and cellulose.  There are no obvious
concerns with residues of the methyl cyclohexane carboxylic acid that
could potentially be in rotational crops as a result of soil metabolism.
 (The use of just phenyl ring radiolabel precluded a determination of
residues of this acid.)  Data provided to EFED show very little
hydrolysis at environmental pH’s.  The pesticide binds quickly and
irreversibly to soil.  Although photolysis occurs in water, the
degradate is dechlorinated and has a very short half-life (not detected
after 10 hours).

5.1.7	Toxicity Profile of Major Metabolites and Degradates

All the glucuronide and sulfate conjugates of the parent compound and of
the hydroxylated metabolites of the cyclohexyl ring are considered to be
considerably less toxic than the parent compound because glucuronide and
sulfate conjugation is well known to be a commonly occurring
“detoxification” mechanism in mammalian species as it results in the
formation of more polar, more water-soluble metabolites which are
readily and easily excreted from the body.  Further, based on
similarities of chemical structure, the non-conjugated hydroxylated
metabolites of the cyclohexyl ring would be expected to be no more toxic
than the parent compound.   TC \l2 "3.2	Absorption, Distribution,
Metabolism, Excretion (ADME) 

 TC \l3 "5.1.7	Toxicity Profile of Major Metabolites and Degradates 

5.1.8	Pesticide Metabolites and Degradates of Concern

There are no pesticide metabolites or degradates of concern for
fenhexamid.

5.1.9	Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were
provided by EFED and summarized in the following memoranda: “Drinking
Water Assessment for the IR-4 Petition for the Use of Fenhexamid on
Asparagus” (DP#: 338651,C. Sutton, 7/26/2007) and incorporated
directly into this dietary assessment.  Water residues were incorporated
in the DEEM-FCID into the food categories “water, direct, all
sources” and “water, indirect, all sources.” 

EDWCs for fenhexamid in surface water and groundwater were calculated
using the screening model FQPA Index Reservoir Screening Tool (FIRST;
v.1.1.0; dated 12/12/2005) and the regression model Screening
Concentration in Ground Water (SCI-GROW; v.2.3; dated 7/29/2003),
respectively.  The maximum application rate for the proposed use on
asparagus does not exceed the previous maximum application rate for any
crop.  Thus, the values reported in the previous drinking water
assessment (DP#: D285210, 5/13/2003), are still current and are
recommended for use in HED’s risk assessment for fenhexamid.

Table 5.1.9.  Maximum EDWCs of Fenhexamid in Groundwater and Surface
Water Based on Fenhexamid Use at the Maximum Total Application Rate.  

Drinking Water Source (Model Used)	Use/Rate Modeled (lb ai/A)	Maximum
EDWC (ppb)

Groundwater

(SCI-GROW2)	Ground spray/0.75 x 2 applications; total of 3.0 	Acute and
Chronic	0.0007

Surface Water (FIRST)	Ground spray/0.75 x 2 applications; total of 3.0
Acute	29

	Ground spray/0.75 x 2 applications; total of 3.0	Chronic	1.1

 TC \l3 "5.1.9	Drinking Water Residue Profile 

5.1.10	Food Residue Profile

The submitted asparagus field trial data (MRID 47056401) are adequate
and support the proposed use pattern.  Although only two field trials
were conducted, HED approved conducting a reduced set of field trials
using an exaggerated 5x application rate.  As residues of fenhexamid
were <LOQ in/on all four samples harvested at 92-100 days after
treatment (DAT) following the 5x applications, residues are unlikely to
be detectable in asparagus spears harvested at 90 DAT following
applications to mature ferns at the proposed 1X rate.  The data support
setting the tolerance for residues of fenhexamid in/on asparagus at the
method LOQ (0.02 ppm).

Based on adequate metabolism studies, results indicate that most of the
terminal residue is unmetabolized parent.  Fenhexamid residues are
non-systemic and primarily surface residues.  The MARC concluded that
only residues of parent fenhexamid need to be included in the tolerance
expression.  

There are no asparagus feed items of regulatory interest.  HED does not
require residue data for any processed commodities associated with
asparagus.  Therefore, data requirements for processed food and feed are
not relevant to this tolerance petition.

5.1.11	International Residue Limits

Canadian, Mexican and Codex MRLs are established for fenhexamid on
various fruit and vegetable crops.  As with the U.S., the regulated
residues for fenhexamid under each organization include only parent
compound.  As there are no established or proposed Canadian, Mexican or
Codex MRLs for fenhexamid on asparagus, there are no issues for
international harmonization for the current petition.

 TC \l3 "5.1.11	International Residue Limits 5.2	Dietary Exposure and
Risk

A fenhexamid chronic dietary-exposure assessment (food and drinking
water) was conducted using DEEM-FCID™ Version 2.03, which incorporates
consumption data from USDA’s CSFII, 1994-1996 and 1998.  The 1994-96,
98 data are based on the reported consumption of more than 20,000
individuals over two non-consecutive survey days.  Foods “as
consumed” (e.g., apple pie) are linked to EPA-defined food commodities
(e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour
- cooked; fresh or N/S, baked) using publicly available recipe
translation files developed jointly by USDA/ARS and EPA.  For chronic
exposure assessment, consumption data are averaged for the entire U.S.
population and within population subgroups, but for acute exposure
assessment are retained as individual consumption events.  Based on
analysis of the 1994-96, 98 CSFII consumption data, which took into
account dietary patterns and survey respondents, HED concluded that it
is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

The dietary exposure analysis was performed by ARIA (DP #: 347171, B.
Hanson, 12/5/2007).

 TC \l2 "5.2  Dietary Exposure and Risk 

5.2.1	Acute Dietary Exposure/Risk

No toxic effects attributable to a single (i.e., acute) exposure to
fenhexamid have been identified; therefore, an acute reference dose
(RfD) has not been established for fenhexamid and an acute dietary
exposure assessment was not conducted.

  TC \l3 "5.2.1  Acute Dietary Exposure/Risk 

5.2.2	Chronic Dietary Exposure/Risk

The chronic dietary risk assessment was conducted for fenhexamid
assuming tolerance-level residues for all commodities with existing and
proposed tolerances, 100%CT information and default DEEM processing
factors. The only exceptions to these assumptions were a 0.5X EPA
processing adjustment factor for grapes destined for wine and sherry
production and a 4.3X factor for currants, dried (grape, raisin PF),
previously established for use in dietary assessments by HED.  The
highest drinking water estimate for chronic exposure, 1.1 ppb, was used
in the analysis.  The results of the analysis indicate that chronic risk
from the dietary (food + drinking water) exposure to fenhexamid will not
exceed HED’s level of concern (i.e. <100% cPAD) for the general U.S.
population, and all population subgroups.  The chronic dietary risk
estimate for the highest reported exposed population subgroup, all
infants (<1 year old), was 27% of the cPAD.  The general US population
utilizes 10% of the cPAD.

Table 5.2.2  Summary of Chronic Dietary (Food and Drinking Water)
Exposure Risk for Fenhexamid

Population Subgroup	Chronic Dietary

	Dietary Exposure (mg/kg/day)	% cPAD

General U.S. Population	0.017657	10

All Infants (< 1 year old)	0.030064	18

Children 1-2 years old	0.045219	27

Children 3-5 years old	0.034218	20

Children 6-12 years old	0.021757	13

Youth 13-19 years old	0.014096	8.3

Adults 20-49 years old	0.014908	8.8

Adults 50+ years old	0.015058	8.9

Females 13-49 years old	0.015358	9.0

  TC \l3 "5.2.2  Chronic Dietary Exposure/Risk 

5.2.3	Cancer Dietary Risk

Fenhexamid has been classified as a “not likely” human carcinogen;
therefore, a cancer dietary risk assessment was not performed.

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

No anticipated residues or %CT information was used in these dietary
analyses 

 TC \l2 "5.3 Anticipated Residue and Percent Crop Treated (%CT)
Information 

6.0	RESIDENTIAL (NON-OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

There are no residential (non-occupational) uses of fenhexamid. 
Therefore, potential risk from such uses is not addressed in this risk
assessment. 

  TC \l1 "6.0	Residential (Non-Occupational) Exposure/Risk
Characterization 

6.1	Other (Spray Drift, etc.)

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

7.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, ARIA must consider and aggregate pesticide
exposures and risks from non-occupational sources, including; food,
drinking water, and residential pathways.  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, ARIA considers both the route and duration of exposure.

No acute or short/long-term or cancer aggregate exposure is expected. 
Acute exposure is not expected because no hazard has been identified for
this endpoint. Short/long-term exposures are not expected since there
are no residential/non-occupational uses of fenhexamid.  Cancer exposure
is not expected because fenhexamid has been classified as a “not
likely” human carcinogen.

Since the chronic aggregate risk exposure includes only food and water
and the chronic dietary analysis already includes both, no further
calculations are necessary.  Since the chronic dietary risk estimates do
not exceed ARIA’s level of concern, the chronic aggregate risk
estimates do not exceed ARIA’s level of concern.   TC \l2 "7.5	Cancer
Risk 

8.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

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

9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

An occupational risk assessment was completed for this IR-4 registration
request of fenhexamid for its use on asparagus (M. Dow, DP#: 340326,
6/15/2007).  For more detailed information on the occupational risks
associated with this proposed use, please see aforementioned assessment.

Proposed Uses

The use pattern summary is taken from the IR4 submission, Section B and
from draft labeling from Arysta.  The product proposed for use is
Elevate® 50 WDG Fungicide (Reg. No. 66330 - 35).  Elevate® is
formulated as a water dispersible granule which contains 50 % by weight,
fenhexamid active ingredient.  The target pest is Botrytis cinerea, the
plant disease organism that causes gray mold. The rate of application is
0.75 lb ai/A applied in a minimum of 40 gallons of water/A.  There is a
maximum of 4 applications/A/season.  Applications should be separated by
7 - 14 days.  There is a maximum permitted of 3.0 lb ai/A/year.  All
applications must be made to asparagus during the fern stage only.  The
ferns must be mowed down or allowed to senesce between the last
application and harvest of the spears.  The preharvest interval (PHI) is
180 days in all states except California.  The PHI in California is 90
days.

See Table 9.0 for a summary of the proposed use pattern.	

Table 9.0 Summary of Proposed Use Pattern for Fenhexamid on Asparagus

Formulation	Elevate® 50 WDG Fungicide; Reg. No. 66330 - 35

water dispersible granule; 50 % by weight ai

Pest	Botrytis cinerea (gray mold)

Method of Applic.	ground boom

Max. Applic. Rate	0.75 lb ai/A

Max. No. Applications	4/season

Applic. Interval	7 - 14 days

Preharvest Interval	180 days except California;  90 days in California

Restricted Entry Interval	12 hours 

Manufacturer	Arysta LifeScience

9.1	Occupational Pesticide Handler Exposure and Risk

Based upon the proposed use pattern, ARIA/RD expects the most highly
exposed occupational pesticide handlers to be 1) mixer/loaders using
open pour loading of granules and 2) applicators using open-cab,
ground-boom spray equipment.  Due to the volume of spray recommended per
acre, ARIA believes aerial application is not a practical option.

ARIA believes that in these cases, most occupational pesticide handlers
are likely to be private, grower handlers.  The number of acres treated
per day is expected to be rather small as compared to most field crops. 
ARIA herein uses a default assumption of 200 acres treated per day.  On
average this is likely to be an overestimate and therefore is a
conservative assumption.  However, 2002 Census of Agriculture data
indicate average asparagus farms in California often exceed 200 acres in
size.  

Short-term duration (1–30 days) exposures are expected.   There might
be occasions where some handlers might experience 2 or more short-term
exposures.  Due to the timing and proposed use, it is unlikely that
intermediate-term duration (1 – 6 months) exposures will occur.  

It is not uncommon for grower (private), pesticide handlers to perform
all three handling activities that is, to mix, load and apply the
material.  However, the available exposure data for combined
mixer/loader/applicator scenarios are limited in comparison to the
monitoring of these two activities separately.  These exposure scenarios
are outlined in the Pesticide Handler’s Exposure Database (PHED)
Surrogate Exposure Guide (August 1998).   

No chemical specific data are available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).  The Elevate® label directs applicators and other handlers
to wear long-sleeved shirt, long pants, socks, shoes and waterproof
gloves. 

The toxicological endpoints used herein for purposes of risk assessment
are taken from HED.  Pertinent to this assessment, a dermal
toxicological endpoint was identified from a 21 day dermal developmental
toxicity study in the rabbit at a NOAEL of 1,000 mg ai/kg bw/day.  A
LOAEL was not observed in this study.  However, results in this study
were consistent with those in the oral developmental toxicity study in
rabbits in which maternal effects were observed, particularly during the
first week of dosing, at a LOAEL of 300 mg/kg/day.  A NOAEL for maternal
toxicity in oral study was 100 mg/kg/day. Using a 20% dermal absorption
factor, the oral NOAEL (100 mg/kg/day) is equivalent to a dermal NOAEL
of 500 mg//kg/day and the oral LOAEL (300 mg/kg/day) is equivalent to a
dermal LOAEL of 1,500 mg/kg/day.  The dermal NOAEL was for short-term
(1-30 days) and intermediate-term (1-6 months) exposure durations. 
Although a dermal absorption factor has been identified, it is not used
for purposes of assessing dermal exposure and risk since the NOAEL was
identified from a 21-day dermal developmental study and dermal
absorption is already accounted for in the study.  

HED did not identify inhalation toxicological endpoints for either
short- or intermediate-term exposures.  It was determined that a
separate inhalation risk assessment is not required for short- and
intermediate-term inhalation risk assessment (TXR NO. 013258).  

Table 9.1   Summary of Exposure & Risk for Occupational Handlers
Applying  Fenhexamid to Asparagus

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

Mixer Loader Open Pour Loading Dry Flowable

Dermal:

SLNoGlove     0.066 LC

SLWithGlove  0.066 HC	0.75 lb ai/A	200 A/day	Dermal:

SLNoGlove    0.14

SLWithGlove 0.14	

7,143

Applicator Using Open-cab Ground-boom Sprayer

Dermal:

SLNoGlove      0.014 HC

SLWithGlove   0.014 MC	0.75 lb ai/A	200 A/day	Dermal:

SLNoGlove     0.03

SLWithGlove  0.03	

33,333

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   SL No Gloves = Dermal Single Layer
Work Clothing No Gloves; SL W Gloves = Dermal Single Layer  Work
Clothing With Gloves;   Units = mg ai/pound of active ingredient
handled.  Data Confidence: LC = Low Confidence, MC = Medium Confidence,
HC = High Confidence.

2.  Applic. Rate. = Taken from IR 4 submissions

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP No. 9.1.   Science Advisory Council for
Exposure;  Revised 5 July 2000  

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated (
Body Weight (70 kg).   A 70 kg bw is used in calculations. 

5.  MOE = Margin of Exposure = No Observeable  Adverse Effect Level
(NOAEL) ( 1000 mg ai/kg bw/day) ( ADD.  (ADD = dermal).  The HED did not
identify an inhalation exposure NOAEL.

6.  HED does not have unit exposure data for water dispersible granules
therefore, as a surrogate, unit exposures for a dry flowable formulation
are used.

A Margin of Exposure of 100 is adequate to protect occupational
pesticide handlers.  Since all estimated MOEs are > 100, the proposed
use does not exceed ARIA/RD’s level of concern.

9.2	Occupational Post-Application Worker Exposure and Risk

There typically is the possibility for agricultural workers to
experience post-application exposure to dislodgeable foliar pesticide
residues (DFR).  The Science Advisory Council for Exposure (ExpoSAC) and
the Agricultural Reentry Task Force (ARTF) have identified numerous
post-application, agricultural activities which can result in worker
exposure to dislodgeable foliar pesticide residues.

In addition to identifying the post-application agricultural activities,
the ExpoSAC also identified Transfer Coefficients (TC) expressed as
cm²/hr for each of the post-application, agricultural activities.  The
TCs are derived from data in surrogate exposure studies conducted during
the various activities listed.  

The TCs used in this assessment are taken from an interim TC SOP
developed by HED’s ExpoSAC using proprietary data from the ARTF
database (SOP No. 3.1).  It is the intention of the ExpoSAC that this
SOP will be periodically updated to incorporate additional information
about agricultural practices in crops and new data on transfer
coefficients.  Much of this information will originate from exposure
studies currently being conducted by the ARTF, from further analysis of
studies already submitted to the Agency, and from studies in the
published scientific literature.

There are no compound-specific foliar dislodgeable residue data
available for use in estimating post-application exposure to fenhexamid.
 The highest TC identified for any agricultural activity in asparagus is
500 cm²/hr and that is for irrigation activities conducted during full
foliage development.  To be conservative, ARIA/RD uses the 500 cm²/hr
value.   Also lacking compound specific data, HED assumes 20% of the
application rate is available as dislodgeable foliar residue (DFR) on
day zero after application.  

The estimated post-application exposure to fenhexamid; MOE = 10,400.

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures to fenhexamid.  The estimated MOE is based
upon conservative assumptions and is >100, therefore estimated risks
from estimated post-application exposures do not exceed ARIA/RD’s
level of concern.

Restricted Entry Interval

The interim Worker Protection Standard (WPS) restricted entry interval
(REI) of 12 hours is adequate to protect agricultural workers from
post-application exposures (i.e., field treatment) to fenhexamid under
these circumstances.

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

None.

REFERENCES

Dietary Exposure Memorandum

	Fenhexamid.  Chronic Dietary Exposure Assessment for the Interregional
Research Project No. 4 (IR-4) Petition Proposing Tolerances for Residues
of Fenhexamid on Asparagus (PP# 7E7187). B. Hanson, DP#: 347171,
12/5/2007.

Drinking Water Memorandum

	Drinking Water Assessment for the IR-4 Petition for the Use of
Fenhexamid on Asparagus. C. Sutton, DP#: 338651, 7/26/2007.  

Residue Chemistry Data Review Memorandum

	Fenhexamid.  Petition for Registration for Use on Asparagus.  Summary
of Analytical Chemistry and Residue Data.  Petition Number 7E7187. D.
Rate; DP #: 346385; 11/30/2007.

Occupational and Residential Exposure Memorandum

	Human, Non-Dietary Exposure/Risk 	Assessment for the Proposed Use of
Fenhexamid on Asparagus.  M. Dow, DP#: 340326; 6/15/2007.

Risk Assessment Document

	Human Health Risk Assessment for Fenhexamid – IR-4 Tolerance Request
on Cilantro (Transplant/Greenhouse), Non-Bell Pepper (Transplant) and
Pomegranate (Post-Harvest). J. Redden, DP#:: 329137, 6/14/2006. 

HED Memorandum

	FENHEXAMID - 2nd Report of the Hazard Identification Assessment Review
Committee.  B. Tarplee, TXR NO.  0051704, 3/26/2003.

Appendix A:	INTERNATIONAL RESIDUE LIMIT STATUS

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:
N-(2,3-dichloro-4-hydroxyphenyl)-1-methylcyclohexanecarboxamide	Common
Name: Fenhexamid

	X Proposed tolerance

    Reevaluated tolerance

    Other	Date:  11/07/2007

Codex Status (Maximum Residue Limits)	U. S. Tolerances

    No Codex proposal step 6 or above

X No Codex proposal step 6 or above for the crops requested	Petition
Numbers: 7E7187

DP Number:  	346385

Other Identifier:  

Residue definition (step 8/CXL): Fenhexamid	Reviewer/Branch:  Debra
Rate/RIMUERB

	Residue definition:  Fenhexamid

Crop (s)	MRL (mg/kg)	Crop(s) 	Tolerance (ppm)

Almond hulls	2	Asparagus	0.02

Almonds	0.02 (*)

Apricot	10

Blackberries	15

Blueberries	5

Cherries	7

Cucumber	1

Currants, Black, Red, White	5

Dewberries (including boysenberry and loganberries)	15

Dried grapes (currants, raisins, and sultanas)	25

Edible offal (mammalian)	0.05 (*)

Egg plant	2

Gherkin	1

Gooseberry	5

Grapes	15

Kiwifruit	15

Lettuce, Head	30

Lettuce, Leaf	30

Meat (from mammals other than marine mammals)	0.05 (*)

Milks	0.01 (*)

Nectarine	10

Peach	10

Peppers	2

Plums, including prunes	1

Raspberries, Red, Black	15

Squash, Summer	1

Strawberry	10

Tomato	2

Bilberry	5

Elderberries	5

Juneberries	5

Limits for Canada	Limits for Mexico

( No Limits

X No Limits for the crops requested	( No Limits

X No Limits for the crops requested

Residue definition: N-(2,3-dichloro-4-hydroxyphenyl)-1-methylcyclohexane
carboxamide	Residue definition:  Fenhexamid

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

Lettuce	23	Durazno (peach)	6

Blackberries, loganberries, raspberries	20	Fresa (strawberry)	3

Apricots, cherries, peaches, nectarines	6	Vid (grapes)	4

Grapes	4

Raisins	6

Blueberries, currants, elderberries, gooseberries, huckleberries	4

Strawberries	3

Plums	0.5

Almonds	0.02

Tomato	1

Notes/Special Instructions: S.Funk, 11/07/2007

Appendix B:	TOXICOLOGY ASSESSMENT  TC \l1 "Appendix A:  Toxicology
Assessment 

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

The requirements for Fenhexamid are in Table B.1. Use of the new
guideline numbers does not imply that the new (1998) guideline protocols
were used.

Table B.1  Toxicology Data Requirements for Fenhexamid

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-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

no

yes

no

no	yes

-

yes

no

no

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	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    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 Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

yes

no

no	-

-

yes

-

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

yes	yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

-

-

-

B.2	Toxicity Profiles

	

Table A.1.a  Acute Toxicity Profile of Fenhexamid 

Guideline No.	

Study Type	

MRID(s)	

Results	

Toxicity Category

870.1100	

Acute Oral

Rats	

44346769	

M: LD50 >5000 mg/kg

F: LD50 >5000 mg/kg

    	

IV

870.1200	

Acute Dermal

Rats	

44346770	

M: LD50 >5000 mg/kg

F: LD50 >5000 mg/kg

           	

IV

870.1300	

Acute Inhalation

Rats	

44366513	

DUST

M: LC50 >5.057 mg/L

F: LC50 >5.057 mg/L

          	

DUST

IV

870.2400	

Primary Eye Irritation

Rabbits

	

44346771	

Not an eye irritant	

IV

870.2500	

Primary Skin Irritation

Rabbits

	

44346771	

Not a dermal irritant	

IV

870.2600	

Dermal Sensitization

Guinea Pigs

	

44346772 	

Not a dermal sensitizer	

N/A

B.3  Executive Summaries TC \l2 "A.3  Executive Summaries 

B.3.1	Subchronic Toxicity

870.3200	21/28-Day Dermal Toxicity – Rat

Study Selected: 21-Day Dermal Toxicity Study, Rabbits

MRID No.:  44346780

Executive Summary:  In a 21-day repeated dose dermal toxicity study in
NZW rabbits (MRID 44346780), KBR 2738 (95.4% purity) was applied to the
shaved skin of 5 rabbits/sex/dose at a dose level of 1000 mg/kg/day
(limit dose), 6 hours/day, for a total of 17 days over a 3-week period. 
 

No rabbits died during this study. No skin irritation was observed in
any treated animals. There were no compound related effects on clinical
signs, body weight, food consumption, hematology, clinical chemistry,
organ weights, or gross and histologic pathology. Dermal administration
of KBR 2738 was well tolerated by both sexes for 21-days at the limit
dose of 1000 mg/kg/day. The NOAEL is 1000 mg/kg/day (limit dose) and the
LOAEL is greater than 1000 mg/kg/day for both systemic and local effects
on the skin.

Dose and Endpoint for Risk Assessment: NOAEL = 1000 mg/kg/day (HDT).

Comments about Study/Endpoint: This study is selected because its
duration and route of exposure are appropriate for short- and
intermediate-term dermal exposure.  Results in this study are consistent
with those in the oral developmental toxicity study in rabbits (MRID
44346801) in which maternal effects (decreased body weight gain and
decreased feed consumption) were observed, particularly during the first
week of dosing, at the LOAEL of 300 mg/kg/day.  The NOAEL for maternal
toxicity in this study was 100 mg/kg/day.  Using a 20% dermal absorption
factor, the oral NOAEL in this study (100 mg/kg/day) is equivalent to a
dermal NOAEL of 500 mg//kg/day and the oral LOAEL (300 mg/kg/day) is
equivalent to a dermal LOAEL of 1500 mg/kg/day.  Since treatment-related
effects were observed at an equivalent dermal dose level of 1500
mg/kg/day, HED concluded it would be appropriate to use the dermal dose
level of 1000 mg/kg/day (NOAEL) from the 21-day dermal study for short-
and intermediate-term dermal risk assessments.

870.3465	90-Day Inhalation – Rat	

Study Selected: 	None

MRID No.:		None

Executive Summary:  None

Dose and Endpoint for Risk Assessment:   Not applicable

Comments about Study and Endpoint:  The acute inhalation LC50 for
technical grade fenhexamid dust (95.5% purity) is >5.057 mg/L (Toxicity
Category IV) for both male and female rats and for technical grade
fenhexamid aerosolized in PEG 400/ethanol mixture at  0.322 mg/L (the
maximum technically possible concentration) is > 0.322 mg/L for both
male and female rats.  In both of these acute inhalation toxicity
studies (MRID 44366513), there were no mortalities, treatment-related
clinical signs, changes in body weights or necropsy findings.  Further,
in a 5-day range-finding inhalation toxicity study in rats using
technical grade fenhexamid dust as the test material (MRID 44366514),
macroscopic gray colouration of the lungs and marginally increased lung
weights were observed at a concentration of 1.092 mg/L, but not at 0.098
mg/L.  It is likely that the effects observed in this study are due to
the physical deposition of fenhexamid dust in the lungs and not to any
systemic effect of the test material.

Based on the low acute inhalation toxicity (Toxicity Category IV), the
low 5-day subchronic toxicity (no systemic toxicity at 1.092 mg/L), the
composition of the formulated product (water dispersible granules
containing 50% ai), the application rate (maximum of 3.0 lb/acre), and
the application method (ground spray, groundboom and airblast), there is
minimal concern for potential inhalation exposure/risk.  HED determined
that a separate inhalation risk assessment is not required for short-
and intermediate-term inhalation risk assessments.  

B.3.2	Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

Study Selected: Developmental Toxicity Study, rat

MRID No.  44346781

Executive Summary:  In a developmental toxicity study (MRID 44346781),
KBR 2738 (95.4% purity) was administered to 30 Sprague-Dawley rats/dose
by gavage at dose levels of 0 and 1000 (1044 determined analytically)
mg/kg/day from days 6 through 15 of gestation. 

When tested at the limit dose of 1000 (1044) mg/kg/day, there were no
treatment-related effects on maternal mortality, clinical signs,
Cesarean parameters or gross pathology. The LOAEL for maternal toxicity
is set at 1044 mg/kg/day based on the observed decrease in body weight
gain(-12% of controls)during gestation days 6-16 and a decrease in food
consumption (10% of controls) during gestation days 6-11.  The NOAEL for
maternal toxicity is < 1044 mg/kg/day. The NOAEL for developmental
toxicity is set at 1044 mg/kg/day (limit dose). No treatment-related
effects were noted in any embryo/fetal parameters. Where noted,
statistically significant differences from concurrent control values
fell within the range of values of the historical control data supplied
by the laboratory for those parameters.  Under the conditions of this
study, therefore, KBR 2738 was not embryotoxic, fetotoxic or teratogenic
at a dose of 1044 mg/kg/day (the highest dose tested).

870.3700b Prenatal Developmental Toxicity Study – Rabbit

Study Selected: Developmental Toxicity Study, rabbit

MRID No.  44346801

Executive Summary:  In a developmental toxicity study (MRID 44346801),
KBR 2738 (95.4% purity) was administered to 16 female Russian rabbits
(CHBB:HM)/dose by gavage at dose levels of 0, 100, 300 or 1000 mg/kg/day
from days 6 through 18 of gestation. Does were naturally inseminated and
were sacrificed on gestation day 29.

No treatment-related effects were seen on mortality, clinical signs or
behavior. The LOAEL for maternal toxicity is set at 300 mg/kg/day based
on observations at this dose and above of alterations of excretory
products (discolored urine, small scybala), decreased body weight gain
and feed consumption (mainly during the first week of the treatment
period) and decreased placental weights. One abortion at 300 mg/kg/day
and one abortion and two total litter resorptions at 1000 mg/kg/day were
not considered to be treatment-related because the incidences fell
within the ranges of historical control data submitted with the study. 
Reduced and/or light feces were also noted at 1000 mg/kg/day.  Pale
livers were noted in the 2 dams that aborted. The NOAEL for maternal
toxicity is set at 100 mg/kg/day. The LOAEL for developmental toxicity
is 1000 mg/kg/day based on marginally decreased male fetal body weights
and evidence of delayed ossification. Administration of the test
compound did not induce any treatment-related fetal malformations or
deviations at any of the doses tested under the conditions of this
study. All effects on intrauterine development were correlated with
maternal toxicity and, therefore, no primary developmental effect was
evident. The NOAEL for developmental toxicity is 300 mg/kg/day. KBR 2738
was not teratogenic up to and including 1000 mg/kg/day, the limit dose. 

Comments:  In neither the developmental toxicity study in rats (MRID
44346781) nor in the developmental toxicity study in rabbits (MRID
44346801) was there any evidence for increased susceptibility of fetuses
to in utero exposure to fenhexamid.  In the rat study, the LOAEL for
maternal toxicity was 1044 mg/kg/day (HDT), but no developmental
toxicity (including any effect on the fetuses) was observed at that dose
level.  In the rabbit study, the NOAEL for maternal toxicity was 100
mg/kg/day and the LOAEL was 300 mg/kg/day.  In the same study, the NOAEL
for developmental toxicity was 300 mg/kg/day and the LOAEL was 1000
mg/kg/day, based on marginally decreased fetal body weights in male
fetuses and delayed ossification in several bones (especially the 5th
sternal segments and the 15th caudal vertebrae).   

B.3.3	Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

Study Selected: 2-generation reproduction study, rats

MRID No.  44346803

Executive Summary:  In a 2-generation reproduction study (1
litter/generation)(MRID 44346803), KBR 2738 (93.8-95.2% purity) was
administered to 30 Sprague-Dawley rats/sex/dose in the diet at dose
levels of 0, 100, 500, 5000 or 20000 ppm (0, 7.6, 38.2, 406 or 1814
mg/kg/day for males and 0, 9.0, 44.8, 477 or 2043 mg/kg/day for females
determined for the 10-week premating period).

There were no compound-related effects on mortality, clinical signs,
behavior or reproductive parameters for adult animals. The NOAEL for
reproductive toxicity was 20000 ppm (1814/2043 mg/kg/day), the highest
dose tested.

The neonatal NOAEL was 500 ppm (38.2/44.8 mg/kg/day); the neonatal LOAEL
was 5000 ppm (406/477 mg/kg/day) based on significantly decreased pup
body weights on lactation days 14 and  21 for F1 pups (6-11% less than
controls) and on lactation days 7, 14 and 21 for F2 pups (9-11% less
than controls).  At 20000 ppm (1814/2043 mg/kg/day), significantly
decreased pup body weights were observed on lactation days 7, 14 and  21
for F1 pups (15-30% less than controls) and for F2 pups (11- 19% less
than controls).  Treatment-related decreased pup body weights were not
observed at birth or on lactation day 4.  An additional effect observed
at 20000 ppm was an increase in the number of pups among the
post-weaning F1 pups selected to be F1 parents which died viz. 0/66,
2/68, 0/68, 0/68 and 10/78 for the control, 100, 500, 5000 and 20000 ppm
dose groups respectively.  This effect was attributed by the testing
laboratory to the small size of the pups at weaning (30% less than
controls).

The parental NOAEL was 500 ppm (38.2/44.8 mg/kg/day); the parental LOAEL
was 5000 ppm (406/477 mg/kg/day) based, in males, on increased
creatinine levels in P-generation (but not F1-generation) males at
premating (20%, p<0.05) and at termination (20%, not significant);
slightly increased alkaline phosphatase levels in P-generation and
F1-generation males at premating and at termination (20-34%, not
significant); decreased absolute liver weight in P-generation and
F1-generation males (11-12%, p<0.05) and decreased liver/body weight
ratios in P-generation and F1-generation males (8-9%, p<0.05 for
P-generation and not significant for F1-generation); decreased absolute
kidney weights in F1-generation (but not P-generation) males (12%,
p<0.05); and decreased kidney/body weight ratios in F1-generation (but
not P-generation) males (8%, p<0.05).  The parental LOAEL was based, in
females, on increased alkaline phosphatase levels in F1-generation (but
not P-generation) females at premating (43%, p<0.05) and at termination
(63%, p<0.05); and on very small increases in GGT (not considered to be
biologically relevant).  In males at 5000 ppm, the increased creatinine
levels and decreased absolute and relative kidney weights suggested a
possible treatment-related effect on the kidney and the increased
alkaline phosphatase levels and decreased absolute and relative liver
weights suggested a possible treatment-related effect on the liver. 
Histopathological examination of kidney and liver in males, however, did
not indicate any treatment-related morphological changes in these organs
(i.e. was negative).  In females at 5000 ppm, the increased alkaline
phosphatase levels and GGT levels suggested a possible treatment-related
effect on the liver.  Histopathological examination of liver in females,
however, was negative.

At 20000 ppm (1814/2043 mg/kg/day), in males, treatment-related effects
on parental parameters were the following: increased creatinine levels
in P-generation males (20%, p<0.05); increased alkaline phosphatase
levels in P-generation and F1-generation males (16-44%, not
significant); slightly increased GGT levels in P-generation males
(p<0.05, but not considered to be biologically relevant); decreased
absolute liver weights in P-generation and F1-generation males (9-19%,
p<0.05 for P-generation, not significant for F1-generation); decreased
liver/body weight ratios in P-generation and F1-generation males (3-11%,
p<0.05 for P-generation, not significant for F1-generation); decreased
absolute kidney weights in F1-generation males (13%, p<0.05); decreased
kidney/body weight ratios in F1-generation males (8%, p<0.05); decreased
body weights (6-16%, p<0.01); and increased food consumption (12-26%,
p<0.01).  Histopathological examination of kidney and liver was
negative.  At 20000 ppm, in females, treatment-related effects on
parental parameters were the following: increased urea nitrogen levels
in P-generation females (43%, not significant) and F1-generation females
(55%, p<0.05); increased creatinine levels in F1-generation females
(17%, p<0.05); increased alkaline phosphatase levels in P-generation
females (23-25%, not significant) and F1-generation females (56-87%,
p<0.05); slightly increased GGT in P-generation females (p<0.05, but not
considered to be biologically relevant); decreased absolute kidney
weights in P-generation and F1-generation females (15-19%, p<0.05);
decreased kidney/body weight ratios in P-generation and F1-generation
females (5-6%, p<0.05); decreased premating body weights (6-16%,
p<0.01); decreased gestation body weights (7-9%. p<0.01); decreased
lactation body weights (7-12%, p<0.01); and increased food consumption
(4-11%, p<0.05).   Histopathological examination of kidney and liver was
negative.  Overall, treatment-related effects observed at 5000 ppm in
males and females were also observed at 20000 ppm, but were slightly
increased in severity.  Toxicologically relevant additional
toxicological effects observed at 20000 ppm were decreased body weights
and increased food consumption in males and increased urea nitrogen and
creatinine levels, decreased kidney weights, decreased body weights and
increased food consumption in females.

Comments:  The results in this reproduction study are equivocal with
respect to evaluating the possibility of increased susceptibility of
pups, as compared to adults, to fenhexamid.  At 5000 ppm (neonatal
LOAEL), statistically significant, treatment-related and dose-related
decreased pup body weights were observed on lactation days 14 and 21 for
F1 pups (6-11% less than controls) and on lactation days 7, 14 and 21
for F2  pups (9-11% less than controls).  At the same dose level of 5000
ppm (parental LOAEL), treatment-related and dose-related effects were
also observed in the adult (parent) animals.  In adult males, increased
creatinine levels (20%) and decreased absolute (12%) and relative (8%)
kidney weights suggested an effect on the kidney and increased alkaline
phosphatase levels (20-34%) and decreased absolute (11-12%) and relative
(8-9%) liver weights suggested an effect on the liver.  In adult
females, increased alkaline phosphatase levels (43-63%) and slightly
increased GGT levels (not considered to be biologically relevant)
suggested a possible effect on the liver.  Histopathological examination
of kidney and liver from these same adult animals, however, did not
reveal any treatment-related morphological changes in these organs at
this dose level (or at the highest dose level of 20000 ppm).  Since
treatment-related effects were observed in both pups and adults at 5000
ppm, but not at 500 ppm, on the basis of NOAELs and LOAELs, no increased
susceptibility of pups to fenhexamid was demonstrated in this study. 
However, the severity of effects in the pups at 5000 ppm (decreased body
weights of up to 11% on lactation days 7 to 21, but not at birth or
lactation day 4) may have been greater than that observed in the adults
at the same dose level (suggestion of mild effects in the kidney and
liver without supporting histopathological changes).  In addition, at
the highest dose level of 20000 ppm, the severity of effects in the pups
(decreased body weights of up to 30% on lactation days 7 to 21 and
increased mortality in F1 pups selected to be F1 parents) was considered
to be greater than that observed at the same dose level in adults (mild
effects in the kidney and liver not supported by histopathological
changes; decreased body weights of up to 16%; and increased food
consumption of up to 26%).  Interpretation of relative severities of
effects in pups and adults at 5000 and 20000 ppm should also consider,
however, that the pups may be consuming significantly greater amounts of
test material than adults (on a mg/kg/day basis) since pups consume
considerably more food per unit body weight than do adults, and  pups
receive test material from not one, but two sources viz. mother’s milk
and treated diet (particularly during the late lactation period).  The
body weight decrements in late lactation (but not through post natal day
4) are supportive of this argument.    

With respect to determining the possible increased susceptibility of
pups to fenhexamid in this reproduction study, HED considered the
results to be equivocal (i.e. subject to two interpretations).  On the
one hand, on the basis of NOAELs and LOAELs, no increased susceptibility
was observed.  On the other hand, the greater severity of effects in
pups and a likely pharmacological explanation for this finding suggested
an increased sensitivity of pups, as compared to adults, to fenhexamid.

B.3.4	Chronic Toxicity

		

870.4100b Chronic Toxicity – Dog

Study Selected: 1-Year Chronic Toxicity Study, Dogs

MRID No.  44346804

Executive Summary:  In a 1-year chronic oral toxicity study (MRID
44346804), KBR 2738 (94.6-95.8% purity) was administered to 4/sex/dose
beagle dogs in the diet at dose levels of 0, 500, 3500 or 25000 ppm (0,
17.4, 124.3 or 917.8 mg/kg/day for males and 0, 19.2, 132.7 or 947.1
mg/kg/day for females) for 52 weeks.

There were no compound related effects on mortality, clinical signs,
clinical tests (ECG, heart rate, blood pressure, pulse, reflexes, body
temperature), ophthalmoscopic examinations, clinical chemistry,
urinalysis, or gross pathology. Decreases in RBC, Hb and Hct and
increases in Heinz bodies in both sexes were noted in mid and high dose
dogs. Decreased body weight gain was observed in both sexes of the 25000
ppm treatment group. The decreased body weight gain by high dose females
may be attributed, in part, to the decreases in food consumption
observed sporadically during the latter half of the study period.
Treatment-related increases in absolute and relative adrenal weights in
mid and high dose females were corroborated by the histopathological
observations of increases in incidence and severity of intracytoplasmic
vacuoles in the adrenal cortex of these animals. No neoplastic changes
were observed in any animals of any dose group.

The LOAEL is 3500 ppm (124.3/132.7 mg/kg/day in males and females,
respectively) based on decreases in RBC, Hb and Hct and on significant
increases in Heinz bodies in both sexes; increased adrenal weight
parameters in females and the presence of intracytoplasmic vacuoles in
the adrenal cortex of 3/4 female dogs.  As well as decreased body weight
gains (both sexes) and decreased food consumption (females) at the
highest dose of 25000 ppm, more pronounced treatment-related effects
were seen in hematology parameters in both sexes (decreased RBC, Hb,
Hct, increased Heinz bodies) and may indicate the potential of KBR 2738
to induce Heinz body anemia in Beagle dogs. The hematotoxic effect of
KBR 2738 was also noted in the 90-day dog study. The NOAEL is 500 ppm
(17.4/ 19.2 mg/kg/day for males and females, respectively). Dosing was
considered adequate based on the observation at the high dose of 25000
ppm of  decreased body weight gains, food consumption and hematotoxic
effects. 

Dose and Endpoint for establishing the RfD:  NOAEL = 17 mg/kg/day. 
Based on decreased RBC counts, hemoglobin and hematocrit, and increased
Heinz bodies in RBC at the LOAEL of 124/133 mg/kg/day in males/females. 
Also, in  females, increased absolute and relative adrenal weights
correlated with histopathological observations of increases in incidence
and severity of intracytoplasmic vacuoles in the adrenal cortex.        
 

Uncertainty Factor: An uncertainty factor of 100 was applied to account
for both interspecies extrapolation (10X) and intraspecies variability
(10X).

Comments about Study/Endpoint/Uncertainty Factor(s): The RfD derived
from the use of the NOAEL and endpoint from the 1-year chronic toxicity
study in dogs and an uncertainty factor of 100 is supported by a similar
RfD that could have been derived from the use of the NOAEL from the
combined chronic/carcinogenicity feeding study in rats (MRID 44346806)
and an uncertainty factor of 100.  In the rat study, the NOAEL = 28
mg/kg/day and the LOAEL = 292/415 mg/kg/day in males/females, based in
males on increased cecal mucosal hyperplasia and increased splenic
extramedullary hematopoiesis, and in females on decreased body weight,
decreased body weight gain, decreased food efficiency and increased
hyperplasia in the bone marrow of the femur and sternum.  Had the RfD
been derived from this rat study, the RfD would have been 28
mg/kg/day/100 = 0.28 mg/kg/day.  The NOAEL from the chronic study in
dogs, rather than the NOAEL from the combined chronic/carcinogenicity
study in rats, was used to calculate the chronic RfD because it is the
lowest NOAEL for this time period.

B.3.5	Carcinogenicity

870.4200b Carcinogenicity (feeding) - Mouse	

MRID No.: 44346805

Executive Summary:  In a carcinogenicity study, KBR 2738 (95.4% purity)
was administered to 50 B6C3F1 mice/sex/dose in the diet at dose levels
of 0, 800, 2400 or 7000 ppm ( 0, 247.4, 807.4 or 2354.8 mg/kg/day for
males, and 0, 364.8, 1054.5 or 3178.2 mg/kg/day for females) for two
years. An additional 10 mice/sex/dose were assigned for the interim
sacrifice at 52 weeks.

Survival was not affected by treatment with KBR 2738. There were no
compound-related effects on clinical signs, food consumption, hematology
or gross pathology. A marginal decrease in body weights (up to 8%) and
body weight gain (17%) was observed in males at 7000 ppm. The LOAEL for
males is 2400 ppm (807.4 mg/kg/day) based on the observation of
decreased kidney weights and decreases in sex-specific vacuolation of
the proximal tubules in the kidneys in males.  Additional
toxicologically significant effects at the highest dose of 7000 ppm
(LOAEL for females)included decreased body weights and weight gain in
males, significantly increased water consumption (both sexes), increased
levels of serum creatinine, bilirubin and albumin(males), decreased
kidney weights (females), renal histopathology (increased incidence of
basophilic cortical tubules in females; chronic renal disease in
males).The LOAEL for females is 7000 ppm (3178.2 mg/kg/day) based on the
observations noted above. The NOAEL for males/females is 800/2400 ppm
(247.4/1054.5 mg/kg/day, respectively). KBR 2738 is non-oncogenic in
mice at doses up to and including 7000 ppm (2354.8 mg/kg/day in males
and 3178.2 mg/kg/day in females). There was no treatment related
increase in tumor incidence, tumor spectrum or latency when compared to
controls.  In this study, KBR 2738 was tested at adequate dose levels
for carcinogenicity testing since it was tested at the limit dose of
7000 ppm (2354.8 mg/kg/day in males and 3178.2 mg/kg/day in females) for
mice.  

Discussion of Tumor Data: There was no evidence of carcinogenicity.

Adequacy of the Dose Levels Tested:  In this study, KBR 2738 was tested
at adequate dose levels for carcinogenicity testing since it was tested
at the limit dose of 7000 ppm (2354.8 mg/kg/day in males and 3178.2
mg/kg/day in females) for mice.

  

Classification of Carcinogenic Potential: HED classified Fenhexamid as a
“not likely” human carcinogen according to the EPA Proposed
Guidelines for Carcinogen Risk Assessment (April 10, 1996).  This
classification is based on the lack of evidence of carcinogenicity in
male and female rats as well as in male and female mice and on the lack
of genotoxicity in an acceptable battery of mutagenicity studies.  

B.3.6	Mutagenicity

Five acceptable mutagenicity studies on technical grade Fenhexamid are
available:

1) Reverse gene mutation, S. typhimurium (MRID 44346807)

2) Forward gene mutation, Chinese hamster lung cells in culture/HGPRT
locus (MRID 44346810) 

3) Chromosome aberration, Chinese hamster ovary cells in culture (MRID
44346809)

4) Unscheduled DNA synthesis, rat hepatocytes in culture (MRID 44346812)

5) In vivo cytogenetics, micronucleus assay in mice (MRID 44346811)

Results in all five studies were negative for genotoxicity.  These five
studies satisfy the new revised mutagenicity guideline requirements for
a new chemical (published in 1991).  

B.3.7	Neurotoxicity

870.6100 Delayed Neurotoxicity Study – Hen

Study Selected: None required				

870.6200 Acute/Subchronic Neurotoxicity Screening Battery

Study Selected: Acute Neurotoxicity Study, Rats				

MRID No.: 44346813

Executive Summary:  In an acute neurotoxicity study, a single oral dose
of KBR 2738 (95.4% purity) was administered to 12 Wistar rats/sex/dose
by gavage at dose levels of 0, 200, 630 or 2000 mg/kg in 2% aqueous
Cremophor EL (10 ml/kg). The rats were observed for 14 days. Functional
Observational Battery (FOB) and motor activity testing were performed 7
days prior to dosing, approximately 20 minutes to 3 hours post-dosing,
and on days 7 and 14. 

There were no compound related effects on mortality, clinical signs,
body weights, brain weights, or gross and histologic pathology or
neuropathology. FOB testing revealed no treatment-related effects in any
females.  High dose males had a marginally lower (p<0.05) mean body
temperature (colonic) on the day of treatment (day 0), but which
reverted to normal by day 7. No treatment-related effects on measures of
motor/locomotor activity or habituation were evident in either sex at
doses up to and including 2000 mg/kg. The LOAEL in males is 2000 mg/kg
based on marginal acute toxicity as evidenced by the lower body
temperatures. The NOAEL in males is 630 mg/kg. The NOAEL in females is
2000 mg/kg, the highest dose tested.

Comments:  Decreased body temperature may be a sign of acute general
systemic toxicity or may possibly be due to a CNS mediated (neurotoxic)
effect of the test material on the brain since the brain controls
temperature regulation in the body.  There is insufficient data in this
study to distinguish between these two possibilities.  Therefore, this
observation should be considered to be a possible neurotoxic effect of
the test material.  Since it is only a marginal effect and occurs only
at a very high dose level (2000 mg/kg), however, this possible effect
should not be considered to be a toxicologically significant neurotoxic
effect and in the absence of additional signs of neurotoxicity in this
or in other studies on fenhexamid is considered to be insufficient
evidence to support requirement of a developmental neurotoxicity study.

B.3.8	Metabolism

870.7600	Dermal Absorption – Rat

Dermal Absorption Factor: 20% (rounded off from 21.0%, highest mean
dermal absorption at 120 hours).  This value is considered to represent
the potential cumulative dermal absorption of test material that might
occur after a 10 hour dermal exposure.  See Comments below.

Study Selected: Dermal Absorption Study, Rats				

MRID No.: 44346815

Executive Summary:  In a dermal absorption study, [Phenyl-UL-14C]-TM-402
50 WP formulation (50% active ingredient) was applied to the shaved skin
of Crl:CD BR male rats weighing 182-219 g at dose levels of 0.00138,
0.0147 or 0.148 mg/cm2.  A volume of 100 uL was applied to a skin area
of approximately 12.5 cm2 on each rat.  Four rats/dose level were
sacrificed at 0.5, 1, 2, 4, 10, 24 and 120 hours postdose.  An
additional 2 rats served as a vehicle (water) control group.  Skin at
the application site was washed just before sacrifice (0.5, 1, 2, 4 and
10 hour postdose groups) or at 10 hours (24 and 120 hour postdose
groups).  Urine and feces were collected at the time of sacrifice or at
24 hour intervals for the 120 hour postdose group.  Mean radioactivity
for each group was determined for skin test site cover, skin test site,
skin wash, urine, feces, blood and carcass.  Corresponding mean
percentages of the applied dose were calculated.  

Mean total recovery of radioactivity ranged from 90.3% to 97.6% of the
applied dose.  The majority of radioactivity was recovered from the skin
wash (69.9% to 96.1%).  Radioactivity in the skin test site ranged from
0.44% to 10.2%; in the urine from “not detectable” to 3.34%; and in
the feces from “not detectable” to 11.6% of the applied dose. 
Radioactivity in blood did not exceed 0.03% and in the carcass did not
exceed 9.37%.  Estimates of dermal absorption were based on the sum of
radioactivity (as test material) in the skin test site, urine, feces,
blood and carcass.  The percentage dermal absorption decreased with
increasing dose level.  The percentage dermal absorption at 10 hours
postdose was 19.85%, 7.62% and 2.63% and at 120 hours postdose was
21.0%, 6.91% and 2.13% for the low, mid and high dose levels
respectively.  

Comments about Dermal Absorption: At 10 hours postdose in the low dose
level group, radioactivity (as test material) in the skin test site was
10.1% and in the urine, feces, blood and carcass was 9.75%, whereas by
120 hours, radioactivity in the skin test site decreased to 6.05% and in
the urine, feces, blood and carcass increased to 14.94%.  These data
indicate that radioactivity in the skin test site continued to be
absorbed after 10 hours (at which time the skin was washed) up to 120
hours (at which time the study was terminated).  Since radioactivity in
the skin test site at 10 hours continued to be absorbed in significant
amounts for up to 120 hours, HED concluded that all the radioactivity in
the test skin site might eventually have been absorbed if the study were
continued beyond 120 hours.  Therefore, 21.0%, the mean total amount of
radioactivity in test skin site, urine, feces, blood and carcass at 120
hours was considered to represent the potential cumulative dermal
absorption of test material that might occur after a 10 hour exposure.  

Appendix C:	REFERENCES (in MRID order)

44346769	Bomann, W. (1991) KBR 2738: Study for Acute Oral Toxicity in
Rats: Lab Project Number: 20640: TMN-028: T 3037355. Unpublished study
prepared by Bayer Ag. 38 p. {OPPTS 870.1100}

44346770	Bomann, W. (1991) KBR 2738: Study for Acute Dermal Toxicity in
Rats: Lab Project Number: 20639: TMN-026: T 4037356. Unpublished study
prepared by Bayer Ag. 37 p. {OPPTS 870.1200}

44346771	Martins, T. (1996) KBR 2738: Study for Skin and Eye
Irritation/Corrosion in Rabbits (Including Amendment): Lab Project
Number: 19884: 19884A: TMN-029. Unpublished study prepared by Bayer Ag.
30 p. {OPPTS 870.2400, 870.2500}

44346772	Dreist, M. (1996) KBR 2738: Studies on Skin Sensitization
Effect in Guinea Pigs (Buehler Test) (Including Amendment): Lab Project
Number: 20973: 20973A: TMN-025. Unpublished study prepared by Bayer Ag.
34 p. {OPPTS 870.2600}	

44346773	Dreist, M. (1992) Reassessment of Buehler Patch Test
Methodology Applied at Bayer Ag Fachbereich Toxikologie in the DHPW
Strain of Guinea Pig Using 2-Mercaptobenzothiazole: Lab Project Number:
21677: TMN-025J: T 7041192. Unpublished study prepared by Bayer Ag. 37
p. {OPPTS 870.2600}

44346780	Vohr, H.; Krotlinger, F.; Rinke, M. (1995) Subacute Dermal
Toxicity Study on Rabbits: (KBR 2738): Lab Project Number: 23715:
TMN-041: T 3050143. Unpublished study prepared by Bayer Ag. 115 p.
{OPPTS 870.3200}

44346781	Astroff, A. (1994) A Developmental Toxicity Study with KBR 2738
Technical in the Sprague-Dawley Rat: Lab Project Number: MOB7438:
TMN-031: 93-612-WG. Unpublished study prepared by Miles Inc. 319 p.
{OPPTS 870.3500}

44346801	Kolb, J. (1996) KBR 2738: Developmental Toxicity Study in
Rabbits After Oral Administration (Including Amendment): Lab Project
Number: 23733: 23733A: TMN-032. Unpublished study prepared by Bayer Ag.
305 p. {OPPTS 870.3700}

44346803	Eigenberg, D.; Hastings, T. (1997) A Two Generation Dietary
Reproduction Study in Rats Using Technical Grade KBR 2738 (Including
Amendment): Lab Project Number: 107461: 8008: TMN-030K. Unpublished
study prepared by Bayer Corp. 1378 p. {OPPTS 870.3800}

44346804	Ruf, J.; Vliegen, M.; Schilde, B. (1997) Chronic Toxicity Study
in Beagle Dogs (52 Week Feeding Study) (with KBR 2738) (Including
Amendment): Lab Project Number: 25618: TMN-030E: T 7 055 692.
Unpublished study prepared by Bayer Ag. 556 p. {OPPTS 870.4100}	

44346805	Eiben, R.; Rinke, M. (1997) Oncogenicity Study in B6C3F1 Mice
(with KBR 2738) (Administration in the Diet Over 2 Years): Lab Project
Number: 25523: TMN-030D: T 4044222. Unpublished study prepared by Bayer
Ag. 1493 p. {OPPTS 870.4200}

44346806	Eiben, R.; GeiB, V.; Kaliner, G. (1996) Study on Chronic
Toxicity and Carcinogenicity in Wistar Rats (Administration in the Diet
Over 2 Years): KBR 2738: Lab Project Number: 25522: TMN-030C: T 5044223.
Unpublished study prepared by Bayer Ag. 1746 p. {OPPTS 870.4300}

44346807	Herbold, B. (1991) KBR 2738: Salmonella/Microsome Test: Lab
Project Number: 20307: TMN-037: T 9037342. Unpublished study prepared by
Bayer Ag. 48 p. {OPPTS 870.5265}

44346809	Gahlmann, R. (1995) KBR 2738: In vitro Mammalian Chromosomal
Aberration Test with Chinese Hamster Ovary (CHO) Cells: Lab Project
Number: 24405: TMN-034B: T 1039216. Unpublished study prepared by Bayer
Ag. 34 p. {OPPTS 870.5300}

44346810	Brendler-Schwaab, S. (1994) KBR 2738: Mutagenicity Study for
the Detection of Induced Forward Mutations in the V79-HGPRT Assay in
vitro: Lab Project Number: 23529: TMN-035: T 2039235. Unpublished study
prepared by Bayer Ag. 36 p.

44346811	Herbold, B. (1993) KBR 2738: Micronucleus Test on the Mouse:
Lab Project Number: 22625: TMN-034: T 8050076. Unpublished study
prepared by Bayer Ag. 48 p.

44346812	Brendler, S. (1992) KBR 2738: Mutagenicity Test on Unscheduled
DNA Synthesis in Rat Liver Primary Cell Structures in vitro: Lab Project
Number: 21312: TMN-036: T 9037351. Unpublished study prepared by Bayer
Ag. 29 p. {OPPTS 870.5550}

44346813	Dreist, M.; Popp, A. (1996) Acute Oral Neurotox Screening Study
in Wistar Rats: KBR 2738: Lab Project Number: 24745: TMN-037A: T
1058242. Unpublished study prepared by Bayer Ag. 408 p. {OPPTS 870.6200}

44346815	Ampofo, S. (1997) Dermal Absorption of (Phenyl-UL-(carbon
14))-TM-402 50 WP Formulation in Male Rats (Preliminary and Definitive
Phases): Lab Project Number: CHW 6775-100: TMN-046: AM 071. Unpublished
study prepared by Corning Hazleton Inc. 189 p. {OPPTS 870.7600}

44366513	Pauluhn, J. (1996) KBR 2738: Studies of the Acute Inhalation
Toxicity in Rats (Including Amendment): Lab Project Number: T2038065
(AEROSOL): T 9037289 (DUST): TMN-030B. Unpublished study prepared by
Bayer Ag. 85 p. {OPPTS 870.1300}

  HYPERLINK
"https://dcwebmail3.epa.gov/mail/brhanson.nsf/0/A8CBE290BD80638F852573A3
004FF87A/$File/47056401.der.doc?OpenElement&FileName=47056401.der.doc"
\o "Size: 146KB;Modified: 11/30/2007 09:33AM" \t "_blank"  47056401 
Mahlburg, W. (2007) MCPA-6 Amine Product Identity and Composition.
Project Number: 2007/1A. Unpublished study prepared by Nufarm Americas
Inc. 26 p.

Appendix D:	REVIEW OF HUMAN RESEARCH 

No MRID - PHED Surrogate Exposure Guide

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