![](media/image1.wmf)

**UNITED STAES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

**OFFICE OF**

**PREVENTION, PESTICIDES**

**AND TOXIC SUBSTANCES**

**[MEMORANDUM]{.underline}**

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

[**1.0** **EXECUTIVE SUMMARY 5**](#__RefHeading___Toc186859490)

[2.0 INGREDIENT PROFILE 9](#__RefHeading___Toc186859491)

[**2.1** **Proposed Use** 10](#__RefHeading___Toc186859492)

[**2.2** **Identification of Active Ingredient**
10](#__RefHeading___Toc186859493)

[**2.3** **Physical and Chemical Properties**
11](#__RefHeading___Toc186859494)

[3.0 HAZARD CHARACTERIZATION 11](#__RefHeading___Toc186859495)

[**3.1** **Hazard and Dose-Response Characterization**
11](#__RefHeading___Toc186859496)

[**3.1.1** **Database Summary** 17](#__RefHeading___Toc186859497)

[**3.1.2** **Toxicological Effects** 17](#__RefHeading___Toc186859498)

[**3.1.3** **Dose-response** 17](#__RefHeading___Toc186859499)

[**3.2** **Absorption, Distribution, Metabolism, Excretion (ADME)**
18](#__RefHeading___Toc186859500)

[**3.3** **FQPA Considerations** 18](#__RefHeading___Toc186859501)

[**3.3.1** **Adequacy of the Toxicity Database**
18](#__RefHeading___Toc186859502)

[**3.3.2** **Evidence of Neurotoxicity**
18](#__RefHeading___Toc186859503)

[**3.3.3** **Developmental Toxicity Studies**
18](#__RefHeading___Toc186859504)

[**3.3.4** **Reproductive Toxicity Study**
18](#__RefHeading___Toc186859505)

[**3.3.5** **Additional Information from Literature Sources**
20](#__RefHeading___Toc186859506)

[**3.3.6** **Pre-and/or Postnatal Toxicity**
20](#__RefHeading___Toc186859507)

[**3.3.7** **Recommendation for a Developmental Neurotoxicity (DNT)
Study** 21](#__RefHeading___Toc186859508)

[**3.4** **FQPA Safety Factor for Infants and Children**
21](#__RefHeading___Toc186859509)

[**3.5** **Hazard Identification and Toxicity Endpoint Selection**
21](#__RefHeading___Toc186859510)

[**3.5.1** **Acute Reference Dose (aRfD) - General Population**
21](#__RefHeading___Toc186859511)

[**3.5.2** **Chronic Reference Dose (cRfD)**
22](#__RefHeading___Toc186859512)

[**3.5.4** **Incidental Oral Exposure (Short- and Intermediate-Term)**
22](#__RefHeading___Toc186859513)

[**3.5.5** **Dermal Absorption** 22](#__RefHeading___Toc186859514)

[**3.5.6** **Dermal Exposure (Short-, Intermediate- and Long-Term)**
23](#__RefHeading___Toc186859515)

[**3.5.7** **Inhalation Exposure (Short-, Intermediate- and Long-Term)**
23](#__RefHeading___Toc186859516)

[**3.5.8** **Level of Concern for Margin of Exposure**
24](#__RefHeading___Toc186859517)

[**3.5.9** **Recommendation for Aggregate Exposure Risk Assessments**
24](#__RefHeading___Toc186859518)

[**3.5.10** **Classification of Carcinogenic Potential**
25](#__RefHeading___Toc186859519)

[**3.5.11** **Summary of Toxicological Doses and Endpoints for
Fenhexamid for Use in Human Risk Assessments**
25](#__RefHeading___Toc186859520)

[**3.6** **Endocrine Disruption** 26](#__RefHeading___Toc186859521)

[4.0 PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA
27](#__RefHeading___Toc186859522)

[**4.1** **Incident Reports** 27](#__RefHeading___Toc186859523)

[5.0 DIETARY EXPOSURE/RISK CHARACTERIZATION
27](#__RefHeading___Toc186859524)

[**5.1** **Pesticide Metabolism and Environmental Degradation**
27](#__RefHeading___Toc186859525)

[**5.1.1** **Metabolism in Primary Crops**
27](#__RefHeading___Toc186859526)

[**5.1.2** **Metabolism in Rotational Crops**
27](#__RefHeading___Toc186859527)

[**5.1.3** **Metabolism in Livestock** 27](#__RefHeading___Toc186859528)

[**5.1.4** **Analytical Methodology** 27](#__RefHeading___Toc186859529)

[**5.1.5** **Environmental Degradation**
28](#__RefHeading___Toc186859530)

[**5.1.6** **Comparative Metabolic Profile**
28](#__RefHeading___Toc186859531)

[**5.1.7** **Toxicity Profile of Major Metabolites and Degradates**
29](#__RefHeading___Toc186859532)

[**5.1.8** **Pesticide Metabolites and Degradates of Concern**
29](#__RefHeading___Toc186859533)

[**5.1.9** **Drinking Water Residue Profile**
29](#__RefHeading___Toc186859534)

[**5.1.10** **Food Residue Profile** 30](#__RefHeading___Toc186859535)

[**5.1.11** **International Residue Limits**
30](#__RefHeading___Toc186859536)

[**5.2.1** **Acute Dietary Exposure/Risk**
31](#__RefHeading___Toc186859537)

[**5.2.2** **Chronic Dietary Exposure/Risk**
31](#__RefHeading___Toc186859538)

[**5.2.3** **Cancer Dietary Risk** 32](#__RefHeading___Toc186859539)

[**5.3** **Anticipated Residue and Percent Crop Treated (%CT)
Information** 32](#__RefHeading___Toc186859540)

[6.0 RESIDENTIAL (NON-OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION
32](#__RefHeading___Toc186859541)

[**6.1** **Other (Spray Drift, etc.)** 32](#__RefHeading___Toc186859542)

[7.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION
33](#__RefHeading___Toc186859543)

[8.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT
33](#__RefHeading___Toc186859544)

[9.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY
33](#__RefHeading___Toc186859545)

[**9.1** **Occupational Pesticide Handler Exposure and Risk**
34](#__RefHeading___Toc186859546)

[**9.2** **Occupational Post-Application Worker Exposure and Risk**
36](#__RefHeading___Toc186859547)

[10.0 DATA NEEDS AND LABEL RECOMMENDATIONS
37](#__RefHeading___Toc186859548)

[REFERENCES 38](#__RefHeading___Toc186859549)

[Appendix A: INTERNATIONAL RESIDUE LIMIT STATUS
39](#__RefHeading___Toc186859550)

[Appendix B: TOXICOLOGY ASSESSMENT 41](#__RefHeading___Toc186859551)

[Appendix C: REFERENCES (in MRID order)
53](#__RefHeading___Toc186859552)

[Appendix D: REVIEW OF HUMAN RESEARCH 55](#__RefHeading___Toc186859553)

[]{#__RefHeading___Toc186859490 .anchor}**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]{.underline}

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]{.underline}

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.

Number range CHAPTER 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]{.underline}

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]{.underline}

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,\"
<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      Recommended    Comments; *Correct
                      Tolerance     Tolerance      Commodity Definition*
                      (ppm)         (ppm)          

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

[]{#__RefHeading___Toc186859491 .anchor}**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.

[]{#__RefHeading___Toc186859492 .anchor}**2.1 Proposed Use**

+-----------+------+---+----+---+-----+--------+-------+-------------------+
| **Table   |      |   |    |   |     |        |       |                   |
| 2.1.      |      |   |    |   |     |        |       |                   |
| Summary   |      |   |    |   |     |        |       |                   |
| of        |      |   |    |   |     |        |       |                   |
| D         |      |   |    |   |     |        |       |                   |
| irections |      |   |    |   |     |        |       |                   |
| for Use   |      |   |    |   |     |        |       |                   |
| of        |      |   |    |   |     |        |       |                   |
| Fenh      |      |   |    |   |     |        |       |                   |
| examid.** |      |   |    |   |     |        |       |                   |
+===========+======+===+====+===+=====+========+=======+===================+
| Applic.   | For  |   | A  |   | M   | Max.   | PHI   | Use Directions    |
| Timing,   | mula |   | pp |   | ax. | Se     |       | and Limitations   |
| Type, and | tion |   | li |   | No. | asonal | (     | ^1^               |
| Equip.    |      |   | c. |   | A   | A      | days) |                   |
|           | \    |   | Ra |   | ppl | pplic. |       |                   |
|           | [EPA |   | te |   | ic. | Rate   |       |                   |
|           | Reg. |   |    |   | per |        |       |                   |
|           | N    |   | (  |   | Sea | (lb    |       |                   |
|           | o.\] |   | lb |   | son | ai/A)  |       |                   |
|           |      |   | a  |   |     |        |       |                   |
|           |      |   | i/ |   |     |        |       |                   |
|           |      |   | A) |   |     |        |       |                   |
+-----------+------+---+----+---+-----+--------+-------+-------------------+
| **As      |      |   |    |   |     |        |       |                   |
| paragus** |      |   |    |   |     |        |       |                   |
+-----------+------+---+----+---+-----+--------+-------+-------------------+
| Broadcast | 50%  | 0 |    | 4 |     | 3.0    | 180   | Apply only at the |
| foliar    | WDG  | . |    |   |     |        | (     | fern stage.       |
| app       |      | 7 |    |   |     |        | excep | Treated ferns     |
| lications | \[66 | 5 |    |   |     |        | t CA) | must be mowed     |
| to        | 330- |   |    |   |     |        |       | down or allowed   |
| asparagus | 35\] |   |    |   |     |        | 90    | to senesce prior  |
| in fern   |      |   |    |   |     |        | (CA)  | to harvest of     |
| stage     |      |   |    |   |     |        |       | asparagus spears. |
| only.     |      |   |    |   |     |        |       |                   |
| Ground    |      |   |    |   |     |        |       | Apply in a        |
| equipment |      |   |    |   |     |        |       | minimum of 40     |
| only      |      |   |    |   |     |        |       | 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.

[]{#__RefHeading___Toc186859493 .anchor}**2.2 Identification of Active
Ingredient**

  ------------------- -----------------------------------------------------------------
  Table 2.2.          
  Fenhexamid          
  Nomenclature.       

  Compound            ![](media/image2.wmf){width="2.15625in" height="1.15625in"}

  Common name         Fenhexamid

  Company             KBR 2738
  experimental name   

  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)
  ------------------- -----------------------------------------------------------------

[]{#__RefHeading___Toc186859494 .anchor}**2.3 Physical and Chemical
Properties**

+--------------------------+--------------------------+-----------------+
| **Table 2.3.             |                          |                 |
| Physicochemical          |                          |                 |
| Properties of the        |                          |                 |
| Technical Grade          |                          |                 |
| Fenhexamid.**            |                          |                 |
+--------------------------+--------------------------+-----------------+
| Parameter                | Value                    | Reference       |
+--------------------------+--------------------------+-----------------+
| Melting point/range      | 153^o^C                  | Fenhexamid:     |
|                          |                          | Pesticide Fact  |
|                          |                          | Sheet (May 20,  |
|                          |                          | 1999)           |
|                          |                          |                 |
|                          |                          | Fenhexamid (KBR |
|                          |                          | 2738)-a         |
|                          |                          | Botryticide     |
|                          |                          | from a New      |
|                          |                          | Chemical Class, |
|                          |                          | Pflanzensch     |
|                          |                          | utz-Nachrichten |
|                          |                          | Bayer 52/1999,  |
|                          |                          | 2               |
+--------------------------+--------------------------+-----------------+
| pH                       | 8.3 in 1% solution of    |                 |
|                          | water                    |                 |
+--------------------------+--------------------------+-----------------+
| Density (20ºC)           | 1.34 g/ml                |                 |
+--------------------------+--------------------------+-----------------+
| Water solubility (mg/L   | 20                       |                 |
| at 20°C)                 |                          |                 |
+--------------------------+--------------------------+-----------------+
| Solvent solubility (g/L  | dichloromethane -- 31    |                 |
| at 20°C)                 |                          |                 |
|                          | 2-propanol - 91          |                 |
|                          |                          |                 |
|                          | n-hexane - \<0.1         |                 |
|                          |                          |                 |
|                          | Toluene -- 5.7           |                 |
+--------------------------+--------------------------+-----------------+
| Vapor pressure at 25°C   | 7x10^-9^ Torr            |                 |
+--------------------------+--------------------------+-----------------+
| Dissociation constant    | 7.3                      |                 |
| (pK~a~)                  |                          |                 |
+--------------------------+--------------------------+-----------------+
| Octanol/water partition  | 3.51 (pH 7, 20^o^C )     |                 |
| coefficient Log(K~OW~)   |                          |                 |
+--------------------------+--------------------------+-----------------+
| UV/visible absorption    | 245 and 290 nm           |                 |
| spectrum                 |                          |                 |
+--------------------------+--------------------------+-----------------+

[]{#__RefHeading___Toc186859495 .anchor}**3.0 HAZARD CHARACTERIZATION**

[]{#__RefHeading___Toc186859496 .anchor}**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 ([\>]{.underline}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 5^th^ sternal
segments and the 15^th^ 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 F~1~ pups on postnatal days 14 and 21 and in F~2~ 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 F~1~ pups selected to be F~1~ 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.

[]{#__RefHeading___Toc186859497 .anchor}**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.

**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.

**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.

[]{#__RefHeading___Toc186859498 .anchor}**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.

[]{#__RefHeading___Toc186859499 .anchor}**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.

[]{#__RefHeading___Toc186859500 .anchor}**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).

[]{#__RefHeading___Toc186859501 .anchor}**3.3 FQPA Considerations**

[]{#__RefHeading___Toc186859502 .anchor}**3.3.1 Adequacy of the Toxicity
Database**

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

[]{#__RefHeading___Toc186859503 .anchor}**3.3.2 Evidence of
Neurotoxicity**

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

[]{#__RefHeading___Toc186859504 .anchor}**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.

[]{#__RefHeading___Toc186859505 .anchor}**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 F~1~ pups selected to
be F~1~ 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 F~1~ pups selected post-weaning to be F~1~
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.

[]{#__RefHeading___Toc186859506 .anchor}**3.3.5 Additional Information
from Literature Sources**

None.

[]{#__RefHeading___Toc186859507 .anchor}**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.

**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 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 F~2~
generation and lactation days 14 and 21 in the F~1~ 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.

[]{#__RefHeading___Toc186859508 .anchor}**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.

[]{#__RefHeading___Toc186859509 .anchor}**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.

[]{#__RefHeading___Toc186859510 .anchor}**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).

[]{#__RefHeading___Toc186859511 .anchor}**3.5.1 Acute Reference Dose
(aRfD) - General Population**

[Study Selected:]{.underline} None

[MRID No.:]{.underline} None

[Dose and Endpoint for Establishing RfD:]{.underline} Not applicable

[Uncertainty Factor(s) (UFs):]{.underline} Not applicable

[Comments about Study/Endpoint/Uncertainty Factor:]{.underline} 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.

[]{#__RefHeading___Toc186859512 .anchor}**3.5.2 Chronic Reference Dose
(cRfD)**

[Study Selected:]{.underline} 1-Year Chronic Toxicity Study, Dogs

[MRID No.:]{.underline} 44346804

[Dose and Endpoint for establishing the RfD:]{.underline} 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:]{.underline} 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):]{.underline} 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.

[]{#__RefHeading___Toc186859513 .anchor}**3.5.4 Incidental Oral Exposure
(Short- and Intermediate-Term)**

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

[]{#__RefHeading___Toc186859514 .anchor}**3.5.5 Dermal Absorption**

[Dermal Absorption Factor]{.underline}: 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]{.underline}: Dermal Absorption Study, Rats

[MRID No.]{.underline}: 44346815

[Comments about Dermal Absorption]{.underline}: 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.

[]{#__RefHeading___Toc186859515 .anchor}**3.5.6 Dermal Exposure (Short-,
Intermediate- and Long-Term)**

*Short- and Intermediate-Term*

[Study Selected:]{.underline} 21-Day Dermal Toxicity Study, Rabbits

[MRID No.:]{.underline} 44346780

[Dose and Endpoint for Risk Assessment:]{.underline} NOAEL = 1000
mg/kg/day (HDT).

[Comments about Study/Endpoint:]{.underline} 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.

[]{#__RefHeading___Toc186859516 .anchor}**3.5.7 Inhalation Exposure
(Short-, Intermediate- and Long-Term)**

*Short- and Intermediate-Term*

[Study Selected:]{.underline} None

[MRID No.:]{.underline} None

[Dose and Endpoint for Risk Assessment:]{.underline} Not applicable

[Comments about Study and Endpoint:]{.underline} 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.

[]{#__RefHeading___Toc186859517 .anchor}**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         |                |                 |                   |
| A            |                |                 |                   |
| ssessment.** |                |                 |                   |
+--------------+----------------+-----------------+-------------------+
| **Route**    | **Short-Term** | **Inte          | **Long-Term**     |
|              |                | rmediate-Term** |                   |
|              | **(1-30        |                 | **(\> 6 Months)** |
|              | Days)**        | **(1 - 6        |                   |
|              |                | Months)**       |                   |
+--------------+----------------+-----------------+-------------------+
| **           |                |                 |                   |
| Occupational |                |                 |                   |
| (Worker)     |                |                 |                   |
| Exposure**   |                |                 |                   |
+--------------+----------------+-----------------+-------------------+
| **Dermal**   | 100            | 100             | NA                |
+--------------+----------------+-----------------+-------------------+
| **           | NA             | NA              | NA                |
| Inhalation** |                |                 |                   |
+--------------+----------------+-----------------+-------------------+
| *            |                |                 |                   |
| *Residential |                |                 |                   |
| (            |                |                 |                   |
| Non-Dietary) |                |                 |                   |
| Exposure**   |                |                 |                   |
+--------------+----------------+-----------------+-------------------+
| **Oral**     | NA             | NA              | NA                |
+--------------+----------------+-----------------+-------------------+
| **Dermal**   | NA             | NA              | NA                |
+--------------+----------------+-----------------+-------------------+
| **           | NA             | NA              | NA                |
| Inhalation** |                |                 |                   |
+--------------+----------------+-----------------+-------------------+

[]{#__RefHeading___Toc186859518 .anchor}**3.5.9 Recommendation for
Aggregate Exposure Risk Assessments**

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

[]{#__RefHeading___Toc186859519 .anchor}**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.

[]{#__RefHeading___Toc186859520 .anchor}**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**  | **Dose Used  | **FQPA SF and  | **Study and         |
|               | in Risk      | Level of       | Toxicological       |
| **Scenario**  | Assessment,  | Concern for    | Effects**           |
|               | UF**         | Risk           |                     |
|               |              | Assessment**   |                     |
+---------------+--------------+----------------+---------------------+
| **Acute       | None         | FQPA SF =      | Not selected. No    |
| Dietary**     |              | **1X**         | appropriate         |
|               | UF = **NA**  |                | toxicological       |
| (General      |              | **aPAD** =     | endpoint            |
| Population    | **Acute      |                | attributable to a   |
| including     | RfD** =      | [acute         | single exposure was |
| infants and   | **None**     | Rf             | identified in the   |
| children)     |              | D]{.underline} | available           |
|               |              |                | toxicology studies. |
|               |              | FQPA SF        |                     |
|               |              |                |                     |
|               |              | = **None**     |                     |
+---------------+--------------+----------------+---------------------+
| **Chronic     | NOAEL = 17   | 1X             | 1-Year Feeding-Dog. |
| Dietary**     | mg ai/kg/day |                |                     |
|               |              | **cPAD** =     | Decreased RBC       |
| (All          | UF = **100** |                | count, hemoglobin   |
| populations)  |              | [chronic       | and hematocrit and  |
|               | **Chronic    | Rf             | increased Heinz     |
|               | RfD** =      | D]{.underline} | bodies in males and |
|               | **0.17**     |                | females; increased  |
|               | mg/kg/day    | FQPA SF        | adrenal weights and |
|               |              |                | intracytoplasmic    |
|               |              | =**0.17**      | vacuoles in adrenal |
|               |              | mg/kg/day      | cortex in females.  |
|               |              |                | at the LOAEL of 124 |
|               |              |                | mg/kg/day.          |
+---------------+--------------+----------------+---------------------+
| *             | NOAEL =      | *              | 21-Day              |
| *Short-Term** | **1000 mg    | *Residential** | **Dermal**-Rabbit.  |
|               | ai/kg/day**  | MOE = **NA**   |                     |
| (1 - 30 days) |              |                | In the              |
| and           |              | **             | developmental       |
|               |              | Occupational** | toxicity study in   |
| **Interm      |              | MOE = **100**  | rabbits, decreased  |
| ediate-Term** |              |                | body weight gain    |
| (1 - 6        |              |                | and food            |
| months)       |              |                | consumption at      |
|               |              |                | LOAEL of 1500       |
| **Dermal**    |              |                | mg/kg/day (dermal   |
|               |              |                | equivalent dose     |
|               |              |                | using 20% dermal    |
|               |              |                | absorption factor); |
|               |              |                | NOAEL was 500       |
|               |              |                | mg/kg/day (dermal   |
|               |              |                | equivalent dose)    |
+---------------+--------------+----------------+---------------------+
| **Long-Term   | None         | *              | Not selected. It    |
| Dermal**      |              | *Residential** | was determined that |
|               |              | MOE = **NA**   | no long term        |
| (\>6 months)  |              |                | exposure would      |
|               |              | **             | occur (see TXR NO.  |
|               |              | Occupational** | 013258).            |
|               |              | MOE = **NA**   |                     |
+---------------+--------------+----------------+---------------------+
| *             | None         | *              | Not selected. It    |
| *Short-Term** |              | *Residential** | was determined that |
|               |              | MOE = **NA**   | a separate          |
| (1 - 30 days) |              |                | inhalation risk     |
| and           |              | **             | assessment is not   |
|               |              | Occupational** | required for short- |
| **Interm      |              | MOE = **NA**   | and                 |
| ediate-Term** |              |                | intermediate-term   |
| (1 - 6        |              |                | inhalation risk     |
| months)       |              |                | assessments (see    |
| *             |              |                | TXR NO. 013258).    |
| *Inhalation** |              |                |                     |
+---------------+--------------+----------------+---------------------+
| **Long-Term   | None         | *              | Not selected. It    |
| Inhalation**  |              | *Residential** | was determined that |
|               |              | MOE = **NA**   | no long term        |
| (\>6 months)  |              |                | exposure would      |
|               |              | **             | occur (see TXR NO.  |
|               |              | Occupational** | 013258).            |
|               |              | MOE = **NA**   |                     |
+---------------+--------------+----------------+---------------------+
| Cancer (oral, | Cla          |                |                     |
| dermal,       | ssification: |                |                     |
| inhalation)   | "Not likely  |                |                     |
|               | to be        |                |                     |
|               | Carcinogenic |                |                     |
|               | to Humans"   |                |                     |
|               | based on the |                |                     |
|               | absence of   |                |                     |
|               | significant  |                |                     |
|               | tumor        |                |                     |
|               | increases in |                |                     |
|               | two adequate |                |                     |
|               | rodent       |                |                     |
|               | car          |                |                     |
|               | cinogenicity |                |                     |
|               | 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

[]{#__RefHeading___Toc186859521 .anchor}**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.

[]{#__RefHeading___Toc186859522 .anchor}**4.0 PUBLIC HEALTH AND
PESTICIDE EPIDEMIOLOGY DATA**

[]{#__RefHeading___Toc186859523 .anchor}**4.1 Incident Reports**

There are no known incidents reported for fenhexamid.

[]{#__RefHeading___Toc186859524 .anchor}**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).

[]{#__RefHeading___Toc186859525 .anchor}**5.1 Pesticide Metabolism and
Environmental Degradation**

[]{#__RefHeading___Toc186859526 .anchor}**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 ^14^C-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.

[]{#__RefHeading___Toc186859527 .anchor}**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.

[]{#__RefHeading___Toc186859528 .anchor}**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.

[]{#__RefHeading___Toc186859529 .anchor}**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.

[]{#__RefHeading___Toc186859530 .anchor}**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.

[]{#__RefHeading___Toc186859531 .anchor}**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).

[]{#__RefHeading___Toc186859532 .anchor}**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.

[]{#__RefHeading___Toc186859533 .anchor}**5.1.8 Pesticide Metabolites
and Degradates of Concern**

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

[]{#__RefHeading___Toc186859534 .anchor}**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 | **Use/Rate       | **Maximum EDWC   |            |
| Source (Model    | Modeled (lb      | (ppb)**          |            |
| Used)**          | ai/A)**          |                  |            |
+------------------+------------------+------------------+------------+
| Groundwater      | Ground           | Acute and        | 0.0007     |
|                  | spray/0.75 x 2   | Chronic          |            |
| (SCI-GROW2)      | applications;    |                  |            |
|                  | total of 3.0     |                  |            |
+------------------+------------------+------------------+------------+
| Surface Water    | Ground           | Acute            | 29         |
| (FIRST)          | spray/0.75 x 2   |                  |            |
|                  | applications;    |                  |            |
|                  | total of 3.0     |                  |            |
+------------------+------------------+------------------+------------+
|                  | Ground           | Chronic          | 1.1        |
|                  | spray/0.75 x 2   |                  |            |
|                  | applications;    |                  |            |
|                  | total of 3.0     |                  |            |
+------------------+------------------+------------------+------------+

[]{#__RefHeading___Toc186859535 .anchor}**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.

[]{#__RefHeading___Toc186859536 .anchor}**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.

**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).

[]{#__RefHeading___Toc186859537 .anchor}**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.

[]{#__RefHeading___Toc186859538 .anchor}**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          \% cPAD
                         (mg/kg/day)               

  General U.S.           0.017657                  10
  Population                                       

  All Infants (\< 1 year 0.030064                  18
  old)                                             

  **Children 1-2 years   **0.045219**              **27**
  old**                                            

  Children 3-5 years old 0.034218                  20

  Children 6-12 years    0.021757                  13
  old                                              

  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    0.015358                  9.0
  old                                              
  ------------------------------------------------------------------------

[]{#__RefHeading___Toc186859539 .anchor}**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.

[]{#__RefHeading___Toc186859540 .anchor}**5.3 Anticipated Residue and
Percent Crop Treated (%CT) Information**

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

[]{#__RefHeading___Toc186859541 .anchor}**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.

[]{#__RefHeading___Toc186859542 .anchor}**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.

[]{#__RefHeading___Toc186859543 .anchor}**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.

[]{#__RefHeading___Toc186859544 .anchor}**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
[[http://www.epa.gov/pesticides/cumulative/.]{.underline}](http://www.epa.gov/pesticides/cumulative/.)

[]{#__RefHeading___Toc186859545 .anchor}**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.           | 4/season                                        |
| Applications       |                                                 |
+--------------------+-------------------------------------------------+
| Applic. Interval   | 7 - 14 days                                     |
+--------------------+-------------------------------------------------+
| Preharvest         | 180 days except California; 90 days in          |
| Interval           | California                                      |
+--------------------+-------------------------------------------------+
| Restricted Entry   | 12 hours                                        |
| Interval           |                                                 |
+--------------------+-------------------------------------------------+
| Manufacturer       | Arysta LifeScience                              |
+--------------------+-------------------------------------------------+

[]{#__RefHeading___Toc186859546 .anchor}**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        | **Applic. | **Units  | **Avg. Daily     | *         |
| Exposure^1^** | Rate^2^** | Trea     | Exposure^4^**    | *MOE^5^** |
|               |           | ted^3^** |                  |           |
| mg ai/lb      | lb        |          | mg ai/kg bw/day  |           |
| handled       | ai/unit   |          |                  |           |
+---------------+-----------+----------+------------------+-----------+
| **Mixer       |           |          |                  |           |
| Loader Open   |           |          |                  |           |
| Pour Loading  |           |          |                  |           |
| Dry           |           |          |                  |           |
| Flowable**    |           |          |                  |           |
+---------------+-----------+----------+------------------+-----------+
| Dermal:       | 0.75 lb   | 200      | Dermal:          | 7,143     |
|               | ai/A      | A/day    |                  |           |
| SLNoGlove     |           |          | SLNoGlove 0.14   |           |
| 0.066 LC      |           |          |                  |           |
|               |           |          | SLWithGlove 0.14 |           |
| SLWithGlove   |           |          |                  |           |
| 0.066 HC      |           |          |                  |           |
+---------------+-----------+----------+------------------+-----------+
| **Applicator  |           |          |                  |           |
| Using         |           |          |                  |           |
| Open-cab      |           |          |                  |           |
| Ground-boom   |           |          |                  |           |
| Sprayer**     |           |          |                  |           |
+---------------+-----------+----------+------------------+-----------+
| Dermal:       | 0.75 lb   | 200      | Dermal:          | 33,333    |
|               | ai/A      | A/day    |                  |           |
| SLNoGlove     |           |          | SLNoGlove 0.03   |           |
| 0.014 HC      |           |          |                  |           |
|               |           |          | SLWithGlove 0.03 |           |
| SLWithGlove   |           |          |                  |           |
| 0.014 MC      |           |          |                  |           |
+---------------+-----------+----------+------------------+-----------+

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.

[]{#__RefHeading___Toc186859547 .anchor}**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.

[]{#__RefHeading___Toc186859548 .anchor}**10.0 DATA NEEDS AND LABEL
RECOMMENDATIONS**

None.

[]{#__RefHeading___Toc186859549 .anchor}**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 - 2^nd^ Report of the Hazard Identification Assessment Review
Committee. B. Tarplee, TXR NO. 0051704, 3/26/2003.

[]{#__RefHeading___Toc186859550 .anchor}**Appendix A: INTERNATIONAL
RESIDUE LIMIT STATUS**

+------------------+------------------+-----------------+-------------+
| INTERNATIONAL    |                  |                 |             |
| RESIDUE LIMIT    |                  |                 |             |
| STATUS           |                  |                 |             |
+==================+==================+=================+=============+
| Chemical Name:   | Common Name:     | X Proposed      | Date:       |
| N-(2,3-dichloro  | Fenhexamid       | tolerance       | 11/07/2007  |
| -4-hydroxyphenyl |                  |                 |             |
| )-1-methylcycloh |                  | Reevaluated     |             |
| exanecarboxamide |                  | tolerance       |             |
|                  |                  |                 |             |
|                  |                  | Other           |             |
+------------------+------------------+-----------------+-------------+
| **Codex Status   |                  | **U. S.         |             |
| (Maximum Residue |                  | Tolerances**    |             |
| Limits)**        |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| No Codex         |                  | **Petition      |             |
| proposal step 6  |                  | Numbers**:      |             |
| or above         |                  | 7E7187          |             |
|                  |                  |                 |             |
| X No Codex       |                  | **DP Number:**  |             |
| proposal step 6  |                  | 346385          |             |
| or above for the |                  |                 |             |
| crops requested  |                  | **Other         |             |
|                  |                  | Identifier:**   |             |
+------------------+------------------+-----------------+-------------+
| **Residue        |                  | **Rev           |             |
| definition (step |                  | iewer/Branch:** |             |
| 8/CXL):**        |                  | Debra           |             |
| Fenhexamid       |                  | 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, | 5                |                 |             |
| Red, White       |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Dewberries       | 15               |                 |             |
| (including       |                  |                 |             |
| boysenberry and  |                  |                 |             |
| loganberries)    |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Dried grapes     | 25               |                 |             |
| (currants,       |                  |                 |             |
| raisins, and     |                  |                 |             |
| sultanas)        |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Edible offal     | 0.05 (\*)        |                 |             |
| (mammalian)      |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Egg plant        | 2                |                 |             |
+------------------+------------------+-----------------+-------------+
| Gherkin          | 1                |                 |             |
+------------------+------------------+-----------------+-------------+
| Gooseberry       | 5                |                 |             |
+------------------+------------------+-----------------+-------------+
| Grapes           | 15               |                 |             |
+------------------+------------------+-----------------+-------------+
| Kiwifruit        | 15               |                 |             |
+------------------+------------------+-----------------+-------------+
| Lettuce, Head    | 30               |                 |             |
+------------------+------------------+-----------------+-------------+
| Lettuce, Leaf    | 30               |                 |             |
+------------------+------------------+-----------------+-------------+
| Meat (from       | 0.05 (\*)        |                 |             |
| mammals other    |                  |                 |             |
| than marine      |                  |                 |             |
| mammals)         |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Milks            | 0.01 (\*)        |                 |             |
+------------------+------------------+-----------------+-------------+
| Nectarine        | 10               |                 |             |
+------------------+------------------+-----------------+-------------+
| Peach            | 10               |                 |             |
+------------------+------------------+-----------------+-------------+
| Peppers          | 2                |                 |             |
+------------------+------------------+-----------------+-------------+
| Plums, including | 1                |                 |             |
| prunes           |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Raspberries,     | 15               |                 |             |
| Red, Black       |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Squash, Summer   | 1                |                 |             |
+------------------+------------------+-----------------+-------------+
| Strawberry       | 10               |                 |             |
+------------------+------------------+-----------------+-------------+
| Tomato           | 2                |                 |             |
+------------------+------------------+-----------------+-------------+
| Bilberry         | 5                |                 |             |
+------------------+------------------+-----------------+-------------+
| Elderberries     | 5                |                 |             |
+------------------+------------------+-----------------+-------------+
| Juneberries      | 5                |                 |             |
+------------------+------------------+-----------------+-------------+
| **Limits for     |                  | **Limits for    |             |
| Canada**         |                  | Mexico**        |             |
+------------------+------------------+-----------------+-------------+
|  No Limits      |                  |  No Limits     |             |
|                  |                  |                 |             |
| X No Limits for  |                  | X No Limits for |             |
| the crops        |                  | the crops       |             |
| requested        |                  | requested       |             |
+------------------+------------------+-----------------+-------------+
| Residue          |                  | Residue         |             |
| definition:      |                  | definition:     |             |
| N-(2             |                  | Fenhexamid      |             |
| ,3-dichloro-4-hy |                  |                 |             |
| droxyphenyl)-1-m |                  |                 |             |
| ethylcyclohexane |                  |                 |             |
| carboxamide      |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Crop(s)          | MRL (mg/kg)      | Crop(s)         | MRL (mg/kg) |
+------------------+------------------+-----------------+-------------+
| Lettuce          | 23               | Durazno (peach) | 6           |
+------------------+------------------+-----------------+-------------+
| Blackberries,    | 20               | Fresa           | 3           |
| loganberries,    |                  | (strawberry)    |             |
| raspberries      |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Apricots,        | 6                | Vid (grapes)    | 4           |
| cherries,        |                  |                 |             |
| peaches,         |                  |                 |             |
| nectarines       |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Grapes           | 4                |                 |             |
+------------------+------------------+-----------------+-------------+
| Raisins          | 6                |                 |             |
+------------------+------------------+-----------------+-------------+
| Blueberries,     | 4                |                 |             |
| currants,        |                  |                 |             |
| elderberries,    |                  |                 |             |
| gooseberries,    |                  |                 |             |
| huckleberries    |                  |                 |             |
+------------------+------------------+-----------------+-------------+
| Strawberries     | 3                |                 |             |
+------------------+------------------+-----------------+-------------+
| Plums            | 0.5              |                 |             |
+------------------+------------------+-----------------+-------------+
| Almonds          | 0.02             |                 |             |
+------------------+------------------+-----------------+-------------+
| Tomato           | 1                |                 |             |
+------------------+------------------+-----------------+-------------+
| Notes/Special    |                  |                 |             |
| Instructions:    |                  |                 |             |
| S.Funk,          |                  |                 |             |
| 11/07/2007       |                  |                 |             |
+------------------+------------------+-----------------+-------------+

[]{#__RefHeading___Toc186859551 .anchor}**Appendix B: TOXICOLOGY
ASSESSMENT**

**B.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            | yes         | yes         |
|                                         |             |             |
| 870.1200 Acute Dermal Toxicity          | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation Toxicity      | yes         | yes         |
|                                         |             |             |
| 870.2400 Primary Eye Irritation         | yes         | yes         |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      | yes         | yes         |
|                                         |             |             |
| 870.2600 Dermal Sensitization           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (rodent)       | yes         | yes         |
|                                         |             |             |
| 870.3150 Oral Subchronic (nonrodent)    | no          | \-          |
|                                         |             |             |
| 870.3200 21-Day Dermal                  | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | no          | no          |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | no          | no          |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity        | yes         | yes         |
| (rodent)                                |             |             |
|                                         | yes         | yes         |
| 870.3700b Developmental Toxicity        |             |             |
| (nonrodent)                             | yes         | yes         |
|                                         |             |             |
| 870.3800 Reproduction                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (rodent)     | yes         | yes         |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | yes         | yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | yes         | yes         |
|                                         |             |             |
| 870.4200b Oncogenicity (mouse)          | yes         | yes         |
|                                         |             |             |
| 870.4300 Chronic/Oncogenicity           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity---Gene Mutation - | yes         | yes         |
| bacterial                               |             |             |
|                                         | yes         | yes         |
| 870.5300 Mutagenicity---Gene Mutation - |             |             |
| mammalian                               | yes         | yes         |
|                                         |             |             |
| 870.5xxx Mutagenicity---Structural      | yes         | yes         |
| Chromosomal Aberrations                 |             |             |
|                                         |             |             |
| 870.5xxx Mutagenicity---Other Genotoxic |             |             |
| Effects                                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | no          | \-          |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | \-          |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | yes         | yes         |
| Battery (rat)                           |             |             |
|                                         | no          | \-          |
| 870.6200b 90-Day Neuro. Screening       |             |             |
| Battery (rat)                           | no          | \-          |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| Special Studies for Ocular Effects      | no          | \-          |
|                                         |             |             |
| Acute Oral (rat)                        | no          | \-          |
|                                         |             |             |
| Subchronic Oral (rat)                   | no          | \-          |
|                                         |             |             |
| Six-month Oral (dog)                    |             |             |
+-----------------------------------------+-------------+-------------+

**B.2 Toxicity Profiles**

+---------+--------------+-----------+-------------------+------------+
| **Table |              |           |                   |            |
| A.1.a   |              |           |                   |            |
| Acute   |              |           |                   |            |
| T       |              |           |                   |            |
| oxicity |              |           |                   |            |
| Profile |              |           |                   |            |
| of      |              |           |                   |            |
| Fenhe   |              |           |                   |            |
| xamid** |              |           |                   |            |
+---------+--------------+-----------+-------------------+------------+
| **Gu    | **Study      | **        | **Results**       | **Toxicity |
| ideline | Type**       | MRID(s)** |                   | Category** |
| No.**   |              |           |                   |            |
+---------+--------------+-----------+-------------------+------------+
| 8       | Acute Oral   | 44346769  | M: LD~50~ \>5000  | IV         |
| 70.1100 |              |           | mg/kg             |            |
|         | Rats         |           |                   |            |
|         |              |           | F: LD~50~ \>5000  |            |
|         |              |           | mg/kg             |            |
+---------+--------------+-----------+-------------------+------------+
| 8       | Acute Dermal | 44346770  | M: LD~50~ \>5000  | IV         |
| 70.1200 |              |           | mg/kg             |            |
|         | Rats         |           |                   |            |
|         |              |           | F: LD~50~ \>5000  |            |
|         |              |           | mg/kg             |            |
+---------+--------------+-----------+-------------------+------------+
| 8       | Acute        | 44366513  | [                 | [DUST]{.   |
| 70.1300 | Inhalation   |           | DUST]{.underline} | underline} |
|         |              |           |                   |            |
|         | Rats         |           | M: LC~50~ \>5.057 | IV         |
|         |              |           | mg/L              |            |
|         |              |           |                   |            |
|         |              |           | F: LC~50~ \>5.057 |            |
|         |              |           | mg/L              |            |
+---------+--------------+-----------+-------------------+------------+
| 8       | Primary Eye  | 44346771  | Not an eye        | IV         |
| 70.2400 | Irritation   |           | irritant          |            |
|         |              |           |                   |            |
|         | Rabbits      |           |                   |            |
+---------+--------------+-----------+-------------------+------------+
| 8       | Primary Skin | 44346771  | Not a dermal      | IV         |
| 70.2500 | Irritation   |           | irritant          |            |
|         |              |           |                   |            |
|         | Rabbits      |           |                   |            |
+---------+--------------+-----------+-------------------+------------+
| 8       | Dermal       | 44346772  | Not a dermal      | N/A        |
| 70.2600 | S            |           | sensitizer        |            |
|         | ensitization |           |                   |            |
|         |              |           |                   |            |
|         | Guinea Pigs  |           |                   |            |
+---------+--------------+-----------+-------------------+------------+

**B.3 Executive Summaries**

**B.3.1 Subchronic Toxicity**

**870.3200 21/28-Day Dermal Toxicity -- Rat**

[Study Selected:]{.underline} 21-Day Dermal Toxicity Study, Rabbits

[MRID No.:]{.underline} 44346780

[Executive Summary:]{.underline} 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:]{.underline} NOAEL = 1000
mg/kg/day (HDT).

[Comments about Study/Endpoint:]{.underline} 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:]{.underline} None

[MRID No.:]{.underline} None

[Executive Summary]{.underline}: None

[Dose and Endpoint for Risk Assessment:]{.underline} Not applicable

[Comments about Study and Endpoint:]{.underline} 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:]{.underline} [Developmental Toxicity Study,
rat]{.underline}

[MRID No.]{.underline} 44346781

[Executive Summary]{.underline}: 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:]{.underline} [Developmental Toxicity Study,
rabbit]{.underline}

[MRID No.]{.underline} 44346801

[Executive Summary]{.underline}: 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]{.underline}: 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 5^th^ sternal segments and the 15^th^ caudal vertebrae).

**B.3.3 Reproductive Toxicity**

**870.3800 Reproduction and Fertility Effects -- Rat**

[Study Selected:]{.underline} [2-generation reproduction study,
rats]{.underline}

[MRID No.]{.underline} 44346803

[Executive Summary]{.underline}: 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 F~1~ pups (6-11% less than
controls) and on lactation days 7, 14 and 21 for F~2~ 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 F~1~ pups (15-30% less than controls) and for F~2~ 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 F~1~ pups selected to be F~1~ 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]{.underline}: 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 F~1~ pups (6-11% less than controls) and on lactation days
7, 14 and 21 for F~2~ 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 F~1~ pups selected to be F~1~
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:]{.underline} 1-Year Chronic Toxicity Study, Dogs

[MRID No.]{.underline} 44346804

[Executive Summary]{.underline}: 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:]{.underline} 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:]{.underline} 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):]{.underline} 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.]{.underline}: 44346805

[Executive Summary]{.underline}: 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]{.underline}: There was no evidence of
carcinogenicity**.**

[Adequacy of the Dose Levels Tested]{.underline}: 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]{.underline}: 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]{.underline}: None required

**870.6200 Acute/Subchronic Neurotoxicity Screening Battery**

[Study Selected]{.underline}: Acute Neurotoxicity Study, Rats

[MRID No.]{.underline}: 44346813

[Executive Summary]{.underline}: 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]{.underline}: Decreased body temperature may be a sign of
acute general systemic toxicity [or]{.underline} 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:]{.underline} 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]{.underline}: Dermal Absorption Study, Rats

[MRID No.]{.underline}: 44346815

[Executive Summary]{.underline}: In a dermal absorption study,
\[Phenyl-UL-^14^C\]-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/cm^2^. A volume of 100 *u*L
was applied to a skin area of approximately 12.5 cm^2^ 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]{.underline}: 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.

[]{#__RefHeading___Toc186859552 .anchor}**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}

[47056401](https://dcwebmail3.epa.gov/mail/brhanson.nsf/0/A8CBE290BD80638F852573A3004FF87A/$File/47056401.der.doc?OpenElement&FileName=47056401.der.doc)
Mahlburg, W. (2007) MCPA-6 Amine Product Identity and Composition.
Project Number: 2007/1A. Unpublished study prepared by Nufarm Americas
Inc. 26 p.

[]{#__RefHeading___Toc186859553 .anchor}**Appendix D: REVIEW OF HUMAN
RESEARCH**

No MRID - PHED Surrogate Exposure Guide