**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

![](media/image1.png){width="0.875in" height="0.8388888888888889in"}

**OFFICE OF PREVENTION, PESTICIDE**

**AND TOXIC SUBSTANCES**

**[MEMORANDUM]{.underline}**

**Date: 6/12/2008**

**SUBJECT: Ingredient:** Fenbuconazole

**Title:** Human Health Risk Assessment for the Proposed Use on Peppers

  ----------------------------------- -----------------------------------
  PC Code: 129011                     DP Barcode: D344351

  Decision No.: 383131                Registration No.: 62719-421

  Petition Nos.: 9E5041, 1E6252, and  Regulatory Action: Section 3
  7E7256                              

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

  TXR No.: None                       CAS No.: 114369-43-6

  MRID No.: None                      40 CFR: 180.480
  ----------------------------------- -----------------------------------

FROM: Douglas Dotson, Ph.D., Chemist

Kim Harper, Toxicologist

Shih-Chi Wang, Ph.D., Biologist

> Registration Action Branch 2
>
> Health Effects Division (7509P)

THROUGH: William Drew, Chemist

Margarita Collantes, Biologist

Richard Loranger, Ph.D., Senior Scientist

Christina Swartz, Branch Chief

> Registration Action Branch 2
>
> Health Effects Division (7509P)

TO: Sidney Jackson/Barbara Madden, RIMUERB

and

John Bazuin/Tony Kish, RM 22, Fungicide Branch

Registration Division (7505P)

**Table of Contents**

1.0 Executive Summary 4

2.0 Ingredient Profile 8

2.1 Summary of Registered/Proposed Uses
[8](#__RefHeading___Toc131319175)

2.2 Structure and Nomenclature 10

2.3 Physical and Chemical Properties 11

3.0 Hazard Characterization/Assessment 12

3.1 Hazard and Dose-Response Characterization 12

3.2 Database Summary 12

3.3 FQPA Considerations 21

3.3.1 Adequacy of the Toxicity Database 21

3.3.2 Evidence of Neurotoxicity 21

3.3.3 Developmental Toxicity Studies 21

3.3.4 Reproductive Toxicity Study 21

3.3.5 Additional Information from Literature Sources 22

3.3.6 Pre- and/or Postnatal Toxicity 22

3.3.6.1 Determination of Susceptibility 22

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre
and/or Post-natal Susceptibility 22

> 3.3.7 Recommendation for a Developmental Neurotoxicity Study 22

3.4 FQPA Safety Factor for Infants and Children 22

3.5 Hazard Identification and Toxicity Endpoint Selection 23

3.5.1 Acute Reference Dose (aRfD) - Females Age 13-49 23

3.5.2 Acute Reference Dose (aRfD) - General Population 23

3.5.3 Chronic Reference Dose (cRfD) 23

3.5.4 Incidental Oral Exposure (Short and Intermediate Term) 24

3.5.5 Dermal Absorption 24

3.5.6 Dermal Exposure (Short, Intermediate and Long Term) 24

3.5.7 Inhalation Exposure (Short, Intermediate and Long Term) 24

3.5.8 Level of Concern for Margins of Exposure 25

3.5.9 Recommendation for Aggregate Exposure Risk Assessments 25

3.5.10 Classification of Carcinogenic Potential 25

3.5.11 Summary of Toxological Doses and Endpoints 25

3.6 Endocrine disruption 27

4.0 Public Health and Pesticide Epidemiology Data 28

4.1 Incident Reports 28

5.0 Dietary Exposure/Risk Characterization 28

5.1 Pesticide Metabolism and Environmental Degradation 28

> 5.1.1 Metabolism in Primary Crops 28
>
> 5.1.2 Metabolism in Rotational Crops 28
>
> 5.1.3 Metabolism in Livestock 28
>
> 5.1.4 Analytical Methodology 28
>
> 5.1.5 Environmental Degradation 29
>
> 5.1.6 Comparative Metabolic Profile 29
>
> 5.1.7 Toxicity Profile of Major Metabolites and Degradates 30
>
> 5.1.8 Pesticide Metabolites and Degradates of Concern 31
>
> 5.1.9 Drinking Water Residue Profile 31
>
> 5.1.10 Food Residue Profile 32
>
> 5.1.11 International Residue Limits 33

5.2 Dietary Exposure and Risk 33

> 5.2.1 Acute Dietary Exposure/Risk 34
>
> 5.2.2 Chronic Dietary Exposure/Risk 34
>
> 5.2.3 Cancer Dietary Exposure/Risk 34

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information 35

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 35

6.1 Other (Spray Drift, etc.) 36

7.0 Aggregate Risk Assessments and Risk Characterization 36

7.1 Acute Aggregate Risk 36

7.2 Short- and Intermediate-Term Aggregate Risk 37

7.3 Long-Term Aggregate Risk 37

7.4 Cancer Risk 37

8.0 Cumulative Risk Characterization/Assessment 37

9.0 Occupational Exposure/Risk Assessment Pathway 38

9.1 Handler Exposure 38

> 9.1.1 Data and Assumptions for Handler Exposure Scenarios 38
>
> 9.1.2 Handler Non-cancer Exposure and Risk 39
>
> 9.1.3 Handler Cancer Exposure and Risk 40

9.2 Post-Application Exposure 42

> 9.2.1 Non-Cancer Post-Application Exposure Scenarios 42
>
> 9.2.2 Cancer Post-Application Exposure Scenarios 42

10.0 Data Needs and Label Requirements 43

10.1 Toxicology 43

10.2 Residue Chemistry 43

> 10.2.1 Deficiencies in Current Tolerance Petitions 43
>
> 10.2.2 Deficiencies Cited in Previous Tolerance Petitions 44

10.3 Occupational and Residential Exposure 46

References: 46

Appendix 47

1.  **EXECUTIVE SUMMARY**

A human health risk assessment has been conducted to support the
proposed new use of fenbuconazole on peppers. Fenbuconazole,
(alpha-(2-(4-chlorophenyl)-ethyl)-alpha-phenyl-3-(1H-1,2,4-triazole)-1-propanenitrile),
is a broad-spectrum, triazole fungicide that acts by inhibiting sterol
biosynthesis in fungi. It is formulated in wettable powder (WP, 75%
a.i.) and flowable concentrate (FlC, 2 lb a.i./gal) forms. Interregional
Research Project No. 4 (IR-4) submitted a petition proposing the use of
the WP formulation on peppers for control of Cercospora leafspot and
powdery mildew. The proposed use is for multiple broadcast foliar
applications to peppers at up to 0.188 lb ai/A/application with a
minimum retreatment interval (RTI) of 10 days, for a maximum of 0.75 lb
ai/A/season. Applications may be made using either ground or aerial
equipment, although use of aerial equipment is not recommended. Ground
applications should be made in a minimum volume of 30 gal/A, and can
include the use of a non-ionic surfactant. The minimum preharvest
interval (PHI) is 7 days for peppers. In conjunction with this use, IR-4
is proposing the establishment of a permanent tolerance of 0.4 ppm for
the combined residues of fenbuconazole and its lactone metabolites,
RH-9129 and RH-9130, expressed as fenbuconazole.

HED completed a human health risk assessment for fenbuconazole in 2006
(M. Collantes, et al., D316607, 8/3/2006). Although bushberries and
cranberries were included in the risk assessment and tolerances were
established, a formal review of the residue chemistry data had not been
completed. The residue chemistry aspects of these commodities are
discussed in this current risk assessment.

Toxicology

The Health Effects Division (HED) has evaluated the toxicity data
submitted by the petitioner and has found it to be of sufficient scope
and quality to assess the human health hazards associated with
fenbuconazole, including potential developmental, reproductive and
neurotoxic effects. Fenbuconazole targets the liver and, to a lesser
degree, the thyroid. Fenbuconazole is classified as a "Group C"
carcinogen based on increased incidence of liver and thyroid cancers in
mice and rats, respectively. Developmental and reproductive studies show
that there is no evidence of increased qualitative or quantitative
susceptibility of the offspring to fenbuconazole. There is no evidence
that fenbuconazole affects the endocrine system. There are no data gaps
associated with the toxicological database.

Metabolic Profile

Adequate studies are available depicting the metabolism of
\[14C\]fenbuconazole in rats, primary crops (peaches, peanuts, wheat,
sugar beets), rotational crops (collards, turnips, wheat), and livestock
(lactating goats, laying hens). Based on these studies, HED has
determined that the residues of concern for risk assessment are
fenbuconazole and the following metabolites: RH-9129, RH-9130,
RH-4911(peanut only), and RH-7905 (peanut only). The current analytical
enforcement method has been validated for the analysis of fenbuconazole,
RH-9129, and RH-9130, which are the residues of concern for tolerance
enforcement. Additionally, HED has identified the common triazole
metabolites, 1,2,4-triazole, triazole alanine, and triazole acetic acid,
as residues of concern for risk assessment. Risks associated with
exposure to these metabolites have been addressed in a separate human
health risk assessment (Memo, D322215, M. Doherty, et al., 2/7/2006) and
in an updated dietary exposure analysis (Memo, M. Doherty, D350314,
3/27/2008).

Residue Chemistry and Dietary Risk Estimates

HED evaluated the residue chemistry database for fenbuconazole. The
residue chemistry data are sufficient to evaluate the nature and
magnitude of residues in crops and livestock commodities. To evaluate
acute, chronic, and cancer dietary risks, HED used information in the
residue chemistry database along with modeled estimates of fenbuconazole
in drinking water to conduct dietary (food + water) exposure
assessments.

Acute, chronic, and cancer dietary risk assessments were conducted using
the Dietary Exposure Evaluation Model (DEEM-FCID, Version 2.03), which
uses food consumption data from the USDA's Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998. The acute
dietary exposure analysis is based on tolerance-level residues and
assumes 100% crop treated. The assessment included a conservative
estimated drinking water concentration (EDWC) based on the pepper use.
As such, it is highly conservative with respect to evaluating potential
impacts of acute dietary exposure to fenbuconazole on human health. The
only population subgroup that is relevant for this acute assessment is
females of child-bearing age (i.e., females 13-49 years old). The acute
risk estimate that results from this analysis is 3.1% of the acute
population adjusted dose (aPAD) at the 95^th^ percentile of exposure.
This risk estimate is considerably lower than HED's level of concern
(100% of the aPAD). The chronic (non-cancer) dietary analysis is more
refined in that it uses average residues from field trials. Because of
the manner in which these data were submitted and reviewed, multiple
averages were calculated for many of the crops. For these crops, the
highest average was used in the analysis. The non-cancer dietary
analysis assumes 100% crop treated. The assessment included a
conservative EDWC based on the cherry use. The most highly exposed
population subgroup is All Infants (\<1 year old) which utilizes 6.8% of
the chronic population adjusted dose (cPAD). The risk estimate for the
general U.S. population is 2.3% of the cPAD. As with the acute
assessment, the risk estimates are all well below HED's level of concern
(100% of the cPAD). The cancer dietary analysis uses the same food
residue inputs as those used in the chronic non-cancer assessment. The
cancer analysis is further refined in that it makes use of average
percent crop treated estimates. The assessment included a conservative
EDWC based on the cherry use. The cancer risk estimate using these food
residue inputs and a worst case use pattern assumption for water is 1.7
x 10^-6^. Typically, HED is concerned when the risk estimate associated
with food and drinking water exceeds 3 x 10^-6^. As a result, cancer
risk to the general U.S. population is below HED's level of concern.

Tolerance Harmonization

As there are no established or proposed Canadian, Mexican, or Codex
maximum residue limits (MRLs) for fenbuconazole on peppers, there are no
international harmonization issues for the pepper tolerance petition.
The U.S. has already established tolerances for cranberries at 0.5 ppm
and bushberries at 0.3 ppm. Mexico established tolerances for these
commodities based on the established U.S. tolerances. Therefore, HED
recommends that the current tolerances remain in effect, even though
they are different than the tolerances that are recommended by HED's
statistical tolerance generator.

Residential Exposure

Currently there are no registered residential uses associated with
fenbuconazole.

Aggregate Exposure

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

Occupational Exposure

The fenbuconazole end-use product to be used on peppers is formulated as
water soluble packets. The product is labeled as Indar 75 WSP, which
contains 75% active ingredient. The fenbuconazole end-use product may be
applied by groundboom or aerial equipment. Duration of exposure is
expected to be short- and intermediate-term. No long-term exposure is
expected.

Occupational exposure and risk estimates resulting in MOEs greater than
100 are not of concern for non-cancer effects. Neither a short-term nor
intermediate-term dermal endpoint was selected up to the limit dose.
Therefore, only short- and intermediate-term inhalation exposure was
assessed for occupational non-cancer handler risk. All calculations used
the maximum application rate to estimate the worst case risk scenario.
All handler inhalation margins of exposure (MOEs) range from 9,100 to
58,000, and therefore, are greater than 100 at baseline level. These
MOEs do not exceed HED's level of concern. EPA considers occupational
cancer risk estimates greater than one in ten thousand (1 x 10^-4^) to
be of concern, and attempts to mitigate such exposures so that cancer
risk estimates are reduced to one in one million (1 x 10^-6^) or less,
where feasible. The handler cancer calculations use the maximum
application rate to estimate risk. All cancer risk estimates for
handlers are less than 1 x 10^-6^ at baseline level and, therefore, are
not of concern.

The non-cancer post-application scenario, inhalation exposure, is
thought to be negligible. Long-term dermal exposure as a result of
post-application activities is not expected. For these reasons, a
non-cancer post-application exposure assessment is not required. In
determining carcinogenicity risk related to post-application exposure,
the dose values were amortized over the working lifetime of occupational
workers. Furthermore, HED considered the following assumptions and
data: 1) the time interval between reapplication of fenbuconazole varies
between 7 days and 30 or more days for the proposed uses, 2) residues
are assumed to decrease over time, and 3) it is unlikely that workers
will be exposed to Day-0 residues 30 days a year. Therefore, HED used
the average residue over 30 days to estimate cancer risk. All cancer
risk estimates are less than 1 x 10^-6^ and, therefore, are not a risk
concern.

Technical grade fenbuconazole has low acute toxicity (Category III for
acute oral and inhalation exposures and Category IV for acute dermal
exposure). Per the Worker Protection Standard (WPS), chemicals in
Toxicity Category III and IV require a 12-hr restricted entry interval
(REI). Therefore the 12-hour REI that appears on the Indar 75WSP label
is adequate.

Environmental Justice Considerations

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

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

Review of Human Research

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

Conclusions

HED concludes that the registrant has submitted adequate data for the
Agency to make the safety finding with respect to the use of
fenbuconazole on peppers. The toxicology, residue chemistry, and
occupational databases are adequate for the purposes of the current
tolerance petition. As a result, HED recommends in favor of a
conditional registration for fenbuconazole, and that permanent
tolerances be established for the combined residues of fenbuconazole,
\[α‑\[2-(4‑chlorophenyl)‑ethyl\]‑α-phenyl‑3‑(1H‑1,2,4‑triazole)‑1-propanenitrile\]
and its metabolites,
*cis*‑5‑(4‑chlorophenyl)-dihydro‑3‑phenyl-3‑(1*H*‑1,2,4-triazole-1-ylmethyl)‑2‑3*H*-furanone
(RH-9129) and
*trans*‑5-(4‑chlorophenyl)dihydro-3-phenyl‑3-(1*H*‑1,2,4‑triazole‑1‑ylmethyl)-2‑3*H*-furanone
(RH-9130) in or on peppers at 0.40 ppm. This recommendation is
contingent upon the use directions being corrected as stated in Section
10.2.1.

In its February 7, 2006 risk assessment for 1,2,4-triazole and its
metabolites, triazole alanine and triazole acetic acid (D322215, M.
Doherty, et al., 2/7/2006), HED recommended that resolution of various
issues be made a condition of registration for new uses of
triazole-derivative fungicides and for new active ingredients which
contain the 1,2,4-triazole ring. The requirement for a chronic
toxicity/oncogenicity study in male rats and female mice in the 2/7/2006
memo was later modified by HED to a 1-year chronic study in male and
female rats (D321328, Kit Farwell, 5/10/2006). The other conditions of
registration that were listed in the 2/7/2006 risk assessment have not
been satisfied and are conditions for the registration of the use of
fenbuconazole on peppers. In addition, the data described in Section
10.2.1 for 1,2,4-triazole, triazole alanine, and triazole acetic acid
are recommended to be made a condition of registration.

RD should note that six deficiencies from previous tolerance petitions
are addressed in Section 10.2.2. Some of these deficiencies are still
not resolved.

The tolerances for fenbuconazole are listed in 40CFR§180.480. Under Part
(a), where the general tolerances are listed, the 40CFR states that the
tolerances in that section have an expiration date of December 31, 2001.
HED recommends that RD take whatever action is necessary to revise or
delete the expiration date.

**2.0 INGREDIENT PROFILE**

Fenbuconazole is a broad-spectrum, triazole-type fungicide that acts by
inhibiting sterol biosynthesis in fungi. It is formulated in wettable
powder (WP, 75% a.i.) and flowable concentrate (FlC, 2 lb a.i./gal)
forms. The requested uses for fenbuconazole are summarized in Table 2.1.

**2.1 Summary of Registered/Proposed
Uses**[]{#__RefHeading___Toc131319175 .anchor}

Fenbuconazole is currently registered for use on the following food/feed
crops: cranberries, the Bushberry Subgroup (Crop Subgroup 13-B),
almonds, apples, bananas, citrus fruit, pecans, peanuts, stone fruit,
sugar beets, and wheat. Tolerances are established for the combined
residues of fenbuconazole and its lactone metabolites, RH-9129 and
RH-9130 \[trans- or
cis-5-(4-chlorophenyl)dihydro-3-phenyl-3-(1*H*-1,2,4-triazol-1-ylmethyl)-2(3*H*)-furanone\],
expressed as parent in/on plant commodities at levels ranging from 0.05
ppm in/on almonds and pecans to 40 ppm in citrus oil \[40 CFR
§180.480(a)\]. Tolerances have also been established at 0.05 ppm for the
combined residues in meat byproducts of cattle, goats, horses, and
sheep. A tolerance of 0.3 ppm is currently in effect for Crop Subgroup
13-B, the Bushberry Subgroup, and a tolerance of 0.5 ppm is in effect
for cranberries. The 40CFR states that the tolerances in §180.480(a)
have an expiration date of December 31, 2001.

The 40CFR also lists time-limited tolerances that were established in
conjunction with Section 18 registrations. These tolerances are for the
fat and meat of cattle, goats, hogs, horses, and sheep (and one for hog,
meat byproducts). These time-limited tolerances are all set to expire on
12/31/2008. As there are no Section 18 uses on animal feed items, these
animal commodity tolerances are no longer necessary (electronic
communication, D. Rosenblatt, 5/16/2008). There is also an expired
tolerance for blueberries that differs from the bushberry tolerance.

There are currently three fenbuconazole end-use products (EPs)
registered to Dow AgroSciences for use in the U.S. on food/feed crops.
These EPs are marketed under the trade names ENABLE^™^ and INDAR^™^, and
include a 2 lb/gal FlC and two 75% WPs. IR-4 is proposing the use of a
75% WP (INDAR^™^ 75 WSP; EPA Reg. No. 62719-421) on peppers. An example
label was provided for the use of the 75% WP on peppers, and the
proposed use directions are summarized below in Table 2.1. A 75% WP
formulation is registered for use on bushberries and cranberries. The
use directions are summarized in Table 2.1.

+--------------+-------+----+-----+-------+----+--------------------+
| **Table 2.1. |       |    |     |       |    |                    |
| Summary of   |       |    |     |       |    |                    |
| Directions   |       |    |     |       |    |                    |
| for Use of   |       |    |     |       |    |                    |
| Fenb         |       |    |     |       |    |                    |
| uconazole.** |       |    |     |       |    |                    |
+==============+=======+====+=====+=======+====+====================+
| Applic.      | F     | A  | M   | Max.  | P  | Use Directions and |
| Timing,      | ormul | pp | ax. | Sea   | HI | Limitations ^2^    |
| Type, and    | ation | li | No. | sonal |    |                    |
| Equip. ^1^   |       | c. | A   | Ap    | (d |                    |
|              | \[EPA | Ra | ppl | plic. | ay |                    |
|              | Reg.  | te | ic. | Rate  | s) |                    |
|              | No.\] |    | per |       |    |                    |
|              |       | (  | Sea | (lb   |    |                    |
|              |       | lb | son | ai/A) |    |                    |
|              |       | a  |     |       |    |                    |
|              |       | i/ |     |       |    |                    |
|              |       | A) |     |       |    |                    |
+--------------+-------+----+-----+-------+----+--------------------+
| **Peppers    |       |    |     |       |    |                    |
| (Including   |       |    |     |       |    |                    |
| but not      |       |    |     |       |    |                    |
| limited to:  |       |    |     |       |    |                    |
| bell, chili, |       |    |     |       |    |                    |
| cooking,     |       |    |     |       |    |                    |
| non-bell,    |       |    |     |       |    |                    |
| pimento and  |       |    |     |       |    |                    |
| sweet)**     |       |    |     |       |    |                    |
+--------------+-------+----+-----+-------+----+--------------------+
| Broadcast    | 75%   | 0  | NS  | 0.75  | 7  | Apply in a minimum |
| foliar       | WP    | .1 |     |       |    | of 30 gal/A, using |
| applications |       | 88 |     |       |    | ground equipment.  |
| to peppers   | \[6   | ^  |     |       |    |                    |
| when disease | 2719- | 3^ |     |       |    | The minimum RTI is |
| first        | 421\] |    |     |       |    | 10-14 days. Use of |
| appears.     |       |    |     |       |    | a non-ionic        |
|              |       |    |     |       |    | surfactant is      |
| Use ground   |       |    |     |       |    | recommended.       |
| or aerial    |       |    |     |       |    |                    |
| equipment    |       |    |     |       |    |                    |
+--------------+-------+----+-----+-------+----+--------------------+
| **Bushberry  |       |    |     |       |    |                    |
| Subgroup     |       |    |     |       |    |                    |
| (including   |       |    |     |       |    |                    |
| blueberry,   |       |    |     |       |    |                    |
| currant,     |       |    |     |       |    |                    |
| e            |       |    |     |       |    |                    |
| lderberry,** |       |    |     |       |    |                    |
|              |       |    |     |       |    |                    |
| *            |       |    |     |       |    |                    |
| *gooseberry, |       |    |     |       |    |                    |
| and          |       |    |     |       |    |                    |
| hu           |       |    |     |       |    |                    |
| ckleberry)** |       |    |     |       |    |                    |
+--------------+-------+----+-----+-------+----+--------------------+
| Broadcast    | 75%   | 0  | 5   | 0.47  | 30 | A minimum          |
| foliar       | WP    | .0 |     |       |    | retreatment        |
| applications |       | 94 |     |       |    | interval of 10     |
| beginning at | \[6   |    |     |       |    | days is specified. |
| bud break    | 2719- |    |     |       |    |                    |
| (green tip)  | 421\] |    |     |       |    | Do not apply       |
| through      |       |    |     |       |    | through any type   |
| fruit        |       |    |     |       |    | of irrigation      |
| development. |       |    |     |       |    | system.            |
|              |       |    |     |       |    |                    |
| Use ground   |       |    |     |       |    | For ground and     |
| or aerial    |       |    |     |       |    | aerial             |
| equipment    |       |    |     |       |    | applications,      |
|              |       |    |     |       |    | apply in a minimum |
|              |       |    |     |       |    | volume of 10 and   |
|              |       |    |     |       |    | 20 gal/A,          |
|              |       |    |     |       |    | respectively.      |
|              |       |    |     |       |    |                    |
|              |       |    |     |       |    | A non-ionic        |
|              |       |    |     |       |    | surfactant should  |
|              |       |    |     |       |    | be used in the     |
|              |       |    |     |       |    | spray mix.         |
+--------------+-------+----+-----+-------+----+--------------------+

+--------------+-------+----+-----+-------+----+--------------------+
| **C          |       |    |     |       |    |                    |
| ranberries** |       |    |     |       |    |                    |
+--------------+-------+----+-----+-------+----+--------------------+
| Broadcast    | 75%   | 0  | 5   | 0.94  | 30 | A minimum          |
| foliar       | WP    | .1 |     |       |    | retreatment        |
| applications |       | 88 |     |       |    | interval of 7 days |
| beginning    | \[6   |    |     |       |    | is specified.      |
| when 50% of  | 2719- |    |     |       |    |                    |
| shoots show  | 421\] |    |     |       |    | Do not apply       |
| ¼ inch of    |       |    |     |       |    | through any type   |
| new growth,  |       |    |     |       |    | of irrigation      |
| through      |       |    |     |       |    | system.            |
| fruit        |       |    |     |       |    |                    |
| development. |       |    |     |       |    | For aerial         |
|              |       |    |     |       |    | applications,      |
| Use ground   |       |    |     |       |    | apply in a minimum |
| or aerial    |       |    |     |       |    | volume of 10       |
| equipment.   |       |    |     |       |    | gal/A.             |
|              |       |    |     |       |    |                    |
|              |       |    |     |       |    | A non-ionic        |
|              |       |    |     |       |    | surfactant should  |
|              |       |    |     |       |    | be used in the     |
|              |       |    |     |       |    | spray mix.         |
+--------------+-------+----+-----+-------+----+--------------------+

^1^ Do not apply through any type of irrigation system. Although
application using aerial equipment is permitted, ground application is
recommended.

^2^ Rotational crop restrictions: the minimum plant-back interval is 35
days when the last application of the product is \<0.188 lb ai/A, and
210 days when the last application is 0.2-1 lb ai/A.

^3^ The maximum use rate is based on the use of 4 oz
product/acre/application.

NS = not specified.

**2.2 Structure and Nomenclature**

  -----------------------------------------------------------------------------------------------------------------
  **Table 2.2.         
  Nomenclature of      
  Fenbuconazole and    
  its Regulated        
  Metabolites**        
  -------------------- --------------------------------------------------------------------------------------------
  Compound             ![](media/image2.wmf){width="2.036111111111111in" height="1.1979166666666667in"}

  Common name          Fenbuconazole

  Company experimental RH-7592
  names                

  IUPAC name           (*RS*)-4-(4-chlorophenyl)-2-phenyl-2-(1*H*-1,2,4-triazol-1-ylmethyl)butyronitrile

  CAS name             α-\[2-(4-chlorophenyl)ethyl\]-α-phenyl-1*H*-1,2,4-triazole-1-propanenitrile

  Molecular weight     336.8

  CAS registry number  114369-43-6 (119611-00-6, racemate)

  End-use products/EP  2 lb/gal FlC and 75% WPs

  Metabolite           

  Common name          *cis* lactone metabolite

  Company experimental RH-9129
  names                

  IUPAC names          (3R,5R)-5-(4-chlorophenyl)-3-phenyl-3-(1H-1,2,4-triazol-1-ylmethyl)dihydrofuran-2(3H)-one

  CAS names            *cis*-5-(4-chlorophenyl)dihydro-3-phenyl-3-(methyl-1-H,2,4-triazole-1-yl-2-(3H)-furanone

  Molecular weight     353.8

  CAS registry number  146887-38-9

  Metabolite           ![](media/image3.wmf){width="2.125in" height="1.4in"}

  Common name          *trans* lactone metabolite

  Company experimental RH-9130
  names                

  IUPAC names          (3S,5R)-5-(4-chlorophenyl)-3-phenyl-3-(1H-1,2,4-triazol-1-ylmethyl)dihydrofuran-2(3H)-one

  CAS names            *trans*-5-(4-chlorophenyl)dihydro-3-phenyl-3-(methyl-1-H,2,4-triazole-1-yl-2-(3H)-furanone

  Molecular weight     353.8

  CAS registry number  146887-37-8
  -----------------------------------------------------------------------------------------------------------------

**2.3 Physical and Chemical Properties**

+--------------------------+--------------+-------------+-------------+
| **Table 2.3. Physical    |              |             |             |
| and Chemical Properties  |              |             |             |
| of the Technical Grade   |              |             |             |
| Fenbuconazole**          |              |             |             |
+==========================+==============+=============+=============+
| Parameter                | Value        |             | Reference   |
+--------------------------+--------------+-------------+-------------+
| Melting point            | 12           |             | D310959, S. |
|                          | 6.5--127.0°C |             | Oonnithan,  |
|                          |              |             | 7/25/2008   |
+--------------------------+--------------+-------------+-------------+
| pH                       | Not          |             |             |
|                          | available    |             |             |
+--------------------------+--------------+-------------+-------------+
| Bulk Density             | 0.50 g/mL    |             |             |
+--------------------------+--------------+-------------+-------------+
| Water solubility at 22°C | 3.8 mg/L     |             |             |
+--------------------------+--------------+-------------+-------------+
| Solvent solubility (g/L) | Acetonitrile | Aromatic    |             |
| at 25°C                  | 231          | 200 77      |             |
|                          |              |             |             |
|                          | C            | Ethyl       |             |
|                          | yclohexanone | acetate 159 |             |
|                          | 445          |             |             |
|                          |              | Heptane 1.0 |             |
|                          | Ethyl        |             |             |
|                          | alcohol 39   |             |             |
|                          |              |             |             |
|                          | 1-octanol 13 |             |             |
+--------------------------+--------------+-------------+-------------+
| Vapor pressure at 25°C   | 0.37 ×10^-7^ |             |             |
| (PAI)                    | mm Hg (4.9 × |             |             |
|                          | 10^-6^Pa)    |             |             |
+--------------------------+--------------+-------------+-------------+
| Dissociation constant    | Not expected |             |             |
| (pK~a~) (PAI)            | to           |             |             |
|                          | dissociate   |             |             |
|                          | in water     |             |             |
+--------------------------+--------------+-------------+-------------+
| Octanol/water partition  | Log(K~OW~) = |             |             |
| coefficient Log(K~OW~)   | 3.22         |             |             |
+--------------------------+--------------+-------------+-------------+
| UV/visible absorption    | [λ max       | [ε          |             |
| spectrum                 | (nm)]        | (L∙mol^-1   |             |
|                          | {.underline} | ^∙cm^-1^)]{ |             |
|                          |              | .underline} |             |
|                          | 196          |             |             |
|                          |              | 53,000      |             |
|                          | 262          |             |             |
|                          |              | 750         |             |
|                          | 268          |             |             |
|                          |              | 740         |             |
|                          | 275          |             |             |
|                          |              | 480         |             |
+--------------------------+--------------+-------------+-------------+

**3.0 HAZARD CHARACTERIZATION/ASSESSMENT**

**3.1 Hazard and Dose-Response Characterization**

Acute studies were conducted on both the technical material and end-use
product (25% a.i.). Technical grade fenbuconazole has low acute toxicity
(Category III for acute oral and inhalation exposures and Category IV
for acute dermal exposure). The end-use product also has low acute
toxicity (Category III for acute inhalation exposure and Category IV for
acute oral and dermal exposures). The technical material and the end-use
product are neither skin nor eye irritants (Category IV), and neither is
a dermal sensitizer. Table 3.1a summarizes the acute toxicity for the
technical material as well as for the end-use product of fenbuconazole.

**3.2 Database Summary**

+---------+----------------+--------+-----------------------+---------+
| **Table |                |        |                       |         |
| 3.1a -  |                |        |                       |         |
| Acute   |                |        |                       |         |
| T       |                |        |                       |         |
| oxicity |                |        |                       |         |
| of      |                |        |                       |         |
| F       |                |        |                       |         |
| enbucon |                |        |                       |         |
| azole - |                |        |                       |         |
| Te      |                |        |                       |         |
| chnical |                |        |                       |         |
| and     |                |        |                       |         |
| End-Use |                |        |                       |         |
| Pr      |                |        |                       |         |
| oduct** |                |        |                       |         |
+=========+================+========+=======================+=========+
| **Gu    | **Study Type** | **     | **Results**           | **Tox   |
| ideline |                | MRID** |                       | icity** |
| No.**   |                |        |                       |         |
|         |                |        |                       | **Cat   |
|         |                |        |                       | egory** |
+---------+----------------+--------+-----------------------+---------+
| **870   | Acute Oral -   | 41     | Oral LD~50~ (M) \>    | III     |
| .1100** | Rats           | 031209 | 2000 mg/kg            |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Acute Oral -   | 41     | Oral LD~50~ (M and F) | III     |
| .1100** | Rats           | 031207 | \> 2000 mg/kg         |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Acute Oral -   | 41     | Oral LD~50~ (M) \>    | IV      |
| .1100** | Rats           | 031221 | 5000 mg/kg            |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Acute Oral -   | 41     | Oral LD~50~ (F) \>    | IV      |
| .1100** | Rats           | 031222 | 5000 mg/kg            |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Acute Dermal - | 41     | LD~50~ (M and F) \>   | IV      |
| .1200** | Rats           | 031208 | 5000 mg/kg            |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Acute Dermal - | 41     | LD~50~ (M) \> 5000    | IV      |
| .1200** | Rats           | 031223 | mg/kg                 |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Acute Dermal - | 41     | LD~50~ (F) \> 5000    | IV      |
| .1200** | Rats           | 031224 | mg/kg                 |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Acute          | 41     | LC~50~ (M and F) \>   | III     |
| .1300** | Inhalation -   | 398201 | 2.1 mg/L              |         |
|         | Rats           |        |                       |         |
|         |                |        | Particle size too     |         |
|         |                |        | large. Requirement    |         |
|         |                |        | was waived because of |         |
|         |                |        | a problem in          |         |
|         |                |        | generating respirable |         |
|         |                |        | dust particles or     |         |
|         |                |        | liquid aerosol.       |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Acute          | 41     | LC~50~ (M and F) \>   | III     |
| .1300** | Inhalation -   | 031225 | 2.1 mg/L              |         |
|         | Rats           |        |                       |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Primary Eye    | 41     | Not irritating to     | IV      |
| .2400** | Irritation-    | 031211 | unwashed eyes         |         |
|         | Rabbits        |        |                       |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Primary Eye    | 41     | Not irritating to the | IV      |
| .2400** | Irritation-    | 031226 | eyes                  |         |
|         | Rabbits        |        |                       |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Primary Dermal | 41     | Not irritating to the | IV      |
| .2500** | Irritation-    | 031212 | skin                  |         |
|         | Rabbits        |        |                       |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Primary Dermal | 41     | Not irritating to the | IV      |
| .2500** | Irritation-    | 031227 | skin                  |         |
|         | Rabbits        |        |                       |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Dermal         | 41     | Is not a sensitizer   | N/A     |
| .2600** | Sensitization- | 031213 | under conditions of   |         |
|         | Guinea pigs    |        | study.                |         |
+---------+----------------+--------+-----------------------+---------+
| **870   | Dermal         | 41     | Is not a sensitizer   | N/A     |
| .2600** | Sensitization- | 031228 | under conditions of   |         |
|         | Guinea pigs    |        | study.                |         |
+---------+----------------+--------+-----------------------+---------+

Subchronic and chronic feeding studies were conducted in the rat, mouse,
and dog. In these studies, the liver was the main target of toxicity in
all three species. At the LOAEL in the subchronic studies, there were
changes in liver histopathology, predominantly hepatocellular
hypertrophy. At doses higher than the LOAEL in the rat, the thyroid was
a secondary target organ with increased follicular cell size. In the
chronic studies, liver effects were seen (including hepatocellular
hypertrophy and vacuolization, changes in liver enzymes, and increased
liver weights), as well as decreased body weight gains in all three
species. Again, in the chronic rat study, the thyroid was a secondary
target with increased thyroid and parathyroid weights and thyroid
follicular cell hypertrophy. In addition, increased mean T4 and
decreased TSH were found in the high-dose rats near the end of the
study. In the chronic dog study, kidney and adrenal weights were also
increased. Males and females throughout the studies appeared to be
equally sensitive to fenbuconazole toxicity, except in the chronic mouse
study, where male mice appeared to be more sensitive than the females.

In the rat and rabbit developmental toxicity studies and the two
generation study in rats, all effects in the pups occurred in the
presence of maternal toxicity, including changes in body weight and body
weight gains in rats and decreased food consumption and clinical signs
in rabbits. Developmental effects included increased post-implantation
loss and decreased fetuses per dam in the rat developmental study;
increased early resorptions in the rabbit developmental study; and
decreased mean pup body weight, increased number of stillborn pups,
decreased number of total offspring delivered, and decreased viability
index of pups in the two generation study in rats. No increased
qualitative or quantitative susceptibility was observed in any of the
studies. There was no evidence of neurotoxicity in any of the studies
available in the toxicology database. Therefore, a developmental
neurotoxicity study is not required at this time.

Fenbuconazole is not mutagenic. On August 11, 1993, the Health Effects
Division Carcinogenicity Peer Review Committee (CPRC) determined that
fenbuconazole should be classified as a Group C, possible human
carcinogen, and recommended that a low dose extrapolation model applied
to the experimental animal tumor data be used for quantification of
human risk (Q~1~\*). The Q~1~\* established for use in cancer risk
analysis is 0.00359 (mg/kg/day)^-1^ in human equivalents.

A dermal absorption study was conducted in rats. The majority of the
radio-labeled compound could be recovered in a skin wash. A value of
4.25% dermal absorption, measured 10 hours after exposure, has been
selected for use in risk assessment.

In rats, fenbuconazole is rapidly absorbed and excreted within 96 hours
of a single low or high dose or following repeated low doses. Low
bioaccumulation of both the parent compound and metabolites was
indicated by low levels in the tissues.

Table 3.1.b summarizes the toxicity profile of fenbuconazole.

+--------+-----------+-------+------------------+---------------------+
| *      |           |       |                  |                     |
| *Table |           |       |                  |                     |
| 3.1b - |           |       |                  |                     |
| To     |           |       |                  |                     |
| xicity |           |       |                  |                     |
| P      |           |       |                  |                     |
| rofile |           |       |                  |                     |
| of     |           |       |                  |                     |
| F      |           |       |                  |                     |
| enbuco |           |       |                  |                     |
| nazole |           |       |                  |                     |
| Techn  |           |       |                  |                     |
| ical** |           |       |                  |                     |
+========+===========+=======+==================+=====================+
| **Gui  | **Study   | **M   | **Doses**        | **Results**         |
| deline | Type**    | RID** |                  |                     |
| No.**  |           |       |                  |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | 90-Day    | 410   | 0, 20, 80, 400,  | **NOAEL** = 1.3/1.5 |
| 3100** | oral      | 73502 | and 1600 ppm     | mg/kg/day (M/F)     |
|        | toxicity  |       |                  |                     |
|        | rodents - |       | **(Males:** 0,   | **LOAEL** = 5.1/6.3 |
|        | rats      |       | 1.3, 5.1, 25.3,  | mg/kg/day (M/F)     |
|        |           |       | and 103.0        | based on liver      |
|        |           |       | mg/kg/day;       | histopathology      |
|        |           |       |                  |                     |
|        |           |       | **Females:** 0,  |                     |
|        |           |       | 1.5, 6.3, 31.1,  |                     |
|        |           |       | and 123.9        |                     |
|        |           |       | mg/kg/day)       |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | 90-Day    | 410   | 0, 20, 60, 180,  | **NOAEL** = 3.8/5.7 |
| 3100** | oral      | 73503 | and 540 ppm      | mg/kg/day (M/F)     |
|        | toxicity  |       |                  |                     |
|        | rodents - |       | (**Males:** 0,   | **LOAEL** =         |
|        | mice      |       | 3.8, 11.1, 28.6, | 11.1/17.6 mg/kg/day |
|        |           |       | and 99.1         | (M/F) based on      |
|        |           |       | mg/kg/day;       | liver               |
|        |           |       |                  | histopathology      |
|        |           |       | **Females:** 0,  |                     |
|        |           |       | 5.7, 17.6, 50.4, |                     |
|        |           |       | and 139.2        |                     |
|        |           |       | mg/kg/day)       |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | 90-Day    | 410   | 0, 30, 100, 400, | **NOAEL** = 3.3/3.5 |
| 3150** | oral      | 73504 | and 1600 ppm     | mg/kg/day (M/F)     |
|        | toxicity  |       |                  |                     |
|        | in        |       | (**Males:** 0,   | **LOAEL** =         |
|        | non       |       | 1.0, 3.3, 13.3,  | 13.3/14.0 mg/kg/day |
|        | rodents - |       | and 50.4         | (M/F) based on      |
|        | dogs      |       | mg/kg/day;       | liver               |
|        |           |       |                  | histopathology      |
|        |           |       | **Females:** 0,  |                     |
|        |           |       | 1.1, 3.5, 14.0,  |                     |
|        |           |       | and 53.3         |                     |
|        |           |       | mg/kg/day)       |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | 21/28-Day | 418   | 0, 250, 625, and | **NOAEL** = 1000    |
| 3200** | dermal    | 75013 | 1000 mg/kg/day   | mg/kg/day (HDT)     |
|        | t         |       |                  |                     |
|        | oxicity - | 428   |                  | **LOAEL** = \>1000  |
|        | rats      | 82701 |                  | mg/kg/day           |
+--------+-----------+-------+------------------+---------------------+
| **870. | 90-Day    | N/A   | N/A              | Not performed       |
| 3250** | dermal    |       |                  |                     |
|        | toxicity  |       |                  |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | 90-Day    | N/A   | N/A              | Not performed       |
| 3465** | i         |       |                  |                     |
|        | nhalation |       |                  |                     |
|        | toxicity  |       |                  |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | Prenatal  | 410   | 0, 30, 75, and   | **Maternal NOAEL**  |
| 3700** | deve      | 31214 | 150 mg/kg/day    | = 30 mg/kg/day      |
|        | lopmental |       |                  |                     |
|        | in        | 410   |                  | **Maternal LOAEL**  |
|        | rodents - | 73505 |                  | = 75 mg/kg/day      |
|        | rats      |       |                  | based on decreased  |
|        |           |       |                  | body weight and     |
|        |           |       |                  | body weight gain    |
|        |           |       |                  |                     |
|        |           |       |                  | **Developmental     |
|        |           |       |                  | NOAEL** = 30        |
|        |           |       |                  | mg/kg/day           |
|        |           |       |                  |                     |
|        |           |       |                  | **Developmental     |
|        |           |       |                  | LOAEL** = 75        |
|        |           |       |                  | mg/kg/day           |
|        |           |       |                  |                     |
|        |           |       |                  | based on increased  |
|        |           |       |                  | post-implantation   |
|        |           |       |                  | loss and a decrease |
|        |           |       |                  | in the number of    |
|        |           |       |                  | live fetuses/dam    |
+--------+-----------+-------+------------------+---------------------+
| **870. | Prenatal  | 418   | 0, 10, 30, and   | **Maternal NOAEL**  |
| 3700** | deve      | 75014 | 60 mg/kg/day     | = 10 mg/kg/day      |
|        | lopmental |       |                  |                     |
|        | in        | 428   |                  | **Maternal LOAEL**  |
|        | non       | 82701 |                  | = 30 mg/kg/day      |
|        | rodents - |       |                  | based on decreased  |
|        | rabbits   |       |                  | food consumption    |
|        |           |       |                  | and increased       |
|        |           |       |                  | incidence of        |
|        |           |       |                  | clinical signs      |
|        |           |       |                  | (soft/scant/no      |
|        |           |       |                  | feces and red       |
|        |           |       |                  | discharge)          |
|        |           |       |                  |                     |
|        |           |       |                  | **Developmental     |
|        |           |       |                  | NOAEL** = 30        |
|        |           |       |                  | mg/kg/day           |
|        |           |       |                  |                     |
|        |           |       |                  | **Developmental     |
|        |           |       |                  | LOAEL** = 60        |
|        |           |       |                  | mg/kg/day           |
|        |           |       |                  |                     |
|        |           |       |                  | based on increased  |
|        |           |       |                  | early resorptions   |
+--------+-----------+-------+------------------+---------------------+
| **870. | Rep       | 418   | 0, 8, 80, and    | **Parental systemic |
| 3800** | roduction | 75015 | 800 ppm (0, 0.4, | NOAEL** = 4         |
|        | and       |       | 4, and 40        | mg/kg/day           |
|        | fertility |       | mg/kg/day)       |                     |
|        | effects - |       |                  | **Parental systemic |
|        | rats      |       |                  | LOAEL** = 40        |
|        |           |       |                  | mg/kg/day           |
|        |           |       |                  |                     |
|        |           |       |                  | based on maternal   |
|        |           |       |                  | death during        |
|        |           |       |                  | delivery, decreased |
|        |           |       |                  | body weight and     |
|        |           |       |                  | food consumption,   |
|        |           |       |                  | increased number of |
|        |           |       |                  | dams not delivering |
|        |           |       |                  | viable or           |
|        |           |       |                  | delivering          |
|        |           |       |                  | nonviable           |
|        |           |       |                  | offspring, and      |
|        |           |       |                  | increased adrenal   |
|        |           |       |                  | and                 |
|        |           |       |                  | thyroid/parathyroid |
|        |           |       |                  | weights             |
|        |           |       |                  |                     |
|        |           |       |                  | **Reproductive      |
|        |           |       |                  | NOAEL** = 40        |
|        |           |       |                  | mg/kg/day (HDT)     |
|        |           |       |                  |                     |
|        |           |       |                  | **Reproductive      |
|        |           |       |                  | LOAEL** = \>40      |
|        |           |       |                  | mg/kg/day           |
|        |           |       |                  |                     |
|        |           |       |                  | **Offspring         |
|        |           |       |                  | systemic NOAEL** =  |
|        |           |       |                  | 4                   |
|        |           |       |                  |                     |
|        |           |       |                  | **Offspring         |
|        |           |       |                  | systemic LOAEL** =  |
|        |           |       |                  | 40 mg/kg/day        |
|        |           |       |                  |                     |
|        |           |       |                  | based on decreased  |
|        |           |       |                  | mean pup body       |
|        |           |       |                  | weight, increased   |
|        |           |       |                  | number of stillborn |
|        |           |       |                  | pups, decreased     |
|        |           |       |                  | number of total     |
|        |           |       |                  | offspring           |
|        |           |       |                  | delivered, and      |
|        |           |       |                  | decreased viability |
|        |           |       |                  | index               |
+--------+-----------+-------+------------------+---------------------+
| **870. | Chronic   |       |                  | See 870.4300        |
| 4100** | t         |       |                  |                     |
|        | oxicity - |       |                  |                     |
|        | rodents   |       |                  |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | Chronic   | 418   | 0, 15, 150, and  | **NOAEL** =         |
| 4100** | t         | 75049 | 1200 ppm (0,     | 3.75/0.38 mg/kg/day |
|        | oxicity - |       | 0.38, 3.75, and  | (M/F)               |
|        | dogs      |       | 30 mg/kg/day)    |                     |
|        |           |       |                  | **LOAEL** = 30/3.75 |
|        |           |       |                  | mg/kg/day (M/F)     |
|        |           |       |                  | based on decreased  |
|        |           |       |                  | body weight gain    |
|        |           |       |                  |                     |
|        |           |       |                  | **Note:**           |
|        |           |       |                  | dose-related        |
|        |           |       |                  | adaptive liver      |
|        |           |       |                  | changes were        |
|        |           |       |                  | observed in         |
|        |           |       |                  | high-dose males and |
|        |           |       |                  | females.            |
+--------+-----------+-------+------------------+---------------------+
| **870. | Carcinog  |       |                  | See 870.4300        |
| 4200** | enicity - |       |                  |                     |
|        | rats      |       |                  |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | Carcinog  | 418   | **Males:** 0,    | **NOAEL** = 1.43    |
| 4200** | enicity - | 93301 | 10, 200, and 650 | mg/kg/day (M & F)   |
|        | mice      |       | ppm (0, 1.43,    |                     |
|        |           | 416   | 28.6, and 92.9   | **LOAEL** =         |
|        |           | 35303 | mg/kg/day)       | 28.6/92.9 mg/kg/day |
|        |           |       |                  | (M/F) based on      |
|        |           |       | **Females:** 0,  | decreased body      |
|        |           |       | 10, 650, and     | weight, increased   |
|        |           |       | 1300 ppm (0,     | relative and        |
|        |           |       | 1.43, 92.9, and  | absolute liver      |
|        |           |       | 186 mg/kg/day)   | weight, and         |
|        |           |       |                  | hepatocellular      |
|        |           |       |                  | hypertrophy and     |
|        |           |       |                  | vacuolization       |
|        |           |       |                  |                     |
|        |           |       |                  | *Evidence of        |
|        |           |       |                  | carcinogenicity*    |
+--------+-----------+-------+------------------+---------------------+
| **870. | Combined  | 416   | **Control** - 0  | **NOAEL** = 3.0/4.0 |
| 4300** | chronic   | 35301 | ppm              | mg/kg/day (M/F)     |
|        | toxicity/ |       |                  |                     |
|        |           | 416   | **Low** - 4 ppm  | **LOAEL** =         |
|        | carcinog  | 35302 | (weeks 1 & 2), 6 | 30.6/43.1 mg/kg/day |
|        | enicity - |       | ppm (weeks 3 &   | (M/F) based on      |
|        | rat       |       | 4), and 8 ppm    | decreased body      |
|        |           |       | (weeks 5-term)   | weight gain (F),    |
|        |           |       |                  | hepatocellular      |
|        |           |       | **Mid** - 40 ppm | enlargement and     |
|        |           |       | (weeks 1 & 2),   | vacuolization (F),  |
|        |           |       | 60 ppm (weeks 3  | increased thyroid   |
|        |           |       | & 4), and 80 ppm | weight (M&F), and   |
|        |           |       | (weeks 5-term)   | histopathological   |
|        |           |       |                  | lesions in the      |
|        |           |       | **High** - 400   | thyroid gland (M)   |
|        |           |       | ppm (weeks 1 &   |                     |
|        |           |       | 2), 600 ppm      | *Evidence of        |
|        |           |       | (weeks 3 & 4),   | carcinogenicity*    |
|        |           |       | and 800 ppm      |                     |
|        |           |       | (weeks 5-term)   |                     |
|        |           |       |                  |                     |
|        |           |       | (**Males:** 0,   |                     |
|        |           |       | 0.31, 3.03, and  |                     |
|        |           |       | 30.62 mg/kg/day; |                     |
|        |           |       |                  |                     |
|        |           |       | **Females:** 0,  |                     |
|        |           |       | 0.4, 4.02, and   |                     |
|        |           |       | 43.07 mg/kg/day) |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | Combined  | 420   | **Control** - 0  | **NOAEL** = Not     |
| 4300** | chronic   | 21901 | ppm              | established         |
|        | toxicity/ |       |                  |                     |
|        |           | 420   | **Low** - 400    | **LOAEL** = 30.4    |
|        | carcinog  | 55001 | ppm (weeks 1 &   | mg/kg/day (M) based |
|        | enicity - |       | 2), 600 ppm      | on decreased body   |
|        | rat       |       | (weeks 3 & 4),   | weight gain,        |
|        |           |       | and 800 ppm      | increased liver     |
|        |           |       | (weeks 5-term)   | weight, and         |
|        |           |       |                  | increased thyroid   |
|        |           |       | **High** - 800   | and parathyroid     |
|        |           |       | ppm (weeks 1 &   | weights             |
|        |           |       | 2), 1200 ppm     |                     |
|        |           |       | (weeks 3 & 4),   | **Note:** only      |
|        |           |       | and 1600 ppm     | males were used in  |
|        |           |       | (weeks 5-term)   | this study.         |
|        |           |       |                  |                     |
|        |           |       | (0, 30.4, and    | *Insufficient       |
|        |           |       | 63.9 mg/kg/day)  | evidence of         |
|        |           |       |                  | carcinogenicity*    |
+--------+-----------+-------+------------------+---------------------+
| **870. | Gene      | 410   | **TA1535** -     | No mutagenic        |
| 5100** | m         | 31216 | 30-300 ug        | activity in         |
|        | utation - |       |                  | bacteria            |
|        | bacterial |       | **TA1537** -     | (*Salmonella        |
|        | reverse   |       | 30-300 ug        | typhimurium*) under |
|        | mutation  |       |                  | conditions of this  |
|        | assay     |       | **TA98** -       | assay.              |
|        |           |       | 0.2-20 ug        |                     |
|        |           |       |                  | **Note:** only      |
|        |           |       | **TA100** -      | TA1535, TA1537,     |
|        |           |       | 160-1600 ug      | TA98, and TA100     |
|        |           |       |                  | were tested. This   |
|        |           |       |                  | study is classified |
|        |           |       |                  | unacceptable.       |
+--------+-----------+-------+------------------+---------------------+
| **870. | Gene      | 410   | **TA1535** -     | No mutagenic        |
| 5100** | m         | 31217 | 30-300 ug        | activity in         |
|        | utation - |       |                  | bacteria            |
|        | bacterial |       | **TA1537** -     | (*Salmonella        |
|        | reverse   |       | 30-300 ug        | typhimurium*) under |
|        | mutation  |       |                  | conditions of this  |
|        | assay     |       | **TA98** -       | assay.              |
|        |           |       | 30-300 ug        |                     |
|        |           |       |                  | **Note:** only      |
|        |           |       | **TA100** -      | TA1535, TA1537,     |
|        |           |       | 30-300 ug        | TA98, and TA100     |
|        |           |       |                  | were tested. This   |
|        |           |       |                  | study is classified |
|        |           |       |                  | unacceptable.       |
+--------+-----------+-------+------------------+---------------------+
| **870. | Cytog     | 410   | 15-50 µg/mL      | No increase in      |
| 5300** | enetics - | 31218 | without S9       | mutant frequency at |
|        | *in       |       | activation       | the HGPRT locus, in |
|        | vitro*    |       |                  | the presence or     |
|        | mammalian |       | 35-60 µg/mL with | absence of S9       |
|        | cell gene |       | S9 activation    | activation.         |
|        | mutation  |       |                  |                     |
|        | test (CHO |       |                  |                     |
|        | Cells)    |       |                  |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | Cyt       | 410   | 0, 0.25, 1.25,   | No increase in      |
| 5385** | ogenetics | 31219 | and 2.5 g/kg     | number of cells     |
|        | *-*       |       |                  | with aberrations or |
|        | mammalian |       |                  | in aberrations per  |
|        | bone      |       |                  | cell.               |
|        | marrow    |       |                  |                     |
|        | ch        |       |                  |                     |
|        | romosomal |       |                  |                     |
|        | a         |       |                  |                     |
|        | berration |       |                  |                     |
|        | test      |       |                  |                     |
|        | (rats)    |       |                  |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | Other     | 410   | 0, 7.5, 10.0,    | No evidence (or a   |
| 5550** | effects - | 31220 | 12.5, and 15.0   | dose-related        |
|        | un        |       | µg/mL            | positive response)  |
|        | scheduled |       |                  | that unscheduled    |
|        | DNA       |       |                  | DNA synthesis was   |
|        | synthesis |       |                  | induced.            |
|        | in        |       |                  |                     |
|        | mammalian |       |                  |                     |
|        | cells in  |       |                  |                     |
|        | culture   |       |                  |                     |
|        | (rats)    |       |                  |                     |
+--------+-----------+-------+------------------+---------------------+
| **870. | M         | 418   | **1)** 1 mg/kg   | The mean recovery   |
| 7485** | etabolism | 75017 | radiolabelled,   | of radioactivity 4  |
|        | and       |       | single dose by   | days after exposure |
|        | pharmacok | 418   | oral gavage      | was 82.6-93.0%      |
|        | inetics - | 75018 |                  | following single or |
|        | rat       |       | **2)** 100 mg/kg | repeated oral doses |
|        |           |       | radiolabelled,   | and 88.2-99.2%      |
|        |           |       | single dose by   | following single    |
|        |           |       | oral gavage      | i.v. doses,         |
|        |           |       |                  | indicating rapid    |
|        |           |       | **3)** 1 mg/kg   | absorption,         |
|        |           |       | unlabelled, 14   | distribution, and   |
|        |           |       | days in the      | elimination. Rapid  |
|        |           |       | diet, PLUS 1     | elimination and low |
|        |           |       | mg/kg            | tissue levels       |
|        |           |       | radiolabelled,   | indicate low        |
|        |           |       | single dose by   | bioaccumulation of  |
|        |           |       | oral gavage      | the parent and      |
|        |           |       |                  | metabolites.        |
|        |           |       | **4)** 1 mg/kg   |                     |
|        |           |       | radiolabelled,   | Elimination         |
|        |           |       | by i.v.          | occurred primarily  |
|        |           |       | injection        | by biliary          |
|        |           |       |                  | excretion because   |
|        |           |       |                  | recovery of         |
|        |           |       |                  | radioactivity was   |
|        |           |       |                  | mostly in the       |
|        |           |       |                  | feces: 75.6-83.7%   |
|        |           |       |                  | following oral      |
|        |           |       |                  | exposure and        |
|        |           |       |                  | 77.2-91.4%          |
|        |           |       |                  | following i.v.      |
|        |           |       |                  | exposure. In urine, |
|        |           |       |                  | radioactivity       |
|        |           |       |                  | recovery was        |
|        |           |       |                  | 5.5-12.6% for all   |
|        |           |       |                  | dose scenarios.     |
|        |           |       |                  | Peak radioactivity  |
|        |           |       |                  | in the blood        |
|        |           |       |                  | occurred 3 hours    |
|        |           |       |                  | following a single  |
|        |           |       |                  | low dose and 3-6    |
|        |           |       |                  | hours after a       |
|        |           |       |                  | single high dose,   |
|        |           |       |                  | indicating biphasic |
|        |           |       |                  | elimination.        |
|        |           |       |                  |                     |
|        |           |       |                  | Only 8.5-14.8% and  |
|        |           |       |                  | 0.0-2.7% of the     |
|        |           |       |                  | parent compound was |
|        |           |       |                  | recovered in the    |
|        |           |       |                  | feces and urine,    |
|        |           |       |                  | respectively,       |
|        |           |       |                  | indicating          |
|        |           |       |                  | extensive           |
|        |           |       |                  | metabolism. A       |
|        |           |       |                  | number of major     |
|        |           |       |                  | metabolites were    |
|        |           |       |                  | identified;         |
|        |           |       |                  | however, 50% and    |
|        |           |       |                  | 20% of metabolites  |
|        |           |       |                  | in the feces and    |
|        |           |       |                  | urine,              |
|        |           |       |                  | respectively, were  |
|        |           |       |                  | not identified.     |
|        |           |       |                  | Sex-related         |
|        |           |       |                  | differences include |
|        |           |       |                  | a greater number of |
|        |           |       |                  | sulfate metabolites |
|        |           |       |                  | in female excreta   |
|        |           |       |                  | compared to males,  |
|        |           |       |                  | and a greater       |
|        |           |       |                  | number of ketoacid  |
|        |           |       |                  | metabolites in male |
|        |           |       |                  | urine compared to   |
|        |           |       |                  | female urine.       |
+--------+-----------+-------+------------------+---------------------+
| **870. | M         | 429   | **1)** 1 mg/kg   | The mean recovery   |
| 7485** | etabolism | 00801 | radiolabelled,   | of radioactivity    |
|        | and       |       | single dose by   | 3-4 days after      |
|        | pharmacok |       | oral gavage      | exposure was        |
|        | inetics - |       |                  | 90.4-104.5%         |
|        | rat       |       | **2)** 100 mg/kg | following single or |
|        |           |       | radiolabelled,   | repeated oral       |
|        |           |       | single dose by   | doses, indicating   |
|        |           |       | oral gavage      | rapid absorption,   |
|        |           |       |                  | distribution, and   |
|        |           |       | **3)** 1 mg/kg   | elimination.        |
|        |           |       | unlabelled, 14   | Bioaccumulation of  |
|        |           |       | days in the      | the parent compound |
|        |           |       | diet, PLUS 1     | and metabolites is  |
|        |           |       | mg/kg            | low. There were no  |
|        |           |       | radiolabelled,   | major sex- or       |
|        |           |       | single dose by   | dose-related        |
|        |           |       | oral gavage      | differences in      |
|        |           |       |                  | absorption,         |
|        |           |       |                  | distribution, or    |
|        |           |       |                  | elimination.        |
|        |           |       |                  |                     |
|        |           |       |                  | Elimination         |
|        |           |       |                  | occurred primarily  |
|        |           |       |                  | by biliary          |
|        |           |       |                  | excretion: recovery |
|        |           |       |                  | of the administered |
|        |           |       |                  | dose occurred       |
|        |           |       |                  | mainly in the bile  |
|        |           |       |                  | (79.1-87.1%) 3 days |
|        |           |       |                  | after exposure and  |
|        |           |       |                  | mostly in the feces |
|        |           |       |                  | (78.7-94.4%) 4 days |
|        |           |       |                  | after exposure. In  |
|        |           |       |                  | contrast,           |
|        |           |       |                  | radioactivity       |
|        |           |       |                  | recovery in the     |
|        |           |       |                  | urine was 3.2-11.5% |
|        |           |       |                  | at 3 and 4 days     |
|        |           |       |                  | after exposure.     |
|        |           |       |                  |                     |
|        |           |       |                  | Extensive           |
|        |           |       |                  | metabolism          |
|        |           |       |                  | occurred; numerous  |
|        |           |       |                  | metabolites were    |
|        |           |       |                  | found in the feces  |
|        |           |       |                  | and urine. There is |
|        |           |       |                  | a dose-related      |
|        |           |       |                  | difference in       |
|        |           |       |                  | metabolism. A       |
|        |           |       |                  | higher amount of    |
|        |           |       |                  | parent compound was |
|        |           |       |                  | found in the feces  |
|        |           |       |                  | following the       |
|        |           |       |                  | single high dose    |
|        |           |       |                  | compared to the     |
|        |           |       |                  | single or repeated  |
|        |           |       |                  | low dose(s), which  |
|        |           |       |                  | suggests that       |
|        |           |       |                  | saturation might be |
|        |           |       |                  | occurring at the    |
|        |           |       |                  | high dose.          |
+--------+-----------+-------+------------------+---------------------+
| **870. | Dermal    | 418   | 0, 0.125, 1.25,  | Mean % of the dose  |
| 7600** | pene      | 75019 | and 12.5 mg/kg   | absorbed (sum of    |
|        | tration - |       |                  | urine, feces,       |
|        | rat       |       | **Note:**        | carcass, and skin)  |
|        |           |       | End-use product  | after 10 hrs of     |
|        |           |       | (23.1%) was      | exposure:           |
|        |           |       | tested           |                     |
|        |           |       |                  | 0.125 mg/kg: 4.25%  |
|        |           |       |                  |                     |
|        |           |       |                  | 1.25 mg/kg: 2.08%   |
|        |           |       |                  |                     |
|        |           |       |                  | 12.5 mg/kg: 0.45%   |
+--------+-----------+-------+------------------+---------------------+

**3.3 FQPA Considerations**

The FQPA Safety Factor was removed (i.e., reduced to 1x) in assessing
the risk posed by fenbuconazole. This recommendation was based on the
following:

-   There are no data gaps for the assessment of the effects of
    fenbuconazole following *in utero* and/or postnatal exposure; a
    developmental neurotoxicity study is not required.

-   There is no indication of quantitative or qualitative susceptibility
    of rats or rabbits to *in utero* and/or postnatal exposure to
    fenbuconazole.

-   The dietary exposure assessment is based on models and input
    parameters designed to be protective of human health.

-   At this time, there are no registered residential uses for
    fenbuconazole. As a result; infants and children are not expected to
    be exposed through residential uses.

**3.3.1 Adequacy of the Toxicity Database**

The toxicology database is complete and adequate for risk assessment.

**3.3.2 Evidence of Neurotoxicity**

Acute and sub-chronic neurotoxicity studies are not required for
fenbuconazole. The available toxicology studies do not indicate that
fenbuconazole is neurotoxic. Neither sub-chronic nor chronic toxicity
studies in rats and mice nor the developmental toxicity studies in rats
or rabbits indicated that the nervous system was specifically affected
by treatment with fenbuconazole.

**3.3.3 Developmental Toxicity Studies**

No quantitative or qualitative susceptibility was observed in either the
developmental rat or rabbit studies. In the developmental rat study,
increased post-implantation loss and decreased live fetuses per dam were
noted at a dose level at which decreased maternal body weight and body
weight gain were observed. As the developmental effects observed in the
rat study were seen in the presence of maternal toxicity, they are not
considered to be qualitatively more severe than the maternal effects.
The maternal LOAEL in the rabbit study, which is based on decreased food
consumption and increased clinical signs, is a lower dose level than the
developmental LOAEL, which is based on increased early resorptions.

**3.3.4 Reproductive Toxicity Study**

In the two-generation reproduction study, a decrease in mean pup body
weight, an increased number of stillborn pups, a decreased number of
total offspring delivered, and a decreased viability index for pups were
seen at the same dose level that produced maternal death and decreased
maternal body weights. The same types of toxicity were seen in dams and
in pups (i.e., death and body weight changes), and these effects were
seen at the same dose level; thus, there is no increase in qualitative
or quantitative susceptibility in the two-generation reproduction study.

**3.3.5 Additional Information from Literature Sources**

A literature search was not conducted for this risk assessment.

**3.3.6 Pre-and/or Postnatal Toxicity**

**3.3.6.1 Determination of Susceptibility**

The data provided no indication of increased susceptibility of rats or
rabbits to *in utero* and/or postnatal exposure to fenbuconazole. In the
prenatal developmental study in rats and rabbits and the two generation
study in rats, effects in the offspring were observed only at, or above,
those treatment levels that resulted in maternal toxicity.

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

The degree of concern for infants and children exposed to fenbuconazole
*in utero* and/or postnatally is low; there are no residual
uncertainties. The toxicology database for fenbuconazole is complete and
adequate for risk assessment purposes. Acceptable developmental studies
in rats and rabbits and the two generation reproduction study in rats
did not show evidence of increased susceptibility in offspring exposed
to fenbuconazole *in* *utero* and/or postnatally. While the toxicology
database does not have an appropriate endpoint for an acute dietary
assessment for the general population, a NOAEL has been selected for the
subpopulation Females 13-49 based on developmental effects (increased
resorptions and decreased live fetuses per dam) seen at the LOAEL in the
developmental rat study. By regulating on the effect of concern for this
subpopulation, the risk assessment is protective of potential effects to
infants and children. There are currently no registered or proposed
residential uses for fenbuconazole, so exposure to fenbuconazole is
limited to dietary exposure.

**3.3.7** **Recommendation for a Developmental Neurotoxicity Study**

The available toxicology database does not indicate that fenbuconazole
is neurotoxic to rats, rabbits, or dogs. In the acceptable rat and
rabbit developmental studies and the rat reproduction study, there was
no evidence of increased quantitative or qualitative susceptibility
resulting from *in utero* and/or postnatal exposure to fenbuconazole.
Therefore, a developmental neurotoxicity study is not required.

4.  **FQPA Safety Factor for Infants and Children**

The FQPA Safety Factor was removed (i.e., reduced to 1x) in assessing
the risk posed by fenbuconazole. This recommendation was based on the
following:

-   There are no data gaps for the assessment of the effects of
    fenbuconazole following *in utero* and/or postnatal exposure; a
    developmental neurotoxicity study is not required.

-   There is no indication of quantitative or qualitative susceptibility
    of rats or rabbits to *in utero* and/or postnatal exposure to
    fenbuconazole

-   The dietary exposure assessment is based on models and input
    parameters designed to be protective of human health.

-   At this time, there are no registered residential uses for
    fenbuconazole; therefore, this type of exposure to infants and
    children is not expected.

**3.5 Hazard Identification and Toxicity Endpoint Selection**

**3.5.1 Acute Reference Dose (aRfD) - Females Age 13-49**

The acute dietary endpoint for females 13-49 is based on increased
resorptions and decreased live fetuses per dam observed at the LOAEL of
75 mg/kg/day in a developmental rat study. This endpoint is considered
appropriate for this population subgroup because the observed
developmental effects are presumed to occur following a single oral
dose. The NOAEL is 30 mg/kg/day, resulting in an acute reference dose
(aRfD) of 0.3 mg/kg/day (standard 10x intraspecies variation and 10x
interspecies extrapolation safety factors were applied). Selection of
this dose and endpoint is supported by the fact that the NOAEL in the
developmental rat study is equal to the NOAEL in the developmental
rabbit study. The LOAEL in the developmental rabbit study is based on
increased resorptions, which could also occur following a single oral
dose.

**3.5.2 Acute Reference Dose (aRfD) - General Population**

The current toxicology database does not have a dose and endpoint
suitable for acute dietary exposure assessment for the general
population. None of the effects seen in the database (excluding
developmental effects) were considered to occur as the result of one
oral dose.

**3.5.3 Chronic Reference Dose (cRfD)**

The chronic dietary endpoint is based on effects in the combined chronic
toxicity/carcinogenicity study in the rat: decreased body weight gain,
increased thyroid weight, and histopathological lesions in the liver and
thyroid gland observed at the LOAEL of 30.6/43.1 mg/kg/day (M/F).
Although a lower NOAEL is identified in the mouse carcinogenicity study
based on liver effects, the mouse study was not chosen as a basis for
the chronic dietary endpoint because it was compromised by a hepatitis
infection that could have potentiated liver toxicity. A lower NOAEL was
also identified for females in the chronic dog study based on decreased
body weight gain; however, the rat study is considered more robust than
the dog study. In addition, liver toxicity was seen at a similar dose in
both the rat and dog studies. The NOAEL was 3 mg/kg/day, with a cRfD of
0.03 mg/kg/day (standard 10x intra-species variation and 10x
interspecies extrapolation safety factors were applied).

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

Currently, there are no proposed or registered residential uses for
fenbuconazole; therefore, an incidental oral exposure risk assessment is
not necessary at this time.

**3.5.5 Dermal Absorption**

The 21-day dermal absorption study in rats indicated that fenbuconazole
is poorly absorbed through the skin, as there was no dermal or systemic
toxicity up to the limit dose. Therefore, a 4.25% (at one hour) dermal
absorption factor was selected from the dermal penetration study in rats
and should be applied to dermal risk assessments.

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

No dermal or systemic toxicity was seen in male and female
Sprague-Dawley rats following 15 repeated dermal applications of
fenbuconazole up to the limit dose in the 21-day dermal toxicity study.
Because toxicity was not seen following dermal exposure over this time
frame, and as there are no residential uses for fenbuconazole at this
time, short- and intermediate-term dermal endpoints were not selected.

At this time, current and proposed uses will not result in long-term
dermal exposure. However, for future long-term dermal risk assessments
involving chronic (non-cancer) effects, the NOAEL of 3 mg/kg/day from
the combined chronic toxicity/carcinogenicity study in the rat should be
used in conjunction with the 4.25% dermal absorption factor described in
Section 3.5.5. Fenbuconazole has been classified as a Group C
carcinogen. For long-term dermal risk assessments involving carcinogenic
effects, the Q~1~^\*^ of 3.59 x 10^-3^ should be used.

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

The dose and endpoint selected for all durations of inhalation risk
assessment were chosen from the combined chronic
toxicity/carcinogenicity study in rats. The NOAEL is 3.0 mg/kg/day,
based on decreased body weight gain, increased thyroid weights, and
histopathological lesions in the liver and thyroid glands observed at
the LOAEL. Body weight effects were evident after 4 weeks of treatment
with fenbuconazole and continued throughout the study, making this
endpoint suitable for all durations of exposure. A sub-chronic
inhalation toxicity study has not been submitted for this chemical;
therefore, the default inhalation absorption factor of 100% should be
applied for risk assessment.

For the purposes of risk assessment, the chronic rat study is considered
to be more robust than either the chronic mouse or dog studies or than
the sub-chronic rat study. Although a lower NOAEL was noted in the
sub-chronic rat toxicity study based on histopathological changes in the
liver, this dose was not selected for short- or intermediate-term
endpoints. Liver histopathology was the basis for the LOAEL in both the
sub-chronic and chronic rat studies. Therefore, the chronic NOAEL (3
mg/kg/day) is protective of this effect, and the lower value of the
subchronic rat NOAEL (1.3 mg/kg/day) is considered an artifact of dose
selection.

**3.5.8 Level of Concern for Margins of Exposure**

All target margins of exposure are 100.

**3.5.9 Recommendation for Aggregate Exposure Risk Assessments**

There are no registered or proposed residential uses for fenbuconazole;
therefore, the aggregate exposure risk assessment should be based on
dietary and drinking water exposure only.

**3.5.10** **Classification of Carcinogenic Potential**

Under the 1986 cancer classification scheme, fenbuconazole was
classified as a Group C, possible human carcinogen, with a low dose
extrapolation model applied to the animal data for the quantification of
human risk (Q~1~\*). This classification was based on increased
incidence of hepatocellular adenomas and carcinomas in male and female
mice and of thyroid follicular adenomas and combined adenomas/carcinomas
in male rats. Based on mechanistic data, quantification of risk was
derived using combined hepatocellular adenomas/carcinomas in female
mice. The upper bound estimate of unit risk, Q~1~\* (mg/kg/day)^-1^ is
3.59 x 10^-3^ in human equivalents.

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

+-------------+-------------+---------------+-------------------------+
| **Table     |             |               |                         |
| 3.5.1       |             |               |                         |
| Summary of  |             |               |                         |
| To          |             |               |                         |
| xicological |             |               |                         |
| Doses and   |             |               |                         |
| Endpoints   |             |               |                         |
| for         |             |               |                         |
| Fe          |             |               |                         |
| nbuconazole |             |               |                         |
| for use in  |             |               |                         |
| Dietary**   |             |               |                         |
|             |             |               |                         |
| **and       |             |               |                         |
| Non-O       |             |               |                         |
| ccupational |             |               |                         |
| Human       |             |               |                         |
| Health Risk |             |               |                         |
| As          |             |               |                         |
| sessments** |             |               |                         |
+=============+=============+===============+=========================+
| *           | **Dose Used | **FQPA SF and | **Study and             |
| *Exposure** | in Risk     | Level of      | Toxicological Effects** |
|             | Assessment, | Concern for   |                         |
| *           | UF**        | Risk          |                         |
| *Scenario** |             | Assessment**  |                         |
+-------------+-------------+---------------+-------------------------+
| Acute       | NOAEL = 30  | FQPA SF =1    | **Developmental rat     |
| Dietary     | mg/kg/day   |               | study**                 |
|             |             | **aPAD** =    |                         |
| (Females    | UF = 100    | [acute        | Developmental LOAEL =   |
| 13-49 years |             | RfD           | 75 mg/kg/day based on   |
| of age)     | **Acute     | ]{.underline} | increased resorptions   |
|             | RfD** = 0.3 |               | and decreased live      |
|             | mg/kg       | FQPA SF       | fetuses per dam.        |
|             |             |               |                         |
|             |             | = 0.3 mg/kg   |                         |
+-------------+-------------+---------------+-------------------------+
| Acute       | None        | None          | **Not selected.**       |
| Dietary     |             |               |                         |
| (General    |             |               | No appropriate dose and |
| population  |             |               | endpoint could be       |
| including   |             |               | identified for these    |
| infants and |             |               | population groups.      |
| children)   |             |               |                         |
+-------------+-------------+---------------+-------------------------+
| Chronic     | NOAEL= 3    | FQPA SF =1    | **Combined chronic      |
| Dietary     | mg/kg/day   |               | toxicity/               |
|             |             | **cPAD** =    | carcinogenicity - Rat** |
| (All        | UF = 100    |               |                         |
| p           |             | [chronic      | LOAEL = 30.6/43.1 (M/F) |
| opulations) | **Chronic   | RfD           | mg/kg/day based on      |
|             | RfD** =     | ]{.underline} | decreased body weight   |
|             | 0.03        |               | gain, increased thyroid |
|             | mg/kg/day   | FQPA SF       | weight, and             |
|             |             |               | histopathological       |
|             |             | = 0.03        | lesions in the liver    |
|             |             | mg/kg/day     | and thyroid gland       |
+-------------+-------------+---------------+-------------------------+
| Incidental  | None        | None          | **Not selected.**       |
| Oral (All   |             |               |                         |
| durations)  |             |               | No registered uses      |
|             |             |               | would result in         |
|             |             |               | residential exposure.   |
+-------------+-------------+---------------+-------------------------+
| Cancer      | **Classi    |               |                         |
| (oral,      | fication:** |               |                         |
| dermal,     | Under the   |               |                         |
| inhalation) | 1986 cancer |               |                         |
|             | cla         |               |                         |
|             | ssification |               |                         |
|             | scheme,     |               |                         |
|             | fe          |               |                         |
|             | nbuconazole |               |                         |
|             | was         |               |                         |
|             | classified  |               |                         |
|             | as a Group  |               |                         |
|             | C -         |               |                         |
|             | Possible    |               |                         |
|             | Human       |               |                         |
|             | Carcinogen  |               |                         |
|             | with a low  |               |                         |
|             | dose        |               |                         |
|             | ex          |               |                         |
|             | trapolation |               |                         |
|             | model       |               |                         |
|             | applied to  |               |                         |
|             | the animal  |               |                         |
|             | data for    |               |                         |
|             | the         |               |                         |
|             | qua         |               |                         |
|             | ntification |               |                         |
|             | of human    |               |                         |
|             | risk        |               |                         |
|             | (Q~1~\*).   |               |                         |
|             | This        |               |                         |
|             | cla         |               |                         |
|             | ssification |               |                         |
|             | was based   |               |                         |
|             | on          |               |                         |
|             | increased   |               |                         |
|             | incidence   |               |                         |
|             | of          |               |                         |
|             | hep         |               |                         |
|             | atocellular |               |                         |
|             | adenomas    |               |                         |
|             | and         |               |                         |
|             | carcinomas  |               |                         |
|             | in male and |               |                         |
|             | female mice |               |                         |
|             | and of      |               |                         |
|             | thyroid     |               |                         |
|             | follicular  |               |                         |
|             | adenomas    |               |                         |
|             | and         |               |                         |
|             | combined    |               |                         |
|             | adenomas    |               |                         |
|             | /carcinomas |               |                         |
|             | in male     |               |                         |
|             | rats. Based |               |                         |
|             | on          |               |                         |
|             | mechanistic |               |                         |
|             | data,       |               |                         |
|             | qua         |               |                         |
|             | ntification |               |                         |
|             | of risk was |               |                         |
|             | derived     |               |                         |
|             | using       |               |                         |
|             | combined    |               |                         |
|             | hep         |               |                         |
|             | atocellular |               |                         |
|             | adenomas    |               |                         |
|             | /carcinomas |               |                         |
|             | in female   |               |                         |
|             | mice. The   |               |                         |
|             | upper bound |               |                         |
|             | estimate of |               |                         |
|             | unit risk,  |               |                         |
|             | Q~1~\*      |               |                         |
|             | (mg/        |               |                         |
|             | kg/day)^-1^ |               |                         |
|             | is 3.59 x   |               |                         |
|             | 10^-3^ in   |               |                         |
|             | human       |               |                         |
|             | e           |               |                         |
|             | quivalents. |               |                         |
+-------------+-------------+---------------+-------------------------+
| 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        |             |               |                         |
+-------------+-------------+---------------+-------------------------+

+-------------+-------------+---------------+-------------------------+
| **Table     |             |               |                         |
| 3.5.2       |             |               |                         |
| Summary of  |             |               |                         |
| To          |             |               |                         |
| xicological |             |               |                         |
| Doses and   |             |               |                         |
| Endpoints   |             |               |                         |
| for         |             |               |                         |
| Fe          |             |               |                         |
| nbuconazole |             |               |                         |
| for use     |             |               |                         |
| in**        |             |               |                         |
|             |             |               |                         |
| **O         |             |               |                         |
| ccupational |             |               |                         |
| Human       |             |               |                         |
| Health Risk |             |               |                         |
| As          |             |               |                         |
| sessments** |             |               |                         |
+=============+=============+===============+=========================+
| *           | **Dose Used | **FQPA SF and | **Study and             |
| *Exposure** | in Risk     | Level of      | Toxicological Effects** |
|             | Assessment, | Concern for   |                         |
| *           | UF**        | Risk          |                         |
| *Scenario** |             | Assessment**  |                         |
+-------------+-------------+---------------+-------------------------+
| Long-Term   | Oral study  | **            | **Combined chronic      |
| Dermal      | NOAEL= 3    | Residential** | toxicity/               |
| (several    | mg/kg/day   | LOC for MOE = | carcinogenicity - Rat** |
| months to   |             | NA            |                         |
| lifetime)   | (dermal     |               | LOAEL = 30.6/43.1 (M/F) |
|             | absorption  | **O           | mg/kg/day based on      |
|             | rate =      | ccupational** | decreased body weight   |
|             | 4.25%)      | LOC for MOE = | gain, increased thyroid |
|             |             | 100           | weight, and             |
|             |             |               | histopathological       |
|             |             |               | lesions in the liver    |
|             |             |               | and thyroid gland       |
+-------------+-------------+---------------+-------------------------+
| Inhalation  | Oral study  | **            | **Combined chronic      |
| (All        | NOAEL= 3    | Residential** | toxicity/               |
| durations)  | mg/kg/day   | LOC for MOE = | carcinogenicity - Rat** |
|             |             | NA            |                         |
|             | Absorption  |               | LOAEL = 30.6/43.1 (M/F) |
|             | factor =    | **O           | mg/kg/day based on      |
|             | 100%        | ccupational** | decreased body weight   |
|             |             | LOC for MOE = | gain, increased thyroid |
|             |             | 100           | weight, and             |
|             |             |               | histopathological       |
|             |             |               | lesions in the liver    |
|             |             |               | and thyroid gland       |
+-------------+-------------+---------------+-------------------------+
| Cancer      | **Classi    |               |                         |
| (oral,      | fication:** |               |                         |
| dermal,     | Under the   |               |                         |
| inhalation) | 1986 cancer |               |                         |
|             | cla         |               |                         |
|             | ssification |               |                         |
|             | scheme,     |               |                         |
|             | fe          |               |                         |
|             | nbuconazole |               |                         |
|             | was         |               |                         |
|             | classified  |               |                         |
|             | as a Group  |               |                         |
|             | C -         |               |                         |
|             | Possible    |               |                         |
|             | Human       |               |                         |
|             | Carcinogen  |               |                         |
|             | with a low  |               |                         |
|             | dose        |               |                         |
|             | ex          |               |                         |
|             | trapolation |               |                         |
|             | model       |               |                         |
|             | applied to  |               |                         |
|             | the animal  |               |                         |
|             | data for    |               |                         |
|             | the         |               |                         |
|             | qua         |               |                         |
|             | ntification |               |                         |
|             | of human    |               |                         |
|             | risk        |               |                         |
|             | (Q~1~\*).   |               |                         |
|             | This        |               |                         |
|             | cla         |               |                         |
|             | ssification |               |                         |
|             | was based   |               |                         |
|             | on          |               |                         |
|             | increased   |               |                         |
|             | incidence   |               |                         |
|             | of          |               |                         |
|             | hep         |               |                         |
|             | atocellular |               |                         |
|             | adenomas    |               |                         |
|             | and         |               |                         |
|             | carcinomas  |               |                         |
|             | in male and |               |                         |
|             | female mice |               |                         |
|             | and of      |               |                         |
|             | thyroid     |               |                         |
|             | follicular  |               |                         |
|             | adenomas    |               |                         |
|             | and         |               |                         |
|             | combined    |               |                         |
|             | adenomas    |               |                         |
|             | /carcinomas |               |                         |
|             | in male     |               |                         |
|             | rats. Based |               |                         |
|             | on          |               |                         |
|             | mechanistic |               |                         |
|             | data,       |               |                         |
|             | qua         |               |                         |
|             | ntification |               |                         |
|             | of risk was |               |                         |
|             | derived     |               |                         |
|             | using       |               |                         |
|             | combined    |               |                         |
|             | hep         |               |                         |
|             | atocellular |               |                         |
|             | adenomas    |               |                         |
|             | /carcinomas |               |                         |
|             | in female   |               |                         |
|             | mice. The   |               |                         |
|             | upper bound |               |                         |
|             | estimate of |               |                         |
|             | unit risk,  |               |                         |
|             | Q~1~\*      |               |                         |
|             | (mg/        |               |                         |
|             | kg/day)^-1^ |               |                         |
|             | is 3.59 x   |               |                         |
|             | 10^-3^ in   |               |                         |
|             | human       |               |                         |
|             | e           |               |                         |
|             | quivalents. |               |                         |
+-------------+-------------+---------------+-------------------------+
| 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, LOC = |             |               |                         |
| level of    |             |               |                         |
| concern, NA |             |               |                         |
| = Not       |             |               |                         |
| Applicable  |             |               |                         |
+-------------+-------------+---------------+-------------------------+

**3.6 Endocrine disruption**

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

When additional appropriate screening and/or testing protocols being
considered under the Agency's EDSP have been developed, fenbuconazole
might be subjected to further screening and/or testing to characterize
more fully the effects related to endocrine disruption.

4**.0 PUBLIC HEALTH and PESTICIDE EPIDEMIOLOGY DATA**

**4.1 Incident Reports**

At this time, there are no clinical acute poisoning cases reported in
the literature for fenbuconazole.

**5.0 DIETARY EXPOSURE/RISK CHARACTERIZATION**

**5.1 Pesticide Metabolism and Environmental Degradation**

**5.1.1 Metabolism in Primary Crops**

The degree of metabolism of fenbuconazole varies depending on the
primary crop. Overall, three routes of metabolism appear to be
important: (i) initial cleavage of the triazole ring can lead to
terminal residues of triazole alanine and/or triazole acetic acid; (ii)
hydroxylation of the chlorophenyl ring leads to glycoside conjugates of
the parent molecule, seen primarily in peanut as the glucose conjugate
of RH-4911; and (iii) hydroxylation of the alkyl chain results in
formation of the ketone (RH-6467), lactone (RH-9129 and RH-9130), and
iminolactone (RH-6468) metabolites.

**5.1.2. Metabolism in Rotational Crops**

Fenbuconazole appears to be extensively metabolized in the environment
prior to uptake of residues by rotational crops. The major residues
observed in rotational crops are triazole alanine and triazole acetic
acid. Studies using radiolabeled fenbuconazole reveal that parent
compound, RH-9129, RH-9130, and RH-6467 might be found in rotational
crop matrices, but only in very small amounts.

**5.1.3.** **Metabolism in Livestock**

As there are no significant animal feed items associated with the use of
fenbuconazole on peppers, bushberries, or cranberries, the metabolism of
fenbuconazole in livestock is not relevant to these tolerance petitions.

4.  **Analytical Methodology**

A GC/NPD method, 34-90-47R, is currently available for enforcing
tolerances of fenbuconazole and its two lactone metabolites, RH-9129 and
RH-9130, in/on stone fruits. A slightly modified version of this method
was demonstrated to be adequate for determining residues in peppers. For
this method, the validated limit of quantitation (LOQ) for residues
in/on peppers is 0.01 ppm for each analyte, for a combined LOQ of 0.03
ppm. The statistically calculated limit of detection (LOD) was
0.003-0.004 ppm for each analyte. The method was adequately validated in
conjunction with the pepper field trials.

Method 34-90-47R was demonstrated to be adequate for determining
residues in bushberries and cranberries. The validated LOQ is 0.01 ppm
for each analyte in/on berries, for a combined LOQ of 0.03 ppm. The LOD
was not reported. As currently written, the method expresses residues of
RH-9129 and RH-9130 in terms of the individual analytes. To calculate
combined residues (expressed as parent), the metabolites must be
multiplied by the molecular weight conversion factor of 0.95x. The above
method was adequately validated in conjunction with the blueberry and
cranberry field trials. The average method recoveries were 89-106% for
the three analytes.

5.  **Environmental Degradation**

Reference: Drinking Water Exposure Assessment for Fenbuconazole Use on
Pepper, D344352, J. Lin, 1/16/2008

Fenbuconazole is considered to be moderately persistent to persistent in
the environment and slightly mobile to mobile in soils. Because of its
adsorption to soil, the potential for fenbuconazole to leach to
groundwater appears to be slight. However, the potential to contaminate
groundwater may be greater at vulnerable sites, i.e., where soils have
low organic matter and where groundwater is relatively close to the
surface. The long half-lives of fenbuconazole in aerobic soil and
terrestrial field dissipation studies indicate that when fenbuconazole
is applied over multiple growing seasons, soil residue accumulation may
result. These residues may be available for rotational crop uptake or
may be transported with sediments during runoff events. For purposes of
human health risk assessment, the residue of concern in water is
fenbuconazole, *per se*.

RH-9129, RH-9130, RH-6467, and RH-0118 (1,2,4-triazole) are degradates
of fenbuconazole. In the aerobic metabolism study, concentrations of the
metabolites RH-9129, RH-9130, and RH-6467 increased with time accounting
for 2.5-9.6% of the applied radioactivi­ty in both soils treated with
both radiolabel­s (RH-9129 and RH-9130 are diastereomers). 1,2,4-Triazole
accounted for 11.2-13.6% and for 6.5-6.6% of the applied
^14^C-tria­zole-RH-7592 in the Lawrenceville and Pasquo­tank soils,
respectively. In the anaerobic metabolism study, RH-9129 and combined
RH-9130/RH-6467 accounted for 0.6% (day 0) to 7.33% (day 60).

**5.1.6 Comparative Metabolic Profile**

Adequate studies are available depicting the metabolism of
\[^14^C\]fenbuconazole in rats, primary crops (peaches, peanuts, wheat,
sugar beets), rotational crops (collards, turnips, wheat), and livestock
(lactating goats, laying hens). Major residues consistently noted in
these studies include parent fenbuconazole and the lactone metabolites
RH-9129, RH-9130, and RH-6467. The common triazole metabolites
1,2,4-triazole, triazole alanine, and triazole acetic acid were observed
in all of the metabolism studies, with the degree of metabolite
formation being highly dependent on the species being studied. A
comparison of the metabolism that occurs in these entities was included
in the previous fenbuconazole risk assessment (D316607, M. Collantes, et
al., 8/3/2006). Sufficient metabolism data have been submitted for the
purposes of the current tolerance petitions.

+-----------+---------------+---------+---------+---------------------+
| **Table   |               |         |         |                     |
| 5.1.a     |               |         |         |                     |
| Summary   |               |         |         |                     |
| of        |               |         |         |                     |
| Me        |               |         |         |                     |
| tabolites |               |         |         |                     |
| and       |               |         |         |                     |
| D         |               |         |         |                     |
| egradates |               |         |         |                     |
| of        |               |         |         |                     |
| Fenbuco   |               |         |         |                     |
| nazole.** |               |         |         |                     |
+===========+===============+=========+=========+=====================+
| **Common  | **Chemical    | **Major | **Minor | **Chemical          |
| na        | name**        | Metab   | Met     | structure**         |
| me/code** |               | olite** | abolite |                     |
|           |               |         | in**    |                     |
+-----------+---------------+---------+---------+---------------------+
| **Fenbuc  | α-\[2-(4-c    | Peach   | Rot     | ![](media/im        |
| onazole** | hlorophenyl)e |         | ational | age2.wmf){width="1. |
|           | thyl\]-α-phen | Peanut  | Crops   | 9388888888888889in" |
| RH-7592   | yl-1*H*-1,2,4 | Vine    |         | height="1.1in"}     |
|           | -triazole-1-p |         |         |                     |
|           | ropanenitrile | Sugar   |         |                     |
|           |               | beet    |         |                     |
|           |               |         |         |                     |
|           |               | Wheat   |         |                     |
|           |               |         |         |                     |
|           |               | Ru      |         |                     |
|           |               | minants |         |                     |
|           |               |         |         |                     |
|           |               | Poultry |         |                     |
|           |               |         |         |                     |
|           |               | Water   |         |                     |
+-----------+---------------+---------+---------+---------------------+
| **Lactone | trans- or     | Peach   | Peanut  | ![](media/im        |
| A and B   | cis-5-(4-ch   |         |         | age4.wmf){width="1. |
| Meta      | lorophenyl)di | Poultry | Sugar   | 8395833333333333in" |
| bolites** | hydro-3-pheny |         | beet    | height="1.2in"}     |
|           | l-3-(1*H*-1,2 | R       |         |                     |
| RH-9129   | ,4-triazol-1- | uminant | Wheat   |                     |
| and       | ylmethyl)-2(3 |         |         |                     |
| RH-9130   | *H*)-furanone |         | Rot     |                     |
|           |               |         | ational |                     |
|           |               |         | Crops   |                     |
+-----------+---------------+---------+---------+---------------------+
| **T       | 1H-1          | Eggs    | Rat     | ![](media/im        |
| riazole** | ,2,4-triazole |         |         | age5.wmf){width="0. |
|           |               | Poultry | R       | 6979166666666666in" |
| RH-0118   |               |         | uminant | height="0.65in"}    |
|           |               |         |         |                     |
|           |               |         | Milk    |                     |
+-----------+---------------+---------+---------+---------------------+
| *         | 2-amino       | Peach   | Milk    | ![](media/im        |
| *Triazole | -3-(1H-1,2,4- |         |         | age6.wmf){width="1. |
| Alanine** | triazol-1-yl) | Peanut  |         | 4555555555555555in" |
|           | propanoic     |         |         | height="0.9in"}     |
| TA        | acid          | Wheat   |         |                     |
|           |               |         |         |                     |
| RH-3968   |               | Rot     |         |                     |
|           |               | ational |         |                     |
|           |               | Crops   |         |                     |
+-----------+---------------+---------+---------+---------------------+
| *         | 1H-1,2,4      | Wheat   | Peach   | ![](media/im        |
| *Triazole | -triazol-1-yl |         |         | age7.wmf){width="1. |
| Acetic    | acetic acid   | Rot     |         | 4527777777777777in" |
| Acid**    |               | ational |         | height="0.7in"}     |
|           |               | Crops   |         |                     |
| TAA       |               |         |         |                     |
|           |               |         |         |                     |
| RH-3779   |               |         |         |                     |
|           |               |         |         |                     |
| RH-4098   |               |         |         |                     |
+-----------+---------------+---------+---------+---------------------+

**5.1.7 Toxicity Profile of Major Metabolites and Degradates**

Toxicological data specific to 1,2,4-triazole, triazole alanine, and
triazole acetic acid have been submitted to the Agency. Risks associated
with exposure to these three metabolites are the subject of a separate
risk assessment (M. Doherty *et al*., D322215, 2/7/06). For major
metabolites of fenbuconazole other than those three compounds,
toxicological data are not available. Structural similarities between
fenbuconazole and the metabolites RH-9129, RH-9130, and RH-4911 lead HED
to believe that these compounds might have similar toxicity. HED also
has concern regarding the potential toxicity of RH-7905 because cleavage
of the labile sugar moiety results in the formation of RH-4911.

**5.1.8 Pesticide Metabolites and Degradates of Concern**

  --------------------------------------------------------------------------------
  **Table 5.1.b                                          
  Summary of                                             
  Metabolites and                                        
  Degradates to be                                       
  included in the                                        
  Risk Assessment                                        
  and Tolerance                                          
  Expression\***                                         
  ---------------- ------------- ----------------------- -------------------------
  **Matrix**                     **Residues included in  **Residues included in
                                 Risk Assessment**       Tolerance Expression**

  Plants           Primary Crop  Fenbuconazole +         Fenbuconazole + RH-9129 +
                                 RH-9129 + RH-9130 +     RH-9130, expressed as
                                 RH-7905 (peanut only) + fenbuconazole
                                 RH-4911 (peanut only)   

                   Rotational    Not Applicable at this  Not Applicable at this
                   Crop          time                    time

  Livestock        Ruminant      Fenbuconazole +         Fenbuconazole + RH-9129 +
                                 RH-9129 + RH-9130       RH-9130, expressed as
                                                         fenbuconazole

                   Poultry       Not Applicable at this  Not Applicable at this
                                 time                    time

  Drinking Water                 Fenbuconazole           Not Applicable
  --------------------------------------------------------------------------------

> \*The common triazole metabolites 1,2,4-triazole, triazole alanine,
> and triazole acetic acid have been identified as residues of concern
> for risk assessment. Separate assessments addressing these compounds
> have been conducted (Memo, M. Doherty, et al., D322215, 2/7/2006 and
> Memo, M. Doherty, D350314, 3/27/2008).

HED has determined that the residues of concern for risk assessment are
fenbuconazole and the following metabolites: RH-9129, RH-9130,
RH-4911(peanut only), and RH-7905 (peanut only). RH-9129 and RH-9130 are
*cis/trans* isomers of the lactone metabolite of fenbuconazole and may
account for approximately one third of the total fenbuconazole residues.
RH-9129 and RH-9130 are residues of concern for both risk-assessment and
tolerance-enforcement purposes. RH-7905 is a minor metabolite except in
peanut. In animals, the glucoside conjugate (RH-7905) will be cleaved to
yield RH-4911. Although RH-4911, being a hydroxy-derivative of
fenbuconazole, is likely to be less toxic than the parent, HED has no
specific toxicological information for this compound. As RH-4911 shares
structural features with the parent, HED is assuming that it has the
same toxicity as fenbuconazole. Therefore, RH-7905 and RH-4911 are being
included as residues of concern for risk assessment (peanuts only). The
current analytical enforcement method has been validated for the
analysis of fenbuconazole as well as RH-9129 and RH-9130.

9.  **Drinking Water Residue Profile**

Drinking Water Exposure Assessment for Fenbuconazole Use on Pepper,
D344352, J. Lin, 1/16/2008

The drinking water exposure assessment performed in support of this risk
assessment addresses the human exposure of fenbuconazole through
ingestion of drinking water from the pepper uses. No monitoring data
were available to the Environmental Fate and Effects Division (EFED). A
drinking water assessment was conducted previously (Memo, D330709, A.
Mudallal, 7/7/2006). Based on that drinking water assessment, the
PRZM/EXAMS Michigan cherry scenario at the highest application rate (8
aerial applications of 0.094 lb ai/A/application at 7-day interval)
generated the highest residue concentrations of fenbuconazole in surface
drinking water of 20.3 µg/L for the peak concentration, 16.5 µg/L for
the annual average concentration, and 11.7 µg/L for the 30 year average
concentration. With the new pepper uses (4 aerial applications of 0.1875
lb ai/A/application), the highest estimated surface water drinking water
concentrations for fenbuconazole are:

**24.1** ug /L for the 1 in 10 year annual peak concentration
(acute)(pepper use)

> **16.5** ug /L for the 1 in 10 year annual mean concentration
> (non-cancer chronic)(Michigan cherry use)
>
> **11.7** ug /L for the 30 year annual mean concentration (cancer
> chronic)(Michigan cherry use)

The SCI-GROW estimated groundwater drinking water concentrations for
fenbuconazole are not expected to exceed 0.031 μg/L (based on Michigan
Cherry Scenario, D330709).

The 1,2,4-triazole degradate is being characterized in a separate,
cumulative assessment.

Therefore, the drinking water assessment addresses the parent compound
only.

+--------------------------+---------------------+---------------------+
| **Table 5.1.c Summary of |                     |                     |
| Estimated Surface and    |                     |                     |
| Ground Water             |                     |                     |
| Concentrations for       |                     |                     |
| Fenbuconazole.**         |                     |                     |
+==========================+=====================+=====================+
| **Exposure Duration**    | **Fenbuconazole**   |                     |
+--------------------------+---------------------+---------------------+
|                          | **Surface Water     | **Groundwater       |
|                          | Conc., ppb ^a^**    | Conc., ppb ^b^**    |
+--------------------------+---------------------+---------------------+
| Acute                    | 24.1                | 0.031               |
+--------------------------+---------------------+---------------------+
| Chronic (non-cancer)     | 16.5                |                     |
+--------------------------+---------------------+---------------------+
| Chronic (cancer)         | 11.7                |                     |
+--------------------------+---------------------+---------------------+
| ^a^ From the Tier II     |                     |                     |
| PRZM-EXAMS - Index       |                     |                     |
| Reservoir model. Input   |                     |                     |
| parameters for the acute |                     |                     |
| value are based on the   |                     |                     |
| pepper use. Input        |                     |                     |
| parameters for the       |                     |                     |
| chronic and cancer       |                     |                     |
| assessments are based on |                     |                     |
| the Michigan cherry      |                     |                     |
| scenario.                |                     |                     |
|                          |                     |                     |
| ^b^ From the SCI-GROW    |                     |                     |
| model assuming a maximum |                     |                     |
| annual use rate of 0.75  |                     |                     |
| lb ai/A, a K~oc~ of 2884 |                     |                     |
| mL/g, and a half-life of |                     |                     |
| 393 days.                |                     |                     |
+--------------------------+---------------------+---------------------+

**5.1.10 Food Residue Profile**

Reference: Fenbuconazole, Petition for Registration for Use on Pepper,
Bushberry Subgroup (13-B), and Cranberry. Summary of Analytical
Chemistry and Residue Data, D313752, D. Dotson, 6/12/2008.

The petitioner submitted adequate studies describing residues of
fenbuconazole and its metabolites RH-9129 and RH-9130 in peppers,
blueberries, and cranberries. No major deficiencies were noted in the
residue chemistry database. Crop field trials resulted in measurable
residues of concern for all crops, though the relative amounts of each
residue of concern varies based on the crop.

Adequate field trial data are available supporting the proposed use on
peppers. Following the last of four or five broadcast foliar
applications of fenbuconazole (WP) at rates totaling 0.66-0.84 lb
ai/A/season (0.9-1.1x rates), the combined residues of fenbuconazole,
RH-9129, and RH-9130 were 0.05-0.23 ppm in/on 18 samples of bell and
non-bell peppers harvested 6-7 days after the last treatment. The field
trials included the use of a non-ionic surfactant. Average combined
residues were 0.14 ppm in/on peppers at approximately 7 days after the
last application, and residues were shown to decline at longer
post-treatment intervals. No processing studies are required for this
petition, as there are no regulated processed commodities associated
with peppers.

The available cranberry data are adequate and support the use of up to
five foliar applications of fenbuconazole (WP or FlC) at up to 0.188 lb
ai/A/application, for a maximum seasonal rate of 0.94 lb ai/A. The data
support the label PHI of 30 days, a minimum RTI of 10 days, and the use
of a non-ionic surfactant in the spray mix. In the five cranberry field
trials, the combined residues of fenbuconazole and its lactone
metabolites were 0.09-0.49 ppm in/on 10 samples harvested 25-28 days
after the final application, and average combined residues were 0.199
ppm.

Nine of the ten submitted blueberry field trials are adequate. Eight
acceptable field trials are needed for blueberries. Data from the
blueberry field trials support the use of up to five foliar applications
of fenbuconazole (WP or FlC) to bushberries at up to 0.094 lb
ai/A/application, for a maximum seasonal rate of 0.47 lb ai/A. The data
support the label PHI of 30 days, a minimum RTI of 10 days, and the use
of a non-ionic surfactant in the spray mix. The combined residues of
fenbuconazole, RH-9129, and RH-9130 (expressed as parent) were
\<0.03-0.24 ppm in/on 18 samples harvested 25-35 days after the last
application, and average combined residues were 0.083 ppm.

**5.1.11 International Residue Limits**

[MRLs for residues of fenbuconazole have been established by Codex,
Canada, and Mexico. The residue definition for both Codex and Mexico is
fenbuconazole, *per se.* The Canadian residue definition, however, is
the combined residues of fenbuconazole and its metabolites, RH-9129 and
RH-9130, each expressed as parent (i.e*.*, the same as the U.S.
tolerance definition). As there are no established or proposed Canadian,
Mexican, or Codex MRLs for fenbuconazole on peppers, there are no
international harmonization issues for the pepper tolerance
petition.]{.mark}

The U.S. has already established tolerances for cranberries at 0.5 ppm
and bushberries at 0.3 ppm. Mexico established tolerances for these
commodities based on the established U.S. tolerances. Therefore, HED
recommends that the current tolerances remain in effect, even though
they are different than the tolerances that are recommended by HED's
statistical tolerance generator. As a result, HED recommends that the
0.3 ppm tolerance for bushberries remain in effect, even though the
tolerance generator recommends a tolerance of 0.25 ppm, and the 0.5 ppm
tolerance for cranberries remain in effect, even though the tolerance
generator recommends a tolerance of 0.70 ppm.

1.  **Dietary Exposure and Risk**

Reference: Fenbuconazole, Acute, Chronic, and Cancer Aggregate Dietary
(Food and Drinking Water) Exposure Analysis for the Section 3
Registration Action, D350321, D. Dotson, 6/12/2008.

Acute, chronic, and cancer dietary risk assessments were conducted using
the Dietary Exposure Evaluation Model (DEEM-FCID, Version 2.03), which
uses food consumption data from the USDA's Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998. The analyses
were performed to estimate the dietary exposures and risks associated
with the uses of fenbuconazole on all registered and proposed
commodities. All three analyses include estimates for residues of
fenbuconazole in water.

**5.2.1 Acute Dietary Exposure/Risk**

The acute dietary exposure analysis is based on tolerance-level residues
and assumes 100% crop treated. The assessment included a conservative
estimated drinking water concentration (EDWC) based on the pepper use.
As such, it is highly conservative with respect to evaluating potential
impacts of acute dietary exposure to fenbuconazole on human health. The
only population subgroup that is relevant for this acute assessment is
females of child-bearing age (i.e., females 13-49 years old). The acute
risk estimate that results from this analysis is 3.1% of the aPAD at the
95^th^ percentile of exposure. This risk estimate is considerably lower
than HED's level of concern (100% of the aPAD).

**5.2.2 Chronic Dietary Exposure/Risk**

The chronic (non-cancer) dietary analysis is more refined in that it
uses average residues from field trials. Because of the manner in which
these data were submitted and reviewed, multiple averages were
calculated for many of the crops. For these crops, the highest average
was used in the analysis. The non-cancer dietary analysis assumes 100%
crop treated. The assessment included a conservative EDWC based on the
cherry use. The most highly exposed population subgroup is All Infants
(\<1 year old) which utilizes 6.8% of the cPAD. The risk estimate for
the general U.S. population is 2.3% of the cPAD. As with the acute
assessment, the risk estimates are all well below HED's level of concern
(100% of the cPAD).

**5.2.3 Cancer Dietary Exposure/Risk**

The cancer dietary analysis uses the same food residue inputs as those
used in the chronic non-cancer assessment. The cancer analysis is
further refined in that it makes use of average percent crop treated
estimates. The assessment included a conservative EDWC based on the
cherry use. The cancer risk estimate for the general U.S. population is
1.7 x 10^-6^. Typically, HED is concerned when the risk estimate
associated with food and drinking water exceeds 3 x 10^-6^. As a result,
cancer risk to the general U.S. population is below HED's level of
concern.

+--------------+--------+-----+----------+-------+---------+----------+
| **Table 5.2. |        |     |          |       |         |          |
| Summary of   |        |     |          |       |         |          |
| Dietary      |        |     |          |       |         |          |
| Exposure and |        |     |          |       |         |          |
| Risk         |        |     |          |       |         |          |
| Estimates    |        |     |          |       |         |          |
| for          |        |     |          |       |         |          |
| Fen          |        |     |          |       |         |          |
| buconazole** |        |     |          |       |         |          |
+==============+========+=====+==========+=======+=========+==========+
| **Population | *      |     | *        |       | **C     |          |
| Subgroup**   | *Acute |     | *Chronic |       | ancer** |          |
|              | Die    |     | D        |       |         |          |
|              | tary** |     | ietary** |       |         |          |
|              |        |     |          |       |         |          |
|              | **(    |     |          |       |         |          |
|              | 95^th^ |     |          |       |         |          |
|              | P      |     |          |       |         |          |
|              | ercent |     |          |       |         |          |
|              | ile)** |     |          |       |         |          |
+--------------+--------+-----+----------+-------+---------+----------+
|              | **Ex   | **% | **Ex     | **%   | **Exp   | **Risk** |
|              | posure | aPA | posure** | c     | osure** |          |
|              | (      | D** |          | PAD** |         |          |
|              | mg/kg/ |     | **(mg/k  |       | *       |          |
|              | day)** |     | g/day)** |       | *(mg/kg |          |
|              |        |     |          |       | /day)** |          |
+--------------+--------+-----+----------+-------+---------+----------+
| General U.S. | Not    |     | 0.000700 | 2.3   | 0       | **1.7 x  |
| Pop.         | Appl   |     |          |       | .000473 | 10^-6^** |
|              | icable |     |          |       |         |          |
+--------------+--------+-----+----------+-------+---------+----------+
| **All        |        |     | **0.     | **    | Not     |          |
| Infants (\<  |        |     | 002027** | 6.8** | App     |          |
| 1 year)**    |        |     |          |       | licable |          |
+--------------+--------+-----+----------+-------+---------+----------+
| Children     |        |     | 0.001842 | 6.1   |         |          |
| (1-2 years)  |        |     |          |       |         |          |
+--------------+--------+-----+----------+-------+---------+----------+
| Children     |        |     | 0.001450 | 4.8   |         |          |
| (3-5 years)  |        |     |          |       |         |          |
+--------------+--------+-----+----------+-------+---------+----------+
| Children     |        |     | 0.000812 | 2.7   |         |          |
| (6-12 years) |        |     |          |       |         |          |
+--------------+--------+-----+----------+-------+---------+----------+
| Youth (13-19 |        |     | 0.000440 | 1.5   |         |          |
| years)       |        |     |          |       |         |          |
+--------------+--------+-----+----------+-------+---------+----------+
| Adults       |        |     | 0.000563 | 1.9   |         |          |
| (20-49       |        |     |          |       |         |          |
| years)       |        |     |          |       |         |          |
+--------------+--------+-----+----------+-------+---------+----------+
| Adults (50+  |        |     | 0.000645 | 2.2   |         |          |
| years)       |        |     |          |       |         |          |
+--------------+--------+-----+----------+-------+---------+----------+
| Females      | **0.00 | *   | 0.000572 | 1.9   |         |          |
| (13-49       | 9155** | *3. |          |       |         |          |
| years)       |        | 1** |          |       |         |          |
+--------------+--------+-----+----------+-------+---------+----------+

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

Reference: Usage Report Package in Support of Registration Review for
the Fungicide Fenbuconazole (129011), A. Grube, 5/20/2008.

In the acute dietary exposure analysis, tolerance level residues and
100% crop treated assumptions were used. In the chronic and cancer
analyses, average field trial values were used, as described above. In
the chronic (non-cancer) analysis, the assumption was made that all
crops would be treated to a level of 100%.

In the cancer analysis, however, estimates of average percent crop
treated provided by BEAD were used for some commodities. The estimates
were provided in a Screening Level Usage Analysis (SLUA) that can be
found in BEAD's usage memo (A. Grube, 5/20/2008, referenced above). The
commodities for which average estimates of percent crop treated were
used are listed in Table 5.3, below.

  -----------------------------------------------------------------------
  **Table 5.3 Cancer                                    
  Dietary Exposure                                      
  Analysis: Average                                     
  Percent Crop                                          
  Treated Estimates                                     
  Used**                                                
  ------------------- ---------------- ---------------- -----------------
  Commodity           Avg. %CT         Commodity        Avg. %CT

  Apples              1                Oranges          1

  Apricots            10               Peaches          15

  Blueberries         40               Pecans           15

  Cherries            20               Prunes           1

  Grapefruit          40               Tangerines       1

  Nectarines          10                                
  -----------------------------------------------------------------------

**6.0 RESIDENTIAL (Non-Occupational) EXPOSURE/RISK CHARACTERIZATION**

There are currently no registered residential uses associated with
fenbuconazole.

**6.1 Other (Spray Drift, etc.)**

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

7.  **AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION**

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

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

**7.1 Acute Aggregate Risk**

Dietary (food + water) consumption is the only source of exposure to
fenbuconazole that is expected to result in acute exposure. Therefore,
the acute aggregate exposure and risk estimates are equivalent to the
acute dietary exposure and risk estimates discussed in Section 5.2.1.
Because of the toxicological properties of fenbuconazole, the only
population subgroup of concern for the acute assessment is females 13-49
years old. This population subgroup utilizes 3.1% of the aPAD. This risk
estimate is below HED's level of concern.

**7.2 Short- and Intermediate-Term Aggregate Risk**

There are no residential uses associated with fenbuconazole; therefore,
short- and intermediate-term aggregate risk assessments are not
required.

**7.3 Long-Term Aggregate Risk**

Dietary (food + water) consumption is the only source of exposure to
fenbuconazole that is expected to be long-term (180-365 days).
Therefore, the long-term aggregate exposure and risk estimates are
equivalent to the chronic dietary exposure and risk estimates discussed
in Section 5.2.2. The most highly exposed population subgroup is All
Infants (\<1 year old) which utilizes 6.8% of the cPAD. The risk
estimate for the general U.S. population is 2.3% of the cPAD. As with
the acute assessment, the risk estimates are all well below HED's level
of concern (100% of the cPAD).

**7.4 Cancer Risk**

Dietary exposure (food + water) is the only source of exposure to
fenbuconazole that is expected to be chronic (lifetime cancer risk).
Therefore, the chronic (cancer) aggregate exposure and risk estimates
are equivalent to the chronic (cancer) dietary exposure and risk
estimates discussed in Section 5.2.3. The cancer risk estimate of the
general U.S. population is 1.7 x 10^-6^. Typically, HED is concerned
when the aggregate cancer risk estimate exceeds 3 x 10^-6^. As a result,
cancer risk to the general U.S. population is below HED's level of
concern. The fenbuconazole Q\* as well as the exposure and risk
estimates are given in Table 7.4.

  ---------------- ----------- ----------------------- --------------------
  **Table 7.4                                          
  Fenbuconazole                                        
  Chronic (Cancer)                                     
  Exposure and                                         
  Risk Estimates**                                     

  **Population**   **Q\***     **Exposure              **Cancer Risk**
                               (mg/kg/day)**           

  U.S. Population  0.00359     0.000473                1.7 x 10^-6^
  ---------------- ----------- ----------------------- --------------------

**8.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT**

Fenbuconazole is a member of the triazole-containing class of
pesticides. Although conazoles act similarly in plants (fungi) by
inhibiting ergosterol biosynthesis, there is not necessarily a
relationship between this pesticidal activity and their mechanism of
toxicity in mammals. Structural similarities do not constitute a common
mechanism of toxicity. Evidence is needed to establish that the
chemicals operate by the same, or essentially the same sequence of major
biochemical events (EPA, 2002). A variable pattern of toxicological
responses is found for conazoles. Some are hepatotoxic and
hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some
induce developmental, reproductive, and neurological effects in rodents.
Furthermore, the conazoles have a diverse range of biochemical events
including altered cholesterol levels, stress responses, and altered DNA
methylation. It is not clearly understood whether these biochemical
events are directly connected to the toxicological outcomes. Thus, there
is currently no evidence to indicate that conazoles share common
mechanisms of toxicity, and EPA is not following a cumulative risk
approach based on a common mechanism of toxicity for the conazoles. For
information regarding EPA's procedures for cumulating effects from
substances found to have a common mechanism of toxicity, see EPA's
website at <http://www.epa.gov/pesticides/cumulative/>.

9.  **OCCUPATIONAL EXPOSURE/RISK ASSESSMENT PATHWAY**

Reference: Occupational and Residential Exposure Assessment for Section
3 Registration for use of Fenbuconazole on Peppers, D345898, S. Wang,
5/28/2008

The occupational risk of exposure to fenbuconazole residues through
application to peppers was evaluated for this tolerance petition. The
blueberry and cranberry uses were evaluated in the previous
fenbuconazole risk assessment (Memo, D316607, M. Collantes, et al.,
8/3/2006).

**9.1 Handler Exposure**

Based on the product label, handler exposures are expected to be
short-and intermediate-term in duration. The quantitative handler
exposure/risk assessment is based on the following scenarios:

-   Mixing/loading water soluble packets (WSPs) for ground application
    (Scenario 1)

-   Mixing/loading WSPs for aerial application (Scenario 2)

-   Applying sprays using ground equipment (Scenario 3)

-   Applying sprays using fix-wing aerial equipment (Scenario 4)

-   Flagging during aerial application (Scenario 5)

**9.1.1 Data and Assumptions for Handler Exposure Scenarios**

**Unit Exposures:**

-   Chemical-specific data for assessing exposure during pesticide
    handling activities were not submitted to the Agency in support of
    this Section 3 application. It is HED policy to use data from the
    Pesticide Handlers Exposure Database (PHED) Version 1.1 to assess
    handler exposures for regulatory actions when chemical-specific data
    are not available (HED Science Advisory Council for Exposure, Policy
    Number 007, January 1999).

-   There are three basic risk mitigation approaches considered
    appropriate for controlling occupational exposure. These mitigation
    approaches include administrative controls, use of personal
    protective equipment (PPE), and the use of engineering controls.
    Occupational handler exposure assessments for the proposed pepper
    use were completed by HED using baseline and, in the case of aerial
    applicators, engineering controls.

-   This risk assessment relies in part on data from studies in which
    adult human subjects were intentionally exposed to a pesticide or
    other chemical. The study, listed below, has been determined to
    require a review of its ethical conduct. It is also subject to
    review by the Human Studies Review Board. The listed study has
    received the appropriate review.

> The PHED Task Force, 1995. The Pesticide Handlers Exposure Database,
> Version 1.1. Task Force members Health Canada, U.S. Environmental
> Protection Agency, and the National Agricultural Chemicals
> Association, released February, 1995.

**Area Treated Daily:** (HED Exposure Science Advisory Committee SOP
Number 9.1)

-   80 acres treated per day for application using ground-boom

-   350 acres treated per day for application using fix-wing aerial
    equipment

-   350 acres for flagging

    **Application Rate**:

```{=html}
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```
-   The maximum application rate as specified on the proposed label is
    0.188 lbs ai/acre.

    **Body Weight:**

-   The average adult body weight of 70 kg was used for estimating
    inhalation exposure and risk for all durations.

**9.1.2 Handler Non-Cancer Exposure and Risk**

HED's level of concern for non-cancer risks (i.e., target level of MOE)
is defined by the uncertainty factors that are applied to the
assessment. HED typically applies a 10x factor to account for
inter-species extrapolation and a 10x factor to account for
intra-species sensitivity. The total uncertainty factor that has been
applied to the non-cancer risk assessment for fenbuconazole is 100 for
occupational exposure. For fenbuconazole, non-cancer occupational
exposure and risk estimates resulting in MOEs greater than 100 are not
of concern to HED. Neither short- nor intermediate-term dermal handler
endpoints were selected up to the limit dose. Therefore, only inhalation
exposure was assessed.

All handler inhalation MOEs (9,100 to 58,000) are greater than 100 at
baseline level (or engineering controls in the case of aerial
applicators) and, therefore, are not of concern to HED. A summary of the
non-cancer short- and intermediate-term risks (MOEs) for handlers is
presented in Table 9.1.a.

+---------+-------+---------+-------+-------+------+--------+-------+
| **Table |       |         |       |       |      |        |       |
| 9.1.a.  |       |         |       |       |      |        |       |
| Non     |       |         |       |       |      |        |       |
| -Cancer |       |         |       |       |      |        |       |
| Short-  |       |         |       |       |      |        |       |
| and     |       |         |       |       |      |        |       |
| Int     |       |         |       |       |      |        |       |
| ermedia |       |         |       |       |      |        |       |
| te-term |       |         |       |       |      |        |       |
| Inh     |       |         |       |       |      |        |       |
| alation |       |         |       |       |      |        |       |
| Risk    |       |         |       |       |      |        |       |
| for     |       |         |       |       |      |        |       |
| Fenbuc  |       |         |       |       |      |        |       |
| onazole |       |         |       |       |      |        |       |
| Han     |       |         |       |       |      |        |       |
| dlers** |       |         |       |       |      |        |       |
+=========+=======+=========+=======+=======+======+========+=======+
| **Sce   | **Mi  | **      | **    | **A   | **A  | **Inha | **    |
| nario** | tigat | Crops** | Inhal | pplic | cres | lation | Inhal |
|         | ion** |         | ation | ation | T    | Dose   | ation |
|         |       |         | Unit  | Rate  | reat | ^d^    | MOE   |
|         |       |         | Exp   | ^b^** | ed** | (      | ^e^** |
|         |       |         | osure |       |      | mg/kg/ |       |
|         |       |         | (µ    | **(lb | *    | day)** |       |
|         |       |         | g/lb) | ai/ac | *(A/ |        |       |
|         |       |         | ^a^** | re)** | day) |        |       |
|         |       |         |       |       | ^    |        |       |
|         |       |         |       |       | c^** |        |       |
+---------+-------+---------+-------+-------+------+--------+-------+
| **      |       |         |       |       |      |        |       |
| Mixer/L |       |         |       |       |      |        |       |
| oader** |       |         |       |       |      |        |       |
+---------+-------+---------+-------+-------+------+--------+-------+
| Mixing/ | Bas   | Peppers | 0.24  | 0.188 | 80   | 0.     | 5     |
| loading | eline |         |       |       |      | 000052 | 8,000 |
| WSP for |       |         |       |       |      |        |       |
| ground  |       |         |       |       |      |        |       |
| appl    |       |         |       |       |      |        |       |
| ication |       |         |       |       |      |        |       |
| (1)     |       |         |       |       |      |        |       |
+---------+-------+---------+-------+-------+------+--------+-------+
| Mixing/ | Bas   | Peppers | 0.24  | 0.188 | 350  | 0      | 1     |
| loading | eline |         |       |       |      | .00023 | 3,000 |
| WSP for |       |         |       |       |      |        |       |
| aerial  |       |         |       |       |      |        |       |
| appl    |       |         |       |       |      |        |       |
| ication |       |         |       |       |      |        |       |
| (2)     |       |         |       |       |      |        |       |
+---------+-------+---------+-------+-------+------+--------+-------+
| **Appli |       |         |       |       |      |        |       |
| cator** |       |         |       |       |      |        |       |
+---------+-------+---------+-------+-------+------+--------+-------+
| A       | Bas   | Peppers | 0.74  | 0.188 | 80   | 0      | 1     |
| pplying | eline |         |       |       |      | .00016 | 9,000 |
| spray   |       |         |       |       |      |        |       |
| using   |       |         |       |       |      |        |       |
| ground- |       |         |       |       |      |        |       |
| boom    |       |         |       |       |      |        |       |
| (3)     |       |         |       |       |      |        |       |
+---------+-------+---------+-------+-------+------+--------+-------+
| A       | E     | Peppers | 0.068 | 0.188 | 350  | 0.     | 4     |
| pplying | ngine |         |       |       |      | 000064 | 7,000 |
| spray   | ering |         |       |       |      |        |       |
| using   | co    |         |       |       |      |        |       |
| f       | ntrol |         |       |       |      |        |       |
| ix-wing | (     |         |       |       |      |        |       |
| a       | consi |         |       |       |      |        |       |
| ircraft | dered |         |       |       |      |        |       |
| (4)     | as    |         |       |       |      |        |       |
|         | base  |         |       |       |      |        |       |
|         | line) |         |       |       |      |        |       |
+---------+-------+---------+-------+-------+------+--------+-------+
| **Fl    |       |         |       |       |      |        |       |
| agger** |       |         |       |       |      |        |       |
+---------+-------+---------+-------+-------+------+--------+-------+
| F       | Bas   | Peppers | 0.35  | 0.188 | 350  | 0      | 9,100 |
| lagging | eline |         |       |       |      | .00033 |       |
|         |       |         |       |       |      |        |       |
| during  |       |         |       |       |      |        |       |
| aerial  |       |         |       |       |      |        |       |
| appl    |       |         |       |       |      |        |       |
| ication |       |         |       |       |      |        |       |
| (5)     |       |         |       |       |      |        |       |
+---------+-------+---------+-------+-------+------+--------+-------+

a\. PHED Version 1.1

b\. Application Rate based on proposed registered label for
fenbuconazole products

c\. Acres Treated = Science Advisory Council Policy \# 9.1

d\. Short- and Intermediate-term Inhalation Dose (mg/kg/day) = \[Rate
(lb ai/A) x UE (mg /lb ai ) x Acres Treated (A/day)\] / BW

e\. Short- and Intermediate-term Inhalation MOE = \[Inhalation NOAEL (3
mg/kg/day)\]/Inhalation Dose (mg/kg/day)

**9.1.3 Handler Cancer Exposure and Risk**

The Agency has defined the range over which occupational cancer risk is
acceptable in the following policy document: "Non-Dietary Cancer Risk
Policy" (D. Barolo, 8/4/1996). To summarize, this policy memo indicates
that occupational carcinogenicity risks that are 1 x 10^-4^ or lower
require no risk management action. EPA considers occupational cancer
risk estimates greater than one in ten thousand (1 x 10^-4^) to be of
concern, and attempts to mitigate occupational exposures so that cancer
risk estimates are one in one million (1 x 10^-6^) or less, where
feasible.

The cancer risk estimates for commercial handlers using fenbuconazole on
peppers range from

3.5 x 10^-8^ to 1.6 x 10^-7^ at baseline level. As these calculations
use conservative estimates of

exposure (i.e., maximum application rate) and the cancer risk estimates
are lower than 1 x 10^-6^ at baseline level, HED does not consider these
scenarios to be of concern. A summary of cancer risks for fenbuconazole
handlers is presented in Table 9.1.b. Cancer risks for individual
farmers (1.2 x 10^-8^ to 5.3 x 10^-8^) are 1/3 of the cancer risks for
the commercial handlers, and they do not exceed HED's level of concern.

+---------+--------+-----+--------+--------+--------+--------+--------+
| **Table |        |     |        |        |        |        |        |
| 9.1.b.  |        |     |        |        |        |        |        |
| Cancer  |        |     |        |        |        |        |        |
| Risks   |        |     |        |        |        |        |        |
| for     |        |     |        |        |        |        |        |
| Fenbuc  |        |     |        |        |        |        |        |
| onazole |        |     |        |        |        |        |        |
| Han     |        |     |        |        |        |        |        |
| dlers** |        |     |        |        |        |        |        |
+=========+========+=====+========+========+========+========+========+
| **Sce   | **     | **  | **     | **Inha | **Co   | **     | **     |
| nario** | Mitiga | Cro | Dermal | lation | mbined | Commer | Commer |
|         | tion** | p** | Dose   | Dose   | ADD    | cial** | cial** |
|         |        |     | ^a^    | ^a^    | ^b^    |        |        |
|         |        |     | (      | (      | (      | **LADD | **Ca   |
|         |        |     | mg/kg/ | mg/kg/ | mg/kg/ | ^c^**  | ncer** |
|         |        |     | day)** | day)** | day)** |        |        |
|         |        |     |        |        |        | **(    | **Risk |
|         |        |     |        |        |        | mg/kg/ | ^d^**  |
|         |        |     |        |        |        | day)** |        |
+---------+--------+-----+--------+--------+--------+--------+--------+
| **      |        |     |        |        |        |        |        |
| Mixer/L |        |     |        |        |        |        |        |
| oader** |        |     |        |        |        |        |        |
+---------+--------+-----+--------+--------+--------+--------+--------+
| Mixing/ | Ba     | P   | 0      | 0.     | 0      | 0.0    | 3.5    |
| loading | seline | epp | .00019 | 000052 | .00024 | 000098 | E-8    |
| WSP for |        | ers |        |        |        |        |        |
| ground  |        |     |        |        |        |        |        |
| appl    |        |     |        |        |        |        |        |
| ication |        |     |        |        |        |        |        |
| (1)     |        |     |        |        |        |        |        |
+---------+--------+-----+--------+--------+--------+--------+--------+
| Mixing/ | Ba     | P   | 0      | 0      | 0.0011 | 0.     | 1.6    |
| loading | seline | epp | .00084 | .00023 |        | 000045 | E-7    |
| WSP for |        | ers |        |        |        |        |        |
| aerial  |        |     |        |        |        |        |        |
| appl    |        |     |        |        |        |        |        |
| ication |        |     |        |        |        |        |        |
| (2)     |        |     |        |        |        |        |        |
+---------+--------+-----+--------+--------+--------+--------+--------+
| **Appli |        |     |        |        |        |        |        |
| cator** |        |     |        |        |        |        |        |
+---------+--------+-----+--------+--------+--------+--------+--------+
| A       | Ba     | P   | 0      | 0      | 0      | 0.     | 4.3    |
| pplying | seline | epp | .00013 | .00016 | .00029 | 000012 | E-8    |
| spray   |        | ers |        |        |        |        |        |
| using   |        |     |        |        |        |        |        |
| ground- |        |     |        |        |        |        |        |
| boom    |        |     |        |        |        |        |        |
| (3)     |        |     |        |        |        |        |        |
+---------+--------+-----+--------+--------+--------+--------+--------+
| A       | Engin  | P   | 0      | 0.     | 0      | 0.     | 3.8    |
| pplying | eering | epp | .00020 | 000064 | .00026 | 000011 | E-8    |
| spray   | c      | ers |        |        |        |        |        |
| using   | ontrol |     |        |        |        |        |        |
| f       | (cons  |     |        |        |        |        |        |
| ix-wing | idered |     |        |        |        |        |        |
| a       | as     |     |        |        |        |        |        |
| ircraft | bas    |     |        |        |        |        |        |
| (4)     | eline) |     |        |        |        |        |        |
+---------+--------+-----+--------+--------+--------+--------+--------+
| **Fl    |        |     |        |        |        |        |        |
| agger** |        |     |        |        |        |        |        |
+---------+--------+-----+--------+--------+--------+--------+--------+
| F       | Ba     | P   | 0      | 0      | 0      | 0.     | 1.2    |
| lagging | seline | epp | .00044 | .00033 | .00077 | 000032 | E-7    |
|         |        | ers |        |        |        |        |        |
| during  |        |     |        |        |        |        |        |
| aerial  |        |     |        |        |        |        |        |
| appl    |        |     |        |        |        |        |        |
| ication |        |     |        |        |        |        |        |
| (5)     |        |     |        |        |        |        |        |
+---------+--------+-----+--------+--------+--------+--------+--------+

a\. Dermal Dose (mg/kg/day) = \[Rate (0.188 lb ai/A) x UE (mg /lb ai ) x
Acres Treated (A/day) x 4.25% DA\] / BW

Dermal Unit Exposures are as follows: For mixing/loading WSP UE = 0.021
mg/lb, For groundboom applicator UE = 0.014 mg/lb, For Aerial Applicator
UE = 0.005 mg/lb, and For flagger UE = 0.011 mg/lb.

> Inhalation Dose (mg/kg/day) = See Table 9.1.a.

b\. Combined ADD (mg/kg/day) = Dermal Dose (mg/kg/day) + Inhalation Dose
(mg/kg/day)

c\. Commercial Applicator LADD (mg/kg/day) = ADD x \[(30 days/yr)/ (365
days/yr)\] x (35 yrs/70yrs)

d Commercial Applicator Cancer Risk = Commercial LADD x Q\* \[3.59 x
10^-3^ (mg/kg/day)^-1^\]

The handler exposure estimates in this assessment are based on a central
tendency estimate of unit exposure and an upper-percentile assumption
for the application rate, and are assumed to be representative of
high-end exposures. The uncertainties associated with this assessment
stem from the use of surrogate exposure data (e.g., differences in use
scenario and data confidence), and assumptions regarding that amount of
chemical handled. The estimated exposures are believed to be reasonable
high-end estimates based on observations from field studies and
professional judgment.

9**.2 Post-Application Exposure**

**9.2.1 Non-Cancer Post-Application Exposure Scenarios**

Neither a short-term nor an intermediate-term dermal exposure endpoint
was selected, and long-term dermal exposure is not expected. As a
result, a non-cancer post-application exposure assessment is not
required.

**9.2.2 Cancer Post-Application Exposure Scenarios**

For purposes of determining post-application cancer exposure/risk, the
following data and assumptions have been used.

No post-application data were submitted in support of this registration
action. Therefore, exposures during post-application activities were
estimated using dermal transfer coefficients and the following
assumptions. The dermal transfer coefficients were taken from the
Science Advisory Council for Exposure Policy Number 3.1: Agricultural
Transfer Coefficients, August 2000 and are summarized in Table 9.2.a
below:

Assumptions:

-   Application Rate = 0.188 lb ai/A

-   Exposure Duration = 8 hours per day

-   Body Weight = 70 kg

-   Dermal Absorption = 4.25% for long-term

-   Fraction of a.i. retained on foliage is assumed to be 20% (0.2) on
    day zero (= % dislodgeable foliar residue, DFR, after initial
    treatment). This fraction is assumed to dissipate further at the
    rate of 10% (0.1) per day on the following days. These are default
    values established by HED's Science Advisory Council for Exposure.

  ------------------ ------------ ------------- -------------- ---------------------------
  **Table 9.2.a.                                               
  Anticipated                                                  
  Post-application                                             
  Activities and                                               
  Dermal Transfer                                              
  Coefficients\***                                             

  **Proposed Crops** **Policy     **Exposure    **Transfer     **Activities**
                     Crop Group   Potential**   Coefficients   
                     Category**                 (cm^2^/hr)**   

  Peppers            Fruiting     Low           500            Irrigation, scouting,
                     Vegetables                                thinning, weeding immature
                                                               plants

                                  Medium        700            Irrigation and scouting
                                                               mature plants

                                  High          1,000          Hand harvesting, pruning,
                                                               staking, tying
  ------------------ ------------ ------------- -------------- ---------------------------

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

As previously described in the handler cancer risk section, the Agency
has defined the range over which occupational cancer risk is acceptable.
Occupational carcinogenicity risks that are 1 x 10^-4^ or lower require
no risk management action. EPA considers occupational cancer risk
estimates greater than one in ten thousand (1 x 10^-4^) to be of
concern, and attempts to mitigate occupational exposures so that cancer
risk estimates are one in one million (1 x 10^-6^) or less, where
feasible.

In determining carcinogenicity risk related to post-application
exposure, the values were amortized over the working lifetime of
occupational workers. Furthermore, HED considered the following
assumptions and data: 1) the time interval between reapplication of
fenbuconazole varies between 7 days and 30 or more days for the proposed
uses, 2) residues are assumed to decrease over time, and 3) it is
unlikely that workers will be exposed to Day-0 residues 30 days a year.
Therefore, HED used the average residue over 30 days to estimate cancer
risk. All cancer risk estimates are lower than 1 x 10^-6^ and,
therefore, are not a risk concern. Cancer risk estimates are summarized
in Table 9.2.b.

The technical material has a Toxicity Category IV for eye irritation,
skin irritation, and acute dermal toxicity. Per the Worker Protection
Standard (WPS), chemicals classified as toxicity III and IV require a
12-hr REI.

+--------+----+-----+---------+------------+------------+-----------+
| *      |    |     |         |            |            |           |
| *Table |    |     |         |            |            |           |
| 9.2.b. |    |     |         |            |            |           |
| Cancer |    |     |         |            |            |           |
| E      |    |     |         |            |            |           |
| xposur |    |     |         |            |            |           |
| e/Risk |    |     |         |            |            |           |
| for    |    |     |         |            |            |           |
| F      |    |     |         |            |            |           |
| enbuco |    |     |         |            |            |           |
| nazole |    |     |         |            |            |           |
| Post   |    |     |         |            |            |           |
| -appli |    |     |         |            |            |           |
| cation |    |     |         |            |            |           |
| Wor    |    |     |         |            |            |           |
| kers** |    |     |         |            |            |           |
+--------+----+-----+---------+------------+------------+-----------+
| **     | *  | **  | **T     | **Daily    | **LADD     | **Cancer  |
| Crop** | *D | DFR | ransfer | Dose ^d^   | ^e^**      | Risk      |
|        | AT | ^b  | Coeffic | (mg        |            | ^f^**     |
|        | ^  | ^** | ient^c^ | /kg/day)** |            |           |
|        | a^ |     | (cm^2   |            |            |           |
|        | ** | **  | ^/hr)** |            |            |           |
|        |    | (ug |         |            |            |           |
|        |    | /cm |         |            |            |           |
|        |    | ^2^ |         |            |            |           |
|        |    | )** |         |            |            |           |
+--------+----+-----+---------+------------+------------+-----------+
| P      | A  | 0.1 | 500     | 0.0003371  | 1.385 E-5  | 5.0 E-8   |
| eppers | vg | 388 |         |            |            |           |
+--------+----+-----+---------+------------+------------+-----------+
|        |    |     | 1,000   | 0.0006742  | 2.771 E-5  | 9.9 E-8   |
+--------+----+-----+---------+------------+------------+-----------+

a.  DAT= 30 day residue average

b.  DFRt (µg/cm^2^) = Application Rate (lb ai/A) x F x\[\[1-(1-D)^30^
    \]/\[1-(1-D)\]}/t x 4.54E8 µg/lb x 24.7E-9 A/cm^2^

c.  Transfer Coefficients selected in accordance with SAC for Exposure
    Policy 3.1 (August 2000)

d.  Daily Dose (mg/kg/day)= DFR (µg/cm^2^) x 0.001 mg/ug x Tc (cm^2^/hr)
    x DA (4.25%) x ET (8 hr/day)/70 kg

e.  LADD (mg/kg/day) = DD x \[(30 days/yr)/ (365 days/yr)\] x (35
    yrs/70yrs)

f.  Cancer Risk = LADD x Q\* \[3.59 x 10^-3^ (mg/kg/day)^-1^\]

**10. DATA NEEDS AND LABEL REQUIREMENTS**

**10.1 Toxicology -None**

**10.2 Residue Chemistry**

**10.2.1 Deficiencies in Current Tolerance Petition**

No major deficiencies were noted in the subject petition that would
preclude establishing a permanent tolerance for fenbuconazole on
peppers. However, an error was noted in the proposed use directions, and
no data were provided on residues of 1,2,4-triazole, triazole alanine,
or triazole acetic acid (see below). The use directions should be
corrected prior to registration, while the additional residue data may
be provided as a condition of registration. HED recommends establishing
a permanent tolerance with a conditional registration for the combined
residues of fenbuconazole and Metabolites RH-9129 and RH-9130, expressed
as parent, in/on pepper at 0.40 ppm.

• The use directions contain an error in the single use rate. The single
application rate is specified as 2-4 oz. of product (75%
WP)/A/application, which is equivalent to 0.09-0.188 lb
ai/A/application. However, in terms of lb ai/A, the directions indicate
that the rate is 0.10-0.167 lb ai/A. This error should be corrected. The
data will support a maximum single use rate of up to 0.188 lb ai/A.

[]{.mark}

• Although adequate residue data were provided on fenbuconazole and its
regulated metabolites RH-9129 and RH-9130, none of the samples were
analyzed for residues of 1,2,4-triazole, triazole alanine, or triazole
acetic acid, as required by current Agency guidance (Memo, D327788, M.
Doherty, 4/25/2006).

**10.2.2 Deficiencies Cited in Previous Tolerance Petitions**

In its risk assessment of 8/3/2006, HED noted several data deficiencies
(Memo, D316607, M. Collantes, et al., 8/3/2006). Dow AgroSciences
addressed some of these deficiencies in two letters that were submitted
to the Agency (3/30/2007 and 7/12/2007). HED has evaluated Dow's
responses to the data deficiencies.

1)  "The analytical reference standards for the two fenbuconazole
    metabolites, RH 9129 and RH 9130, are present in insufficient
    quantities at the Agency's Analytical Chemistry Branch repository.
    The registrant must submit one gram each of the reference standards
    for the two fenbuconazole metabolites, RH 9129 and RH 9130."

HED's Conclusion: Analytical reference standards for fenbuconazole and
its metabolites, RH-9129 and RH-9130, have been submitted and are
available at the EPA National Standards Repository (Electronic
communication, D. Wright, 4/21/2008). Their expiration dates are as
follows: fenbuconazole (3/21/2009), RH-9129 (1/4/2009), and RH-9130
(8/17/2009).

2\) "Prior to being accepted as an enforcement method, the GC/NPD method
(TR 34-94-142, MRID 43524907) for determining residues in livestock
commodities must undergo a Tolerance Method Validation (TMV). HED will
initiate the TMV."

HED's Conclusion: BEAD/ACB has not performed the validation.

3\) "The petitioner must conduct another citrus processing study.
Samples from the processing study must be analyzed within the intervals
that fenbuconazole and metabolite residues have been shown to be stable
(30 months for fruit and 12 months for oil and dried pulp). The required
study does not need to include the analysis of juice samples; the
current study is adequate to demonstrate that residues of fenbuconazole
and its metabolites RH-9129 and RH-9130 do not concentrate in citrus
juice. Granting of a registration should be made conditional upon
resolution of this issue."

HED's Conclusion: In the original study, samples were not analyzed
within the time interval for which residues have been demonstrated to be
stable. Fenbuconazole residues have been shown to be stable in fruit for
8 months and in oil and dried pulp for 12 months (the 30-month interval
for fruit quoted above refers to metabolite RH-7905). In the citrus
processing study, the maximum storage durations were 24 months for fruit
and 39 months for oil and dried pulp. Rather than performing another
citrus processing study, Dow requested that the Agency translate peach
and apple storage stability data to the processed citrus fractions. In
peaches and apples, very little decay occurred in residues of
fenbuconazole and the metabolites RH-9129 and RH-9130 over a period of
54 months (4.5 years) and 36 months, respectively. In peaches, percent
recovery after 54 months for the 3 analytes was as follows:
fenbuconazole (94%), RH-9129 (91%), and RH-9130 (87%). In apples,
percent recovery after 36 months for the 3 analytes was as follows:
fenbuconazole (103%), RH-9129 (97%), and RH-9130 (93%). The available
storage stability data for peaches, apples, and processed citrus
fractions demonstrate to the satisfaction of HED that residues of
fenbuconazole, RH-9129, and RH-9130, would be stable in citrus fruit for
24 months and in oil and dried pulp for 39 months. As a result, another
citrus processing study is not needed.

4)  "The Agency has not reviewed an acceptable apple processing study
    for fenbuconazole. Granting of a registration should be made
    conditional upon resolution of this issue. We note that MRID
    43621001 is under review."

HED's Conclusion: This study has been submitted; however, it has not
been reviewed by HED.

5\) "As a condition of registration, two additional field trials are
required for blueberries, one each from Regions 2 and 5."

HED's Conclusion: As discussed in this document, two acceptable studies
were submitted. Eight field trials are recommended and nine acceptable
trials were submitted. No additional blueberry data are needed.

6)  "A complete set of 20 field trials are required on wheat forage and
    an additional 12 tests are required on wheat hay. These tests should
    be conducted using the [currently]{.underline} proposed use pattern,
    which reflects one application on forage and up to two applications
    on hay at 0.063 lb ai/A/application. Although conditions will vary
    between test sites, the sampling intervals for forage and hay should
    be consistent enough for the Agency to be able to compare residues
    and assess an appropriate PHI. Granting of a registration should be
    made conditional upon resolution of this issue."

HED's Conclusion: Dow has not submitted the requested data. Dow's
representative responded by stating that Dow is of the opinion that the
8 field trials that were performed for each commodity should be
sufficient. The OPPTS Series 860 Guidelines recommend that 20 field
trials be performed for each of these commodities. As stated above, Dow
performed 8 trials for each. The forage trials were performed at a 2x
application rate. Dow's representative gave 3 reasons as to why Dow felt
that the original 8 trials should be satisfactory: (1) the maximum
application rates used in the 8 trials were the same or lower than the
currently labeled ones, (2) the cattle dietary intake of fenbuconazole
residues through ingestion of wheat forage and hay is insignificant
because very little wheat is treated with fenbuconazole (compared to
other commodities), and because wheat forage and hay make up a small
fraction of cattles' diets, and (3) based on the results of the ruminant
metabolism study, the secondary residues in cattle would be very low.

Most forage and hay used for cattle feed is grown in the Southern United
States. The field trials were performed in Ohio, Michigan, Minnesota,
North Dakota, South Dakota, Nebraska, Montana, and Wyoming. Most of
these states are more northern. HED continues to request that twenty
field trials be performed for forage and 12 trials be performed for hay.
HED bases this request on the following three factors: 1) considerably
fewer trials were performed than are generally needed, 2) all of the
forage trials were performed at a 2x rate, and 3) the trials were not
performed in major feedstuff producing geographic regions.

**10.3 Occupational and Residential Exposure - None**

**REFERENCES**

Fenbuconazole, Petition for Registration for Use on Pepper, Bushberry
Subgroup (13-B), and Cranberry. Summary of Analytical Chemistry and
Residue Data, D313752, D. Dotson, 6/12/2008.

Occupational and Residential Exposure Assessment for Section 3
Registration for use of Fenbuconazole on Peppers, D345898, S. Wang,
5/28/2008)

Fenbuconazole, Acute, Chronic, and Cancer Aggregate Dietary (Food and
Drinking Water) Exposure Analysis for the Section 3 Registration Action,
D350321, D. Dotson, 6/12/2008.

Drinking Water Exposure Assessment for Fenbuconazole Use on Pepper,
D344352, J. Lin, 1/16/2008.

Usage Report Package in Support of Registration Review for the Fungicide
Fenbuconazole (129011), A. Grube, 5/20/2008.

Fenbuconazole: Human Health Risk Assessment for Proposed Uses on
Almonds, Apples, Bananas, Bushberries, Citrus Fruit, Cranberries,
Grapes, Peanuts, Pecans, Stone Fruits, Sugar Beets, and Wheat. PC Code:
129011, DP Barcode: D316607, M. Collantes, et al, 8/3/2006.

Dietary Exposure Assessments for the Common Triazole Metabolites
1,2,4-Triazole, Triazolylalanine, Triazolylacetic Acid, and
Triazolylypyruvic Acid; Updated to Include New Uses of Fenbuconazole,
Ipconazole, Metconazole, Tebuconazole, and Uniconazole; and a Change in
Plant-back Restriction for Tetraconazole, D350314, M. Doherty,
3/27/2008.

Appendix 1: Tolerance Summary for Fenbuconazole

+-----------------+--------------+-------------+-----------------------+
| **Table A.1.    |              |             |                       |
| Tolerance       |              |             |                       |
| Summary for     |              |             |                       |
| F               |              |             |                       |
| enbuconazole.** |              |             |                       |
+-----------------+--------------+-------------+-----------------------+
| Commodity       | Proposed     | Recommended | Comments;             |
|                 | Tolerance    | Tolerance   |                       |
|                 | (ppm)        | (ppm)       | Correct Commodity     |
|                 |              |             | Definition            |
+-----------------+--------------+-------------+-----------------------+
| Pepper          | 0.4          | 0.40        | Adequate field trial  |
|                 |              |             | data for peppers are  |
|                 |              |             | available.            |
|                 |              |             |                       |
|                 |              |             | Commodity definition: |
|                 |              |             | Pepper                |
+-----------------+--------------+-------------+-----------------------+