UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

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 7E7256	Regulatory Action:  Section 3


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

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)  SEQ CHAPTER \h \r 1 		

		

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)  SEQ CHAPTER \h \r 1 	

		

TO:		Sidney Jackson/Barbara Madden, RIMUERB

		and

		John Bazuin/Tony Kish, RM 22, Fungicide Branch

		Registration Division (7505P)



Table of Contents

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

2.0	Ingredient Profile	8

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc131319175 \h  8 

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

 

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-p
ropanenitrile), 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 95th 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).

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-propane
nitrile] and its metabolites,
cis-5-(4-chlorophenyl)-dihydro-3-phenyl-3-(1H-1,2,4-triazole-1-ylmethyl)
-2-3H-furanone (RH-9129) and
trans-5-(4-chlorophenyl)dihydro-3-phenyl-3-(1H-1,2,4-triazole-1-ylmethyl
)-2-3H-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  TC \l1 "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  TC \l2 "2.1	Summary of
Registered/Proposed Uses 

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-(1H-1,2,4-triazol-1-ylmethyl)-2
(3H)-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.

™ 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 Fenbuconazole.

Applic. Timing, Type, and Equip. 1	Formulation

[EPA Reg. No.]	Applic. Rate 

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

(lb ai/A)	PHI

(days)	Use Directions and Limitations 2

Peppers (Including but not limited to: bell, chili, cooking, non-bell,
pimento and sweet)

Broadcast foliar applications to peppers when disease first appears.

Use ground or aerial equipment	75% WP

[62719-421]	0.188 3	NS	0.75	7	Apply in a minimum of 30 gal/A, using
ground equipment.

The minimum RTI is 10-14 days. Use of a non-ionic surfactant is
recommended.

Bushberry Subgroup (including blueberry, currant, elderberry, 

gooseberry, and huckleberry)

Broadcast foliar applications beginning at bud break (green tip) through
fruit development.

Use ground or aerial equipment

	75% WP

[62719-421]	0.094	5	0.47	30	A minimum retreatment interval of 10 days is
specified.

Do not apply through any type of irrigation system.

For ground and aerial applications, apply in a minimum volume of 10 and
20 gal/A, respectively.

A non-ionic surfactant should be used in the spray mix.



Cranberries

Broadcast foliar applications beginning when 50% of shoots show ¼ inch
of new growth, through fruit development.

Use ground or aerial equipment.

	75% WP

[62719-421]	0.188	5	0.94	30	A minimum retreatment interval of 7 days is
specified.

Do not apply through any type of irrigation system.

For aerial applications, apply in a minimum volume of 10 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  TC \l2 "2.2	Structure and Nomenclature 



Common name	trans lactone metabolite

Company experimental names	RH-9130

IUPAC names
(3S,5R)-5-(4-chlorophenyl)-3-phenyl-3-(1H-1,2,4-triazol-1-ylmethyl)dihyd
rofuran-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  TC \l2 "2.3	Physical and Chemical
Properties 

  SEQ CHAPTER \h \r 1 Table 2.3.  Physical and Chemical Properties of
the Technical Grade Fenbuconazole

Parameter	Value	Reference

Melting point	126.5–127.0°C	D310959, S. 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) at 25°C	Acetonitrile	231

Cyclohexanone	445

Ethyl alcohol	39

1-octanol	13	Aromatic 200	      77

Ethyl acetate	     159

λ max (nm)

196

262

268

275	ε (L∙mol-1∙cm-1)

53,000 

750

740

480

	

3.0	HAZARD CHARACTERIZATION/ASSESSMENT

3.1	Hazard and Dose-Response Characterization  tc "4.1	Hazard
Characterization " \l 2 

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 Toxicity of Fenbuconazole - Technical and End-Use
Product

Guideline No.	Study Type	MRID	Results	Toxicity

Category

870.1100	Acute Oral - Rats	41031209	Oral LD50 (M) > 2000 mg/kg	III

870.1100	Acute Oral - Rats	41031207	Oral LD50 (M and F) > 2000 mg/kg	III

870.1100	Acute Oral - Rats	41031221	Oral LD50 (M) > 5000 mg/kg	IV

870.1100	Acute Oral - Rats	41031222	Oral LD50 (F) > 5000 mg/kg	IV

870.1200	Acute Dermal - Rats	41031208	LD50 (M and F) > 5000 mg/kg	IV

870.1200	Acute Dermal - Rats	41031223	LD50 (M) > 5000 mg/kg	IV

870.1200	Acute Dermal - Rats	41031224	LD50 (F) > 5000 mg/kg	IV

870.1300	Acute Inhalation - Rats	41398201	LC50 (M and F) > 2.1 mg/L

Particle size too large.  Requirement was waived because of a problem in
generating respirable dust particles or liquid aerosol.	III

870.1300	Acute Inhalation - Rats	41031225	LC50 (M and F) > 2.1 mg/L	III

870.2400	Primary Eye Irritation- Rabbits	41031211	Not irritating to
unwashed eyes	IV

870.2400	Primary Eye Irritation- Rabbits	41031226	Not irritating to the
eyes	IV

870.2500	Primary Dermal Irritation- Rabbits	41031212	Not irritating to
the skin	IV

870.2500	Primary Dermal Irritation- Rabbits	41031227	Not irritating to
the skin	IV

870.2600	Dermal Sensitization- Guinea pigs	41031213	Is not a sensitizer
under conditions of study.	N/A

870.2600	Dermal Sensitization- Guinea pigs	41031228	Is not a sensitizer
under conditions of study.	N/A



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 (Q1*).  The Q1* 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 - Toxicity Profile of Fenbuconazole Technical

Guideline No.	Study Type	MRID	Doses	Results

870.3100	90-Day oral toxicity rodents - rats	41073502	0, 20, 80, 400,
and 1600 ppm 

(Males:  0, 1.3, 5.1, 25.3, and 103.0 mg/kg/day; 

Females:  0, 1.5, 6.3, 31.1, and 123.9 mg/kg/day)	NOAEL = 1.3/1.5
mg/kg/day (M/F)

LOAEL = 5.1/6.3 mg/kg/day (M/F) based on liver histopathology

870.3100	90-Day oral toxicity rodents - mice	41073503	0, 20, 60, 180,
and 540 ppm

(Males:  0, 3.8, 11.1, 28.6, and 99.1 mg/kg/day; 

Females:  0, 5.7, 17.6, 50.4, and 139.2 mg/kg/day)	NOAEL = 3.8/5.7
mg/kg/day (M/F)

LOAEL = 11.1/17.6 mg/kg/day (M/F) based on liver histopathology

870.3150	90-Day oral toxicity in nonrodents - dogs	41073504	0, 30, 100,
400, and 1600 ppm

(Males:  0, 1.0, 3.3, 13.3, and 50.4 mg/kg/day; 

Females:  0, 1.1, 3.5, 14.0, and 53.3 mg/kg/day)	NOAEL = 3.3/3.5
mg/kg/day (M/F)

LOAEL = 13.3/14.0 mg/kg/day (M/F) based on liver histopathology

870.3200	21/28-Day dermal toxicity - rats	41875013

42882701	0, 250, 625, and 1000 mg/kg/day	NOAEL = 1000 mg/kg/day (HDT)

LOAEL = >1000 mg/kg/day

870.3250	90-Day dermal toxicity	N/A	N/A	Not performed

870.3465	90-Day inhalation toxicity	N/A	N/A	Not performed

870.3700	Prenatal developmental in rodents - rats	41031214

41073505	0, 30, 75, and 150 mg/kg/day	Maternal NOAEL = 30 mg/kg/day

Maternal LOAEL = 75 mg/kg/day  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

870.3700	Prenatal developmental in nonrodents - rabbits	41875014

42882701	0, 10, 30, and 60 mg/kg/day	Maternal NOAEL = 10 mg/kg/day

Maternal LOAEL = 30 mg/kg/day  based on decreased 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

870.3800	Reproduction and fertility effects - rats	41875015	0, 8, 80,
and 800 ppm (0, 0.4, 4, and 40 mg/kg/day)	Parental systemic NOAEL = 4
mg/kg/day

Parental systemic 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

870.4100	Chronic toxicity - rodents

	See 870.4300

870.4100	Chronic toxicity - dogs	41875049	0, 15, 150, and 1200 ppm (0,
0.38, 3.75, and 30 mg/kg/day)	NOAEL = 3.75/0.38 mg/kg/day (M/F)

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.

870.4200	Carcinogenicity - rats

	See 870.4300

870.4200	Carcinogenicity - mice	41893301

41635303	Males:  0, 10, 200, and 650 ppm (0, 1.43, 28.6, and 92.9
mg/kg/day)

Females:  0, 10, 650, and 1300 ppm (0, 1.43, 92.9, and 186 mg/kg/day)
NOAEL = 1.43 mg/kg/day (M & F)

LOAEL = 28.6/92.9 mg/kg/day (M/F) based on decreased body weight,
increased relative and absolute liver weight, and hepatocellular
hypertrophy and vacuolization

Evidence of carcinogenicity

870.4300	Combined chronic toxicity/

carcinogenicity - rat	41635301

41635302	Control - 0 ppm

Low - 4 ppm (weeks 1 & 2), 6 ppm (weeks 3 & 4), and 8 ppm (weeks 5-term)

Mid - 40 ppm (weeks 1 & 2), 60 ppm (weeks 3 & 4), and 80 ppm (weeks
5-term)

High - 400 ppm (weeks 1 & 2), 600 ppm (weeks 3 & 4), 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)	NOAEL = 3.0/4.0 mg/kg/day
(M/F)

LOAEL = 30.6/43.1 mg/kg/day (M/F) based on decreased body weight gain
(F), hepatocellular enlargement and vacuolization (F), increased thyroid
weight (M&F), and histopathological lesions in the thyroid gland (M)

Evidence of carcinogenicity

870.4300	Combined chronic toxicity/

carcinogenicity - rat	42021901

42055001	Control - 0 ppm

Low - 400 ppm (weeks 1 & 2), 600 ppm (weeks 3 & 4), and 800 ppm (weeks
5-term)

High - 800 ppm (weeks 1 & 2), 1200 ppm (weeks 3 & 4), and 1600 ppm
(weeks 5-term)

(0, 30.4, and 63.9 mg/kg/day)	NOAEL = Not established

LOAEL = 30.4 mg/kg/day (M) based on decreased body weight gain,
increased liver weight, and increased thyroid and parathyroid weights

Note:  only males were used in this study.

Insufficient evidence of carcinogenicity

870.5100	Gene mutation - bacterial reverse mutation assay	41031216
TA1535 - 30-300 ug

TA1537 - 30-300 ug

TA98 - 0.2-20 ug

TA100 - 160-1600 ug	No mutagenic activity in bacteria (Salmonella
typhimurium) under conditions of this assay.

Note: only TA1535, TA1537, TA98, and TA100 were tested.  This study is
classified unacceptable.

870.5100	Gene mutation - bacterial reverse mutation assay	41031217
TA1535 - 30-300 ug

TA1537 - 30-300 ug

TA98 - 30-300 ug

TA100 - 30-300 ug	No mutagenic activity in bacteria (Salmonella
typhimurium) under conditions of this assay.

Note: only TA1535, TA1537, TA98, and TA100 were tested.  This study is
classified unacceptable.

870.5300	Cytogenetics -  in vitro mammalian cell gene mutation test (CHO
Cells)	41031218	15-50 µg/mL without S9 activation

35-60 µg/mL with S9 activation	No increase in mutant frequency at the
HGPRT locus, in the presence or absence of S9 activation.

870.5385	Cytogenetics - mammalian bone marrow chromosomal aberration
test (rats)	41031219	0, 0.25, 1.25, and 2.5 g/kg	No increase in number
of cells with aberrations or in aberrations per cell.

870.5550	Other effects - unscheduled DNA synthesis in mammalian cells in
culture (rats)	41031220	0, 7.5, 10.0, 12.5, and 15.0 µg/mL	No evidence
(or a dose-related positive response) that unscheduled DNA synthesis was
induced.

870.7485	Metabolism and pharmacokinetics - rat	41875017

41875018	1) 1 mg/kg radiolabelled, single dose by oral gavage

2) 100 mg/kg radiolabelled, single dose by oral gavage

3) 1 mg/kg unlabelled, 14 days in the diet, PLUS 1 mg/kg radiolabelled,
single dose by oral gavage

4) 1 mg/kg radiolabelled, by i.v. injection	The mean recovery of
radioactivity 4 days after exposure was 82.6-93.0% following single or
repeated oral doses and 88.2-99.2% following single i.v. doses,
indicating rapid absorption, distribution, and elimination.  Rapid
elimination and low tissue levels indicate low bioaccumulation of the
parent and metabolites.

Elimination occurred primarily 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.



870.7485	Metabolism and pharmacokinetics - rat	42900801	1) 1 mg/kg
radiolabelled, single dose by oral gavage

2) 100 mg/kg radiolabelled, single dose by oral gavage

3) 1 mg/kg unlabelled, 14 days in the diet, PLUS 1 mg/kg radiolabelled,
single dose by oral gavage	The mean recovery of radioactivity 3-4 days
after exposure was 90.4-104.5% following single or repeated oral doses,
indicating rapid absorption, distribution, and elimination. 
Bioaccumulation of the parent compound and metabolites is low.  There
were no major sex- or dose-related 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.

870.7600	Dermal penetration -  rat	41875019	0, 0.125, 1.25, and 12.5
mg/kg

Note:  End-use product (23.1%) was tested	Mean % of the dose absorbed
(sum of urine, feces, carcass, and skin) after 10 hrs of exposure:

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  tc "4.2.1	Adequacy of the
Toxicity Data Base " \l 3 

The toxicology database is complete and adequate for risk assessment.  

3.3.2	Evidence of Neurotoxicity  tc "4.2.2	Evidence of Neurotoxicity "
\l 3 

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  tc "4.2.3	Developmental Toxicity
Studies " \l 3 

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  tc "4.2.4	Reproductive Toxicity Study
" \l 3 

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  tc
"4.2.5Additional Information from Literature Sources " \l 3 

			

A literature search was not conducted for this risk assessment.

3.3.6	 Pre-and/or Postnatal Toxicity

 tc "4.2.6  Pre-and/or Postnatal Toxicity " \l 3 3.3.6.1	 Determination
of Susceptibility  tc "4.2.6.1Determination of Susceptibility " \l 4 

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.

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  tc "4.4
Hazard Identification and Toxicity Endpoint Selection " \l 2 

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.    tc "4.4.1   Acute Reference Dose (aRfD) - Females age 13-49 "
\l 3 

3.5.2	Acute Reference Dose (aRfD) - General Population  tc "4.4.2	Acute
Reference Dose (aRfD) - General Population " \l 3 

			

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)  tc "4.4.3	Chronic Reference Dose
(cRfD) " \l 3 

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)  tc "4.4.4
Incidental Oral Exposure (Short and Intermediate Term) " \l 3 

		

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  tc "4.4.5	Dermal Absorption " \l 3 

		

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 Q1* 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.  

 tc "4.4.8	Margins of Exposure " \l 3 

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.    tc "4.4.9	Recommendation
for Aggregate Exposure Risk Assessments " \l 3 

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 (Q1*).  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, Q1* (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 tc "4.4.10	Classification of
Carcinogenic Potential " \l 3 

Table 3.5.1  Summary of Toxicological Doses and Endpoints for
Fenbuconazole for use in Dietary

and Non-Occupational Human Health Risk Assessments

Exposure

Scenario	Dose Used in Risk Assessment, UF 	FQPA SF and Level of Concern
for Risk Assessment	Study and Toxicological Effects

Acute Dietary

(Females 13-49 years of age)	NOAEL = 30 mg/kg/day

UF = 100

Acute RfD = 0.3 mg/kg	FQPA SF =1

aPAD = acute RfD

              FQPA SF

= 0.3 mg/kg	Developmental rat study

Developmental LOAEL = 75 mg/kg/day based on increased resorptions and
decreased live fetuses per dam.

Acute Dietary (General population including infants and children)	None

	None	Not selected.

No appropriate dose and endpoint could be identified for these
population groups.

Chronic Dietary

(All populations)	NOAEL= 3 mg/kg/day

UF = 100

Chronic RfD = 0.03 mg/kg/day	FQPA SF =1

cPAD = 

chronic RfD

 FQPA SF

= 0.03 mg/kg/day	Combined chronic toxicity/ carcinogenicity - Rat

LOAEL = 30.6/43.1 (M/F) mg/kg/day based on decreased body weight gain,
increased thyroid weight, and histopathological lesions in the liver and
thyroid gland

Incidental Oral (All durations)

	None	None	Not selected.

No registered uses would result in residential exposure.

Cancer (oral, dermal, inhalation)	Classification: 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 (Q1*).   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, Q1* (mg/kg/day)-1 is 3.59 x 10-3 in human
equivalents. 

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 Toxicological Doses and Endpoints for
Fenbuconazole for use in

Occupational Human Health Risk Assessments

Exposure

Scenario	Dose Used in Risk Assessment, UF 	FQPA SF and Level of Concern
for Risk Assessment	Study and Toxicological Effects

Long-Term Dermal (several months to lifetime)	Oral study NOAEL= 3
mg/kg/day

(dermal absorption rate = 4.25%)	Residential LOC for MOE = NA

Occupational LOC for MOE = 100 	Combined chronic toxicity/
carcinogenicity - Rat

LOAEL = 30.6/43.1 (M/F) mg/kg/day based on decreased body weight gain,
increased thyroid weight, and histopathological lesions in the liver and
thyroid gland

Inhalation (All durations)

	Oral study NOAEL= 3 mg/kg/day

Absorption factor = 100%

	Residential LOC for MOE = NA

Occupational LOC for MOE = 100 	Combined chronic toxicity/
carcinogenicity - Rat

LOAEL = 30.6/43.1 (M/F) mg/kg/day based on decreased body weight gain,
increased thyroid weight, and histopathological lesions in the liver and
thyroid gland

Cancer (oral, dermal, inhalation)	Classification: 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 (Q1*).   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, Q1* (mg/kg/day)-1 is 3.59 x 10-3 in human
equivalents. 

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  tc "4.6	Endocrine disruption " \l 2 

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

4.1	Incident Reports

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  TC \l3 "3.2.3	Description of
Rotational Crop Metabolism  

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  TC \l3 "3.2.2	Description of Livestock
Metabolism 

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.

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.

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
14C-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  TC \l2 "3.1 	Comparative 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).  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 Metabolites and Degradates of Fenbuconazole.

Common name/code	Chemical name	Major Metabolite	Minor Metabolite in
Chemical structure

Fenbuconazole

α-[2-(4-chlorophenyl)ethyl]-α-phenyl-1H-1,2,4-triazole-1-propanenitril
e	Peach

Peanut Vine

Sugar beet

Wheat

Ruminants

Poultry

Water	Rotational Crops	

Lactone A and B Metabolites

RH-9129 and RH-9130	trans- or
cis-5-(4-chlorophenyl)dihydro-3-phenyl-3-(1H-1,2,4-triazol-1-ylmethyl)-2
(3H)-furanone

	Peach

Poultry 

Ruminant	Peanut

Sugar beet

Wheat

Rotational Crops

	

Triazole

RH-0118	1H-1,2,4-triazole	Eggs

Poultry	Rat

Ruminant

Milk

	

Triazole Alanine 

TA

RH-3968	2-amino-3-(1H-1,2,4-triazol-1-yl) propanoic acid	Peach

Peanut

Wheat

Rotational Crops	Milk	

Triazole Acetic Acid

TAA

RH-3779

RH-4098	1H-1,2,4-triazol-1-yl acetic acid	Wheat

Rotational Crops	Peach	



5.1.7	Toxicity Profile of Major Metabolites and Degradates   TC \l2 "3.5
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  TC \l2 "3.6
Summary of Residues for Tolerance Expression and Risk Assessment 

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

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

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

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

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

	Poultry	Not Applicable at this time	Not Applicable at this 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.

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)  

   

 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.

  TC \l2 "6.2	Water Exposure/Risk Pathway Table 5.1.c  Summary of
Estimated Surface and Ground Water Concentrations for Fenbuconazole.

Exposure Duration	Fenbuconazole

	Surface Water Conc., ppb a	Groundwater 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 Koc of  2884 mL/g, and a half-life of 393 days.



5.1.10	Food Residue Profile  TC \l3 "6.1.1	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.

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.

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
95th 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
Fenbuconazole

Population Subgroup	Acute Dietary

(95th Percentile)	

Chronic Dietary	

Cancer

	Exposure (mg/kg/day)	% aPAD	Exposure

(mg/kg/day)	% cPAD	Exposure

(mg/kg/day)	Risk

General U.S. Pop.	Not Applicable	0.000700	2.3	0.000473	1.7 x 10-6

All Infants (< 1 year)

0.002027	6.8	Not Applicable

Children (1-2 years)

0.001842	6.1

	Children (3-5 years)

0.001450	4.8

	Children (6-12 years)

0.000812	2.7

	Youth (13-19 years)

0.000440	1.5

	Adults (20-49 years)

0.000563	1.9

	Adults (50+ years)

0.000645	2.2

	Females (13-49 years)	0.009155	3.1	0.000572	1.9

	

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  TC
\l2 "6.3	Residential (Non-Occupational) Exposure/Risk Pathway 

There are currently no registered residential uses associated with
fenbuconazole.

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

Spray drift is always a potential source of exposure to residents living
in close proximity to spraying operations.  This situation is
particularly the case with aerial application.  However, to a lesser
extent, spray drift resulting from the ground application of
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.

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.

  TC \l1 "7.0	Aggregate Risk Assessments and Risk Characterization 

For most pesticide active ingredients, water monitoring data are
considered inadequate to determine surface and groundwater drinking
water exposure estimates, so model estimates have been used to estimate
residues in drinking water.  EFED and HED have agreed that acute,
chronic, and cancer EDWCs can be used directly in dietary exposure
assessments to calculate aggregate dietary (food + water) risk.  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  TC \l2 "7.2	Short-Term
Aggregate Risk 

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

7.3	Long-Term Aggregate Risk

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  TC \l2 "7.5	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.  TC \l2 "7.4	Long-Term Aggregate Risk 

Table 7.4    Fenbuconazole Chronic (Cancer) Exposure and Risk Estimates 

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



U.S. Population

	

0.00359	

0.000473	

1.7 x 10-6



													

8.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT  TC \l1 "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   HYPERLINK "http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

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).  TC \l1 "9.0	Occupational Exposure/Risk Pathway 

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:

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 Intermediate-term Inhalation Risk
for Fenbuconazole Handlers

Scenario	Mitigation	Crops	Inhalation Unit Exposure (µg/lb) a
Application Rate b

(lb ai/acre)	Acres Treated

(A/day) c

	Inhalation Dose d (mg/kg/day)	Inhalation  MOEe

Mixer/Loader

Mixing/loading WSP for ground application (1)	Baseline	Peppers	0.24
0.188	80	0.000052	58,000

Mixing/loading WSP for aerial application (2)	Baseline	Peppers	0.24
0.188	350	0.00023	13,000

Applicator

Applying spray using ground- boom (3)	Baseline	Peppers	0.74	0.188	80
0.00016	19,000

Applying spray using fix-wing aircraft (4)	Engineering control
(considered as baseline)	Peppers	0.068	0.188	350	0.000064	47,000

Flagger

Flagging 

during aerial application (5)	Baseline	Peppers	0.35	0.188	350	0.00033
9,100

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.

  SEQ CHAPTER \h \r 1 

Table 9.1.b.  Cancer Risks for Fenbuconazole Handlers 

Scenario	Mitigation	Crop	Dermal  Dose a (mg/kg/day)	Inhalation Dose a
(mg/kg/day)	Combined ADD b (mg/kg/day)	Commercial

LADD  c

(mg/kg/day)	Commercial

Cancer

Risk d

Mixer/Loader

Mixing/loading WSP for ground application (1)	Baseline	Peppers	0.00019
0.000052	0.00024	0.0000098	3.5 E-8

Mixing/loading WSP for aerial application (2)	Baseline	Peppers	0.00084
0.00023	0.0011	0.000045	1.6 E-7

Applicator

Applying spray using ground- boom (3)	Baseline	Peppers	0.00013	0.00016
0.00029	0.000012	4.3 E-8

Applying spray using fix-wing aircraft (4)	Engineering control
(considered as baseline)	Peppers	0.00020	0.000064	0.00026	0.000011	3.8
E-8

Flagger

Flagging 

during aerial application (5)	Baseline	Peppers	0.00044	0.00033	0.00077
0.000032	1.2 E-7

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  SEQ CHAPTER \h \r 1 .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 Crop Group Category	Exposure Potential	Transfer
Coefficients (cm2/hr)	Activities   

Peppers	Fruiting Vegetables	Low	500	Irrigation, scouting, 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 Exposure/Risk for Fenbuconazole Post-application
Workers 

Crop	DAT a	DFR b

(ug/cm2)	Transfer Coefficientc (cm2/hr)	Daily Dose  d (mg/kg/day)	LADD e
Cancer Risk f

Peppers	Avg	0.1388	500	0.0003371	1.385 E-5	5.0 E-8



	1,000	0.0006742	2.771 E-5	9.9 E-8

DAT= 30 day residue average

DFRt (µg/cm2) = 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/cm2  

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

Daily Dose (mg/kg/day)= DFR (µg/cm2) x 0.001 mg/ug x Tc (cm2/hr) x DA
(4.25%) x ET (8 hr/day)/70 kg

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

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

10.	DATA NEEDS AND LABEL REQUIREMENTS  TC \l1 "10.0	Data Needs and Label
Requirements 

10.1	Toxicology -None  TC \l2 "10.1	Toxicology 

10.2	Residue Chemistry  TC \l2 "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.

	•	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.

“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.

“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.

“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 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  TC \l2 "10.3
Occupational and Residential Exposure 

REFERENCES  TC \l1 "References: 

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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)  TC \l1 "9.0	Occupational Exposure/Risk Pathway 

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 Fenbuconazole.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance
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灰牥〇㐮〇㐮ܰ摁煥慵整映敩摬琠楲污搠瑡⁡潦⁲数灰
牥⁳牡⁥癡楡慬汢⹥䌍浯潭楤祴搠晥湩瑩潩㩮†敐灰牥
ܠഇ഍഍̍഍ഄ̍഍ഄ഍഍

