UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:		23-JULY-2008

Subject:		Tetraconazole:  Human-Health Risk Assessment for New Use on
Grapes and a Label Amendment for Pecans.

PC Code:	120603	DP No.:	347084

Decision No.:	385084	Registration No.:  	80289-XXX,

60063-12

Petition No.:	7E7273	Regulatory Action:	Section 3 Registration

Risk Assessment Type: 	Single Chemical/

Aggregate Assessment	Case No.:	NA

TXR No.:	NA	CAS No.:	112281-77-3

MRID No.:	NA	40 CFR	180.557

From:	Mary Clock-Rust, Biologist

	Tom Bloem, Chemist

	Robert Mitkus, Ph.D, Toxicologist

	Registration Action Branch 1, Health Effects Division (RAB1/HED; 7509P)

Thru:	Dana M. Vogel, Branch Chief

	George F. Kramer, Ph.D., Senior Chemist

	RAB1/HED (7509P)

To:	Susan Stanton (RM 05)

	And

	Lisa Jones (RM 21)

	Registration Division (RD; 7505P)

The current action proposes a new use of tetraconazole on grapes and,
therefore, a revised human-health risk assessment is needed.  A change
in the pecan use pattern is also being requested.  A summary of the
findings and an assessment of human-health risk resulting from all
registered and proposed tetraconazole uses are provided in this
document.  Mary Clock-Rust provided the occupational and residential
exposure assessment, Tom Bloem provided the residue chemistry and
dietary exposure assessment, and the drinking water assessment was
provided by Iwona Maher of EFED.

Table of Contents

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc204569170"  1.0  Executive
Summary	  PAGEREF _Toc204569170 \h  4

  HYPERLINK \l "_Toc204569171"  2.0  Background	  PAGEREF _Toc204569171
\h  8

  HYPERLINK \l "_Toc204569172"  3.0  Ingredient Profile	  PAGEREF
_Toc204569172 \h  9

  HYPERLINK \l "_Toc204569173"  3.1  Summary of Registered/Proposed Uses
  PAGEREF _Toc204569173 \h  9

  HYPERLINK \l "_Toc204569174"  4.0  Hazard Assessment and Dose-Response
Characterization	  PAGEREF _Toc204569174 \h  10

  HYPERLINK \l "_Toc204569175"  4.1  Parent Tetraconazole	  PAGEREF
_Toc204569175 \h  10

  HYPERLINK \l "_Toc204569176"  4.2  FQPA SF	  PAGEREF _Toc204569176 \h
11

  HYPERLINK \l "_Toc204569177"  4.3  Dose-Response Assessment for
Tetraconazole	  PAGEREF _Toc204569177 \h  11

  HYPERLINK \l "_Toc204569178"  4.4  Toxicity of Tetraconazole
Metabolites	  PAGEREF _Toc204569178 \h  14

  HYPERLINK \l "_Toc204569179"  4.5.  Endocrine Disruption	  PAGEREF
_Toc204569179 \h  15

  HYPERLINK \l "_Toc204569180"  4.6  Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc204569180 \h  15

  HYPERLINK \l "_Toc204569181"  5.0  Dietary Exposure/Risk
Characterization	  PAGEREF _Toc204569181 \h  15

  HYPERLINK \l "_Toc204569182"  5.1.  Tetraconazole Residues	  PAGEREF
_Toc204569182 \h  16

  HYPERLINK \l "_Toc204569183"  5.1.1  Tetraconazole Metabolism and
Residues of Concern	  PAGEREF _Toc204569183 \h  16

  HYPERLINK \l "_Toc204569184"  5.1.2  Environmental Fate and Drinking
Water Residue Profile	  PAGEREF _Toc204569184 \h  17

  HYPERLINK \l "_Toc204569185"  5.1.3  Food Residue Profile and
Enforcement Methods	  PAGEREF _Toc204569185 \h  17

  HYPERLINK \l "_Toc204569186"  5.1.4  International Residue Limits
PAGEREF _Toc204569186 \h  19

  HYPERLINK \l "_Toc204569187"  5.1.5  Grape Tolerance Recommendation
PAGEREF _Toc204569187 \h  19

  HYPERLINK \l "_Toc204569188"  5.2  Dietary Exposure and Risk	  PAGEREF
_Toc204569188 \h  19

  HYPERLINK \l "_Toc204569189"  6.0  Residential (Non-Occupational)
Exposure Pathway	  PAGEREF _Toc204569189 \h  21

  HYPERLINK \l "_Toc204569190"  7.0  Aggregate Risk Assessment	  PAGEREF
_Toc204569190 \h  22

  HYPERLINK \l "_Toc204569191"  8.0  Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc204569191 \h  22

  HYPERLINK \l "_Toc204569192"  9.0  Occupational Risk Assessment
PAGEREF _Toc204569192 \h  22

  HYPERLINK \l "_Toc204569193"  9.1  Occupational Handler Risk	  PAGEREF
_Toc204569193 \h  24

  HYPERLINK \l "_Toc204569194"  9.1.1  Data and Assumptions for Handler
Exposure Scenarios	  PAGEREF _Toc204569194 \h  24

  HYPERLINK \l "_Toc204569195"  9.1.2  Occupational Handler Exposure and
Risk	  PAGEREF _Toc204569195 \h  25

  HYPERLINK \l "_Toc204569196"  9.2  Occupational Post-Application Risk
 PAGEREF _Toc204569196 \h  26

  HYPERLINK \l "_Toc204569197"  9.3  Occupational Cancer Risk	  PAGEREF
_Toc204569197 \h  28

  HYPERLINK \l "_Toc204569198"  9.3.1  Occupational Handler Cancer Risk
 PAGEREF _Toc204569198 \h  28

  HYPERLINK \l "_Toc204569199"  9.3.2  Occupational Post-Application
Cancer Risk	  PAGEREF _Toc204569199 \h  29

  HYPERLINK \l "_Toc204569200"  9.3.3  REI	  PAGEREF _Toc204569200 \h
29

  HYPERLINK \l "_Toc204569201"  10.0  Data Needs and Label Requirements
 PAGEREF _Toc204569201 \h  29

  HYPERLINK \l "_Toc204569202"  10.1  Toxicology	  PAGEREF _Toc204569202
\h  29

  HYPERLINK \l "_Toc204569203"  10.2  Residue Chemistry	  PAGEREF
_Toc204569203 \h  29

  HYPERLINK \l "_Toc204569204"  Attachment 1.  Chemical Structures
PAGEREF _Toc204569204 \h  31

  HYPERLINK \l "_Toc204569205"  Appendix A:  Hazard Assessment	  PAGEREF
_Toc204569205 \h  33

 1.0  Executive Summary

Background

Tetraconazole
(1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)propyl]-1H-1,2,4
-triazole) is a systemic fungicide and is a member of the
conazole/triazole class of pesticides. Tetraconazole acts by inhibiting
the metabolic pathway leading to fungal sterol production
[sterol-demethylation inhibitor (DMI)].  Tetraconazole is currently
registered for application to sugar beet, soybean, peanut, and pecan
with tolerances for residue of tetraconazole per se ranging from
0.04-1.0 ppm (40 CFR 180.557).  Tetraconazole tolerances as a result of
secondary residues are also established in/on poultry and ruminant
commodities (0.01-0.25 ppm).

In January, 2007, HED completed a human-health risk assessment
associated with the application of tetraconazole to several crops,
including sugar beet (D321751, M. Clock-Rust et al., 26-Jan-2007).
Subsequently, HED assessed risks from an increase in the sugar beet
tolerance (D340169, T. Bloem, 8/28/2007).  The current action proposes a
new use of tetraconazole on grapes and a reduction of the seasonal
application rate for pecans.

While the dietary, aggregate and occupational risk assessments have been
updated in this document, the hazard assessment and Food Quality
Protection Act (FQPA) decision presented in HED’s January, 2007 risk
assessment have not changed (D321751. M. Clock-Rust et al.,
26-Jan-2007).  Therefore, a summary of the hazard assessment is
presented in this document, with details on the hazard assessment and
FQPA decision available in the January, 2007 risk assessment cited
above.

Proposed Use: Grapes

The petitioner requests a registration for application of Mettle® 125ME
Fungicide (emulsifiable concentrate (EC); 1 lb ai/gallon; EPA Reg. No.
80289-8) on grapes.  The proposed registration of tetraconazole for use
on grapes is for control of various diseases in grapes (powdery mildew,
black rot).  The proposed label for Mettle® indicates that it may be
applied by ground boom or aircraft sprayer.  The rate of application is
5 fluid ounces of product per acre (0.04 lb ai/A).  The label advises
application at pre-bloom and to continue at spray intervals of up to 21
days in low to moderate disease pressure.  A maximum of 2 applications
of tetraconazole may be made per season (seasonal maximum is 0.08 lb
ai/A).  There is a 14-day pre-harvest interval (PHI).

The proposed label indicates a restricted-entry interval (REI) of 12
hours.  The label requires applicators and other handlers to wear
long-sleeved shirt, long pants, chemical-resistant gloves and shoes plus
socks.

Proposed Change in Pecan Application Pattern

Tetraconazole is currently registered for use on pecans at the rate of
0.125 lb ai/A.  In the current action, the registrant proposes amending
the labels for the end-use product, Eminent® 125 SL Fungicide (EPA Reg.
No. 60063-12) from 8 applications per season (seasonal maximum of 1 lb
ai/A) to 4 applications per season (seasonal maximum of 0.5 lb ai/A).
The single application rate is unchanged.

Hazard and Dose-Response Assessment

Tetraconazole has low acute toxicity via the oral, dermal, and
inhalation routes.  It is a slight eye irritant, but is not a dermal
irritant or a dermal sensitizer.  The liver and kidney are the primary
target organs of tetraconazole.  In the subchronic, chronic, and
reproduction rat studies, subchronic and carcinogenicity mouse studies,
and the chronic dog study increases in liver weight, increases in liver
serum enzymes, or gross and microscopic liver pathology were noted at
various doses, providing evidence of liver toxicity.

An endpoint of concern for acute dietary risk assessment for the general
population was not identified.  Therefore, an acute dietary risk
assessment was not performed.  However, the endpoint for dietary risk
assessment for females 13-50 years of age is based on increased
incidence of supernumerary ribs seen in a rat developmental toxicity
study.  The acute reference dose (aRfD)/acute population-adjusted dose
(aPAD) is 0.225 mg/kg/day [FQPA Safety Factor (SF) = 1x; see below].

The chronic toxicity study in dogs is the basis for the chronic dietary
reference dose (cRfD).  Absolute and relative kidney weights and
histopathological changes in the male kidney were seen at the
lowest-observed adverse-effect level (LOAEL) of 2.9 mg/kg/day.  The
cRfD/chronic population-adjusted dose (cPAD) is 0.0073 mg/kg/day.

The HED CARC (November 10, 1999) classified tetraconazole as "likely to
be carcinogenic to humans" by the oral route based on the occurrence of
liver tumors in male and female mice, in accordance with the EPA Draft
Guidelines for Carcinogen Risk Assessment (July, 1999).  The CARC
recommended that a low-dose extrapolation model be applied to the
experimental animal tumor data and that quantifications of risk be
estimated for male and female mouse liver tumors for tetraconazole.
Tetraconazole did not show evidence of mutagenicity in in vitro or in
vivo studies.  The Q1* for cancer risk assessment is 2.3 x 10-2
(mg/kg/day)-1.

The results of the 2-generation reproduction toxicity study were the
basis for short- and intermediate-term incidental oral risk assessments
and short-term dermal and inhalation risk assessments.  At the LOAEL of
40.6 mg/kg/day, decreased litter weight and mean pup weight in litters
of all generation before weaning and increased relative liver weights at
weaning in both sexes of all litters were observed.  The dose for risk
assessment is the no-observed adverse-effect level (NOAEL) of 5.9
mg/kg/day.

The dose and endpoint for intermediate- and long-term inhalation and
dermal risk assessments were based on the results of the chronic
toxicity study in dogs (absolute and relative kidney weights and
histopathological changes in the male kidney were seen at the LOAEL of
2.9 mg/kg/day).  The oral NOAEL is 0.73 mg/kg/day.  Effects were the
same as those described above for the cRfD.

HED notes that 40 CFR Part 158 was revised in 2007 to require
immunotoxicity, acute neurotoxicity, and subchronic neurotoxicity tests
for registration of a pesticide (food and non-food uses).  These data
have not been submitted and are required for tetraconazole.

FQPA

The RAB1 tetraconazole team recommended that the 10X FQPA SF for the
protection of infants and children be reduced to 1X since there is no
evidence of increased susceptibility and there are no concerns or
residual uncertainties for pre and/or post-natal toxicity.  In addition,
dietary, drinking water and residential exposure assessments are not
expected to underestimate exposure, and a developmental neurotoxicity
(DNT) study is not required.

Tetraconazole Metabolites

The residues of concern following application of tetraconazole include
compounds which HED has determined to be toxicologically different from
tetraconazole.  HED’s dietary exposure analysis includes exposure to
those compounds which HED has determined are toxicologically equivalent
to tetraconazole.

Dietary Exposure

For the proposed use on grapes, acute, chronic, and cancer dietary risk
assessments (food and drinking water) were conducted using the Dietary
Exposure Evaluation Model - Food Consumption Intake Database
(DEEM-FCID™, ver. 2.03) which incorporates the food consumption data
from the USDA’s Continuing Surveys of Food Intakes by Individuals
(CSFII; 1994-1996 and 1998).  These analyses were conducted in support
of the proposed application of tetraconazole to grapes.  The proposed
use pattern change for pecans does not impact the dietary exposure
assessment.  The following paragraphs are summaries of the acute,
chronic, and cancer analyses.

Acute:  The Tier 1 acute analysis (assuming tolerance-level residues and
100% crop treated) resulted in an exposure estimate for females 13-49
years old less than HED’s level of concern (0.75% acute population
adjusted dose (aPAD); acute endpoint of concern was not identified for
the general population including infants and children).

Chronic:  The chronic analysis was refined through the incorporation of
empirical processing factors, average field trial residues, average
residues from the feeding studies, and projected percent crop treated
estimates for the feed commodities (100% crop treated assumed for food
commodities).  The resulting exposure estimates do not exceed HED's
level of concern (7.7% cPAD; all infants <1 year old were the most
highly exposed population subgroup).

Cancer:  The cancer analysis was refined through the incorporation of
empirical processing factors, average field trial residues, average
residues from the feeding studies, and projected percent crop treated
estimates (food and feed).  The resulting exposure estimates yielded a
cancer risk for the U.S. population of 3 x 10-6 which does not exceed
HED's level of concern.  A critical commodity analysis indicated that
water (62% of total exposure) and soybean oil (21% of total exposure)
were the major contributors to the cancer exposure.

Aggregate Risk Assessment

Since there are no registered/proposed uses which result in residential
exposures, aggregate exposure to tetraconazole consists of exposure from
food and drinking water sources only.  Since the dietary exposure
analysis included the drinking water estimates, the discussion and
exposure estimates presented in the dietary section of this document
represent aggregate acute, aggregate chronic and aggregate cancer risk.

Occupational Handler Risk

For the proposed use on grapes, handler exposure is expected for
mixer/loaders and applicators.  Conservative assessments of short-,
intermediate-term and cancer risk were conducted.  All short- and
intermediate-term   SEQ CHAPTER \h \r 1 handler exposures resulted in
margins of exposure (MOEs) that do not exceed HED’s level of concern,
provided mixer/loaders wear chemical-resistant gloves (as required on
the label).  Cancer risks for handlers also did not exceed HED’s level
of concern.  Cancer risks were in the range of 10-6 to 10-7 provided
mixer/loaders wear chemical-resistant gloves as stated on the label.

The proposed change in the number of applications per season for pecans
does not impact the occupational exposure assessment for the pecan use.
See the last risk assessment for details (Memo, M. Clock-Rust, D321751,
1/26/07).

Occupational Post-Application Exposure

A conservative assessment of short-term risk was assessed for workers
turning table grape canes, the post-application activity for which
exposure is the highest.  The estimated risk for these workers results
in an MOE of 1600 and does not exceed HED’s level of concern.
Estimated cancer risk for this post-application exposure scenario in
grapes (1.2 x 10-5) also does not exceed HED’s level of concern.

ORE Conclusions and Recommendations

HED concludes that the proposed use of tetraconazole on grapes will not
exceed its level of concern for occupational risk, provided that
handlers wear chemical-resistant gloves, as stated on Mettle® labels.
Further, HED concurs with the proposed REI of 12 hours as it appears on
Mettle® labels.

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), were previously determined to require a review of their
ethical conduct, and have received that review. The studies in PHED were
considered appropriate (or ethically conducted) for use in risk
assessments.

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered for this human health risk assessment, in
accordance with US Executive Order 12898, Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,   HYPERLINK
"http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.
pdf_"
http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.p
df .

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 USDA under the 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.
Whenever appropriate, non-dietary exposures based on home use of
pesticide products, associated risk for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
post-application are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

HED Recommendations

Provided revised Sections B and F are submitted, HED concludes that the
hazard, residue chemistry and exposure databases support a conditional
registration for application of the proposed tetraconazole formulation
to grape and supports establishment of a permanent tolerance in/on grape
of 0.20 ppm for residues of tetraconazole per se.  The residue chemistry
database may support an unconditional registration upon submission of
storage stability data demonstrating the stability of residues of
tetraconazole per se in/on grape (236 days) and 1,2,4-triazole (T),
triazolyl alanine (TA), and triazolyl acetic acid (TAA) residues in/on
grape (236 days), grape juice (64 days), and raisin (68 days).  Storage
stability data for T, TA, and TAA has been requested as part of a
previous human-health aggregate risk assessment (D322215, M. Doherty, et
al., 7-Feb-2006).  Submission of the data requested in the 7-Feb-2006
document will satisfy storage stability data requirements for T, TA, and
TAA of the subject petition.

Summary of Data Requirements for Proposed Use on Grape

Revised Section B

Revised Section F

Frozen storage stability data demonstrating the stability of residues of
tetraconazole per se in/on grape (236 days) and T, TA, and TAA residues
in/on grape (236 days), grape juice (64 days), and raisin (68 days).

Guideline immunotoxicity study (OPPTS 870.7800) and acute and subchronic
neurotoxicity screening batteries (OPPTS 870.6200) with tetraconazole

The toxicology database for is essentially complete and there is no
evidence of neurotoxicity or immunotoxicity in the hazard database for
tetraconazole. However, the Revised Part 158 requires immunotoxicity and
neurotoxicity studies be submitted.  While the new Part 158 requirement
for an immunotoxicity study and acute and subchronic neurotoxicity
studies have not yet been fulfilled for tetraconazole, the existing data
are sufficient for endpoint selection for exposure/risk assessment
scenarios and for evaluation of the requirements under the FQPA.

Note that data requirements pertaining to immunotoxicity and subchronic
neurotoxicity (see Section 10.1) must be fulfilled as a condition of
registration.

2.0  Background

Tetraconazole is a systemic fungicide and is a member of the
conazole/triazole class of pesticides.  It acts by inhibiting the
metabolic pathway leading to fungal sterol production (sterol-DMI).
Tetraconazole is currently registered for application to sugar beet,
peanut, pecan, and soybean with tolerances ranging from 0.05-0.80 ppm
(40 CFR 180.557).  Tolerances as a result of secondary residues are also
established in/on poultry and ruminant commodities (0.01-0.25 ppm).

HED has recently completed a human-health risk assessment associated
with the application of tetraconazole to several crops including sugar
beet (D321751. M. Clock-Rust et al., 26-Jan-2007).

While the dietary, aggregate and occupational risk assessments have been
updated in this document, the hazard assessment and FQPA decision
presented in HED’s January, 2007 risk assessment has not changed
(D321751. M. Clock-Rust et al., 26-Jan-2007).  Therefore, a summary of
the hazard and dose-response assessment and the FQPA decision is
presented in this document.

For information concerning hazard characterization, FQPA SF,
plant/livestock/rat metabolism, residues of concern for tolerance
enforcement and risk assessment, drinking water exposure, triazole(s)
dietary/aggregate exposure, and occupational/residential exposure,
please refer to the previous risk assessment (D321751, M. Clock-Rust et
al., 26-Jan-2007).

3.0  Ingredient Profile

3.1  Summary of Registered/Proposed Uses

The tetraconazole formulations Eminent® 125SL Fungicide (EC; 1 lb
ai/gallon; EPA Reg. No. 60063-12) and/or Domark® 230ME Fungicide (EC;
1.9 lb ai/gallon; EPA Reg. No. 80287-7) are currently registered for
application to sugar beet (2 x 0.10 lb ai/acre), peanut (4 x 0.1 lb
ai/acre), pecan (8 x 0.125 lb ai/acre), and soybean (2 x 0.075 lb
ai/acre).  The petitioner is requesting registration for application of
Mettle( 125ME Fungicide (EC; 1 lb ai/gallon; EPA Reg. No. 80289-8) to
grape for control of numerous diseases including powdery mildew and
black rot.  The label indicates a REI of 12 hours.

Tetraconazole is currently registered for use on pecans at the rate of
0.125 lb ai/A.  In the current action, the registrant proposes amending
the labels for the end-use product, Eminent® 125 SL Fungicide (EPA Reg.
No. 60063-12) from 8 applications per season (seasonal maximum of 1 lb
ai/A) to 4 applications per season (seasonal maximum of 0.5 lb ai/A).
The single application rate is unchanged.

Table 3.1 is a summary of the proposed application scenarios for grapes
and pecans.

The proposed label for grape does not indicate a minimum spray volume
for ground applications.  Based on the submitted magnitude of the
residue data, HED requests that the label indicate a minimum spray
volume of 20 gallons per acre (GPA) for ground applications.  A revised
Section B is requested.

Table 3.1.  Proposed Application Scenario for Grapes and Pecans.

Formulation	Rate

(lb ai/acre)	No. Apps.	RTI1 (days)	PHI2 (days)	Comments

Grapes

Mettle( 125Me Fungicide;

microemulsion; 1 lb ai/gal.;

EPA Reg. No. 80289-8	0.03-0.04	2	14	14	-Ground (sufficient volume for
thorough coverage) and aerial (≥10 GPA) applications are permitted;
chemigation is prohibited.

-Do not apply more than 0.08 lb ai/acre/season.

-First application may be made pre bloom (1-3 inches of new shoot).

Pecans

Eminent® 125SL Fungicide

(water soluble liquid; 1 lb ai/gallon; EPA Reg. No. 60063-12))	0.125	4
14-21	14	-ground, aerial, and chemigation applications are permitted in
spray volumes sufficient to provide complete coverage

-addition of a surfactant is acceptable

1. RTI:  Re-treatment interval.

2. PHI:  Pre-harvest interval.

4.0  Hazard Assessment and Dose-Response Characterization

For details on the hazard assessment and dose-response assessment, see
the last risk assessment for tetraconazole (D321751. M. Clock-Rust et
al., 26-Jan-2007).

HED has determined that three toxicologically different groups of
compounds are of concern following application of tetraconazole (see
Section 4.4 for a discussion and Attachment 1 for structures).  The
hazard assessment for tetraconazole metabolites is discussed in Section
4.4 below.

HED notes that 40 CFR Part 158 was revised in 2007 to require
immunotoxicity, acute neurotoxicity, and subchronic neurotoxicity tests
for registration of a pesticide (food and non-food uses).  These data
have not been submitted and are required for tetraconazole.

4.1  Parent Tetraconazole

Tetraconazole has low acute toxicity via the oral, dermal, and
inhalation routes.  It is a slight eye irritant, but is not a dermal
irritant or a dermal sensitizer.  The liver and kidney are the primary
target organs of tetraconazole.  In the subchronic, chronic, and
reproduction rat studies, subchronic and carcinogenicity mouse studies,
and the chronic dog study increases in liver weight, increases in liver
serum enzymes, or gross and microscopic liver pathology were noted at
various doses, providing evidence of liver toxicity.

In all of the above studies, except the subchronic mouse study,
increases in kidney weight or gross pathology and cortical tubular
hypertrophy (dog) were noted at various doses, indicating renal
toxicity.

Certain changes in multiple organs were seen in the database that may be
due to various mechanisms including possible liver-pituitary-thyroid
homeostatic disruption or inhibition of steroid synthesis.

Long-term dietary administration of tetraconazole resulted in an
increased incidence of combined benign and malignant liver tumors in
mice of both sexes.  The levels of the doses tested were adequate.  No
tumors were noted in male or female rats after long-term dietary
administration of tetraconazole.  The HED CARC (November 10, 1999)
classified tetraconazole as "likely to be carcinogenic to humans" by the
oral route based on the occurrence of liver tumors in male and female
mice, in accordance with the EPA Draft Guidelines for Carcinogen Risk
Assessment (July, 1999).  The CARC recommended that a low-dose
extrapolation model be applied to the experimental animal tumor data and
that quantifications of risk be estimated for male and female mouse
liver tumors for tetraconazole.  The Q1*= 2.3 x 10-2 (mg/kg/day)-1 based
on male mouse liver benign and/or malignant combined tumor rates.
Tetraconazole did not show evidence of mutagenicity in in vitro or in
vivo studies.

Oral rat and rabbit developmental studies showed no increased
susceptibility of the fetus to tetraconazole in utero.  Maternal
toxicity and developmental toxicity occur at the same dose level of 100
mg/kg/day in the rat study.  No developmental toxicity was seen in the
rabbit study with the maternal toxicity level noted at the highest dose
tested (30 mg/kg/day).

A two-generation rat reproduction study also revealed no increased
susceptibility to offspring.  Decreased litter weight and mean pup
weight and increased liver weight were noted at a dose of 35.5 mg/kg/day
(males) and 40.6 mg/kg/day (females) while parental toxicity resulted in
decreased body weight gain and food consumption during pre-mating,
increased relative liver and kidney weights, hepatocellular hypertrophy
and gastric irritation in males and females at 35.5 and 40.6 mg/kg/day,
respectively.

No evidence of neurotoxicity was noted in any oral study.  No acute or
subchronic neurotoxicity studies were submitted.

Rat metabolism data indicate that tetraconazole is well absorbed from
the gastro-intestinal tract and almost 100% of the administered dose was
recovered in urine (52-76%) and feces (12-36%) and less than 6%
(2.8-5.8%) of the administered dose remained in the carcass/tissues
within 72 hours post-dosing.  There was no major difference in
absorption and elimination of tetraconazole between sexes and dose
levels.  Position of labeling [14C-phenyl or 14C-triazole] resulted in
slight differences in the blood time to reach maximum (Tmax) levels and
T1/2 lives between sexes and doses.  Males had slightly higher Tmax
levels than females.  Metabolic identification revealed triazole as the
major urinary and fecal metabolite.

4.2  FQPA SF

It is recommended that the 10X FQPA SF for the protection of infants and
children be reduced to 1X since there is no evidence of increased
susceptibility and there are no concerns or residual uncertainties for
pre and/or post-natal toxicity based on the following:

The dietary food exposure assessment is not likely to underestimate
exposure/risk.

The dietary drinking water assessment utilizes water concentration
values generated by models and associated modeling parameters which are
designed to provide conservative, health-protective, high-end estimates
of water concentrations which will not likely be exceeded.

There are no residential uses.

There was no evidence of neurotoxicity in any submitted study.

There was no evidence of adverse effects on the organs of the immune
system at the LOAEL in any study with tetraconazole.  In addition,
tetraconazole does not belong to a class of chemicals (e.g., the
organotins, heavy metals, or halogenated aromatic hydrocarbons) that
would be expected to be immunotoxic.  Based on the above considerations,
HED does not believe that conducting a special series 870.7800
immunotoxicity study will result in a point of departure less than the
NOAEL of 0.73 mg/kg/day used in calculating the cRfD for tetraconazole,
and therefore, an additional uncertainty factor (UFDB) for database
uncertainties does not need to be applied.

A DNT study is not required.

4.3  Dose-Response Assessment for Tetraconazole

An endpoint of concern for acute dietary risk assessment for the general
population was not identified.  Therefore, this risk assessment was not
performed.  However, the endpoint for dietary risk assessment for
females 13-50 years of age is based on increased incidence of
supernumerary ribs seen in a rat developmental toxicity study.  The
aRfD/aPAD is 0.225 mg/kg/day (FQPA SF = 1x).

The chronic toxicity study in dogs is the basis for the cRfD.  Absolute
and relative kidney weights and histopathological changes in the male
kidney were seen at the LOAEL of 2.9 mg/kg/day.  The cRfD/cPAD is 0.0073
mg/kg/day.

The results of the 2-generation reproduction toxicity study were the
basis for short- and intermediate-term incidental oral risk assessment,
short-term dermal and inhalation risk assessment.  At the LOAEL of 40.6
mg/kg/day, decreased litter weight and mean pup weight in litters of all
generation before weaning and increased relative liver weights at
weaning in both sexes of all litters were observed.  The dose for risk
assessment is the NOAEL of 5.9 mg/kg/day.

The dose and endpoint for intermediate- and long-term inhalation and
dermal risk assessments were based on the results of the chronic
toxicity study in dogs (the same study was used as the basis for the
cRfD).  The oral NOAEL is 0.73 mg/kg/day.  Effects were the same as
those described above for the cRfD.

Table 4.3.1.  Summary of Levels of Concern (MOEs) for Risk Assessment.

Route	Short-Term

(1-30 Days)	Intermediate-Term

(1-6 Months)	Long-Term

(>6 Months)

Residential

Dermal	100	100	100

Inhalation	100	100	100

Incidental oral	100	100	100

Occupational Exposure

Dermal	100	100	100

Inhalation	100	100	100

Table 4.3.2.  Summary of Toxicological Doses and Endpoints for
Tetraconazole for Use in Human-health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA SFs	RfD, PAD, Level of
Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary

General Population	None	None	None	An endpoint of concern attributable to
a single dose was not identified.  An acute RfD was not established.

Acute Dietary

Females 13-50 years of age	NOAEL = 22.5 mg/kg/day	UFA = 10x

UFH = 10x

SFFQPA = 1 	aRfD = 0.225 mg/kg/day

aPAD = 0.225 mg/kg/day	Developmental toxicity study in rats

Developmental LOAEL = 100 mg/kg/day based on increased incidence of
small fetuses and supernumerary ribs.

Chronic Dietary (All Populations)	NOAEL = 0.73 mg/kg/day	UFA = 10x

UFH = 10x

SFFQPA = 1	cRfD = 0.0073 mg/kg/day

cPAD = 0.0073 mg/kg/day	Chronic oral toxicity - dog

LOAEL = 2.95/3.33 (M/F) mg/kg/day, based on absolute and relative kidney
weights and histopathological changes in the male kidney.

Incidental Oral Short-Term

(1-30 days)

And

Intermediate-term

(1-6 months)	Offspring Toxicity NOAEL = 5.9 mg/kg/day	UFA = 10x

UFH= 10x

SFFQPA = 1	LOC = 100 (occupational)

LOC = 100 (residential)	Reproductive toxicity - rat

Offspring LOAEL = 35.5 mg/kg/day, based on decreased litter weight and
mean pup weight in litters of all generations before weaning and
increased relative liver weights at weaning in both sexes of all
litters.

Dermal

Short-Term (1-30 days)

	Oral study Offspring Toxicity NOAEL = 5.9 mg/kg/day (dermal absorption
rate = 12%)	UFA = 10x

UFH = 10x

SFFQPA = 1

	LOC = 100 (occupational)

LOC = 100 (residential)	Reproductive toxicity - rat

Offspring LOAEL = 35.5 mg/kg/day, based on decreased litter weight and
mean pup weight in litters of all generations before weaning and
increased relative liver weights at weaning in both sexes of all
litters.

Dermal Intermediate-Term (1-6 months)

And

Long-term

(>6 months)

	Oral study NOAEL = 0.73 mg/kg/day

(dermal absorption rate = 12%)	UFA = 10x

UFH = 10x

SFFQPA = 1	LOC = 100 (occupational)

LOC = 100 (residential)	Chronic oral toxicity - dog

LOAEL = 2.95/3.33 (M/F) mg/kg/day, based on absolute and relative kidney
weights and histopathological changes in the male kidney.

Inhalation

Short-term

(1-30 days)

	oral study

offspring NOAEL = 5.9 mg/kg/day

(inhalation absorption rate = 100%)	UFA = 10x

UFH = 10x

SFFQPA = 1	LOC = 100 (occupational)

LOC = 100 (residential)	Reproductive toxicity - rat

Offspring LOAEL = 35.5 mg/kg/day, based on decreased litter weight and
mean pup weight in litters of all generations before weaning and
increased relative liver weights at weaning in both sexes of all
litters.

Inhalation Intermediate-term (1-6 months)

And

Long-term

(>6 months)

	oral study

NOAEL = 0.73 mg/kg/day

(inhalation absorption rate = 100%)	UFA = 10x

UFH = 10x

SFFQPA = 1	LOC = 100 (occupational)

LOC = 100 (residential)	Chronic oral toxicity - dog

LOAEL = 2.95/3.33 (M/F) mg/kg/day, based on absolute and relative kidney
weights and histopathological changes in the male kidney.

Cancer

(Adults; dietary, dermal, inhalation)	Classification:  “Likely to be
Carcinogenic to Humans.”  Q1* = 2.3 x 10-2 (mg/kg/day)-1 based on male
mouse liver benign and/or malignant combined tumor rates.

NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed
adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (interspecies).  UFH = potential variation in
sensitivity among members of the human population (intraspecies).
SFFQPA = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute,
c = chronic).  RfD = reference dose.  LOC = level of concern.

Recommendation for Aggregate Risk Assessments

Comparison of the complete toxicity profile across studies indicates
that it is appropriate to aggregate risk estimates for short-term oral,
dermal, and inhalation routes of exposure and for intermediate- and
long-term dermal and inhalation exposures.  For short-term aggregate
exposure risk assessment, common toxicological endpoints of concern
(decreased pup weights and increased liver weights) were selected via
the oral, dermal, and inhalation routes.  Therefore, these routes (oral,
dermal and inhalation) can be combined for short-term exposure duration.

Common toxicological end-points of concern (nephrotoxicity) were also
selected for intermediate- and long-term dermal and inhalation routes.
Therefore, exposure from these routes can be combined.

4.4  Toxicity of Tetraconazole Metabolites

Free triazole metabolites  (includes T, TA, TAA, triazolyl
hydroxypropionic acid (THP), and/or all labile conjugates of these
compounds):

HED has previously addressed the toxicity of T, TA and TAA in D322215
(HED Risk Assessment Document; M. Doherty et al., 7-Feb-2006).  Please
refer to this document for information concerning the toxicity of these
free triazole metabolites.

The free triazole risk assessment mentioned above pertains to exposure
to T, TA, and TAA from the conazole/triazole fungicides.  Tetraconazole
results in the formation of these compounds as well as THP.  THP is a
residue of concern in rotational crops and livestock (included as a
residue of concern in livestock based on the identification in
rotational crops and therefore as a potential residue in feed).  Based
on the proposed application rates and the results of the confined
rotational crop studies, HED has concluded that residues in rotational
crops will be negligible; therefore, risk due to residues of THP are
expected to be negligible and the previous free-triazole risk assessment
is adequate to address risk resulting from all tetraconazole
metabolites.

Metabolites in common with propiconazole (M14360-ketone,
M14360-CP(C-1)-alcohol, and M14360(C-1)-alcohol):

The tetraconazole plant metabolism, livestock metabolism, and/or
confined rotational crop studies resulted in the identification of
M14360-ketone, M14360(C-1)-alcohol, and M14360-CP(C-1)-alcohol
(structurally similar to M14360(C-1)-alcohol); these compounds are also
metabolites/degradates of propiconazole (identified as CGA-91304 and
CGA-91305 in the propiconazole risk assessment).  These common
metabolites/degradates will be referred to as CGA-91304/CGA-91305 from
hereon.  HED concluded that the toxicity of these metabolites/degradates
are accounted for in the propiconazole toxicity database (because they
are identified in the propiconazole mouse and rat metabolism studies);
whereas they were not identified in the tetraconazole rat metabolism
study, and are therefore not accounted for in the tetraconazole toxicity
database.

Although the identification of common metabolites/degradates often
triggers the need for an aggregate risk assessment, this is not
necessary at this time for the following reasons:

Residues of CGA-91304/CGA-91305 in/on plant and livestock commodities
resulting from application of tetraconazole are expected to be at
negligible levels in comparison to the magnitude of these residues
following application of propiconazole.

Since exposure to these compounds resulting from tetraconazole is
insignificant, the propiconazole risk assessment can act as a
'worst-case' risk assessment for CGA-91304/CGA-91305, since they were
included in the residues of concern for the propiconazole risk
assessment.

However, if and when application of tetraconazole results in significant
exposure to CGA-91304/CGA-91305, at that time it will be necessary to
include the magnitude of these compounds resulting from application of
tetraconazole in the propiconazole risk assessment.

4.5.  Endocrine Disruption

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

4.6  Public Health and Pesticide Epidemiology Data

There were no reports of ill effects from exposure to tetraconazole in
the available databases.  Therefore, no recommendations are made based
on the limited information available.

5.0  Dietary Exposure/Risk Characterization

References:

Residue Chemistry Summary – D353020, T. Bloem, 26-June-2008

Dietary Exposure Analysis- D353708, T. Bloem, 26-June-2008

Estimated Drinking Water Concentrations - EFED memorandum D347085, I.
Maher, 5-June-2008

See Attachment 1 for Structures of tetraconazole metabolites.

The subsequent text refers to the “free triazole metabolites” and
the “non-free triazole metabolites”.  These terms refer to the
following compounds:  (1) free triazole metabolites:  T, TA, TAA, THP,
and/or all labile conjugates of these compounds and (2) non-free
triazole metabolites:  tetraconazole metabolites of concern for risk
assessment other than T, TA, TAA, THP and/or all labile conjugates of
these compounds.

5.1.  Tetraconazole Residues

5.1.1  Tetraconazole Metabolism and Residues of Concern

In the 2007 human-health risk assessment for tetraconazole, HED
concluded that the toxicological effects resulting from exposure to T,
TA, TAA, THP, and all labile conjugates of these compounds and
M14360(C-1)-alcohol are different from that resulting from exposure to
tetraconazole; HED concluded that the toxicity of the remaining
metabolites are identical to that of tetraconazole.  For a discussion
concerning these conclusions, see HED’s 2007 risk assessment (D321751,
M Clock-Rust et al., 26-Jan-2007).  A summary of the residues of concern
for risk assessment and tolerance enforcement is presented in Table
5.1.1.

The plant metabolism, livestock metabolism, and/or confined rotational
crop studies for tetraconazole resulted in the identification of
M14360-ketone, M14360-CP(C-1)-alcohol, and M14360(C-1)-alcohol.  HED
concluded that the toxicity of these compounds is likely to be similar
to propiconazole and not to tetraconazole.  Based on the magnitude of
these residues relative to the other identified compounds in the
tetraconazole metabolism and confined rotational crop studies, HED
concluded that only M14360 (C-1)-alcohol was a residue of concern and
only in rotational crops following application of tetraconazole (not of
concern in plants or livestock).  However, the magnitude of these
compounds following application of tetraconazole may be such that they
are not of concern when compared to the magnitude of the propiconazole
residues.

livestock metabolism studies (ruminants ≤31% TRR; poultry ≤79% TRR)
but were insignificant residues in the tetraconazole livestock
metabolism studies (M14360-ketone was identified in ruminant tissue at
≤4.5% TRR; M14360-CP(C-1)-alcohol and M14360(C-1)-alcohol were not
identified); and (3) Based on the tetraconazole field rotational crop
study, HED concludes that residues of M14360(C-1)-alcohol will be
insignificant in rotational crops following application of tetraconazole
at the currently registered rates (grapes, the proposed crop, are not
rotated).

Table 5.1.1.  Residues for Tolerance Expression and Risk Assessment.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Shelled Pea

and Bean	tetraconazole and T, TA, TAA, and all labile conjugates of
these compounds	Tetraconazole

Remaining Plants	tetraconazole, M14360-alcohol (free and conjugated),
M14360-acid, M14360-DFA, M14360-hydroxydetriazolyl-O-malonyldiglucoside,
and T, TA, TAA and all labile conjugates of these compounds
Tetraconazole

Livestock	tetraconazole, M14360-alcohol (free and conjugated),
M14360-acid, M14360-DFA, M14360(C-1)-alcohol (free and conjugated),
M14360-hydroxydetriazolyl-O-malonyldiglucoside, and T, TA, THP, and TAA
and all labile conjugates of these compounds	Tetraconazole

Rotational Crops	tetraconazole, M14360-acid, M14360-DFA,
M14360(C-1)-alcohol (free and conjugated), and TA, THP, and TAA and all
labile conjugates of these compounds	Tetraconazole

Drinking Water	Tetraconazole	Not Applicable

5.1.2  Environmental Fate and Drinking Water Residue Profile

Tetraconazole is persistent in the environment and has moderate to
slight mobility in soils.  Laboratory and field half-lives ranged from
107 days to more than 1 year; however, the dissipation of tetraconazole
applied directly to foliage is much more rapid.  Foliar dissipation
studies suggest that tetraconazole is taken up quickly and extensively
metabolized in plants yielding tetraconazole acid, tetraconazole
alcohol, TA and TAA as metabolites.  Successive applications of
tetraconazole are expected to result in year-to-year soil accumulation.
Tetraconazole has potential to reach surface water via runoff and spray
drift, but its tendency to reach ground water is expected to be reduced
due to its lack of mobility in soil.

EFED provided modeled surface water estimates [using the Pesticide Root
Zone Model (PRZM 3.12) and Exposure Analysis Modeling System (EXAMS
2.98.04)] for tetraconazole per se.  Ground water estimates were also
reported [using the Screening Concentration In Ground Water (SCIGROW)
model] but were not used by HED because surface water estimates were
much higher and therefore, more conservative.  It is HED policy to use
the most conservative estimates of drinking water risk in the dietary
exposure assessment.

Tetraconazole is currently registered for application to sugar beet,
peanut, pecan and soybean and is being proposed for application to
grape.  Since the application rates for grape and soybean are
significantly lower than the application rates for sugar beet, peanut,
and pecans, EFED concluded that modeling using the grape and soybean
application scenarios were unnecessary.  Also, the surface/ground water
estimate for pecan has dropped considerably from those attained as part
of the previous assessment as the petitioner has changed the pecan
application scenario permitting only four applications rather than
eight.

The water estimates were incorporated directly into the dietary exposure
analysis.

EDWC (μg/l)	Source

Acute Drinking Water Exposure	10.45	Pecans/Surface Water; 1-in-10 year
annual peak concentration

Chronic Non-Cancer Exposure	4.68	Sugar Beets/Surface Water; 1- in-10
year annual average concentration

Cancer/Chronic Exposure	3.29	Sugar Beets/Surface Water; 30-year annual
average

5.1.3  Food Residue Profile and Enforcement Methods

Magnitude of the Residue - Grapes

IR-4 submitted field trial and processing residue data for
tetraconazole, T, TA, and TAA in/on grape.  Twelve field trials were
established during 2006 in the North American Free Trade Agreement
(NAFTA) Zones 1 (n=2), 10 (n=8), and 11 (n=2).  Each field trial
consisted of a single control plot and two treated plots (plots A and
B).  Treatment plots A and B received two airblast applications
(retreatment interval (RTI) = 14-16 days) of the 125 g/L liquid
tetraconazole formulation (1.04 lb ai/gal; emulsifiable concentrate
(EC)) at ~0.040 lb ai/acre (1x; 77-104 GPA).  Treatment plot A received
the first application 43-47 days prior to harvest and the samples were
harvested 28-31 days after the last application (DALA).  Treatment plot
B received the first application 28-32 days prior to harvest and samples
were harvested from 14-16 DALA.  At two of the trials, a third treated
plot received two airblast applications (RTI = 14-15 days) of the 125
g/L liquid tetraconazole formulation using the application scenario
employed for plot B but at rates of ~0.200 lb ai/acre (5x).  These
samples were harvested 15 DALA and were processed into juice (cold
press) and raisin (<14% moisture) using simulated commercial practices.

The samples were analyzed for residues of tetraconazole, T, TA, and TAA
using an adequately validated method (limit of quantitation (LOQ) = 0.01
ppm for all analyte/matrices).  However, data demonstrating the
stability of residues of tetraconazole per se in/on grape (236 days) and
T, TA, and TAA residues in/on grape (236 days), grape juice (64 days),
and raisin (68 days) samples should be submitted.  Following two
broadcast foliar applications of tetraconazole totaling ~0.080 lb
ai/acre (1x), residues of tetraconazole per se ranged as follows:  plot
A - <0.01-0.091 ppm (average = 0.022 ppm) and plot B <0.01-0.096 ppm
(average = 0.031 ppm).  Only samples from plot B were analyzed for T,
TA, and TAA with the following residues:  T:  <0.01 ppm in/on all
samples; TA:  <0.01-0.053 ppm (average = 0.016 ppm); and TAA:
<0.01-0.017 ppm (average = 0.011 ppm).  The processing residue data
yielded the following processing factors:  tetraconazole:  juice -
0.01-0.06x and raisin - 0.71-0.91x; T:  a processing factor could not be
determined for grape juice and raisin as residues were <LOQ in/on all
the samples; TA:  a processing factor for grape juice could not be
determined as residues were <LOQ in the RAC and processed commodity;
processing factor for raisin was determined to be >2.0x; TAA:  a
processing factor could not be determined for grape juice and raisin as
residues were <LOQ in/on all the samples.

Since the samples from plot B employed the requested PHI and resulted in
higher residues of tetraconazole per se, only these data were used for
calculation of the appropriate tolerance.  Based on these data and the
maximum residue limit (MRL) calculator (see attachment 2), HED concludes
that a grape tolerance of 0.20 ppm for residues of tetraconazole per se
is appropriate.  A revised Section F is requested.

Magnitude of the Residue - Livestock/Rotational Crops

Based on the revisions made to the livestock feedstuff portion of Table
1 (communication from J. Stokes, 6/2008), there are no grape feed
commodities.  In addition, grape vines are not rotated.  Therefore, the
nature/magnitude of the residue in livestock and rotational crops are
not relevant to the current petition.

Enforcement Method

Adequate analytical methods are available to enforce the currently
established tetraconazole per se plant tolerances (D259205, W. Donovan,
8-May-2000 and D280006, W. Donovan, 10-Jan-2002).  The method employed
in the field trial/processing study for determination of tetraconazole
per se employed the same extraction solvent as that used for the
enforcement method (acetone) but differed from the current enforcement
method in that the residues were quantified via liquid chromatography
(LC)/mass spectrometry (MS)/MS (enforcement method employed
quantification via gas chromatography/electron-capture detection
(GC/ECD)).  The data collection method also eliminated the
dichloromethane partition and alumina column purification employed in
the enforcement method.  HED notes that the independent laboratory
validation (ILV) data submitted for the current enforcement method
employed grape as a sample matrix and resulted in acceptable recoveries
(D264681, W. Donovan, 7-Apr-2000).  Therefore, HED concludes that the
current enforcement method is acceptable for enforcement of the
recommended grape tolerance.

5.1.4  International Residue Limits

There are currently no established Codex, Canadian, or Mexican MRLs for
residues of tetraconazole per se in/on grape.  Therefore, harmonization
is not an issue.

5.1.5  Grape Tolerance Recommendation

Table 5.1.5 is a summary of the proposed and recommended tolerances for
residues of tetraconazole per se.  A revised Section F is requested.

Table 5.1.5.  Tolerance Summary.

Proposed	Recommended

Commodity Definition	Tolerance (ppm)	Commodity Definition	Tolerance
(ppm)

Grape	0.15	Grape	0.20

5.2  Dietary Exposure and Risk

The residues of concern in grape for risk assessment are tetraconazole,
M14360-alcohol (free and conjugated), M14360-acid, M14360-DFA,
M14360-hydroxydetriazolyl-O-malonyldiglucoside, and T, TA, TAA and all
labile conjugates of these compounds.  HED has concluded that the
toxicological effects resulting from exposure to T, TA, TAA, THP, and
all labile conjugates of these compounds are different from that
resulting from exposure to tetraconazole (D321751, M. Clock-Rust et al.,
26-Jan-2007); HED concluded that the toxicity of the remaining
metabolites are identical to that of tetraconazole.  The following
paragraphs are summaries of the dietary exposure to these compounds.

Free Triazole Metabolites:  Based on the available toxicological
information, HED has concluded that TA and TAA are toxicologically
identical but different from T; therefore, two exposure assessments are
necessary when assessing exposure to the free triazole metabolites (one
for T and one for TA and TAA). T and TA/TAA are common metabolites of
many triazole derivative fungicides and HED has recently conducted a
dietary risk assessment for T and TA/TAA (D350314, M. Doherty,
27-Mar-2008).

Table 5.2.1 is a summary of the T and TA/TAA grape residue estimates
incorporated in this dietary risk assessment and the estimates of these
compounds in grape, grape juice, and raisin as a result of application
of tetraconazole.  Based on a comparison of these residues, HED
concludes that a revised dietary assessment for the proposed use on
grapes is unnecessary because residues of T, TA and TAA from the
proposed use of tetraconazole on grapes are expected to be negligible in
comparison with the grape residues included in the latest free triazole
risk assessment ((D350314, M. Doherty, 27-Mar-2008).

HED notes that the analytical method used for quantification of T and
TA/TAA did not include a hydrolysis step and therefore did not measure
the labile conjugates.  The only free triazole labile conjugate detected
in the tetraconazole metabolism studies (soybean, sugar beet, wheat, and
grape) was a glucose conjugate of TA found in soybean seed.  Therefore,
HED concludes that analysis for the labile conjugates of T, TA, and TAA
in grape is unnecessary.

Table 5.2.1.  Comparison of Grape Residue Estimates for T and TA/TAA
Incorporated into the Most Recent Dietary Risk Assessment and those
in/on Grape Following Application of Tetraconazole.

Analyte	Commodity	Residue Estimates used in the Most

Recent Dietary Exposure Assessment1	Residue Based on the Grape Residue
Data Following Application of Tetraconazole

Acute	Chronic

	T	grape	0.05	0.0337	<0.012

	grape juice	0.05	0.0337	<0.013

	grape leaves	0.05	0.0337	--

	grape raisin	0.6123	0.3492	<0.013

	grape wine/sherry	0.05	0.0337	--

TA/TAA	grape	2.53	0.82	<0.0632

	grape juice	2.53	0.82	<0.023

	grape leaves	2.53	0.82	--

	grape raisin	5.40	2.43	<0.033

	grape wine/sherry	2.53	0.82	--

1  For the free triazoles: D350314, M. Doherty, 27-Mar-2008.

2  Based on field trial data conducted at 1x (47270101.der.doc).

3  Based on processing data conducted at 5x (47270101.der.doc).

Tetraconazole and Metabolites Identified as being Toxicologically
Identical to Tetraconazole

™, ver. 2.03) which incorporates the food consumption data from the
USDA’s CSFII (1994-1996 and 1998).  These analyses were conducted in
support of the proposed application of tetraconazole to grape.  The
following paragraphs are summaries of the acute, chronic, and cancer
analyses (Tables 5.2.2 and 5.2.3 are summaries of the acute/chronic and
cancer dietary exposure analyses, respectively).

Acute:  The Tier 1 acute analysis (assuming tolerance-level residues and
100% crops treated) resulted in exposure estimate for females 13-49
years old less than HED’s level of concern (0.75% aPAD; acute endpoint
of concern was not identified for the general population including
infants and children).

concern (≤7.7% cPAD; all infants <1 year old were the most highly
exposed population subgroup).

Cancer:  The cancer analysis was refined through the incorporation of
empirical processing factors, average field trial residues, average
residues from the feeding studies, and projected percent crop treated
estimates (food and feed).  The resulting exposure estimates yielded a
cancer risk for the U.S. population of 3 x 10-6 (2.6 x 10-6 rounded to
3.0 x 10-6).

Cancer risks presented in this assessment are expressed to one
significant figure.  However, it should be noted that, in general, the
precision which can be assumed for cancer risk estimates is best
described by rounding to the nearest integral order of magnitude on the
log scale; e.g., 3.16 x 10-7 to 3.16 x 10-6, expressed as 10-6.  Risks
are generally reported to one significant figure in HED risk assessments
to allow better characterization of changes in risk which might result
from potential risk mitigation.  This rounding procedure indicates that
risks should generally not be assumed to exceed the benchmark level of
concern of 10-6 until the calculated risks exceed approximately 3 x
10-6.  Discretion should be used in interpreting the significance of
these calculated risks with consideration given to the precision in the
risk estimates.

Table 5.2.2.  Summary of the Acute and Chronic Dietary Exposure and
Risk.

Population	aPAD (mg/kg/day)	Exposure (mg/kg/day)1	%aPAD	cPAD (mg/kg/day)
Exposure (mg/kg/day)	%cPAD

General U.S. Population	no acute endpoint identified for these
population subgroups	0.073	0.000210	2.9

All Infants (< 1 year old)

	0.000563	7.7

Children 1-2 years old

	0.000399	5.5

Children 3-5 years old

	0.000385	5.3

Children 6-12 years old

	0.000267	3.7

Youth 13-19 years old

	0.000178	2.4

Adults 20-49 years old

	0.000182	2.5

Adults 50+ years old

	0.000173	2.4

Females 13-49 years old	0.225	0.001697	0.75

0.000178	2.4

1	95th percentile (Tier 1 analysis)

Table 5.2.3.  Summary of the Cancer Dietary Exposure and Risk.

Population1	Exposure (mg/kg/day)	Q1*	Cancer risk

General U.S. population	0.000112	0.023	3 x 10-6

1	Exposure for the general U.S. population; HED performs cancer analyses
for only the general U.S. population.

6.0  Residential (Non-Occupational) Exposure Pathway

There are no proposed residential uses of tetraconazole or other uses
that will result in post-application residential exposure.  Therefore,
neither a residential handler nor a residential post-application
assessment is required.

Spray Drift

Spray drift is a potential source of exposure for 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 tetraconazole could also
be a potential source of exposure.  The Agency has been working with the
Spray Drift Task Force (a membership of US 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 appropriately
apply the data and the AgDRIFT® computer model to its risk assessments
for pesticides applied by air, orchard airblast, and ground hydraulic
methods.  After the policy is in place, the Agency may impose further
refinements in spray drift management practices to reduce off-target
drift, and risks associated with pesticide application.

7.0  Aggregate Risk Assessment

FQPA requires EPA to aggregate exposures from food, water, and
residential settings.  Acute, chronic and cancer aggregate risks were
assessed.  Because there are no residential uses, aggregate exposure
consists of food and drinking water exposures only (dietary exposure).
Since the dietary exposure analysis included the drinking water
estimates, the discussion and exposure estimates presented in Section
5.2 represent aggregate acute and aggregate chronic exposure.  All
aggregate risk estimates are not of concern to HED.

8.0  Cumulative Risk Characterization/Assessment

Tetraconazole 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 their 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).  In conazoles, however, a variable
pattern of toxicological responses is found; 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 produce 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 their toxicological
outcomes.  Thus, there is currently no evidence to indicate that
conazoles share common mechanisms of toxicity and EPA is not following a
cumulative risk approach based on a common mechanism of toxicity for the
conazoles.  For information regarding EPA’s procedures for cumulating
effects from substances found to have a common mechanism of toxicity,
see EPA’s website at http://www.epa.gov/pesticides/cumulative.

Tetraconazole is a triazole-derived pesticide.  This class of compounds
can form the common metabolite T and two triazole conjugates (TA and
TAA).  To support existing tolerances and to establish new tolerances
for triazole-derivative pesticides, including tetraconazole, U.S. EPA
conducted a human-health risk assessment for exposure to T, TA, and TAA
resulting from the use of all current and pending uses of any
triazole-derived fungicide.  The risk assessment is a highly
conservative, screening-level evaluation in terms of hazards associated
with common metabolites (e.g., use of a maximum combination of
uncertainty factors) and potential dietary and non-dietary exposures
(i.e., high-end estimates of both dietary and non-dietary exposures).
In addition, the Agency retained the additional 10X FQPA SF for the
protection of infants and children.  The assessment includes evaluations
of risks for various subgroups, including those comprised of infants and
children.  The Agency’s complete risk assessment is found in the
propiconazole reregistration docket at http://www.regulations.gov,
Docket Identification (ID) Number EPA-HQ-OPP-2005-0497.

9.0  Occupational Risk Assessment

Occupational exposure from the proposed use on grapes is expected.
Exposure to applicators and mixer/loaders is possible, as is
post-application exposure to workers that enter treated grape growing
areas.  An occupational assessment of the proposed use follows.

Grapes

The proposed registration of tetraconazole for use on grapes is for
control of various diseases in grapes (powdery mildew, black rot).  The
proposed label for Mettle® indicates that it may be applied by ground
boom or aircraft sprayer.  Airblast application is also expected.  The
rate of application is 5 fluid ounces of product per acre (0.04 lb
ai/A).  The label advises application at pre-bloom and to continue at
spray intervals of up to 21 days in low to moderate disease pressure. A
maximum of 2 applications of tetraconazole may be made per season
(seasonal maximum is 0.08 lb ai/A). There is a 14-day PHI.

The proposed label indicates a REI of 12 hours.  The label requires
applicators and other handlers to wear long-sleeved shirt, long pants,
chemical-resistant gloves and shoes plus socks.  See Table 9.0 for a
summary of the proposed use pattern.

Table 9.0. Summary of Proposed Use of Tetraconazole on Grapes.

Formulation

1 lb ai/gallon ‘micro-emulsion’ liquid Mettle® 125ME Fungicide

Method of Application

Airblast, Ground-boom, Aerial

Use Site

Grape

Pest

Various diseases including powdery mildew and black rot

Rate of Application

0.04 lb ai/A

Maximum Rate/Yr

0.08 lb ai/A/season

Frequency of Applic.

2 application per year

Application interval

14 - 21 days

PHI

14 days

REI

12 hours

Manufacturer

Isagro USA

Pecans

Tetraconazole is currently registered for use on pecans at the rate of
0.125 lb ai/A.  The registrant proposes amending the labels for the
end-use product, Eminent® 125 SL Fungicide (EPA Reg. No. 60063-12) from
8 applications per season (seasonal maximum of 1 lb ai/A) to 4
applications per season (seasonal maximum of 0.5 lb ai/A).  The single
application rate is unchanged.  The proposed amendment does not impact
the conclusions made in the occupational exposure assessment for pecans
in the last risk assessment (Memo, M. Clock-Rust, D321751, 1/26/07).

The occupational assessment is a conservative (health-protective)
estimation of risk to workers due to the use of high-end assumptions
such as the acreage treated per day and the amount of contact workers
experience while performing post-application activities in treated
areas.  Further, this assessment assumes workers enter fields on “day
zero,” the day of application, after sprays have dried.

In calculating risk, since the dermal and inhalation doses and endpoints
are the same, and since dermal and inhalation exposures may occur
simultaneously, these exposures were combined to determine a total MOE.

9.1  Occupational Handler Risk

Occupational handlers may experience short-/intermediate-term exposure
to tetraconazole while mixing/loading and applying sprays to grapes.  No
chemical-specific handler exposure data were submitted in support of
this use pattern.  It is the policy of the HED to use data from the PHED
(Version 1.1) as presented in PHED Surrogate Exposure Guide (8/98) to
assess handler exposures when chemical-specific monitoring data are not
available [HED Science Advisory Council for Exposure (ExpoSAC) Draft
Policy # 7, dated 1/28/99].

Mettle® 125ME contains 11.6% tetraconazole in a micro emulsion/liquid
formulation for use as an agricultural fungicide on grapes.  The
proposed maximum single application rate is 0.04 lb ai/A.  Based on the
anticipated application practices for the product and information
provided by the registrant, handler exposures are expected to be of
short- (1-30 days) and intermediate-term (1-6 months) durations.  In
this assessment, HED has addressed the following occupational handler
exposure scenarios.

•	Mixing/loading liquid formulations for fixed-wing aerial application

•	Applying sprays by airblast equipment

•	Applying sprays by groundboom equipment

•	Applying sprays aerially (fixed-wing aircraft)

9.1.1  Data and Assumptions for Handler Exposure Scenarios

Chemical-specific data for assessing exposure during pesticide handling
activities were not submitted to the Agency in support of this action.
It is HED policy to use data from the PHED (Version 1.1) to assess
handler exposures for regulatory actions when chemical-specific data are
not available (HED ExpoSAC SOP Number .007, January 1999).

Occupational handler exposure assessments were completed by HED using
baseline attire which includes long pants, a long-sleeved shirt, shoes,
socks, no gloves, and no respirator.

For dermal exposures, risks initially are assessed at baseline attire.
The label requires applicators and other handlers to wear long-sleeved
shirt, long pants, chemical-resistant gloves and shoes plus socks.

Exposure Data

The available exposure data for combined mixer/loader/applicator
scenarios are limited in comparison to the data available for monitoring
of these two activities separately.  These exposure scenarios are
outlined in the PHED Surrogate Exposure Guide (August, 1998).  HED has
adopted a methodology to present the exposure and risk estimates
separately for the job functions in some scenarios and to present them
as combined in other cases.  Most exposure scenarios for hand-held
equipment (such as hand wands, backpack sprayers, and push-type granular
spreaders) are assessed as a combined job function.  With these types of
hand-held operations, all handling activities are assumed to be
conducted by the same individual.  The available monitoring data support
this and HED presents them in this way.  Conversely, for equipment types
such as fixed-wing aircraft, groundboom tractors, or air-blast sprayers,
the applicator exposures are assessed and presented separately from
those of the mixers and loaders.  By separating the two job functions,
HED determines the most appropriate levels of PPE for each aspect of the
job without requiring an applicator to wear unnecessary PPE that might
be required for a mixer/loader (e.g., chemical-resistant gloves may only
be necessary during the pouring of a liquid formulation).

Area Treated

Based on professional judgment and HED’s Exposure ExpoSAC SOP Number
9.1, the following acres per day treated were assumed:

40 acres/day for application with airblast equipment

80 acres/day for application with groundboom equipment

350 acres/day for application with aerial equipment

Body Weight

A body weight of 60 kg was used for short-term dermal and inhalation
calculations because NOAEL is from a reproductive toxicity study.  A
body weight of 70 kg was used for intermediate-term risk calculations.

  SEQ CHAPTER \h \r 1 Equations/Calculations

The following equations were used to calculate handler exposure and
risk:

Dermal or Inhalation Dose (mg/kg/day) =  Rate (lb ai/A) x UE (mg /lb ai
) x  Acres Treated (A/day) x AF

      				               	                                           BW
(kg)

	Where:

	Rate (Application Rate)	= Maximum application rate on product label (lb
ai/A)

	UE (Unit Exposure) 	= Exposure value derived from August 1998 PHED
Surrogate Exposure Table

	Acres Treated 		= Maximum number of acres treated per day (A/day)

	AF			=Absorption Factor (dermal absorption is 12%; inhalation
absorption is 100%)

	BW			= Body weight (60 kg for short-term; 70 kg for intermediate-term)

Short-term MOE = NOAEL (5.9 mg/kg/day)/ Dose (mg/kg/day)

Intermediate-term MOE = NOAEL (0.73 mg/kg/day)/ Dose (mg/kg/day)

9.1.2  Occupational Handler Exposure and Risk

Short- and intermediate-term dermal and inhalation handler risks were
estimated.  HED assumes 100% inhalation absorption and 12% dermal
absorption for tetraconazole.  Short-term dermal and inhalation
exposures were summed and compared to the short-term NOAEL of 5.9
mg/kg/day identified for short-term dermal and inhalation risk
assessment.  Intermediate-term dermal and inhalation exposures were
summed and compared to the NOAEL of 0.73 mg/kg/day identified for
intermediate-term dermal and inhalation risk assessment.  Exposure and
risk estimates are presented in Table 9.1.2 below.  The risk estimates
for the proposed use on grapes do not exceed HED’s level of concern
for occupational pesticide handlers.

All   SEQ CHAPTER \h \r 1 short-term handler exposures resulted in MOEs
that do not exceed HED’s LOC with the use of protective gloves
(chemical-resistant gloves are required on the label).   SEQ CHAPTER \h
\r 1

HED recommends that the proposed label recommendations of PPE (i.e.,
long pants, long-sleeved shirt, chemical-resistant gloves, shoes and
socks) are followed by all handlers.

Table 9.1.2.  Estimated Short- and Intermediate-term Handler Exposure
and Risk to Tetraconazole.

Unit Exposure1

mg/lb handled	Application Rate2

lb ai/A	Units Treated3

Per Day	Short-term

Average Daily

Dose4

mg/kg/day	Short-term

MOE5

	Intermediate-term

Average Daily

Dose4

mg/kg/day	Intermediate-term

MOE5

Mixer/Loader -Liquid - Open Pour - Supporting Aerial  Operations-Grapes

Dermal:

No Glove     2.9   HC

With Glove  0.023  HC

Inhalation    0.0012 HC

0.04

350 Acres

No Glove  0.081

W/Glove  0.00092

No Glove 72

W/Glove 6400

No Glove 0.070

W/Glove 0.00079

No Glove 10

W/Glove 920

Applicator – Airblast Sprayer-Open Cab –Grapes

Dermal:

No Glove      0.36 HC

With Glove  0.24 HC

Inhalation    0.0045 HC

0.04

40 Acres

No Glove 0.0013

W/Glove 0.00089

No Glove 4600

W/Glove 6600

No Glove 0.0011

W/Glove 0.00076

No Glove  670

W/Glove  960

Applicator –Groundboom Sprayer-Open Cab –Grapes

Dermal:

No Glove     0.014 HC

With Glove  0.014 MC

Inhalation    0.00074 MC

0.04

80 Acres	No Glove or W.Glove

0.000129	No Glove or W/Glove

46,000	No Glove or W.Glove

0.00011	No Glove or W.Glove

6600

Applicator - Fixed-wing Aircraft- Grapes-Applicators Wear No Gloves

Dermal:

No Glove      0. 0050 MC

Inhalation     0.000068 MC

0.04

350 Acres

No Glove  0.00016

No Glove 38000

No Glove  0.00013

No Glove 5500

1.  Unit Exposures are taken from “PHED Surrogate Exposure Guide,”
PHED Version 1.1, August, 1998.  Dermal = Single Layer Work Clothing No
Gloves; Single Layer Work Clothing With Gloves; Units = mg ai/lb ai
handled.  Data Confidence: MC = Medium Confidence, HC = High Confidence.

2.  Application Rate. = Taken from proposed Mettle® 125ME label.

3.  Units Treated are taken from ExpoSAC SOP No. 9.1 “Standard Values
for Daily Acres Treated in Agriculture” Revised 9/25/2001.

4.  Average Daily Dose = Unit Exposure * Application Rate * Units
Treated * Absorption Rate (12% dermal absorption, 100% inhalation
absorption) ÷ Body Weight (60 kg used for short-term estimates; 70 kg
used for intermediate-term).

5.  MOE = Margin of Exposure = NOAEL ÷ ADD.  Short-term NOAEL = 5.9 mg
ai/kg/day and intermediate-term NOAEL = 0.73 mg ai/kg/day.

9.2  Occupational Post-Application Risk

There is a potential for agricultural workers to have post-application
exposure to pesticides during the course of typical agricultural
activities.  HED in conjunction with the Ag Re-Entry Task Force (ARTF)
has identified a number of post-application agricultural activities that
may occur.  HED has also identified transfer coefficients (TCs; cm²/hr)
relative to the various activities, which express the amount of foliar
contact over time during each of the activities identified.  The
activity and crop with the highest TC associated with the
post-application activities for the proposed use in grapes is cane
turning in table grapes (TC = 10,000 cm2/hr).  A post-application risk
assessment was provided for the proposed use on grapes based on this
high-end TC.

Short-term (1-30 days) dermal risks were assessed.  Inhalation risk is
expected to be negligible.  Intermediate-term risks were not assessed
since HED does not expect workers to engage in post-application
activities for more than 30 consecutive days.

The TCs used in this assessment are from an interim TC SOP developed by
HED’s ExpoSAC using proprietary data from the ARTF database (SOP #
3.1).  It is the intention of HED’s ExpoSAC that this SOP will be
periodically updated to incorporate additional information about
agricultural practices in crops and new data on TCs.  Much of this
information will originate from exposure studies currently being
conducted by the ARTF, from further analysis of studies already
submitted to the Agency, and from studies in the published scientific
literature.

Lacking compound-specific dislodgeable foliar residue (DFR) data, HED
assumes 20% of the application rate is available as DFR on day zero
after application (adapted from ExpoSAC SOP No. 3.1, August 7, 2000).

The following convention may be used to estimate post-application
exposure.  All estimates are for “day zero” or the day of treatment.

Surrogate DFR = application rate * 20% available as dislodgeable residue
* (1-D)t * 4.54 x 108 µg/lb * 2.47 x 10-8 A/cm2

Average Daily Dose (ADD) (mg ai/kg/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/60 kg bw

MOE = NOAEL ( ADD; An MOE of 100 is adequate to protect agricultural
workers.

Calculations for the risk estimate for the proposed use on grapes are
shown below.

The estimate is conservative in that it is based upon the maximum rate
of application and on TCs derived from ARTF monitoring studies.  The DFR
estimates and MOE may be refined if compound-specific data for these
activities and these use sites are available.

Occupational Post-Application Calculations: Cane Turning in Table
Grapes: “Day Zero”

DFR = 0.04 lb/A * 0.2 * 4.54 x 108 µg/lb * 2.47 x 10-8 A/cm2 = 0.090
µg/cm²

and

0.090 µg/cm² * 10,000 cm²/hr * 8 hr/day * 0.001 mg/µg * 0.12 (dermal
absorption)/60 kg = 0.014 mg/kg/day.

MOE = 5.9 mg/kg/day ( 0.014 mg/kg/day = 410.

Since the MOE for grape cane turning is greater than 100, estimated
post-application risk for the proposed use on grapes does not exceed
HED’s level of concern.

9.3	  Occupational Cancer Risk

Cancer risk is calculated by adjusting daily exposure to account for
long-term exposure.  This is performed by calculating a lifetime average
daily dose (LADD).  The LADD is derived by summing (when appropriate)
the dermal and inhalation exposures to obtain an ADD, then multiplying
the ADD by the assumed factors of:

30 days exposure per year 	* 	35 years worked per lifetime  = 0.041

365 days per year                 		 70 years expected lifetime

Cancer Risk is estimated by multiplying the Q1* (0.023 mg/kg/day) by the
LADD.  Estimates of cancer risk are based on short- and
intermediate-term exposure estimates as shown above in Sections 9.1.2
and 9.2.

9.3.1	  Occupational Handler Cancer Risk

The daily dermal and inhalation exposures for handlers are taken from
Table 9.1.2.  Intermediate-term exposure estimates are conducted using a
70-kg body weight.  In all exposure scenarios, workers are assumed to
wear protective gloves, except aerial applicators (pilots are not
required to wear gloves).  The occupational handler cancer risk
assessment is conservative estimate of risk because the maximum
application rate used (average application rates were not available).
Further, HED also used standard assumptions such as assuming workers are
exposed to tetraconazole 30 days per working year and 35 years of a
70-year lifetime are spent working.  Cancer risk estimates for handlers
are provided in Table 9.3.1 below.

Table 9.3.1.  Estimated Cancer Risk for Occupational Handlers.

Intermediate-term

Average Daily

Dose1 (mg/kg/day)	Factor to Convert to LADD2	Q1*

(mg/kg/day)3	Estimated Cancer Risk4

Mixer/Loader-Liquid-Open Pour-Supporting Aerial Operations-Grapes

W/Gloves:   0.00079 	0.041	0.023	7 x 10-7

Applicator-Airblast Sprayer-Open Cab-Grapes

No Gloves: 0.0011

W/Gloves: 0.00076	0.041	0.023	No Gloves:  1 x 10-6

W/Gloves:  7 x 10-7

Applicator-Groundboom Sprayer-Open Cab-Grapes

No Glove or W.Glove

0.00011	0.041	0.023	No Gloves or W/Gloves:

1 x 10-7

Applicator-Fixed-Wing Aircraft-Grapes

No Gloves:  0.00013   	0.041	0.023	No Gloves:  1 x 10-7

1.  Exposure values taken from Table 9.1.2 (dermal + inhalation
exposure).

2.  0.041 = 30 days exposure per year * 35 years worked per lifetime

       365 days per year            70 years expected lifetime

3.  Q1* (0.023 mg/kg/day).

4.  Cancer Risk = LADD * Q1*.

The highest estimated cancer risk is for airblast applicators without
gloves.  The estimated risk is 1 x 10-6 for this use.  HED’s level of
concern for occupational cancer risk is 1 x 10-4 to 1 x 10-6.
Therefore, the proposed use on grapes does not exceed HED’s level of
concern.

9.3.2  Occupational Post-Application Cancer Risk

The occupational post-application cancer risk assessment is a
conservative estimate of risk because the maximum application rate used
(average application rates were not available).  Further, HED also used
standard assumptions such as assuming workers are exposed to
tetraconazole 30 days per working year and 35 years of a 70-year
lifetime are spent working.  The daily dermal exposure for handlers is
taken from Section 9.2 and the dose was calculated using a 70-kg body
weight.  Only dermal exposure was considered because inhalation exposure
is considered negligible for post-application exposure.  Workers are
expected to work 30 days per year over a 70-year lifetime.

Table 9.3.2.  Estimated Occupational Post-application Cancer Risk.

Average Daily

Dose1

mg/kg/day	Factor to Convert to LADD2	Q1*

(mg/kg/day)3	Estimated Cancer Risk4

Grapes-Cane Turning in Table Grapes

0.012	0. 041	0.023	1 x 10-5

1.  Exposure values taken from Section 9.2, and averaged over 30 days
(adjusted to a 70 kg body weight).

2.  0.041 = 30 days exposure per year * 35 years worked per lifetime

       365 days per year            70 years expected lifetime

3.  Q1* (0.023 mg/kg/day)

4.  Cancer Risk = LADD * Q1*

Estimated post-application cancer risk for workers turning canes in
table grapes treated with tetraconazole is 1 x 10-5.  HED’s level of
concern for occupational cancer risk is 1 x 10-4 to

1 x 10-6.  Therefore, the proposed use on grapes does not exceed HED’s
level of concern.

9.3.3  REI

Tetraconazole is classified in Acute Toxicity Category III for acute
dermal toxicity and for primary eye irritation.  It is classified in
Acute Toxicity Category IV for acute inhalation toxicity and primary
skin irritation.  It is not a dermal sensitizer.  The proposed Mettle®
label indicates a 12-hour REI.  The REI on labels is adequate to protect
agricultural workers from post-application exposures to tetraconazole
during the course of typical agricultural activities.

10.0  Data Needs and Label Requirements

10.1  Toxicology

-Guideline immunotoxicity study (OPPTS 780.7800)

-Guideline acute neurotoxicity study (OPPTS 780.6200)

-Guideline subchronic neurotoxicity study (OPPTS 780.6200)

10.2  Residue Chemistry

-Revised Section B

-Revised Section F

-Frozen storage stability data demonstrating the stability of residues
of tetraconazole per se in/on grape (236 days) and T, TA, and TAA
residues in/on grape (236 days), grape juice (64 days), and raisin (68
days).

10.3  Occupational and Residential Exposure

None.

Attachment 1.  Chemical Structures

Common Name; Chemical Name	Structure

Tetraconazole

CAS:  1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)

propyl]-1H-1,2,4-triazole

IUPAC:  (±)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propyl
1,1,2,2-tetrafluoroethyl ether

Triazole (T)

1,2,4-triazole

Triazolyl alanine (TA)

Triazolyl acetic acid (TAA)

Triazolyl hydroxypropionic acid (THP)

Glucose conjugated of Triazole Alanine (gluc-TA)

M14360-acid

M14360-difluoroacetic acid (M14360-DFA)

M14360-alcohol

M14360-ketone

M14360(C-1)-alcohol

Appendix A:  Hazard Assessment

The toxicology data requirements (CFR §158.340) for food uses of
tetraconazole are in Table A1.

Table A1.  Data Requirements.

Test

	Technical

	Required	Satisfied

870.1100	Acute Oral Toxicity

870.1200	Acute Dermal Toxicity

870.1300	Acute Inhalation Toxicity

870.2400	Primary Eye Irritation

870.2500	Primary Dermal Irritation

870.2600	Dermal Sensitization		Yes

Yes

Yes

Yes

Yes

Yes	Yes

Yes

Yes

Yes

Yes

Yes

870.3100	Oral Subchronic (rodent)

870.3150	Oral Subchronic (nonrodent)

870.3200	21-Day Dermal

870.3250	90-Day Dermal

870.3465	90-Day Inhalation		Yes

Yes

Yes

No

No	Yes

Yesa

Yes

No

No

870.3700a	Developmental Toxicity (rodent)

870.3700b	Developmental Toxicity (nonrodent)

870.3800	Reproduction		Yes

Yes

Yes	Yes

Yes

Yes

870.4100a	Chronic Toxicity (rodent)

870.4100b	Chronic Toxicity (nonrodent)

870.4200a	Oncogenicity (rat)

870.4200b	Oncogenicity (mouse)

870.4300	Chronic/Oncogenicity		Yes

Yes

Yes

Yes

Yes	Yesb

Yes

Yesb

Yes

Yesb

870.5100	Mutagenicity—Gene Mutation - bacterial

870.5300	Mutagenicity—Gene Mutation - mammalian

870.5375	Mutagenicity—Structural Chromosomal Aberrations

870.5395	Mutagenicity—Other Genotoxic Effects		Yes

Yes

Yes

Yes	Yes

Yes

Yes

Yes

870.6100a	Acute Delayed Neurotoxicity (hen)

870.6100b	90-Day Neurotoxicity (hen)

870.6200a	Acute Neurotoxicity Screening Battery (rat)

870.6200b	90-Day Neurotoxicity Screening Battery (rat)

870.6300	Developmental. Neurotoxicity		No

No

Yesc

Yesc

No	–

–

No

No

--

870.7485	General Metabolism

870.7600	Dermal Penetration

870.7800	Immunotoxicity	Yes

No

Yesc	Yes

–

No

870.7200    Companion Animal Safety 		No	–

a	The dog chronic oral toxicity study (870.4100) satisfies the data
requirements for 870.3150

b 	The combined chronic toxicity/oncogenicity study in the rat satisfies
the requirements for guidelines 870.4100a, 870.4200a, and 870.4300

c	This is a new requirement (40 CFR Part 158; 2007) for all food and
non-food use pesticides.

Table A2.  Toxicity Profile for Tetraconazole.

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

870.3100

4-Week Oral toxicity rodents (rat)	44751304 (1988)

Acceptable/nonguideline

0, 70, 200, or 500 mg/kg/day via gavage	NOAEL was not established.

LOAEL= 70 mg/kg/day, based on decreased body weight gains in and
increased liver weights both sexes, and increased kidney weights in
males and ovary weighs in females.

870.3100

4-Week Oral toxicity rodents (rat)	44751305 (1988)

Acceptable/nonguideline

0, 40, 160, 640, 2500 or 10000 ppm

M: 0, 4.4, 17.5, 68.4, 229 mg/kg/day;

F: 0, 3.8, 16.1, 62.3, 217 mg/kg/day	NOAEL = 3.8 (F) mg/kg/day

LOAEL = 4.4/15.3 (M/F) mg/kg/day, based on increased liver weights,
enlarged livers and enlarged centrilobular hepataocytes

870.3100

4-Week Oral toxicity rodents (rat)	44751306 (1989)

Acceptable/nonguideline

0, 2, 5, 15 or 40 ppm

M: 0, 0.21, 0.52, 1.57 or 4.19 mg/kg/day	NOAEL = 4.19 mg/kg/day(M)

LOAEL was not established.

870.3100

90-Day oral toxicity rodents (rat)	44335504 (1988)

Acceptable/guideline

0, 10, 60, or 360 ppm

M : 0, 0.7, 4.1, or 23.9 mg/kg/day

F: 0, 0.9, 5.5, or 28.7 mg/kg/day

	NOAEL = 4.1/5.5 mg/kg/day (M/F)

LOAEL = 23.9/28.7 mg/kg/day, was based upon increased body weight gains
in males, decreased body weight gains in females, increased absolute and
liver weights in both sexes, enlarged livers in males, enlarged
centrilobular hepatocytes in males and females.

870.3100

90-Day oral toxicity rodents (mice)	44778701 (1989)

Acceptable/guideline

0, 5, 25, 125, or 625 ppm

M : 0, 1, 4, 16, or 85 mg/kg/day

F: 0, 1, 4, 20, or 103  mg/kg/day

	NOAEL = 4 mg/kg/day (M/F)

LOAEL = 16/20 mg/kg/day, based on single liver cell degeneration in
males, and increased SGPT and SGOT, decreased BUN levels, increased
absolute and relative liver weights and presence hepatocellular single
cell necrosis in females.

870.3150

90-Day oral toxicity in nonrodents (dog)	NA1	NA

870.3200

21/28-Day dermal toxicity (rat)	44751307 (1992)

Aceptable/guideline

0, 250, 100 or 2000 (> Limit Dose) mg/kg/day	Systemic Toxicity

NOAEL = 2000 (240.8 mg ai/kg/day)

LOAEL was not established

Dermal Toxicity

LOAEL = 250 (30 mg ai) mg/kg/day, based on dermal irritation.

870.3250

90-Day dermal toxicity	NA	NA

870.3465

90-Day inhalation toxicity	NA	NA

870.3700a

Prenatal developmental in rodents (rat)	44335505 (1990)

Acceptable/guideline

F: 0, 5, 22.5, or 100 mg/kg/day (GD 2-15)	Maternal NOAEL = 22.5
mg/kg/day

LOAEL = 100 mg/kg/day, based on decreased body weight gain, and food
consumption and increased water intake, and increased liver and kidney
weights.

Developmental NOAEL = 22.5 mg/kg/day

LOAEL = 100 mg/kg/day, based on increased incidence of small fetuses,
supranumerary ribs and hydroureter and hydronephrosis.

870.3700b

Prenatal developmental in nonrodents (rabbit)	44335506 (1990)

Acceptable/guideline

F: 0, 7.5, 15, or 30 mg/kg/day	Maternal NOAEL = 13 mg/kg/day

LOAEL = 30 mg/kg/day, based upon decreased decreased body weight gain.

Developmental NOAEL = 30 mg/kg/day

LOAEL was not established

870.3800

Reproduction and fertility effects (rats)	44305306 (1991)

Acceptable/guideline

0, 10, 70, and 490 ppm

M: 0, 0.7, 4.9, and 35.5 mg/kg/day

F: 0, 0.8, 5.9, and 40.6 mg/kg/day	Parental/Systemic NOAEL = 0.7/0.8
mg/kg/day

LOAEL = 4.9/5.9 mg/kg/day (M/F), based on increased mortality in P
females.

Reproductive NOAEL = 0.7/0.8 mg/kg/day

LOAEL = 4.9/5.9 (M/F), based on increased mean gestation duration in P
parental females and related evidence of compound toxicity on the
parturition process.

Offspring NOAEL = 5.9 mg/kg/day

LOAEL = 40.6 [F]), based on decreased litter weight and mean pup weight
in litters of all generations before weaning and increased relative
liver weights at weaning in both sexes of all litters.

870.4300

Combined chronic toxicity/carcinogenicity rodents (rat)	44305304 (1992)

Acceptable/guideline

M: 0, 10, 80, 640 or 1280 ppm

F: 0, 10, 80, 640 ppm

M: 0, 0.4, 3.4, 27.7, or 59 mg/kg/day

F: 0, 0.6, 4.4, or 39.4 mg/kg/day	NOAEL = 3.4/4.4 mg/kg/day (M/F)

LOAEL = 27.7/39.4 (M/F), based upon histopathology of the bone (osseous
hypertrophy of the cranium/parietal bone), pale and thickened incisors,
and decreased absolute and relative adrenal and pituitary weights in
males; decreased body weight (at terminal sacrifice) in females.

Dosing was considered adequate.

No treatment-related increases in tumor incidence were observed.

870.4100b

Chronic toxicity dogs	44305303 (1990)

Acceptable/guideline

M & F: 0, 22.5, 90 or 360 ppm.

M: 0, 0.73, 2.95r 12.97 mg/kg/day

F: 0, 0.82, 5.9, or 40.6 mg/kg/day	NOAEL = 0.73/0.82 mg/kg/day

LOAEL = 2.95/3.33 (M/F), based upon increased absolute and relative
kidney weights and histopathological changes in the male kidney.

870.4300

Carcinogenicity mice	44305305 (1998)

Acceptable/guideline

0, 10, 90, 800, or 1250 ppm

M: 0, 1.4, 12, 118, or 217 mg/kg/day

F: 0, 1.6, 14.8, 140, or 224 mg/kg/day	NOAEL = 1.4/1.6 (M/F) mg/kg/day

LOAEL = 12/14.5 (M/F), based upon increased liver weights and
hepatocellular vacuolation in both sexes and increased kidney weights in
males.

Dosing was considered adequate based on above findings.

Treatment-related increased incidence of combined benign and malignant
liver tumors in both sexes.

Gene Mutation

870.5265

reverse gene mutation assay in bacteria	44335511 (1987)

Acceptable/guideline

0, TA1535, TA1537 and TA1538 at concentrations ranging 125 - 2000
μg/plate ± S9 activation.	Cytotoxicity was evident for the majority of
strains at ≥1000 µg/plate -S9 and at 2000 µg/plate +S9.  All strains
responded in the expected manner to the appropriate positive controls.
There was no evidence of induced mutant colonies over background

Gene Mutation

870.5300

forward gene mutation assay in mammalian cells	44335508 (1988)

Acceptable/guideline

25 μg/mL ±  S9 activation 	Cytotoxicity was observed in all trials at
≥ 100 μg/mL +/-S9.  Findings with the positive controls confirmed the
sensitivity of the test system to detect mutagenesis.  There was no
indication that M 14360 induced a mutagenic response, either in the
presence of absence of S9 activation.

Cytogenetics

870.5375

in vitro mammalian cytogenetic assay	44335507 (1989)

Acceptable/guideline

CHO cells exposed to tetraconazole at doses ranging 0.5-250 μg/mL ± S9
activation.	Cytotoxicity was observed at ≥31.3 μg/mL -S9 (6-hr.
treatment and 24-hr. cell harvest or 24 hrs. of continuous treatment
before sampling); ≥15 μg/mL -S9 (48 hrs of continuous treatment
before sampling) and at ≥15.6 μg/mL +S9 (6-hr. treatment and a 24-hr.
cell harvest). Not clastogenic with or without S9 activation, at any
dose tested.  The positive controls induced the expected high yield of
cells with structural and/or numerical chromosome aberrations.

Other Effects

870.5395

in vivo mammalian cytogenetic assay	44335509 (1989)

Acceptable/guideline

0, 185, 370 or 740 mg/kg	Did not induce micronucleated polychromatic
erythrocytes (MPEs) in bone marrow at any dose.  The test material was
not cytotoxic to the target tissue.  The positive control induced the
expected high yield of MPEs.

Other Genotoxic Effects

870.5550

UDS synthesis in mammalian cell culture	44335510 (1989)

Acceptable/guideline

HeLa cells exposed to doses ranging from 0.25-512 μg/mL ± S9
activation	Cytotoxicity was evident in all trials at ≥64 μg/mL +/-S9.
The positive controls induced significant and dose-related increases in
UDS.  No evidence of genotoxic effect under any test condition.

870.6200a

Acute neurotoxicity screening battery	NA	NA

870.6200b

Subchronic neurotoxicity screening battery	NA	NA

870.6300

Developmental neurotoxicity	NA	NA

870.7485

Metabolism and pharmacokinetics (rat)	44305307 (1993)

Acceptable/guideline

M & F: 14C-phenyl]tetraconazole or [14C-triazole]tetraconazole were
given single oral gavage dose of 5 or 60 mg/kg. 	About 92.0-100.7% of
the administered dose was recovered in urine, feces, and tissues
within72 hours of dosing.  Absorption of [14C]tetraconazole from the
G.I. tract of rats was evident in both low- and high-dose animals based
on the high level of urinary excretion, with ranged from 50.7-71.0% by
48 hours post-dose. Only minor differences were noted in the pattern of
excretion between the sexes, labels, and dose levels.  About 3 - 6% of
the dose was recovered in the carcass/tissues.  Differences were noted
maximum blood concentrations between the doses, sexes and label.  No
differences were noted in the half-life.

870.7485

Metabolism and pharmacokinetics (rat)	45068403 (1992)

Acceptable/guideline for excretion, distribution and metabolic
identification portion of the study.

Single oral doses of [14C] triazole ring labeled M-14360 administered at
dose levels of 5 or 60 mg/kg, urine and feces were collected from five
rats/sex/dose for 168 hours at which time these animals were killed and
their tissues and organs were harvested.  The remaining five
animals/sex/group were killed at peak blood levels of radioactivity
occurring at 8-28 hours of post dosing and their tissues and organs were
harvested.  Radioactivity was measured in urine, feces, blood, tissues,
organs, carcasses and cage washes from all animals. 	Total recovery of
radioactivity ranged from 95% to 102% of the administered dose.  Most of
the dose (75%) was recovered in the urine after 7 days.  Feces accounted
for 15 to 18% of the administered dose.  Triazole was the major
metabolite identified in the urine and feces.  In the urine M-14360 acid
along with minor metabolite of M-14360 alcohol and its glucuronide
conjugate (M3) were isolated.  In the feces minor amounts of parent
M-14360, the acid and alcohol were isolated.  Data suggest M-14360 or
its metabolites do not accumulate in the tissues following single oral
administration.  95-98% of the urinary and fecal metabolites were
identified.

There is a qualitative and quantitative difference in the metabolites in
the males and females and the dose levels.  Male rats produced more
triazole than females (65-67% of the AD vs 48%in females) in the urine,
while urine of females had more of M-14360 acid.  The same pattern was
also seen in the multiple dosing studies, although the differences were
not pronounced.  In the multiple dosing studies, triazole (3.2-3.9% of
the AD for males and females at the low dose vs 6.5-6.8% for the high
dose), M-14360 acid, M-14360 alcohol, M-14360, M6 and others were
reported while in the single dosing only triazole (5.6 - 10.4% of the
administered low and high doses in both sexes), M-14360 acid and M-14360
were reported. Based on the results, the study authors postulated that
cleavage of —14360 to yield triazole appears to be a major step
through glutathione mediated path.  A metabolic pathway was proposed
where the initial step is the formation of an aldehyde intermediate of
M-14360 following dealkylation of the fluoro-alkyl group of the
molecule.

870.7485

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؀ pharmacokinetics (rat)	44268114 (1990)

Acceptable/guideline for single dose excretion and distribution

Single oral doses of 14C-Tetraconazole phenyl labeled or triazole ring
labeled were administered at dose levels of 5 or 60 mg/kg, urine, feces
and expired air were collected for 168 hours and radioactivity in blood,
tissues, organs, carcass and cage washes were determined.	Total
recovered radioactivity ranged from 99% to 114% for the phenyl label and
96% to 109% for the triazole label of the AD. Most of the radioactivity
was recovered in the urine, particularly the triazole label.  In the
triazole study, males excreted the radio label into the urine more and
faster than in the females.  Compared to the phenyl label, more of the
triazole label was excreted at both doses in the urine.  Radioactivity
in the tissues was minimal and accounted for less than 1% in the phenyl
label.  For the triazole label 0.9% to 1.4% radioactivity was recovered
in tissues.  In the feces, more phenyl label (21-32%) than in the
triazole label (12-16% of the AD) radioactivity was excreted.  Male rats
generally excreted the radiolabel into the feces faster than in the
females for both labels.

870.7485

Metabolism and pharmacokinetics (rat)	44268119 (1994)

Acceptable/guideline for excretion and distribution of triazole labeled
M-14360 following repeated oral administration.

Groups of rats received single oral dose of nonradiolabeld M 14360 at 5
or 60 mg/kg for 14 days followed by single oral dose of [14C] triazole
ring labeled M 41360; animals were placed metabolism cages where urine
and feces were collected and radioactivity in blood, tissues, organs,
carcass and cage washes were determined upon sacrifice.	The test
material was readily absorbed and distributed in the body within 8 hours
after dosing and about 100.9 ± 4.0% of the administered dose was
recovered.  Urine was the major route of excretion accounting for nearly
87% of the AD after 7 days of exposure.  Most of the urinary
radioactivity was excreted during the first 48 hours.  Fecal elimination
of the radioactivity was the next major route accounting for 12-16% of
the AD after 7 days of exposure.  Less than 1% of the AD was recovered
in tissues.  Sex has no effect on excretion and distribution.

870.7600

Dermal penetration	NA	NA

Non-guideline - rats

Liver enzyme induction	44751310 (1998)

Acceptable/nonguideline

In diet at doses of 0, 10, 80, 640 ppm; the positive control was
Phenobarbital (Na) salt, 75 mg/kg/day for 4 weeks.	Dietary
administration of tetraconazole for 4 weeks results in liver enzyme
induction at dose levels of 80 and 640 ppm.  Induction at the 640 ppm
dose level was similar to that induced by phenobarbital at 75 mg/kg/day.

Non-guideline - mice

Liver enzyme induction	44751309 (1996)

Acceptable/nonguideline

Tetraconazole administration for 4 weeks results in liver enzyme
induction. At doses ≥ 20 ppm in females an apparent increases in
microsomal protein, cytochrome P450, and ethylmorphine N-demethylase
were observed.  At all dose levels in males and females,
7-pentoxyresorufin O-depentylase values were statistically elevated.  At
800 and 1250 ppm, statistically significant findings were typically
noted.   However, dose response increases were not apparent in these
findings at the 1250 ppm level as compared to the lower 800 ppm level.

1 Study requirement satisfied by chronic dog study

Page   PAGE  39  of   NUMPAGES  39