Document ID: EPA-HQ-OPP-2009-0276-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-01-27T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		7-AUG-2009

SUBJECT:	Triticonazole.  Human Health Risk Assessment for Proposed Seed
Treatment Use on Cereal Grains (Crop Group 15) Including Barley, Field
Corn, Oats, Popcorn, Rye, Sorghum Grain, Sweet Corn, Triticale, and
Wheat (Excluding Rice); and Forage, Fodder, and Straw of Cereal Grains
(Crop Group 16), Excluding Rice.

PC Code:  125620	DP Barcode:  358614

Decision No.: 399232	Registration No.: 7969-EIT

Petition No.:  8F7420	Regulatory Action:  Section 3 Registration 

Risk Assessment Type:  Single Chemical/Aggregate	Case No.: NA

TXR No.:  NA	CAS No.:  131983-72-7

MRID No.:  NA	40 CFR: 180.583

FROM:	Nancy J. Tsaur, Risk Assessor

	Amelia Acierto, Chemist

	Myron Ottley, Toxicologist

	Risk Assessment Branch 3 (RAB3)

	Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief 

Risk Assessment Branch 3 (RAB3)

Health Effects Division (7509P)

TO:	

Tony Kish/Bryant Crowe, Risk Management Team 22

	and

Cynthia Giles-Parker, Branch Chief

	Fungicide Branch (FB)

	Registration Division (7505P)

Table of Contents

  TOC \o "1-3" \u  INTRODUCTION	  PAGEREF _Toc237150413 \h  4 

1.0	EXECUTIVE SUMMARY	  PAGEREF _Toc237150414 \h  6 

2.0	SUMMARY OF PROPOSED USES	  PAGEREF _Toc237150415 \h  9 

3.0	HAZARD CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc237150416 \h  10 

3.1	Database Summary	  PAGEREF _Toc237150417 \h  11 

3.1.1	Sufficiency of studies/data	  PAGEREF _Toc237150418 \h  11 

3.1.2	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc237150419 \h  11 

3.1.3	Toxicological Effects	  PAGEREF _Toc237150420 \h  11 

3.2	FQPA Considerations	  PAGEREF _Toc237150421 \h  12 

3.2.1	Adequacy of the Toxicity Database	  PAGEREF _Toc237150422 \h  12 

3.2.2	Evidence of Neurotoxicity	  PAGEREF _Toc237150423 \h  13 

3.2.3	Developmental Toxicity Studies	  PAGEREF _Toc237150424 \h  13 

3.2.4	Reproductive Toxicity Study	  PAGEREF _Toc237150425 \h  13 

3.2.5	Additional Information from the Literature	  PAGEREF _Toc237150426
\h  13 

3.2.6	FQPA Safety Factor for Infants and Children	  PAGEREF
_Toc237150427 \h  13 

3.3	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc237150428 \h  14 

3.3.1	Level of Concern for Margin of Exposure/Population Adjusted Dose	 
PAGEREF _Toc237150429 \h  14 

3.3.2	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc237150430 \h  14 

3.3.3	Summary of Toxicological Doses and Endpoints for Triticonazole for
Use in Human Risk Assessments	  PAGEREF _Toc237150431 \h  15 

3.4	ENDOCRINE DISRUPTION	  PAGEREF _Toc237150432 \h  17 

4.0	PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA	  PAGEREF
_Toc237150433 \h  18 

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc237150434 \h 
18 

5.1	Drinking Water Residue Profile	  PAGEREF _Toc237150435 \h  18 

5.2	Metabolism in Primary Crops	  PAGEREF _Toc237150436 \h  19 

5.3	Metabolism in Livestock	  PAGEREF _Toc237150437 \h  19 

5.4	Analytical Methodology	  PAGEREF _Toc237150438 \h  20 

5.5	Food Residue Profile	  PAGEREF _Toc237150439 \h  21 

5.6	International Residue Limits	  PAGEREF _Toc237150440 \h  22 

5.7	Dietary Exposure and Risk	  PAGEREF _Toc237150441 \h  23 

6.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION	 
PAGEREF _Toc237150442 \h  25 

7.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	  PAGEREF
_Toc237150443 \h  25 

7.1	Acute Aggregate Risk	  PAGEREF _Toc237150444 \h  26 

7.2	Short-Term and Intermediate-Term Aggregate Risk	  PAGEREF
_Toc237150445 \h  26 

7.3	Long-Term Chronic Aggregate Risk	  PAGEREF _Toc237150446 \h  27 

7.5	Cancer Aggregate Risk	  PAGEREF _Toc237150447 \h  27 

8.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc237150448
\h  27 

9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	  PAGEREF _Toc237150449 \h  28 

9.1	Short-/Intermediate -Term Handler Risk	  PAGEREF _Toc237150450 \h 
28 

9.2	Short-/Intermediate-Term Postapplication Risk	  PAGEREF
_Toc237150451 \h  31 

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS	  PAGEREF _Toc237150452 \h  31

10.1	Toxicology	  PAGEREF _Toc237150453 \h  31 

10.2	Residue Chemistry	  PAGEREF _Toc237150454 \h  32 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc237150455 \h 
32 

Appendix A:  TOXICOLOGY ASSESSMENT	  PAGEREF _Toc237150456 \h  33 

A.1	Toxicology Data Requirements	  PAGEREF _Toc237150457 \h  33 

A.2	Acute Toxicity	  PAGEREF _Toc237150458 \h  34 

A.3	Toxicity Profile	  PAGEREF _Toc237150459 \h  34 

Appendix B:  INTERNATIONAL RESIDUE LIMIT STATUS	  PAGEREF _Toc237150460
\h  37 

Appendix C:  METABOLISM ASSESSMENT	  PAGEREF _Toc237150461 \h  38 

 INTRODUCTION

The Health Effects Division (HED) has conducted a human health risk
assessment for the fungicidal active ingredient (ai), triticonazole, for
the purpose of a registration eligibility decision to establish
tolerances for the seed treatment uses (cereal grains, except rice)
requested by the petitioner, BASF Corporation (BASF).  Triticonazole is
currently formulated for use as a seed treatment on barley and wheat
seeds (for which there are associated tolerances on barley and wheat
commodities), as well as on turfgrass.

BASF has submitted a petition (PP#8F7420) to register the end use
product (EP) Triticonazole HL Fungicide Seed Treatment, a 43.5% ai (4.17
lbs ai/gallon) liquid flowable formulation of triticonazole
(1RS)-(E)-5-[(4-chlorophenyl)methylene]-2,2-dimethyl-1-(1 H
-1,2,4-triazol-1-ylmethyl)cyclopentanol, for use in/on cereal grains
(crop group 15, excluding rice) and forage, fodder, and straw of cereal
grains (crop group 16, excluding rice) and proposed the following
tolerances:

Commodity	Proposed Tolerance (ppm)

Grain, cereal, group 15 (except rice)	0.05

Grain, cereal, forage, fodder, and straw, group 16 (except rice)	0.10

HED recommends that a revised Section F be submitted to reflect the
tolerance recommendation of 0.01 ppm for grain, cereal, group 15 (except
rice); to reflect the tolerance recommendation of 0.25 ppm for grain,
cereal, forage, fodder, and straw, group 16 (except rice); and to
reflect the correct commodity definitions as listed in the tolerance
summary below:

Tolerance Summary for Triticonazole

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

Established tolerances under 180.583(a)

Barley, grain	0.05	Remove	Barley grain will be covered with the
establishment of the cereal grain, group 15 (except rice) tolerance.

Barley, hay	0.05	Remove	Increase in the tolerance based on residues
resulting from new uses. Barley hay and straw and wheat forage will be
covered with the establishment of the cereal grain group 16 (except
rice) tolerance.

Barley, straw	0.05	Remove

	Wheat, forage	0.05	Remove

	Wheat grain	0.05	Remove	Wheat grain will be covered with the
establishment of the cereal grain, group 15 (except rice) tolerance

Wheat, hay	0.05	Remove	Increase in the tolerance based on residues
resulting from new uses. Wheat hay and straw and will be covered with
the establishment of the cereal grain group 16 (except rice) tolerance.

Wheat, straw	0.05	Remove

	Tolerances to be established under 180.583(a)

Grain, cereal, group 15 (except rice)	0.05	0.01	NA

Grain, cereal, forage, fodder, and straw, group 16 (except rice)	0.10
0.25	NA

 

The most recent prior human health risk assessment was conducted in
conjunction with a request for use of triticonazole on turfgrass (S.
Winfield, DP#316612, 12/20/2006).  The following information from the
12/20/2006 risk assessment can be applied directly to this action:

Sections 2.2-2.3: Structure and Nomenclature, Physical and Chemical
Properties,

Section 3.0: Hazard Characterization/Assessment, and

Sections 5.1.1-5.1.8: Pesticide Metabolism and Environmental
Degradation.

This document contains only those aspects of the risk assessment which
are affected by the proposed Section 3 request for use of triticonazole
for seed treatments of the cereal grain crop groups (15 and 16),
excluding rice.

This document provides a summary of the findings from the data
evaluation and subsequent 

assessment of human health risk resulting from these requests.  The
hazard assessment and characterization were conducted by Myron Ottley
(RAB3), the residue chemistry data review and dietary exposure
assessment were completed by Amelia Acierto (RAB3), and the occupational
residential exposure data review and human health risk assessment were
performed by Nancy J. Tsaur (RAB3); additionally, the drinking water
assessment was conducted by Cheryl Sutton of the Office of Pesticide
Program’s (OPP’s) Environmental Fate and Effects Division (EFED).

1.0	EXECUTIVE SUMMARY

Triticonazole is a triazole fungicide that is proposed for use as a seed
treatment on cereal grains, except rice, for the control of various
seed-borne plant diseases.  As a triazole fungicide, the contribution of
triazole derivatives [1,2,4-triazole, triazolylalanine, and
triazolylacetic acid] from the use of triticonazole on cereal grains
must be considered in the aggregate exposure for a triazole human health
risk assessment.  The requested seed treatment uses of triticonazole do
not result in increases in dietary exposure estimates for free triazole
or conjugated triazoles and thus, no updated risk assessments are needed
for the triazole derivatives.  

Use Profile

Triticonazole is currently registered and formulated for use as a seed
treatment for barley and wheat, and for use in fungicidal products to
control certain diseases of residential and commercial turfgrass, golf
courses, and sod farms.  The proposed formulated end use product
evaluated in this assessment is labeled under the trade name
Triticonazole HL Fungicide Seed Treatment (liquid flowable containing
43.5% ai or 4.17 lbs ai/gallon).  The proposed use rates for seed
treatment range from 0.155 to 1.55 fl oz/100 lbs seed (0.005 – 0.05
lbs ai/100 lbs seed).  The formulation is to be applied once in a
commercial seed treatment facility.

Toxicity/Hazard Assessment

Triticonazole has low acute toxicity, is not a skin, eye, or respiratory
irritant, or a dermal sensitizer.  Dermal absorption was reported to be
less than 2%.  Non-acute toxicity studies show that the liver (rat,
mouse, dog) and adrenals (rat, dog, rabbit) are target organs across
species.  Adverse body weight changes (rat, dog, rabbit, mouse) and
clinical signs (rat, dog, mouse) also were observed in multiple species.
 In the developmental and reproductive toxicity studies, adverse effects
on the offspring occurred only at dose levels which were toxic in the
adults, and the offspring were not qualitatively more susceptible
compared with adults.  In the rat subchronic study, decreased thymus
weights were reported at a dose level (2309.3 mg/kg/day) two times
higher than the limit dose (1000 mg/kg/day).  Triticonazole was negative
for mutagenicity, and the cancer classification is “Not Likely to Be
Carcinogenic to Humans” based on a lack of evidence of carcinogenicity
in the two guideline studies conducted on rats and mice.  The nature and
severity of toxicity from triticonazole exposure are adequately
characterized, and the no observed adverse effect levels (NOAELs) and
lowest observed adverse effect levels (LOAELs) established for the
studies in the database are judged by HED to be adequately protective
for risk assessment purposes. 

Food Quality Protection Act (FQPA) Considerations

There is a complete toxicity database for triticonazole, with the
exception of a required immunotoxicity study, and exposure is estimated
based on data that reasonably account for potential exposures. There is
no evidence of increased susceptibility following in utero and/or
postnatal exposure in the developmental toxicity studies in rats or
rabbits, and in the 2-generation rat reproduction study. There are no
residual uncertainties concerning pre- and post-natal toxicity and no
neurotoxicity concerns. The acute and chronic dietary food and drinking
water exposure assessments utilize screening-level and modeled residue
values which will not underestimate exposures/risks. Based on these data
and conclusions, the FQPA Safety Factor can be reduced to 1X.

Dietary Exposure/Risk (food + water)

Acute and chronic dietary exposure and risk assessments were conducted
using the Dietary Exposure Evaluation Model (DEEM-FCIDTM, Version 2.03)
which uses food consumption data from the U.S. Department of
Agriculture’s Continuing Surveys of Food Intakes by Individuals
(CSFII) from 1994-1996 and 1998.  The proposed new uses do affect and
add food commodities to the dietary assessment but they do not trigger
new modeled estimated drinking water concentrations (EDWCs) of the
1-in-10 year annual peak concentration of 75.5 ppb (for acute) and the
1-in-10 annual mean concentration of 32.8 ppb (for chronic), which are
reflected in this assessment.  Both the acute and chronic dietary
assessments assumed that tolerance level residues of triticonazole were
found in all commodities and that all commodities consumed were 100%
crop treated (100% CT).  The dietary exposures for food and drinking
water are well below the level of concern (LOC) for all populations for
acute and chronic risk.  Combined acute dietary exposure from food and
drinking water is <1% of the acute population adjusted dose (aPAD) for
the most highly exposed population subgroup, females 13-49 years old. 
For the general U.S. population and for all infants <1 year old, the
exposure is also <1% of the aPAD.  The chronic dietary exposure is
estimated to be <1% of the chronic adjusted population dose (cPAD) for
the general U.S. population and 1.4% of the cPAD for all infants (<1
year old), the population subgroup with the highest estimated chronic
dietary exposure to triticonazole.  The assessment is conservative and
actual exposure is likely to be much lower.

Residential Exposure/Risk

Based on the proposed label restrictions, non-occupational (residential)
handler exposure is not expected.  However, exposure is possible during
postapplication activities on treated turf (existing use) and such risks
have been previously assessed (S. Winfield, DP#316612, 12/20/2006). 
This document only presents the assessment of the proposed new
agricultural uses of triticonazole.  No residential uses are being
requested at this time; therefore, no residential risk assessment has
been conducted. 

Aggregate Risk

Acute and chronic aggregate assessments consider dietary (food +
drinking water) exposure only and are therefore, addressed in the
dietary risk assessments (dietary risk estimates were not of concern). 
However, short- and intermediate-term aggregate assessments consider
residential postapplication incidental oral exposure for children in
addition to background dietary exposure.  All aggregate risk assessments
indicated risks were not of concern as the margins of exposure (MOEs)
ranged from 740 to 1100 and are greater than the LOC of 100.

Occupational Exposure/Risk

Occupational handler exposure is expected for individuals involved in
commercial seed treatment (primary handlers) and planting treated seeds
(secondary handlers).  The results of the occupational handler exposure
and risk assessment indicate that inhalation risks do not exceed HED’s
LOC (i.e., MOEs, ranging from 2,200 to 3,200,000, are greater than the
LOC of 100) at the baseline level of risk mitigation (i.e., no
respirator) for any of the cereal seed treatment scenarios.  

There is the potential for postapplication exposures following the
planting of triticonazole-treated seeds.  Sustained levels of contact
with treated seed after it has been placed in the soil or other planting
media would not be expected because no routine cultural practice
required for the production of agricultural commodities involves such an
activity as defined in the no/low contact criteria in the Worker
Protection Standard (WPS).  Therefore, no quantitative postapplication
assessment is required for exposure to treated seeds that have already
been planted.

The triticonazole ai has been classified in Toxicity Category III for
acute dermal toxicity and Toxicity Category IV for primary eye
irritation and primary skin irritation.  The Worker Protection Standard
(WPS) requires a 12-hour restricted entry interval (REI) for active
ingredients classified as Toxicity Category III or IV for these routes
of exposure.

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent
possible, were considered in the human-health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"
(http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustic
e.pdf).  OPP typically considers the highest potential exposures from
the legal use of a pesticide when conducting human health risk
assessments including, but not limited to, people who obtain drinking
water from sources near agricultural areas, the variability of diets
within the U.S., and people who may be exposed when harvesting crops. 
Should these highest exposures indicate potential risks of concern, OPP
further refines the risk assessments to ensure that the risk estimates
are based on the best available information.

Review of Human Research

This risk assessment relies in part on data from studies (PHED and Seed
Treatment Standard Operating Procedures, or SOPs) in which adult human
subjects were intentionally exposed to a pesticide or other chemical. 
These studies have been determined to require a review of their ethical
conduct, have received that review, and have been determined ethical.

Label Recommendations 

The labeling should state:  Seed that has been treated with this product
that is then packaged or bagged for future use must contain the
following labeling on the outside of the seed package or bag:

"Treated Seed - Do Not Use for Food, Feed, or Oil Purposes.

When opening this bag or loading/pouring the treated seed, wear
long-sleeved shirt, long pants, shoes, socks, and chemical resistant
gloves.

After the seeds have been planted, do not enter or allow worker entry
into treated areas during the restricted-entry interval (REI) of 12
hours. Exception: Once the seeds are planted in soil or other planting
media, the Worker Protection Standard allows workers to enter the
treated area without restriction if there will be no worker contact with
the treated seeds in the soil or planting media."

For directions for use: The label for Triticonazole HL Fungicide must be
amended to include the following rotational crop restrictions:  a
120-day plantback interval for leafy vegetables, a 365-day plantback
interval for root and tuber vegetables, and a prohibition of the
planting of all other crops not listed on the label.

Tolerance Recommendations

For tolerances for the cereal grain crop group 15, except rice: A
revised Section F must be submitted to reflect the tolerance
recommendation of 0.01 ppm for grain, cereal, group 15 (except rice); to
reflect the tolerance recommendation of 0.25 ppm for grain, cereal,
forage, fodder, and straw, group 16 (except rice); and to reflect the
correct commodity definitions.

Conditions of Registration

HED recommends conversion of conditional registration to unconditional
registration for the cereal grains (except rice) upon adequate
resolution of data pertaining to storage stability, field accumulation
in rotational crops, and immunotoxicity.

Deficiencies

860.1380 Storage Stability: To support the reported results for
1,2,4-triazole and the triazole conjugates, the final report of the
ongoing storage stability study with free triazole and triazole
conjugates in plant commodities must be submitted.

860.1900 Field Accumulation in Rotational Crops: Data from limited field
accumulation studies on rotational crops are required.

Biliary Excretion Study.

Immunotoxicity Study.

2.0	SUMMARY OF PROPOSED USES

A summary of the proposed use directions is presented in Table 2.0. 
Information pertaining to the proposed use pattern was obtained from a
2008 specimen label submitted for Triticonazole HL Fungicide Seed
Treatment (4.17 lb/gal FS).  The EP is proposed for the control of
various seed-borne diseases in cereal crops, excluding rice.  

Table 2.0 shows that Triticonazole HL Fungicide Seed Treatment is
proposed for seed treatment on cereal grains (except rice) at a maximum
rate of 0.05 lb ai/100 lb seed.  The EP, Charter® Fungicide Treatment
(EPA Reg. No. 7969-386; accepted 6/27/2007), is currently registered on
barley and wheat for preplant seed treatment at a maximum rate of 0.005
lb ai/100 lb seed.

Table 2.0.  Summary of Proposed Seed Treatment Use of Triticonazole.

Application Type	Formulation

[EPA Reg. No.]	Seed Treatment 

Application Rate

fl ozs/100 lbs seed

(lbs ai/100 lbs seed)	Maximum 

Seeding Rate 1 

(lb seed planted/A)	Maximum Equivalent 

Field Application Rate 2

(lb ai/A)

Barley

Seed Treatment	4.17 lb/gal FS

[7969-EIT]	0.155-1.55

(0.005-0.050)	96	0.048



Field Corn and Popcorn (includes seed production)

Seed Treatment	4.17 lb/gal FS

[7969-EIT]	0.155-1.55

(0.005-0.050)	15	0.008

Sweet Corn

Seed Treatment	4.17 lb/gal FS

[7969-EIT]	0.31

(0.010)	15	0.002

Oats

Seed Treatment	4.17 lb/gal FS

[7969-EIT]	0.155-1.55

(0.005-0.050)	128	0.064

Rye

Seed Treatment	4.17 lb/gal FS

[7969-EIT]	0.155-1.55

(0.005-0.050)	112	0.056

Sorghum

Seed Treatment	4.17 lb/gal FS

[7969-EIT]	0.31-0.62

(0.010-0.020)	10	0.002

Wheat and Triticale

Seed Treatment	4.17 lb/gal FS

[7969-EIT]	0.155-1.55

(0.005-0.050)	150	0.075

General Use Directions and Limitations:  To be applied as a water-based
mixture using standard or mist-type seed treatment application
equipment.  A colorant must be added to identify the treated seed.  The
proposed label does not include water amounts needed to provide the
mixture or slurry rate for optimum coverage, but recommends consulting a
seed-treatment specialist.  The product may be tank-mixed with other
water-based seed treatments.  Use of treated seed for food, feed, or oil
processing is prohibited.  Planting of any crop not listed on the label
within 30 days after planting treated seed is not allowed. 

1	From Science Advisory Council for Exposure, Standard Operating
Procedure, SOP#15, 3/2/04.

2	Calculated by the study reviewer using the maximum seed treatment rate
and maximum seeding rate.

3.0	HAZARD CHARACTERIZATION/ASSESSMENT

References: 

Triticonazole – Report of the Hazard Identification Assessment Review
Committee.  A. Assaad, TXR#014698, 10/11/2001.

Triticonazole – Report of the FQPA Safety Factor Committee.  C.
Christensen, TXR#0050801, 06/13/2002.

Triticonazole: Report of the Cancer Assessment Review Committee.  J.
Kidwell, TXR#0054249, 06/15/2006.

Response to Bayer CropScience Request to Waive the Requirement of a
28-day Inhalation Toxicity Study for Triticonazole.  A. Assaad,
TXR#0054207, 04/12/2006.

Triticonazole (PC Code 125620) Developmental Neurotoxicity Study Waiver
Request.  S. Dapson, TXR#0053424, 11/13/2006.

Triticonazole: HED Human Health Risk Assessment for Proposed Use on
Turf. PC Code: 125620, Reg Nos. 264-ANR, 432-REAI.  S. Winfield,
DP#s316612 and 313844, 12/20/2006.

With the exception of a new data requirement for immunotoxicity, the
hazard characterization, toxicological effects, mode of action, dose
response considerations, and absorption, distribution, metabolism,
excretion (ADME) determinations have not changed since completion of the
previous risk assessment (S. Winfield, DP#316612, 12/20/2006).  A
biliary excretion study in the rat has been submitted (MRID#47158901)
and is currently under review.  The results of this study are not
expected to change the hazard assessment or endpoints selected for risk
assessment. Refer to the listed references for further extensive
details.  Refer to Appendix A for the toxicity profile of triticonazole.
 Since no new toxicity data are associated with this action, the hazard
characterization and endpoint selection for triticonazole summarized
below are supported by the data evaluations and conclusions from the
previous risk assessment which apply directly to this section. 

3.1	Database Summary

3.1.1	Sufficiency of studies/data

With the exception of an immunotoxicity study, the toxicology database
for triticonazole is complete.  There are acceptable studies available
for endpoint selection that include: 1) subchronic oral toxicity studies
in rats; 2) chronic oral toxicity studies in rats and dogs, and
carcinogenicity studies in rats and mice; 3) developmental studies in
rats and rabbits and a reproduction study in rats; 4) acute and
subchronic neurotoxicity studies in rats; and 5) subchronic dermal
toxicity and dermal penetration studies in rats.  There is also a
complete mutagenicity battery, and a set of metabolism studies in rats. 
A waiver for a developmental neurotoxicity (DNT) study has been granted.

3.1.2	Mode of action, metabolism, toxicokinetic data

Triticonazole is in the class of fungicides known as azoles which
commonly inhibit the synthesis of ergosterol (specifically C-14
demethylation).  The data show that at higher dose levels the absorption
mechanism can become saturated.  The extent of absorption following oral
dosing was not determined.  It was not widely distributed in rat tissue.
Excretion was rapid, >90% within 48 hours following a single dose.  It
was excreted mostly from the GI tract in bile and feces, and also from
the kidney. The major metabolites identified were diastereo isomers
(acid metabolites) and hydroxylated derivatives.

3.1.3	Toxicological Effects

Toxicity Summary

Triticonazole has low acute toxicity, is not a skin, eye, or respiratory
irritant, and does not cause dermal sensitization in guinea pigs. 
Dermal absorption was reported to be less than 2%.  Repeated dosing
studies show that the liver (rat, mouse, dog) and adrenals (rat, dog,
rabbit) are target organs across species.  Adverse body weight changes
(rat, dog, rabbit, mouse) and neurotoxic signs (rat, dog, mouse) also
were observed in multiple species.  

The data does not demonstrate susceptibility in the offspring.  In the
developmental and reproductive toxicity studies, adverse effects on the
offspring (supernumery ribs and cranial variations) occurred only at
dose levels where maternal and parental toxicities were seen.  In
addition, toxicity in the offspring was more severe compared with adults
(in rabbits, an increase in mortality was observed in both dams and
offspring at the same dose).

Triticonazole was negative for mutagenicity, and the cancer
classification is “Not Likely to Be Carcinogenic to Humans” based on
a lack of evidence of carcinogenicity in rats and mice up to the limit
dose at 24 and 18 months, respectively.

Immunotoxicity

In the oral subchronic rat study (MRID 44802102) triticonazole was
offered in feed for 13 weeks to 10 CD rats/sex at dose levels of 0, 25,
250, 12,500 or 25,000 ppm (males: 0, 2.0, 19.8, 1117.0, or 2309.3 mg/kg
body weight/day; females: 0, 2.2, 22.3, 1183.5, or 2368.8 mg/kg/day). 
In addition to adverse effects on body weight and food consumption,
primary target organ effects involved the thymus (decreased weight),
adrenals (decreased weight, and increased lesions), liver (hypertrophy),
blood (decreases in hematocrit, hemoglobin, and red blood cells) and
skin (hair loss).

The decrease in thymus weights was reported at the high dose level
(2309.3 mg/kg/day).  The NOAEL for thymus weight changes was 1117
mg/kg/day.  The NOAEL for the study was 2 mg/kg/day (males) and the
LOAEL was 19.8 mg/kg/day, based on adverse effects on the adrenals (a
statistically significant increase in the incidence of adrenocortical
fatty vacuolation).

No other adverse effects indicative or suggestive or indicative of
immunotoxicity were observed in any other studies in the available
database.  A clear NOAEL for thymus effects has been established, and
the points of departure for risk assessment are protective of the
adverse thymus weight change.  Additionally, triticonazole does not
belong to a class of chemicals that would be expected to be immunotoxic.
 It is not likely that conducting a special 870.7800 immunotoxicity
study will result in a NOAEL less than 17 mg/kg/day which is presently
used as the cRfD POD.  Therefore, there an additional uncertainty factor
(UFDB) does not need to be applied at this time.

3.2	FQPA Considerations

3.2.1	Adequacy of the Toxicity Database

The toxicity database for triticonazole is considered complete except
for: 

1.	additional information on absorption.  A biliary excretion study in
the rat has been submitted (MRID 47158901) and is currently in review. 
The results of this study will provide the needed information on the
extent of absorption of triticonazole in the rat, but are not expected
to change the hazard assessment, endpoints selected for risk assessment,
or Uncertainty Factors for FQPA.

2.	the current requirement for an immunotoxicity study.

3.2.2	Evidence of Neurotoxicity

Neurotoxicity was observed as transient signs (tremors, hyperactivity or
hypoactivity, convulsions, and ataxia) in the one-year dog study at 150
mg/kg/day.  However, no neurological effects were seen in rats, mice, or
rabbits at dose levels that caused death (rabbits) or at the limit dose
(rats).  Increases in motor activity were observed in a rat oral acute
neurotoxicity study above the limit dose (i.e., at 2000 mg/kg), but a
LOAEL for neurological effects could not established in the rat oral
subchronic neurotoxicity study (NOAEL = 695 mg/kg/day (M), 820 mg/kg/day
(F)).  A DNT study waiver was submitted and granted (S. Dapson,
TXR#0053424, 11/13/2006).  Thus, there are no concerns for neurotoxicity
associated with exposure to triticonazole at this time.

3.2.3	Developmental Toxicity Studies

In the rat developmental study, extra ribs (unilateral and bilateral
supernumerary ribs) were observed at the dose level where maternal
toxicity (reduced body weight gain) was observed.  The LOAEL was 1000
mg/kg/day and the NOAEL was 200 mg/kg/day.  

In the rabbit developmental study, a reduction in maternal body weight
and food consumption and increased mortality was observed at the LOAEL
of 50 mg/kg/day (NOAEL = 25 mg/kg/day).  No effects in the fetus were
observed at the maternal LOAEL.  At the developmental LOAEL of 75
mg/kg/day cranial variations, abortion and increased pre- and
post-implantation losses were observed. 

3.2.4	Reproductive Toxicity Study

The multigeneration reproduction study yielded all NOAELs (parental,
reproductive, offspring) occurring at 37.5 mg/kg/day and all LOAELS
occurring at 250 mg/kg/day.  The parental LOAEL is based on reduced body
weights, mortality and microscopic lesions in adrenals.  The
reproductive LOAEL is based on decreased fertility.  The offspring LOAEL
is based on decreased pup survival and decreased pup body weights.

3.2.5	Additional Information from the Literature

A literature search did not reveal information that would impact the
risk assessment. 

3.2.6	FQPA Safety Factor for Infants and Children

EPA has determined that reliable data show the safety of infants and
children would be adequately protected if the FQPA SF were reduced to
1X. That decision is based on the following findings:

There is a complete toxicity database for triticonazole, with the
exception of a required immunotoxicity study, and exposure is estimated
based on data that reasonably account for potential exposures.

A clear NOAEL for thymus effects was established in the available
database and the PODs for risk assessment are protective of these thymus
effects.  Therefore, there is no basis for concern for immunotoxicity or
for retaining the 10X FQPA factor due to concerns for immunotoxicity at
this time.

There is no evidence of increased susceptibility following in utero
and/or postnatal exposure in the developmental toxicity studies in rats
or rabbits, and in the 2-generation rat reproduction study. 

There are no residual uncertainties concerning pre- and post-natal
toxicity and there are no neurotoxicity concerns. 

The acute and chronic dietary food and drinking water exposure
assessments utilize screening-level and modeled residue values which
will not underestimate exposures/risks. 

3.3	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.4
Hazard Identification and Toxicity Endpoint Selection 

3.3.1	Level of Concern for Margin of Exposure/Population Adjusted Dose 
TC \l3 "3.4.1	Level of Concern for Margin of Exposure/Population
Adjusted Dose 

Table 3.3.1.   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Inhalation	MOE < 100	MOE  < 100	NA

Residential Exposure

Inhalation	MOE < 100	MOE < 100	NA

Incidental Oral	MOE < 100	MOE < 100	NA

Dietary (Food and Water)	exposure > 100% aPAD

(acute, 1-day exposure)	NA	exposure > 100% cPAD 

(chronic exposure)

The LOCs for the inhalation and incidental oral routes (MOEs) are based
on the conventional interspecies extrapolation (10X) and intraspecies
variation (10X) uncertainty factors.  No additional uncertainty factors
are necessary.  The LOCs for the dietary route are expressed as a
percentage of a maximum acceptable dose (i.e., the dose which HED has
concluded will result in no unreasonable adverse health effects).  This
dose is referred to as the population adjusted dose (PAD).  For acute
and non-cancer chronic exposures, HED is concerned when estimated
dietary risk exceeds 100% of the PAD.

											

3.3.2	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.4.2	Recommendation for Aggregate Exposure Risk Assessments 

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major routes: oral, dermal and inhalation exposures.  No systemic
toxicity was observed in the rat dermal toxicity study and there are no 
developmental or neurotoxic concerns; therefore, no hazard was
identified via the dermal route that would contribute to aggregate
exposure/risk.   However, the toxicity endpoints were selected for
short- and intermediate-term incidental oral and inhalation routes of
exposure may be aggregated due to the presence of a common toxicity
endpoint (short-term: decreased body weight gain, reduced food
consumption, and mortality; intermediate-term: decreased body weight
gain and liver toxicity).  Even though these exposures may be aggregated
due to common toxicity endpoints, residential exposure via the
inhalation route is not expected to occur due to label restrictions. 
Therefore, short- and intermediate-term incidental oral exposures were
aggregated with background dietary (food and drinking water) exposure
and compared to the short- and intermediate-term incidental oral
quantitative hazard estimates.  Expected sources of exposure for acute
and chronic durations are dietary alone (i.e., food and drinking water
exposures are aggregated).

3.3.3	Summary of Toxicological Doses and Endpoints for Triticonazole for
Use in Human Risk Assessments  TC \l3 "3.4.3	Summary of Toxicological
Doses and Endpoints for Triticonazole for Use in Human Risk Assessments 

Tables 3.3.3.1 and 3.3.3.2 summarize the up-to-date toxicological doses
and endpoints for triticonazole for use in dietary and occupational
human health risk assessments, respectively.

Table 3.3.3.1. Summary of Toxicological Doses and Endpoints for
Triticonazole for Use in Dietary and Non-Occupational Human Health Risk
Assessments.

Exposure/

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

Acute Dietary (General Population, including Infants and Children)
NOAEL=400 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Acute RfD = 

4 mg/kg/day

aPAD =

4 mg/kg/day	Acute Neurotoxicity - Rat

LOAEL = 2000 mg/kg/day based on increased motor activity in both sexes.

Acute Dietary

(Females 13-49 years of age)	NOAEL = 50 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Acute RfD = 

0.5 mg/kg/day

aPAD =

0.5 mg/kg/day	Developmental - Rabbit

LOAEL = 75 mg/kg/day based on cranial variations, abortion, and
increased pre- and post-implantation losses assumed to occur following a
single dose (developmental toxicity).

Chronic Dietary (All Populations)	NOAEL= 17.4 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Chronic RfD = 0.17 mg/kg/day

cPAD = 0.17 mg/kg/day	Carcinogenicity - Mouse

LOAEL of ~ 200 mg/kg/day based on decreased body weight gain and liver
toxicity.

[LOAEL=202/209.5 mkd for males/females]

Incidental Oral Short-Term (1-30 days)	NOAEL= 25 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Residential LOC for MOE = 100	Developmental - Rabbit

LOAEL = 50 mg/kg/day based on decreased body weight gain, reduced food
consumption, and mortality (maternal toxicity).

Incidental Oral Intermediate

-Term (1-6 months)	NOAEL= 17.4 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Residential LOC for MOE = 100	Carcinogenicity - Mouse

LOAEL of ~ 200 mg/kg/day based on decreased body weight gain and liver
toxicity.

Dermal 

Short- (1-30 days), Intermediate- (1-6 months), and Long-Term (>6
months)

	None	Dermal absorption is minimal (<2% of the total administered dose)
regardless of dose, and rats treated by dermal occlusion for 6-7
hours/day for 23 days at doses up to 1000 mg/kg/day (Limit-Dose) did not
exhibit any signs of systemic toxicity or dermal irritation, and no
treatment-related histopathological effects were noted.  Therefore,
quantification of dermal risk was not conducted. 

Inhalation Short- Term (1-30 days)	NOAEL= 25 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Residential LOC for MOE = 100	Developmental - Rabbit

LOAEL = 50 mg/kg/day based on decreased body weight gain, reduced food
consumption, and mortality (maternal toxicity).

Inhalation Intermediate-Term (1-6 months) and Long-Term (>6 months)
NOAEL= 17.4 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Residential LOC for MOE = 100	Carcinogenicity - Mouse

LOAEL of ~ 200 mg/kg/day based on decreased body weight gain and liver
toxicity.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies as per the CARC
report dated June 15, 2006, TXR No.: 005249.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  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).  FQPA SF = FQPA Safety Factor.  PAD = population
adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE =
margin of exposure.  LOC = level of concern.

Table 3.3.3.2.  Summary of Toxicological Doses and Endpoints for
Triticonazole for Use in Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal 

Short- (1-30 days), Intermediate- (1-6 months), and Long-Term (>6
months)

	None	Dermal absorption is minimal (<2% of the total administered dose)
regardless of dose, and rats treated by dermal occlusion for 6-7
hours/day for 23 days at doses up to 1000 mg/kg/day (Limit-Dose) did not
exhibit any signs of systemic toxicity or dermal irritation, and no
treatment-related histopathological effects were noted.  Therefore,
quantification of dermal risk was not conducted.

Inhalation Short- Term (1-30 days)	NOAEL= 25 mg/kg/day	UFA= 10x

UFH=10x	Occupational LOC for MOE = 100	Developmental - Rabbit

LOAEL = 50 mg/kg/day based on decreased body weight gain, reduced food
consumption, and mortality (maternal toxicity).

Inhalation Intermediate-Term (1-6 months) and Long-Term (>6 months)
NOAEL= 17.4 mg/kg/day	UFA= 10x

UFH=10x	Occupational LOC for MOE = 100	Carcinogenicity - Mouse

LOAEL of ~ 200 mg/kg/day based on decreased body weight gain and liver
toxicity.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies as per the CARC
report dated June 15, 2006, TXR No.: 005249.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  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).  MOE = margin of exposure.  LOC = level of concern.

3.4	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 (EDSP).

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

4.0	PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

References: 

Review of Triticonazole Incident Reports.  M. Hawkins, DP#325380,
9/19/2006.

There were no reports and/or cases related to triticonazole in the OPP
Incident Data System (IDS), Poison Control Centers data, California
Department of Pesticide Regulation data, the National Pesticide
Information Center (NPIC) data, and the National Institute of
Occupational Safety and Health’s Sentinel Event Notification System
for Occupational Risks (NIOSH SENSOR).  Furthermore, no scientific
literature was found concerning human poisoning or other adverse effects
from exposure to triticonazole.

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

References: 

Triticonazole:  HED Human Health Risk Assessment for Proposed Use on
Turf.  S. Winfield, DP#s316612 and 313844, 12/20/2006.

Triticonazole Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for a Section 3 Registration Action
for Seed Treatment of Cereals.  A. Acierto, DP#366041, 06/10/2009.

MARC Decision Memo.  N. Dodd and A. Assaad, TXR#0050233, 06/04/2001.

Tier II Drinking Water Assessment for the Triticonazole Proposed Section
3 Registration for Use on Crop Group 15 (Cereal Grains, Except Rice) and
Crop Group 16 (Forage Fodder and Hay of the Cereal Grains Group, Except
Rice).  C. Sutton, DP#313847, 10/11/2006.

The exposure pathways resulting from use of this chemical are dietary
(food and drinking water), residential, and occupational.  The residue
chemistry data submitted in support of the proposed use and increased
existing tolerances were summarized in the HED memorandum by A. Acierto
(DP#360624, 06/12/2009).  The acute and chronic dietary exposure
assessment was completed in a HED memorandum by A. Acierto (DP#366041,
06/10/2009).

Pesticide metabolism (in primary crops, rotational crops, and
livestock), associated analytical methodology), and environmental
degradation (metabolic profiles of major metabolites and degradates)
were previously assessed in a human health risk assessment (S. Winfield,
DP#316612, 12/20/2006).  See Appendix C for the chemical structure and
metabolic profile.

5.1	Drinking Water Residue Profile

Triticonazole and its transformation products are very persistent and
moderately mobile in terrestrial and aquatic environments.  These fate
properties suggest that it has a potential to move into surface water
and shallow ground water while undergoing slow degradation.

The EDWCs used in the dietary risk assessment were provided by EFED and
incorporated directly into the dietary assessment (C. Sutton, DP#358625,
03/24/2009).  The EDWCs used in the dietary assessment were modeled
using the surface water model PRZM-EXAMS.  For the acute point estimate,
the PRZM-EXAMS 1-in-10 yr annual maximum EDWC was used.  For the chronic
point estimate, the PRZM-EXAMS 1-in-10 year annual mean EDWC was used. 
PRZM-EXAMS EDWCs were used because they were higher (and therefore more
protective) than the groundwater model’s (SCI-GROW’s) EDWC.  The
modeled EDWCs are shown in Table 5.1.

Table 5.1.  Summary of Estimated Surface Water and Groundwater
Concentrations for Triticonazole.

	Surface Water Conc., ppb a	Ground Water Conc., ppb b

Acute (1-in-10-year annual concentration)	75.5	5.7

Chronic (non-cancer; 1-in-10-year avg. annual concentration)	32.8

	Chronic (cancer; 30-year avg. annual concentration)	21.4

	a From the Tier II PRZM-EXAMS - Index Reservoir model.  Based on the FL
turf scenario, using the application rate on the CHIPCO brand TRITON
label (resubmitted 9/22/06) of 1.15 lb ai/A, applied by ground equipment
3 times with 14-day inter-application intervals.

b From the SCI-GROW model assuming a maximum seasonal use rate of 1.15
lb ai/A, a Koc of 533 mL/g, and a half-life considered stable.

5.2	Metabolism in Primary Crops

The nature of the residue in plant commodities is considered adequately
understood only for the purpose of the proposed/registered seed
treatment uses on cereal grain-type crops.  Based on the barley and
wheat metabolism studies, triticonazole is metabolized primarily via
hydroxylation of the dimethylcyclopentane moiety to form a series of
dihydroxy metabolites which subsequently cleave to form numerous minor
polar metabolites.  The residue of concern for cereal grain commodities,
excluding rice commodities, for risk assessment and tolerance expression
is parent only.  Although hydroxylated metabolites were identified in
the plant metabolism studies, they were not included as residues of
concern because exposure to metabolites is not significant relative to
parent, and exposure is very low from the seed treatment uses.  No
triazole metabolites [1,2,4-triazole (T), triazolylalanine (TA), or
triazolylacetic acid (TAA)] were detected in barley or wheat grain.  

5.3	Metabolism in Livestock

The nature of the residue in livestock commodities is considered
adequately understood only for the purpose of the proposed/registered
seed treatment uses on cereal grain-type crops, based on marginally
adequate dairy cattle and laying hen studies with phenyl-labeled
triticonazole only.  HED has previously deemed that triticonazole is the
residue of concern in ruminants and poultry from seed treatment uses on
barley and wheat.  This determination may be extended to include seed
treatment uses for all crop commodities in the cereal grains crop group.
   

5.4	Analytical Methodology

The contribution of triazole derivatives [1,2,4-triazole,
triazolylalanine, and triazolylacetic acid] from the use of
triticonazole on barley and wheat to the aggregate exposure for human
health risk assessment was previously considered (M. Doherty, DP#322215,
02/07/2006).  The requested seed treatment uses of triticonazole do not
result in increases in dietary exposure estimates for free triazole or
conjugated triazoles.  Therefore, the last dietary exposure analyses for
the triazole metabolites have not changed.

Plant Commodity Methods

An adequate LC/MS and LC/MS/MS method (Method 148.02) is available for
the enforcement of the proposed tolerances for triticonazole in cereal
grain matrices.  A similar method, LC/MS/MS method (Method 562/0), was
used for data collection in the cereal grain field trial and processing
studies.  The method was adequate for data collection based on
acceptable method verification and concurrent method recoveries.  The
validated LOQ was 0.01 ppm for triticonazole in/on all cereal grain crop
matrices.  Analytical standards for triticonazole are currently
available in the EPA National Pesticide Standards Repository.

Livestock Commodity Methods

Livestock feeding studies, livestock tolerances, and livestock
enforcement methods are not required for the purpose of this petition. 
Based on the recommended tolerances for triticonazole residues in
livestock feedstuffs, the maximum reasonable dietary burdens (MRDB) for
livestock were calculated at 0.089 ppm for beef cattle, 0.346 ppm for
dairy cattle, 0.038 ppm for poultry, and 0.042 ppm for swine.  The
results of the reviewed cow and poultry metabolism studies along with
the low levels of residues found in the cereal grain field trials
indicate that there is no reasonable expectation that quantifiable
residues of triticonazole will occur in livestock commodities [40 CFR
§180.6(a)(3)].  HED will re-examine this determination if additional
uses on livestock feedstuffs are proposed in the future. 

Multiresidue Methods

The data requirements for testing with multiresidue methods have been
fulfilled.  Based on the results of the testing, the multiresidue
methods are not appropriate for determining triticonazole residues.

Storage Stability Methods

Adequate data are available supporting the stability of triticonazole
residues during frozen storage of samples collected from the cereal
grain crop field trials and processing studies.  Adequate storage
stability data are also available for the triazole-related metabolites
(T, TA, and TAA) to support the storage conditions and durations of
wheat, corn, sorghum, and rice grain samples from the field studies, and
wheat flour and polished rice from the processing study.  The adequacy
of the additional triazole storage stability data to support the storage
durations of cereal grain forages, fodders and/or straws, corn kernel
plus cob with husk removed (K+CWHR), and sorghum stalks from the cereal
grain field trial studies will be determined when the final results of
an ongoing triazole storage stability study are submitted to the Agency.
 According to current Agency policy, storage stability in the raw
agricultural commodity (RAC) can be translated to the processed
commodity.

5.5	Food Residue Profile

Primary Crops

The submitted magnitude of the residue data are adequate to support the
requested seed treatment uses for cereal grain crops (except rice). 
There are adequate data for the representative crops of the cereal grain
groups 15 and 16 to establish crop group tolerances.  The number and
locations of field trials were conducted according to the OPPTS 860.1500
guidelines.  The seed treatment rate (0.05 lb ai/100 lbs seed) used in
the field trials reflects the proposed use of  Triticonazole HL
Fungicide (EPA Reg. No. 7969-EIT) on barley, field corn and popcorn,
oats, rye, wheat, and triticale.  However, the rate reflects 5X and 2.5X
the proposed seed treatment rate for sweet corn and sorghum,
respectively.  

The registered uses of triticonazole as a seed treatment on cereal
grains, excluding rice, are expected to result in limited residues in
the food supply.  The field trial data indicate very low and/or
non-detectable residues on edible portions of cereal grains, excluding
rice.  Residues of triticonazole were below the LOQ of 0.01 ppm in
treated wheat grain, corn grain, corn K+CWHR, and sorghum grain.  Low
but quantifiable residues of triticonazole were observed in rice grain. 
The available data support a tolerance level of 0.01 ppm for cereal
grains, group 15 (except rice).  The value of 0.05 ppm proposed by the
petitioner is excessive, when rice is excluded.  Moreover, the 0.01 ppm
level harmonizes with Canada.  A revised Section F must be submitted to
reflect the tolerance recommendation of 0.01 ppm for cereal grains,
group 15 (except rice).  The individual tolerances established for
barley grain and wheat grain at 0.05 ppm in 40 CFR §180.583(a) should
be deleted when the crop group tolerance is established. 

Residues of triticonazole were also nonquantifiable in treated field and
sweet corn forage and stover, and sorghum forage and stover. 
Quantifiable residues of triticonazole were observed in treated wheat
forage, hay and straw, and rice straw.  Appropriate tolerance levels
were determined statistically according to Guidance for Setting
Pesticide Tolerances Based on Field Trial Data SOP.  The residue data
for rice straw was excluded from the spreadsheet because the petitioner
is not applying for use on rice.  The tolerance spreadsheet calculated
tolerances of 0.20 ppm for wheat forage, 0.25 ppm for wheat hay, and
0.20 ppm for wheat straw.  HED recommends a crop group tolerance of 0.25
ppm based on the highest calculated value for the representative crop
(wheat hay).  

A revised Section F must be submitted to reflect the tolerance
recommendation of 0.25 ppm for the forage, fodder, and straw of cereal
grains, group 16 (except rice).  The individual tolerances established
for barley hay and straw, and wheat forage, hay and straw in 40 CFR
§180.583(a) should be deleted when the crop group tolerance is
established. 

Processed Food and Feed

The processing data for field corn, rice, sweet sorghum, and wheat are
adequate.  The results indicate that residues of triticonazole were
nonquantifiable (<0.01 ppm) in the cereal grain RACs (corn, rice, wheat,
and sorghum) grown from seeds treated at 250 g triticonazole/100 kg seed
(5X the maximum proposed seed treatment rate).  Analysis of rice
processed matrices showed that residues of triticonazole may concentrate
in hulls (2.8X) but not significantly in bran (1.1X); residues in
polished rice were nonquantifiable.  As the petitioner is not seeking to
register use on rice at this time, no tolerances are required for rice
processed matrices.

Rotational Crops

The confined rotational crop study is acceptable.  The application rate
used in the study reflects 1.4X the equivalent per acre rate for cereal
grain crops.  The metabolism of triticonazole in rotated crops appears
similar to those observed for primary crops, except that
triazole-related metabolites were detected in the rotated crops.  The
data indicate that residues of triticonazole may be present at >0.01 ppm
in 30-DAT rotated lettuce (0.017 ppm), radish tops (0.049 ppm) and wheat
forage (0.041 ppm), straw (0.133 ppm) and chaff (0.139 ppm); 120-DAT
rotated radish tops (0.016 ppm), and wheat forage (0.019 ppm), straw
(0.150 ppm), and chaff (0.114 ppm); and 365-DAT rotated wheat forage
(0.025 ppm), straw (0.086 ppm) and chaff (0.133 ppm).  Wheat hay was not
analyzed but forage and straw were analyzed, and residues of
triticonazole were found in forage and straw.

The proposed label for the 4.17 lb/gal FS specifies that “planting of
any crop not listed on the label within 30 days after planting treated
seed is not allowed”.  The results of the submitted confined
rotational crop study do not support this restriction.  The data from
the confined rotational crop study indicate that triticonazole residues
greater than 0.01 ppm were detected at the 30-day PBI.  To support a
30-day plantback restriction on the label, limited field rotational crop
data for leafy vegetables, root and tuber vegetables, foliage of root
and tuber vegetables, and a cereal grain are required.  Until the
requested data are provided, the label must be modified to specify a
120-day (4-month) plantback restriction for leafy vegetables, a 365-day
(12-month) plantback restriction for root and tuber vegetables, and to
prohibit the planting of all other crops not listed on the label.

5.6	International Residue Limits

There are no established Codex or Mexican MRLs/tolerances on wheat or
barley.  In Canada, triticonazole is registered as a seed treatment for
oats, barley, and wheat, and established with the following MRLs
(expressed as parent only):

Eggs ………………………………..…….	0.05 ppm

Meat and meat byproducts of cattle, goats, hogs, horses, poultry, and
sheep …………	0.05 ppm

Barley ……………………………………	0.01 ppm

Milk  ..……………………………………	0.01 ppm

Oats ………………………………………	0.01 ppm

Wheat ……………………………………	0.01 ppm

The Canadian MRL levels at 0.01 ppm on barley, oats, and wheat harmonize
with the recommended U.S. 0.01 ppm tolerance level.  Additionally, no
U.S. tolerances have been established on livestock commodities.  No
harmonization issues exist in connection with the proposed use on turf. 
See Appendix B for the International Residue Limit Status (IRLS).

5.7	Dietary Exposure and Risk

™ (Version 2.03), incorporating food consumption data from USDA’s
CSFII from 1994-1996 and 1998.  For both acute and chronic dietary
exposure assessments, only the expansion of cereal grain crop group 15
was considered because cereal grain crop group 16 consists of livestock
feed items which do not contribute to the human diet.

Acute Dietary Exposure/Risk

™ into the food categories “water, direct, all sources” and
“water, indirect, all sources.”

The acute dietary (food and drinking water) exposure assessment for
females 13-49 years was performed separately, since the acute
toxicological endpoint of concern was different from that identified for
the general U.S. population.  The most highly exposed population
subgroup is females 13-49 years old.  Combined acute dietary exposure
from food and drinking water is less than 1% of the aPAD for females
13-49 years old.  For the general U.S. population and for all infants <1
year old, the exposure is also less than 1% of the aPAD.  The results of
the acute dietary exposure analyses are reported in Table 5.7, and all
exposures are below the LOC.

With all included commodities from the expanded use of cereal grains
(crop group 15), risk estimates have not increased.  Thus, for all
registered and proposed uses, the acute dietary risk estimates do not
exceed HED’s LOC (i.e., <100% aPAD).

Chronic Dietary Exposure/Risk

The chronic analyses assumed that triticonazole residues are present in
all registered and proposed food commodities at tolerance levels and
that 100% of all commodities are treated.  All processing factors were
set to 1, based on the results of processing studies indicating that
residues of triticonazole in processed commodities would not exceed the
raw agricultural commodity RAC tolerances.  Drinking water residues were
incorporated directly into the dietary assessment using the EDWCs for
triticonazole in surface water, generated using the PRISM/EXAMS models. 
For the chronic assessment, the 1-in-10 annual mean concentration of
32.8 ppb was used.  The water residues were incorporated in the
DEEM-FCID into the food categories “water, direct, all sources” and
“water, indirect, all sources.”

With the increased dietary exposure from the expanded use of cereal
grains (crop group 15), the chronic dietary risk estimates have not
increased.  Currently, for all included commodities for all registered
and proposed uses, the chronic dietary risk estimates do not exceed
HED’s LOC (i.e., <100% cPAD).  For the general U.S. population the
exposure from food and drinking water utilized is still less than 1% of
the cPAD.  The most highly exposed population subgroup at 1.4% of the
cPAD was all infants (<1 year old) and all other population subgroups
are at less than 1% of the cPAD.  The results of the chronic dietary
exposure analyses are also reported in Table 5.7, and again, all
exposures are below the LOC.

Table 5.7.  Result of Acute and Chronic Dietary Exposure and Risk
Estimates for Triticonazole.

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary

	Dietary Exposure (mg/kg/day)	% aPAD*	Dietary Exposure

(mg/kg/day)	% cPAD*

General U.S. Population	0.004192	<1.0	0.000865	<1.0

All Infants (< 1 year old)	0.015052	<1.0  (0.38)	0.002431	1.4

Children 1-2 years old	0.006674	<1.0	0.001422	<1.0

Children 3-5 years old	0.006171	<1.0	0.001376	<1.0

Children 6-12 years old	0.004301	<1.0	0.000959	<1.0

Youth 13-19 years old	0.003414	<1.0	0.000694	<1.0

Adults 20-49 years old	0.003806	<1.0	0.000787	<1.0

Adults 50+ years old	0.003426	<1.0	0.000781	<1.0

Females 13-49 years old*	0.003813	<1.0  (0.76)	0.000777	<1.0

* The acute endpoint for females 13-49 years old is different than the
acute endpoint for all other subpopulations, which is why females 13-49
have a lower dietary exposure estimate than all infants, but a higher
risk estimate.

Note: The bolded values indicate the population with the highest risk
estimate for each type of risk assessment

All dietary (food with modeled EDWCs) risk estimates were below the LOC.
 The assessments can be considered highly conservative as they assume
all the subject crops are treated and bear residues at the tolerance
level (compounded by the conservative tolerance).  Actual dietary
exposure is likely to be much lower.

Cancer Dietary Risk

There is no evidence that triticonazole is carcinogenic to humans;
therefore, a dietary cancer assessment is not required. 

				

6.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

There is potential for exposure to homeowners in residential settings
during the application of existing registered products containing
triticonazole, and from entering areas previously treated with
triticonazole, such as lawns where children might play, or golf courses
and home gardens that could lead to exposures for adults.  As a result,
risk assessments were previously completed for both residential handler
and postapplication scenarios (S. Winfield, DP#316612, 12/20/2006).  The
proposed uses of triticonazole on cereal grain crop groups (15 and 16)
do not add any additional residential exposures or risks.  Spray drift
is not expected to pose a risk to residents as seed treatment does not
result in spray applications.  Residential postapplication has also been
previously assessed and is not of concern with the currently proposed
action.  For aggregate calculations, Table 6.0 presents the exposure and
risk estimates calculated in the previous memo for children’s
incidental oral postapplication scenarios (S. Winfield, DP#316612,
12/20/2006).

	Table 6.0.  Children’s Total Exposure and Risk Estimates from
Residential Lawns.

Children’s Scenarios	

TTR/GR/SR0 (ug/cm2 or g) 1	

PDR0-norm

(mg/kg/day) 2	

Short-Term MOE 3	Int-Term

 MOE 3	

Total MOE 4

	Short- Term	Intermediate-Term

(1) Hand-to-Mouth	0.64	0.017	1,500	1,000	1,200	800

(2) Mouthing Grass	2.6	0.0043	5,800	4,100

(3) Soil Ingestion	8.6	0.000058	430,000	300,000

1 TTR=turf transferable residue on day “0”; GR=grass residue on day
“0”; SR0=soil residue on day “0”.

2 PDR0norm=potential dose rate on day “0”.

3 MOE = NOAEL/PDR; where Short- and Intermediate-term NOAELs = 25
mg/kg/day and 17.4 mg/kg/day, respectively.

4 Total MOE = S-T or I-T NOAEL/total incidental oral exposure
(hand-to-mouth + mouthing grass + soil ingestion = 0.021358 mg/kg/day)

7.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, HED must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.

The aggregate assessments in this document use a deterministic approach,
in that point estimates of exposure from each source are added together;
and each of the point estimates used are deterministic (dietary exposure
estimates use point estimates for food and drinking water residues
[tolerance level and modeled values, respectively] and the residential
SOP scenarios also employ point estimates [central to high-end values
considered protective]).  Exposures are assumed to occur over the same
time frame, and no use frequency data are considered.  In sum, these
aggregate risk assessments are screening-level assessments.

7.1	Acute Aggregate Risk

Refer to Section 5.7, which discusses dietary exposure (food and
drinking water).  The dietary route alone is relevant for acute exposure
and risk assessment.

7.2	Short-Term and Intermediate-Term Aggregate Risk

Short-term aggregate exposures are compared to the oral NOAEL of 25
mg/kg/day (based on decreased body weight gain and food consumption at
the LOAEL of 50 mg/kg/day in the rabbit developmental study) to estimate
the risk from short-term exposure.  Intermediate-term exposures are
compared to the NOAEL of 17.4 mg/kg/day (based on decreased body weight
and liver toxicity at the LOAEL of ~ 200 mg/kg/day in the mouse
carcinogenicity study) to estimate the risk from intermediate-term
exposure.  The LOC for non-occupational aggregate risk is expressed as
an MOE = 100. 

Over the short-term (1 to 30 days), both dietary and residential
postapplication incidental oral exposure may co-occur (exposures and
risks are shown in Table 7.2.1).  The short-term aggregate MOEs do not
exceed the LOC and, therefore, are not of concern.

Table 7.2.1.  Short-Term Aggregate Risk Calculations (Incidental oral
exposure with background dietary exposure).

Population	NOAEL

mg/kg/day	LOC1	Max Allowable

Exposure2

mg/kg/day	Average

Food & Water

Exposure

mg/kg/day	Residential Exposure3

mg/kg/day	Aggregate Exposure (dietary and residential)

mg/kg/day	Aggregate MOE

(food and

residential)4

Children 1-2	25	100	0.25	0.0014	0.021	0.022	1100

All Infants   

(< 1 year old)5	25	100	0.25	0.0024	0.021	0.023	1100

1 The LOC is based on standard inter- and intra- species uncertainty
factors (10x and 10x, for a total of 100).

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = Incidental Oral exposure (postapplication
inhalation exposure is not expected, and there is no hazard via the
dermal route). See S. Winfield, DP#316612, 12/20/2006 for source of
residential exposure values.

4 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential
Exposure)]

5 Highest exposed child subpopulation.  Although the incidental oral
exposure estimates are calculated with the activities of children 1-3 in
mind (toddlers), the dietary exposure for the highest exposed child
subpopulation is also aggregated with the incidental oral exposure
estimate for comparison and characterization purposes.

Although less likely over the intermediate-term (1 to 6 months), both
dietary and residential postapplication incidental oral exposure may
co-occur (exposures and risks are shown in Table 7.2.2).  The
intermediate-term aggregate MOEs do not exceed the LOC and, therefore,
are not of concern.

Table 7.2.2.  Intermediate-Term Aggregate Risk Calculations (Incidental
oral exposure with background dietary exposure)

Population	NOAEL

mg/kg/day	LOC1	Max Allowable

Exposure2

mg/kg/day	Average

Food & Water

Exposure

mg/kg/day	Residential Exposure3

mg/kg/day	Aggregate Exposure (dietary and residential)

mg/kg/day	Aggregate MOE

(food and

residential)4

Children 1-2	17.4	100	0.174	0.0014	0.021	0.022	780

All Infants   

(< 1 year old)5	17.4	100	0.174	0.0024	0.021	0.023	740

1The LOC is based on standard inter- and intra- species uncertainty
factors (10x and 10x, for a total of 100)

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = Incidental Oral exposure (postapplication
inhalation exposure is not expected, and there is no hazard via the
dermal route). See S. Winfield, DP#316612, 12/20/2006 for source of
residential exposure values.

4 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential
Exposure)]

5 Highest exposed child subpopulation.  Although the incidental oral
exposure estimates are calculated with the activities of children 1-3 in
mind (toddlers), the dietary exposure for the highest exposed child
subpopulation is also aggregated with the incidental oral exposure
estimate for comparison and characterization purposes.

7.3	Long-Term Chronic Aggregate Risk

Refer to Section 5.7, which discusses dietary exposure (food and
drinking water).  The dietary route alone is relevant for
long-term/chronic exposure and risk assessment.

7.5	Cancer Aggregate Risk

Triticonazole is classified as “not likely to be carcinogenic to
humans” based on the absence of significant tumor increases in two
adequate rodent carcinogenicity studies (J. Kidwell, TXR#0054249,
06/15/2006).  Thus, no aggregate cancer risk needs to be assessed.

8.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

Triticonazole 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.   In conazoles, however, a variable pattern of
toxicological responses is found.   Some are hepatotoxic and
hepatocarcinogenic in mice; some induce thyroid tumors in rats; and 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.

Triticonazole and other triazole-containing pesticides can form the
common metabolite 1,2,4-triazole and two triazole conjugates
(triazolylalanine and triazolylacetic acid).  To support existing
tolerances and to establish new tolerances for triazole-derivative
pesticides, including triticonazole, U.S. EPA conducted a human health
risk assessment for exposure to 1,2,4-triazole, triazolylalanine, and
triazolylacetic acid 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 safety factor
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 EXPOSURE/RISK PATHWAY

  SEQ CHAPTER \h \r 1 Based upon the proposed use on seeds, occupational
handler exposure is expected for individuals involved in commercial seed
treatment and on-farm planting.  Postapplication exposure to
agricultural workers is possible if they perform tasks that involve the
soil subsurface following planting of treated seeds. 

9.1	Short-/Intermediate -Term Handler Risk

Occupational handlers may experience short- and intermediate-term
exposure to triticonazole while performing seed treatment activities in
commercial settings.  In addition, occupational secondary handlers may
experience short- and intermediate-term exposure while planting
triticonazole -treated seeds.  No chemical-specific handler exposure
data were submitted in support of this use pattern.  For assessing
commercial seed treatment and seed planting activities, unit exposure
data were taken from HED ExpoSAC Policy 14: SOPs for Seed Treatment. 
The amount of ai handled depends on the application rate (lb ai/100 lb
seed) and the pounds of seed treated in a day (or the pounds of seed
that can be planted in a day), all of which vary depending upon the seed
type.  Values for the amount of seed treated and planted per day were
obtained from HED SOP#15.  The results are presented in Table 9.1.

For all cereal seeds, potential occupational exposure scenarios from the
use of triticonazole as a commercial seed treatment include: mixing,
loading, applying liquid formulations; bagging treated seed; sewing
bags; multiple activities; and planting treated seed (secondary
handler).

Typically for large-scale commercial seed treatments, workers only
perform the specific individual tasks listed above; however, it is
assumed that workers may also perform multiple activities throughout the
day.  As a result a “multiple activities” scenario (i.e., where one
worker performs all seed treatment tasks such as   SEQ CHAPTER \h \r 1
loading/applying, sewing, bagging, cleaning, calibrating, repairing,
forklift driving, etc.) will be addressed.  Planting treated seed
consists of the farmer purchasing bags of treated seed, placing the seed
in the hopper, and applying seed to fields.  This is considered a
secondary handler exposure scenario.

HED is currently in the process of revising ExpoSAC SOP#15 (Amount of
Seed Treated or Planted per Day, 03/02/2004) in efforts to update the
daily amount of seed treated in commercial seed treatment facilities. 
With the increasing demand for hybridized treated seeds, there have been
modifications not only in the seed treatment equipment, but in the
market shares of new and currently registered pesticide products.  HED
understands that due to high cost to produce hybrid seeds, direct
seeding is done in a precise manner which requires lower volumes of seed
per acre.  However, this does not provide a direct correlation to the
amount of seed which is treated in the commercial seed treatment
facilities.  The amount of seed treated per day at a commercial facility
is summarized below for each crop.   

Barley – 718,000 lbs,

Field Corn and Popcorn – 550,000 lbs,

Oats– 718,000 lbs,

Rye – 718,000 lbs,

Sorghum Grain – 718,000 lbs, 

Sweet Corn – 194,000 lbs,

Triticale – 718,000 lbs, and

Wheat – 718,000 lbs.

Based on SOP#15, the amount of seed planted per day is summarized below
for each crop.

Barley – 19,000 lbs (96 lb seed/A * 200 A/day),

Field Corn and Popcorn – 3,000 lbs (15 lb seed/A * 200 A/day),

Oats – 26,000 lbs (128 lb seed/A * 200 A/day),

Rye – 22,000 lbs (112 lb seed/A * 200 A/day),

Sorghum Grain – 800 lbs (10 lb seed/A * 200 A/day) ,

Sweet Corn – 3,000 lbs (15 lb seed/A * 200 A/day),

Triticale – 20,000 lbs (100 lb seed/A * 200 A/day), and

Wheat – 30,000 lbs (150 lb seed/A * 200 A/day).

A summary of the inhalation risks for each exposure scenario is
presented below in Table 9.1 for short-term and intermediate-term
inhalation exposures.  

The results of the short- and intermediate-term occupational handler
exposure and risk assessment indicate that inhalation risks do not
exceed HED’s LOC (i.e., MOEs range from 2,200 to 3,200,000 which are
greater than the LOC of 100) at baseline level of risk mitigation (i.e.,
no respirator) for any of the cereal seed treatment scenarios.

Table 9.1. Short- and Intermediate-Term Triticonazole Handler Inhalation
Exposures and Risks.

Crop	Exposure Scenario	lbs seed treated or planted/ daya	Application
Rateb

(lb ai/lb seed)	Baseline Inhal. Unit Exposurec,d

(µg/lb ai)	Baseline Inhalation Dosee (mg/kg/day)	Baseline Inhalation
MOEf

(Target MOE = 100)

Short-Term	Intermediate-Term

Barley	Loader/Applicator	718,000	0.00049	0.34	1.7E-03	15,000	10,000

	Sewer	718,000	0.00049	0.23	1.2E-03	22,000	15,000

	Bagger	718,000	0.00049	0.16	8.0E-04	31,000	22,000

	Multiple Activities	718,000	0.00049	1.6	8.0E-03	3,100	2,200

	Planter (Secondary Handler)	19,000	0.00049	3.4	4.5E-04	55,000	38,000

Corn (field & popcorn)	Loader/Applicator	550,000	0.00049	0.34	1.3E-03
19,000	13,000

	Sewer	550,000	0.00049	0.23	8.9E-04	28,000	20,000

	Bagger	550,000	0.00049	0.16	6.2E-04	41,000	28,000

	Multiple Activities	550,000	0.00049	1.6	6.2E-03	4,100	2,800

	Planter 

(Secondary Handler)	3,000	0.00049	3.4	7.1E-05	350,000	240,000

Corn (sweet)	Loader/Applicator	194,000	0.0001	0.34	9.4E-05	270,000
180,000

	Sewer	194,000	0.0001	0.23	6.4E-05	390,000	270,000

	Bagger	194,000	0.0001	0.16	4.4E-05	560,000	390,000

	Multiple Activities	194,000	0.0001	1.6	4.4E-04	56,000	39,000

	Planter 

(Secondary Handler)	3,000	0.0001	3.4	1.5E-05	1,700,000	1,200,000

Oats	Loader/Applicator	718,000	0.00049	0.34	1.7E-03	15,000	10,000

	Sewer	718,000	0.00049	0.23	1.2E-03	22,000	15,000

	Bagger	718,000	0.00049	0.16	8.0E-04	31,000	22,000

	Multiple Activities	718,000	0.00049	1.6	8.0E-03	3,100	2,200

	Planter 

(Secondary Handler)	26,000	0.00049	3.4	6.2E-04	40,000	28,000

Rye	Loader/Applicator	718,000	0.00049	0.34	1.7E-03	15,000	10,000

	Sewer	718,000	0.00049	0.23	1.2E-03	22,000	15,000

	Bagger	718,000	0.00049	0.16	8.0E-04	31,000	22,000

	Multiple Activities	718,000	0.00049	1.6	8.0E-03	3,100	2,200

	Planter 

(Secondary Handler)	22,000	0.00049	3.4	5.2E-04	48,000	33,000

Sorghum Grain	Loader/Applicator	718,000	0.0002	0.34	7.0E-04	36,000
25,000

	Sewer	718,000	0.0002	0.23	4.7E-04	53,000	37,000

	Bagger	718,000	0.0002	0.16	3.3E-04	76,000	53,000

	Multiple Activities	718,000	0.0002	1.6	3.3E-03	7,600	5,300

	Planter 

(Secondary Handler)	800	0.0002	3.4	7.8E-06	3,200,000	2,200,000

Triticale	Loader/Applicator	718,000	0.00049	0.34	1.7E-03	15,000	10,000

	Sewer	718,000	0.00049	0.23	1.2E-03	22,000	15,000

	Bagger	718,000	0.00049	0.16	8.0E-04	31,000	22,000

	Multiple Activities	718,000	0.00049	1.6	8.0E-03	3,100	2,200

	Planter 

(Secondary Handler)	20,000	0.00049	3.4	4.8E-04	53,000	37,000

Wheat	Loader/Applicator	718,000	0.00049	0.34	1.7E-03	15,000	10,000

	Sewer	718,000	0.00049	0.23	1.2E-03	22,000	15,000

	Bagger	718,000	0.00049	0.16	8.0E-04	31,000	22,000

	Multiple Activities	718,000	0.00049	1.6	8.0E-03	3,100	2,200

	Planter 

(Secondary Handler)	30,000	0.00049	3.4	7.1E-04	35,000	24,000

a. HED default for lb seed treated per day from HED Science Advisory
Council for Exposure Policy # 15.   

b. Application Rates based on proposed uses on label for Triticonazole
HL Fungicide.

c. Unit Exposures from HED Science Advisory Council for Exposure Policy
#14.  

d. Baseline Inhalation: No respirator

e. Inhalation Dose (mg/kg/day) = daily unit exposure (μg/lb ai)  x
application rate (lb ai/lb seed) x amount treated or planted (lb
seed/day) x conversion factor (1 mg/1,000 μg) x absorption factor (100
%) / body weight (70 kg adult).

f. Inhalation MOE = NOAEL (25 mg/kg/day for short-term exposure and 17.4
mg/kg/day for intermediate-term exposure) / inhalation daily dose
(mg/kg/day). Level of concern = 100.

9.2	Short-/Intermediate-Term Postapplication Risk

There is the potential for postapplication exposures following the
planting of triticonazole-treated seeds.  Sustained levels of contact
with treated seed after it has been placed in the soil or other planting
media would not be expected because no routine cultural practice
required for the production of agricultural commodities involves such an
activity as defined in the no/low contact criteria in the Worker
Protection Standard (WPS).  Therefore, no quantitative postapplication
assessment is required for exposure to treated seeds that have already
been planted.

The restricted entry interval (REI) is based on the acute toxicity of
triticonazole technical material.  The WPS allows workers to enter
treated areas without restriction if there will be no worker contact
with the treated seeds in the soil or planting media.  Certain tasks,
even though they are not routine, may involve contact with the soil
subsurface (e.g. repair of certain irrigation equipment) and they are
covered by the REI.  HED recommends that the Registration Division
ensure that appropriate language is placed on the product label to
require the label on treated seed to include the REI following the
planting of treated seed.

Triticonazole technical material which is classified as Category III for
acute dermal toxicity and Toxicity Category IV for primary eye
irritation and primary skin irritation.  Triticonazole is not a dermal
sensitizer.  Under the WPS for Agricultural Pesticides, the default REI
is 12 hours for active ingredients classified as acute toxicity
categories III or IV for these routes of entry.  WPS allows workers to
enter treated areas without restriction if there will be no contact with
anything that has been treated with the pesticide.  

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

10.1	Toxicology

The following deficiencies should be made conditions of the registration
of triticonazole for use on cereal grains:

A biliary excretion study.  The metabolism study in the rat is
classified Unacceptable/Guideline and does not satisfy the guideline
requirement for a metabolism study [OPPTS 870.7485, OECD 417] because
the extent of absorption of the test material was not determined.  It is
upgradeable to Acceptable/Guideline if the registrant conducts a biliary
excretion study with the test compound (compound water solubility is too
low for intravenous administration).  The registrant has submitted this
study and the study is currently in review by HED.  These study results
will not affect FQPA determinations.

An Immunotoxicity Study [OPPTS 870.7800, OECD 407] is currently
required.  This guideline is required to provide information on
suppression of the immune system which might occur as a result of
repeated exposure to triticonazole, after dosing by either oral or
parental routes. Results are intended to be used along with data from
routine toxicity testing, to provide more accurate information on risk
to the immune system.

10.2	Residue Chemistry

860.1200 Directions for Use

	

The label for Triticonazole HL Fungicide must be amended to include the
following rotational crop restrictions:  a 120-day plantback interval
for leafy vegetables, a 365-day plantback interval root and tuber
vegetables, and a prohibition of the planting of all other crops not
listed on the label.

860.1550 Proposed Tolerances

A revised Section F must be submitted to reflect the tolerance
recommendation of 0.01 ppm for cereal grains, group 15 (except rice); to
reflect the tolerance recommendation of 0.25 ppm for grain, cereal,
forage, fodder, and straw, group 16 (except rice); and to reflect the
correct commodity definitions as listed in the introduction.

(DATA Requirement)

HED recommends conversion of conditional registration to unconditional
registration for the cereal grains (except rice) upon adequate
resolution of data pertaining to storage stability and field
accumulation in rotational crops.

860.1380 Storage Stability

To support the reported results for 1,2,4-triazole and the triazole
conjugates, the final report of the ongoing storage stability study with
free triazole and triazole conjugates in plant commodities must be
submitted.

860.1900 Field Accumulation in Rotational Crops

Data from limited field accumulation studies on rotational crops are
required. 

10.3	Occupational and Residential Exposure

The labeling should state:  Seed that has been treated with this product
that is then packaged or bagged for future use must contain the
following labeling on the outside of the seed package or bag:

"Treated Seed - Do Not Use for Food, Feed, or Oil Purposes.”

When opening this bag or loading/pouring the treated seed, wear
long-sleeved shirt, long pants, shoes, socks, and chemical resistant
gloves.

After the seeds have been planted, do not enter or allow worker entry
into treated areas during the restricted-entry interval (REI) of 12
hours. Exception: Once the seeds are planted in soil or other planting
media, the Worker Protection Standard allows workers to enter the
treated area without restriction if there will be no worker contact with
the treated seeds in the soil or planting media." 

Appendix A:  TOXICOLOGY ASSESSMENT

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.340) for food and non food for
triticonazole are in the table below. Use of the new guideline numbers
does not imply that the new (1998) guideline protocols were used.

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

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5265    Mutagenicity—Gene Mutation 	

870.5300    Mutagenicity—Cytogenics 	

870.5375    Mutagenicity—Chromosome Aberration 	

870.5395    Mutagenicity—Micronucleus 		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

yes

yes

no	-

-

yes

yes

-

870.7485    General Metabolism	

870.7600    Dermal Penetration	

870.7800    Immunotoxicity		yes

yes 

yes	yes

yes 

no

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		       

no

no

no	

-

-

-

A.2	Acute Toxicity

Table A.2.  Acute Toxicity of Technical Grade Triticonazole.

Guideline No.	Study Type	MRID No.	Results	Toxicity Category

870.1100	Acute Oral Toxicity	44802028

44802029	LD50 = > 2000 mg/kg

LD50 = > 2000 mg/kg	III

870.1200	Acute Dermal Toxicity	44802030	LD50 = > 2000 mg/kg	III

870.1300	Acute Inhalation Toxicity	44802031	LC50 = > 2.63 mg/L	IV

870.2400	Acute Eye Irritation	44802032	Minimally irritating	IV

870.2500	Acute Dermal Irritation	44802033	Not an irritant	IV

870.2600	Dermal Sensitization	46817301	Not a sensitizer in the Buehler
test in guinea pigs	N/A

A.3	Toxicity Profile

Table A.3.  Toxicity Profile of Triticonazole Technical.

Guideline No.	

Study Type 

(All Studies Acceptable)	

Results

870.3100	

90-Day oral toxicity rodents- rat	

NOAEL = M: 2, F: 22.3 mg/kg/day

LOAEL = M: 19.8, F: 1183.5 mg/kg/day based on 

M:  Increases in the incidence of adrenocortical fatty vacuolation in
males receiving (250-ppm (19.8 mg/kg/day).  See also 870.6200 and
870.4200 – adrenal vacuolation not seen at low doses.

F:  Hair loss, decreased food efficiencies, adrenocortical fatty
vacuolation, zona reticularis degeneration, centriacinar hepatocytic
fatty vacuolation, and more severe anisocytosis and spherocytosis in
females receiving (12,500 ppm.

M and F:  decreases in hematocrit, hemoglobin, and red blood cells
(RBC), and decreased thymus weights, were noted at the high-dose. 

870.3150	

90-Day oral toxicity in nonrodents- dog	

Study not available.  Refer to 870.4100b below. 

870.3200	

28-Day dermal toxicity- rat	

NOAEL = Dermal and systemic: 1000 mg/kg/day (limit-dose).

LOAELs > 1000 mg/kg/day.

870.3250	

90-Day dermal toxicity	

Study not available.  

870.3465	

90-Day inhalation toxicity	

Request for a waiver granted as per memo from A. Assad dated April 12,
2006 (TXR # 0054207).  

870.3700a	

Prenatal developmental in rodents- rat	

Maternal NOAEL = 200 mg/kg/day

LOAEL = 1000 mg/kg/day based on reduction in mean body weight gain from
GD 12-16.

Developmental NOAEL = 200 mg/kg/day

LOAEL = 1000 mg/kg/day based on increases in unilateral and bilateral
supernumerary ribs.

870.3700b	

Prenatal developmental in nonrodents- rabbit	

Maternal NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on decreased body weight gain, reduced food
consumption, and mortality.

Developmental NOAEL = 50 mg/kg/day

LOAEL = 75 mg/kg/day based on cranial variations, abortion, and
increased pre- and post-implantation losses.

870.3800	

Reproduction and fertility effects- rat	

Parental/Systemic NOAEL = 37.5 mg/kg/day

LOAEL = 250 mg/kg/day based on reduced body weights of the F0 females
and the F1 males and females, F0 maternal mortality, and microscopic
lesions in the adrenal gland of F0 and F1 males and females.

Reproductive NOAEL = 37.5 mg/kg/day

LOAEL = 250 mg/kg/day based on decreased fertility of the F1 animals,
reduced F1 and F2 pup survival, and reduced F1 and F2 pup body weight. 

870.4100b	

Chronic toxicity dogs	

NOAEL = 25 mg/kg/day

LOAEL = 150 mg/kg/day based on decreased absolute body weights of
females, decreased weight gain by males and females, and
treatment-related toxicity to the eye, liver, adrenals, and transient
neurological signs (tremors, hyperactivity or hypoactivity, convulsions,
and ataxia)

870.4300	

Carcinogenicity

Rats	

NOAEL = M: (203.6, F: 38.3 mg/kg/day

LOAEL = M - Not established.  F: 286.6 mg/kg/day based on decreased
body weight and body weight gain, adrenal cortical and liver toxicity.

No evidence of compound-induced carcinogenicity as per CARC report June
15, 2006).

870.4200b	

Carcinogenicity mice	

NOAEL = M: 17.4; F: 20.1 mg/kg/day.

LOAEL = M: 202.2, F: 209.5 mg/kg/day based on decreased body weight gain
and liver toxicity. No significant increase in the incidence of
neoplastic lesions.

No evidence of compound-induced carcinogenicity as per CARC report June
15, 2006.

870.5265	

Gene Mutation	

There was no evidence of induced mutant colonies over background.

870.5300	

Cytogenetics	

There was no consistent evidence of chromosomal aberrations induced over
background.

870.5375	

Chromosome aberration	

There was no significant increase in the frequency of micronucleated
polychromatic erythrocytes in bone marrow after any tested triticonazole
dose at any harvest time. 

870.5395 	

Micronucleus	

There was no evidence that unscheduled DNA synthesis, as determined by
radioactive tracer procedures [nuclear silver grain counts] was induced.

870.6200a	

Acute neurotoxicity screening battery- rat	

NOAEL = 400 mg/kg/day

LOAEL = 2000 mg/kg/day (limit-dose) based on increases in motor activity
in both sexes.

870.6200b	

Subchronic neurotoxicity screening battery-rat	

NOAEL = M: 695; F 820 mg/kg/day (Highest doses tested). 

LOAEL > 695mg/kg/day.

870.6300	

Developmental

Neurotoxicity	

Request for a waiver was granted (Triticonazole (PC Code 125620)
Developmental Neurotoxicity Study Waiver Request.  S. Dapson,
TXR#0053424, 11/13/2006).

870.7485	

Metabolism and pharmacokinetics - rat	This metabolism study in the rat
is classified Unacceptable/Guideline and does not satisfy the guideline
requirement for a metabolism study [OPPTS 870.7485, OECD 417] because
the extent of absorption of the test material was not determined.  It is
upgradeable to Acceptable/Guideline if the registrant conducts a biliary
excretion study or provides data that will help determine the extent of
absorption.  

870.7600	

Dermal penetration – rat	

Dermal Absorption Factor [C14]: 2 %.

Appendix B:  INTERNATIONAL RESIDUE LIMIT STATUS

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:  (1RS)-(E)-5-[4-chlorophenyl)

methylene]-2,2-dimethyl-1-(1H-1,2,4-triazol-1ylmethyl)cyclopentanol
Common Name:

Triticonazole

	X Proposed tolerance

□ Reevaluated tolerance

□ Other	Date:  02/2009

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

X No Codex proposal step 6 or above

□ No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#8F7420

DP#360624

□  No Limits

□ No Limits for the crops requested	X No Limits

□ No Limits for the crops requested

Residue definition: 
5-[(4-chlorophenyl)methylene]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethy
l)cyclopentanol

	Residue definition:  N/A

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

Barley	0.01

Wheat	0.01

Oats	0.01

Notes/Special Instructions: S.Funk, 02/19/2009.

Appendix C:  METABOLISM ASSESSMENT

Table C.  Major Metabolites and Degradates

Common Name (codes)

Chemical Name	Structure	Matrices

Triticonazole

(RPA 400727)

(1RS)-(E)-5-[(4-chlorophenyl)methylene]-2,2-dimethyl-1-(1H-1,2,4-triazol
-1-ylmethyl)cyclopentanol

(1RS)-(E)-2-(4-chlorobenzylidene)-5,5-dimethyl-1-(1H-1,2,4-triazol-1-ylm
ethyl)cyclopentan-1-ol	

	

Primary crops: wheat and barley (up to 93% TRR)

Rotational crops: lettuce, radish, and wheat

Livestock commodities: cow liver (<10% TRR) and kidney (11% TRR),
poultry liver (11% TRR), eggs (30% TRR), and peritoneal fat (<10% TRR)

Rat feces: up to 74% of applied dose

RPA 406341

(E)-2-(4-chlorobenzylidene)-trans-1,3-dihydroxy-5,5-dimethyl-1-(1H-1,2,4
-triazol-1-yl methyl)-cyclopentane 

RPA 404766

(Z)-2-(4-chlorobenzylidene)-5,5-dimethyl-1-(1H-1,2,4-triazol-1-yl
methyl)-1,3-cyclopentanediol 	

 	

Primary crops: wheat and barley (up to 12-25% TRR, 37% TRR total)

Rotational crops: lettuce and wheat

Livestock commodities: poultry eggs (<10% TRR 404766, 16% 406341) and
peritoneal fat (<10% TRR 406341); and cow liver (<10% TRR, both) and
kidney (<10% TRR, both)

Rat urine: 404766 identified at levels too low to be detected by
radio-HPLC, 406341 possibly identified

Fate and effects: identified in soil photolysis, aerobic soil and
anaerobic soil studies

RPA 406780

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methyl)-cyclopentane 	

 	

Primary crops: wheat and barley (<10% TRR)

Livestock commodities: eggs (<10% TRR) and cow liver (30.8% TRR)

Rat urine: identified at levels too low to be detected by radio-HPLC

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RPA 404886

(E)-2-(4-chlorobenzylidene)-5-methyl-5-hydroxymethyl-1-(1H-1,2,4-triazol
-1-ylmethyl)-1-cyclopentanol			

 	

Primary crops: wheat and barley (up to 25% TRR)

Rotational crops: wheat

Livestock commodities: cow liver (<10% TRR) and kidney (67.8% TRR); and
poultry liver (12% TRR), eggs (16% TRR) and peritoneal fat (<10% TRR)

Rat urine: identified at levels too low to be detected by radio-HPLC
(and RPA 405826)

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Fate and effects: identified in aerobic and anaerobic (and RPA 405826)
soil studies 

RPA 406203

z-isomer of parent

(Z)-2-(4-chlorobenzylidene)-5,5-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)
cyclopentan-1-ol	

 

	

Primary crops:  barley (<10% TRR)

Fate and effects: identified in aqueous photolysis and soil photolysis
studies

RPA 406972

(E)-2-methyl-2-carboxylate-5-(4-chlorobenzylidene)-1-(1H-1,2,4-triazol-1
-ylmethyl)-1-cyclopentanol		

	

 

	

Livestock commodities: cow liver (<10% TRR), and kidney (<10% TRR),
poultry eggs (<10% TRR) and liver (19% TRR).

Rat urine: diastereomers up to 25% of applied dose

Rat feces: present

1,2,4-Triazole or free triazole	

	

Not identified in wheat and/or barley grain

Fate and effects: data limited, from <10% to up to 30% of the applied
radiolabeled parent remained unidentified in different studies

Triazole acetic acid	

	Not identified in wheat and/or barley grain

Fate and effects: data limited, from <10% to up to 30% of the applied
radiolabeled parent remained unidentified in different studies

  PAGE  2  of   NUMPAGES  39 

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