UNITED STATES ENVIRONMENTAL PROTECTION
AGENCY![](media/image1.png){width="0.7993055555555556in" height="0.8in"}

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

**[MEMORANDUM]{.underline}**

Date: 27-FEB-2008

SUBJECT: Petition No: 6F7072. Cyproconazole: **Revised** Human-Health
Risk Assessment for Proposed Uses on Corn, Soybean and Wheat.

> PC Code: 128993
>
> DP No: 349841 Decision No: 367588

Chemical Class: Triazole Fungicide

FROM: Mary Clock-Rust, Biologist

> George F. Kramer, Ph.D., Chemist
>
> Mohsen Sahafeyan, Chemist
>
> Kelly M. Lowe, Environmental Scientist
>
> William Greear, M.P.H., D.A.B.T., Toxicologist
>
> Registration Action Branch 1 (RAB1)
>
> Health Effects Division (HED) (7509P)

THRU: Dana M. Vogel, Branch Chief

P.V. Shah, Branch Senior Scientist

RAB1, HED (7509P)

TO: Mary Waller, Risk Manager 21

Registration Division (RD; 7505P)

**NOTE**: This document supersedes "Petition No: 6F7072. Cyproconazole:
Human-Health Risk Assessment for Proposed Uses on Corn, Soybean and
Wheat," M. Clock-Rust, *et al*., D330274, dated 16-NOV-2007. This
assessment has been revised to correct inconsistencies in the
recommended tolerance levels.

Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide
Act (FIFRA), as amended, Syngenta has requested registration of the
fungicide cyproconazole. The HED of the Office of Pesticide Programs
(OPP) is charged with estimating the risk to human health from exposure
to pesticides. The RD of OPP has requested that HED evaluate hazard and
exposure data and conduct dietary, occupational, residential, and
aggregate exposure assessments, as needed, to estimate the risk to human
health that will result from the proposed uses of cyproconazole in/on
corn, soybean and wheat.

A summary of the findings and an assessment of human-health risk
resulting from the proposed and registered uses of cyproconazole are
provided in this document. The residue chemistry review was provided by
George Kramer (RAB1); the dietary exposure assessment was provided by
Mohsen Sahafeyan (RAB1); the occupational/residential exposure
assessment was provided by Kelly Lowe (RAB1); the hazard assessment and
dose-response assessment were provided by William Greear (RAB1), the
risk assessment was provided by Mary Clock-Rust (RAB1) and the drinking
water assessment was provided by James Hetrick of the Environmental Fate
and Effects Division (EFED).

Table of Contents

[**1.0** **Executive Summary** 5](#__RefHeading___Toc182970171)

[**2.0** **Ingredient Profile** 10](#__RefHeading___Toc182970172)

[**2.1** **Cyproconazole Structure and Nomenclature**
11](#__RefHeading___Toc182970173)

[**2.2** **Summary of Proposed and Registered Uses**
11](#__RefHeading___Toc182970174)

[**3.0** **Hazard Assessment** 12](#__RefHeading___Toc182970175)

[**3.1** **Hazard and Dose-Response Assessment**
13](#__RefHeading___Toc182970176)

[**3.2** **Absorption, Distribution, Metabolism and Excretion in Rats**
13](#__RefHeading___Toc182970177)

[**3.3** **FQPA Considerations** 14](#__RefHeading___Toc182970178)

[**3.3.1** **Adequacy of the Toxicity Database**
14](#__RefHeading___Toc182970179)

[**3.3.2** **Evidence of Neurotoxicity**
14](#__RefHeading___Toc182970180)

[**3.3.3** **Developmental Toxicity Studies**
14](#__RefHeading___Toc182970181)

[**3.3.3.1** **Developmental Toxicity Study in the New Zealand White
Rabbit** 14](#__RefHeading___Toc182970182)

[**3.3.3.2** **Developmental Toxicity Study in the Chinchilla Rabbit**
15](#__RefHeading___Toc182970183)

[**3.3.3.3** **Developmental Toxicity Study in Rats**
16](#__RefHeading___Toc182970184)

[**3.3.4** **Reproductive Toxicity** 17](#__RefHeading___Toc182970185)

[**3.3.5** **Pre- and Post-Natal Toxicity**
17](#__RefHeading___Toc182970186)

[**3.3.5.1** **Determination of Susceptibility**
17](#__RefHeading___Toc182970187)

[**3.3.5.2** **Degree of Concern** 18](#__RefHeading___Toc182970188)

[**3.3.6** **Recommendation for a Developmental Neurotoxicity Toxicity
(DNT) Study** 18](#__RefHeading___Toc182970189)

[**3.4** **FQPA Safety Factor** 19](#__RefHeading___Toc182970190)

[**3.5** **Hazard Identification and Endpoint Selection**
19](#__RefHeading___Toc182970191)

[**3.5.1** **Acute Dietary Endpoint** 19](#__RefHeading___Toc182970192)

[**3.5.2** **Chronic Dietary Endpoint**
20](#__RefHeading___Toc182970193)

[**3.5.3** **Short- and Intermediate-Term Incidental Oral Endpoints**
20](#__RefHeading___Toc182970194)

[**3.5.4** **Short and Intermediate-Term Dermal and Inhalation
Endpoints** 20](#__RefHeading___Toc182970195)

[**3.5.5** **Long-Term Dermal and Inhalation Endpoints**
21](#__RefHeading___Toc182970196)

[**3.5.6** **Carcinogenicity** 21](#__RefHeading___Toc182970197)

[**3.6** **Endocrine Disruption** 23](#__RefHeading___Toc182970198)

[**4.0** **Dietary Exposure/Risk Characterization**
23](#__RefHeading___Toc182970199)

[**4.1** **Pesticide Metabolism and Environmental Degradation**
23](#__RefHeading___Toc182970200)

[**4.1.1** **Metabolism in Primary Crops**
24](#__RefHeading___Toc182970201)

[**4.1.2** **Metabolism in Rotational Crops**
24](#__RefHeading___Toc182970202)

[**4.1.3** **Metabolism in Livestock** 24](#__RefHeading___Toc182970203)

[**4.1.4** **Analytical Methodology** 24](#__RefHeading___Toc182970204)

[**4.1.5** **Environmental Degradation**
25](#__RefHeading___Toc182970205)

[**4.1.6** **Comparative Metabolic Profile**
25](#__RefHeading___Toc182970206)

[**4.1.7** **Toxicity Profile of Major Metabolites and Degradates**
26](#__RefHeading___Toc182970207)

[**4.1.8** **Pesticide Metabolites and Degradates of Concern**
27](#__RefHeading___Toc182970208)

[**4.1.9** **Drinking Water Residue Profile**
28](#__RefHeading___Toc182970209)

[**4.1.10** **Food Residue Profile** 29](#__RefHeading___Toc182970210)

[**4.1.11** **International Residue Limits**
32](#__RefHeading___Toc182970211)

[**4.2** **Dietary Exposure and Risk** 32](#__RefHeading___Toc182970212)

[**4.2.1** **Acute Dietary Risk Characterization (Females 13-49 years
old)** 33](#__RefHeading___Toc182970213)

[**4.2.2** **Chronic Dietary Risk Characterization**
34](#__RefHeading___Toc182970214)

[**5.0** **Residential (Non-Occupational) Risk**
34](#__RefHeading___Toc182970215)

[**6.0** **Aggregate Risk Assessments**
34](#__RefHeading___Toc182970216)

[**6.1** **Acute Aggregate Risk** 35](#__RefHeading___Toc182970217)

[**6.2** **Chronic Aggregate Risk** 35](#__RefHeading___Toc182970218)

[**7.0** **Cumulative Risk Characterization**
35](#__RefHeading___Toc182970219)

[**8.0** **Occupational Risk Assessment**
35](#__RefHeading___Toc182970220)

[**8.1** **Occupational Handler Risk Assessment**
36](#__RefHeading___Toc182970221)

[**8.2** **Occupational Post-application Exposure**
40](#__RefHeading___Toc182970222)

[**8.3** **REI** 41](#__RefHeading___Toc182970223)

[**9.0** **Data Needs and Label Recommendations**
41](#__RefHeading___Toc182970224)

[**9.1** **Regulatory Recommendations and Residue Chemistry
Deficiencies** 41](#__RefHeading___Toc182970225)

[**Appendix A** 45](#__RefHeading___Toc182970226)

[**Appendix B** 61](#__RefHeading___Toc182970227)

[]{#__RefHeading___Toc182970171 .anchor}**1.0 Executive Summary**

Cyproconazole is a broad-spectrum triazole fungicide (Group 3) that is a
mixture of two distereoisomers (2RS,3RS:2RS,3SR; \~1:1). Cyproconazole
is currently registered to Syngenta Crop Protection for use on
greenhouse- and field-grown roses and as a wood preservative. The use on
turf is no longer being supported (personal communication with C.
Grable, 10/31/07). Aside from a Section 18 Emergency Exemption for use
on soybeans, there are currently no food/feed uses for cyproconazole in
the U.S. A permanent tolerance is established for the residues of
cyproconazole,
(2RS,3RS)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1*H*-1,2,4-triazol-1-yl)butan-2-ol,
on imported green coffee beans at 0.1 ppm \[40 CFR §180.485(a)\], and a
temporary tolerance, set to expire on 12/31/09, is established for
cyproconazole in/on soybean seed at 0.10 ppm.

The last HED risk assessment for cyproconazole was performed in 2005
(Memo, G. Kramer, D318617, 9/27/2005 on a Section 18 Emergency Exemption
for use on soybean.

*Proposed Uses*

In the current action, Syngenta proposes new food/feed uses of
cyproconazole on corn (field and seed), soybeans and wheat. Application
rates are 0.036 lb ai/A for application to corn, soybean and wheat at
the first signs of disease development. The maximum seasonal use rate is
0.036 lb ai/A for corn and wheat and 0.072 lb ai/A for soybeans, and the
specified minimum retreatment intervals (RTIs) are 7 days for corn and
14 days for soybeans and wheat. Based on the proposed uses, dietary and
occupational exposures are expected.

*Hazard Characterization*

Cyproconazole was moderately acutely toxic by the oral, dermal and
inhalation routes (Toxicity Category III). It was neither an eye nor
dermal irritant (Toxicity Category IV). Cyproconazole did not cause
dermal sensitization in the guinea pig.

The critical toxicological effects in mammals appeared to be indicative
of hepatotoxicity. These included elevated LDH ((lactic dehydrogenase)
and AST (aspartate transaminate), increased liver weight (relative and
absolute), vacuolation, fatty changes, hepatocytomegaly, hypertrophy and
single-cell necrosis. Adenomas and carcinomas were only observed in
mice. Hepatotoxicity was observed in rats, mice and dogs; all of these
species appeared to be equally sensitive to cyproconazole toxicity. The
chemical has been classified by The Cancer Peer Review Committee as "Not
Likely to be Carcinogenic to Humans," based on the weight of evidence
that supports a non-genotoxic mitogenic mode of action for
cyproconazole. Except for the one of three *in vitro*
chromosomal-aberration assays, cyproconazole exhibited a negative
response in all other genotoxicity screening assays. Thus, it appears
that cyproconazole is not genotoxic.

Cyproconazole is a developmental toxicant. Rabbits appeared to be more
sensitive for developmental effects than the rat. Cyproconazole produced
increased incidences of malformed fetuses (hydrocephale and kidney
agenesis) and litters with malformed fetuses at doses lower than the
doses that produced maternal toxicity in rabbits. Cyproconazole
increased the incidences of supernumerary ribs in offspring in rats at
the same doses at which maternal adverse effects were observed. There
was no evidence of reproductive toxicity in the 2-generation
reproduction toxicity study. The maternal toxicity in a 2-generation
reproduction study was manifested as fatty changes and increased lipid
storage in the liver. No offspring toxicity was observed at any doses
tested in the 2-generation reproduction study.

The dermal-penetration study indicated that for cyproconazole, the
percent absorbed increased with duration of exposure and decreased with
dose. The quantity absorbed increased with dose and duration of
exposure. At the 10-hour exposure time point, 10.81% of the low dose was
absorbed. For risk assessment, since an oral study was selected for the
short- and intermediate-term dermal exposure assessment, an 11%
dermal-absorption factor was applied.

*Food Quality Protection Act (FQPA)*

The cyproconazole risk assessment team evaluated the quality of the
hazard and exposure data and determined that based on the hazard and
exposure data, the FQPA safety factor (SF) is reduced to 1X. In terms of
hazard, there are low concerns and no residual uncertainties with regard
to pre- and/or post-natal toxicity.

*Dose-Response Assessment*

The acute dietary endpoint for child-bearing females (females 13+years
old) was based on the developmental toxicity in New Zealand white
rabbits; the lowest-adverse effect level (LOAEL) = 10 mg/kg/day. The
no-observed adverse effect level (NOAEL) is 2 mg/kg/day. An uncertainty
factor (UF) of 100X (10-fold for interspecies extrapolation and 10-fold
for intra-species variability) was applied to the NOAEL of 2 mg/kg/day
to derive the acute reference dose (aRfD). The FQPA safety factor of 1X
is applicable for acute dietary risk assessment. Therefore, the acute
population-adjusted dose (aPAD) is 0.02 mg/kg/day. In a recent section
18 risk assessment (D318617, dated 8/27/05), the acute dietary endpoint
for child-bearing females (females 13+years old) was based on the
developmental toxicity study in Chinchilla rabbits; the lowest-adverse
effect level (LOAEL) = 2.0 mg/kg/day. In this study, the no-observed
adverse effect level (NOAEL) was not established. The FQPA SF of 3X was
applied for the use of LOAEL instead of the NOAEL. Up on detailed review
of the cyproconazole toxicological database for this action, RAB1
toxicologists concluded that the developmental toxicity in New Zealand
white rabbits is more appropriate for this exposure scenario (details
provided under section 3.3.5.1 Determination of Susceptibility).

The aRfD for the general population, including infants and children, was
not established since an endpoint of concern attributable to a single
dose was not identified.

The chronic RfD (cRfD) of 0.01 mg/kg/day was determined on the basis of
the chronic oral-toxicity study in dogs. The LOAEL of 3.2 mg/kg/day is
based on liver effects manifested as increased in liver weights
(absolute and relative) , elevated alkaline phosphatase and ALT levels
(males), decreased total protein, albumin and cholesterol levels. This
study provided the lowest NOAEL (1.0 mg/kg/day) in the database (most
sensitive endpoint) and will also provide the most protective limits for
human effects. An UF of 100X (10-fold for interspecies extrapolation and
10-fold for intra species variability) was applied to the NOAEL of 1
mg/kg/day to derive the cRfD. Therefore, the chronic population-adjusted
dose (cPAD) is 0.01 mg/kg/day.

Endpoints for short- and intermediate-term incidental oral risk
assessment are based on the 90-day oral rat study with a LOAEL of 27.3
mg/kg/day based on decreased body-weight gain in males and increased
liver weight in females (NOAEL 1.5 mg/kg/day).

Endpoints for short and intermediate-term dermal and inhalation risk
assessments were based on the developmental toxicity study in New
Zealand white rabbits with a LOAEL of 10 mg/kg/day. The NOAEL is 2
mg/kg/day.

Endpoints for long-term dermal and inhalation risk assessments are based
on the chronic oral toxicity study in dogs with a LOAEL of 3.2 mg/kg/day
based on liver effects (NOAEL = 1.0 mg/kg/day). The endpoint is
appropriate for the duration of exposure.

Since oral studies were selected for the dermal-exposure assessment, a
dermal-penetration factor of 11% (based on a dermal-penetration study in
rats) should be used. Since oral NOAELs were selected for the
inhalation-exposure assessment, an inhalation-absorption factor of 100%
oral equivalent should be used.

HED's level of concern (LOC) for cyproconazole occupational and
residential dermal and inhalation exposures is 100 \[i.e., a margin of
exposure (MOE) greater than 100 is not of concern to HED\]. The LOC is
based on a 10X uncertainty factor (UF) to account for interspecies
extrapolation to humans from the animal test species and 10X UF to
account for intra-species sensitivity.

*Environmental Fate and Drinking Water Assessment*

Although cyproconazole is a triazole fungicide, laboratory environmental
fate studies do not show formation of 1,2,4-triazole and triazole
conjugates \[i.e., triazole alanine (TA) and triazole acetic acid
(TAA)\] in soil or aquatic environments. Therefore, the drinking water
assessment was conducted for the parent compound.

The drinking water assessment for parent cyproconazole is based on Tier
I modeling. Tier I FQPA Index Reservoir Screening Tool (FIRST) modeling
indicate percent crop area corrected (PCA-corrected) cyproconazole
concentrations in surface source drinking water are not expected to
exceed 1.14 µg/L for the annual peak concentration and 0.11 µg/L for the
annual average concentration. Tier I Screening Concentration In Ground
Water (SCI-GROW) modeling indicates the peak and average cyproconazole
concentration in shallow groundwater is not expected to exceed 0.05
µg/L. These estimates were used in the dietary risk analysis.

*Dietary Risk*

Tier I acute and chronic aggregate (food + water) dietary risk
assessments to support Section 3 registration of cyproconazole on
soybean, wheat and corn were conducted using the Dietary Exposure
Evaluation Model software with the Food Commodity Intake Database
(DEEM-FCID, ver. 2.03) model and assumed tolerance-level residues, 100%
crop treated (CT), and DEEM default processing factors. Drinking water
was included in the dietary assessments. The resulting acute and chronic
aggregate exposure estimates were not of concern to HED; therefore,
acute and chronic dietary risks are not of concern to HED. An acute
dietary exposure analysis was conducted only for females 13-49 years old
since an endpoint of concern attributable to a single dose for general
population was not identified. The acute food exposure risk estimate for
female 13-49 years old was 3% aPAD at the 95^th^ percentile of the
exposure distribution. The highest chronic food exposure estimate was
for children 1-2 years old at 13% of the cPAD. A chronic cancer dietary
assessment was [not]{.underline} conducted since it was determined that
cyproconazole is not likely to be a human carcinogen.

*Residential Risk*

All residential uses of cyproconazole have been withdrawn and are no
longer being supported. Therefore, residential risk assessments were not
performed.

*Aggregate Risk*

Acute and chronic aggregate risks were assessed based on dietary
exposure from food and drinking water sources. Since there are no
residential uses, short- and intermediate-term aggregate risks were not
assessed. Cancer aggregate risk was not assessed since a cancer risk
assessment is not needed.

Acute aggregate risk is made up of food and water exposure and is the
same as reported for acute dietary exposure for females 13-49 years old.
The risk estimate was 3% aPAD at the 95^th^ percentile of the exposure
distribution, and is not of concern to HED.

Chronic aggregate risk is made up of food and water exposure and is the
same as reported for chronic dietary exposure (\<100% cPAD for U.S.
general population and all population sub-groups; the most highly
exposed population subgroup was children 1-2 years old with 13% cPAD).
Therefore, the chronic aggregate risk to cyproconazole is not of concern
to HED.

HED has also determined that 1,2,4-triazole, triazole alanine (TA) and
triazole acetic acid (TAA) are also potential residues of concern in
plants and livestock for all triazole fungicides. However, these
triazole-related residues will not be regulated for specific triazole
pesticides, but will be evaluated for the entire class of triazole
compounds. HED has recently completed a comprehensive risk assessments
considering 1,2,4-triazole and TA + TAA based on established and
proposed uses of triazole fungicides. These risk assessments were last
updated in October 2007 (DP#: 341803 and DP#: 344298, M. Sahafeyan,
10/30/07; note: separate memorandums). Along with other uses, these risk
assessments considered the use of cyproconazole on soybeans and the use
of related triazole fungicides on wheat and corn. Triazole-related
residues from the application of cyproconazole to the subject crops will
not be sufficiently different from those used in the in the previous
risk assessment. Therefore, a separate risk assessment for these
triazole-related residues will not be required for the current petition.

*Occupational Handler Risk*

Based on the proposed uses in corn, wheat and soybean crops, handlers
may be potentially exposed to cyproconazole. Handlers include
mixer/loaders who handle concentrated liquid cyproconazole and
applicators using aerial or groundboom equipment, and flaggers for
aerial applications. Based upon the proposed use pattern, HED expects
the *most highly* exposed occupational pesticide handlers are likely to
be mixer/loaders handling liquids for aerial applications and
applicators applying sprays using aerial equipment.

Short- and intermediate-term dermal and inhalation risks were assessed
for the two representative exposure scenarios at baseline, and with
additional personal protective equipment (PPE). Chemical-specific data
were not available, so surrogate data from the Pesticide Handlers
Exposure Database (PHED) were used. The combined dermal and inhalation
exposure risks for mixer/loaders are not of concern (i.e., MOEs\>100),
**provided the mixer/loaders wear protective gloves as directed on the
label.** For aerial applicators, risks were assessed using the
engineering controls (enclosed cockpits) and baseline attire
(long-sleeve shirt, long pants, shoes, and socks); pilots are not
required to wear protective gloves. With this level of protection, there
are no risks of concern for applicators.

*Occupational Post-application Risk*

Following cyproconazole application to corn, wheat and soybean,
occupational exposure is possible. Post-application activities may
include scouting, maneuvering irrigation equipment, hand weeding and
hand harvesting. HED assessed short-term post-application dermal risk
for workers using dermal transfer coefficients (TCs) from the Science
Advisory Council for Exposure (ExpoSAC) Policy Number 3.1: Agricultural
TCs, August 2000. Risks are not of concern (i.e., MOE\>100) on day 0
(restricted-entry interval (REI) = 12 hours) for all of the exposure
activities.

*Number range CHAPTERRegulatory Recommendations and Residue Chemistry
Deficiencies*

Provided the petitioner submits revised Sections B and F and independent
laboratory validations (ILVs) of the high-performance liquid
chromatography/mass spectrometry (HPLC/MS) method for metabolite M14 in
liver and the HPLC/UV method for M36 in milk, HED concludes that the
residue chemistry database is sufficient for conditional registration
and establishment of permanent tolerances for free and conjugated
residues of cyproconazole
\[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1*H*-1,2,4-triazole-1-ethanol\]
in or on the following commodities:

> Aspirated Grain Fractions 2.5
>
> Corn, field, forage 0.60
>
> Corn, field, grain 0.01
>
> Corn, field, stover 1.2
>
> Soybean, seed 0.05
>
> Soybean, forage 1.0
>
> Soybean hay 3.0
>
> Soybean, oil 0.10
>
> Wheat, forage 0.80
>
> Wheat, hay 1.3
>
> Wheat, straw 0.90
>
> Wheat, grain 0.05
>
> Wheat, grain, milled byproducts 0.10
>
> Fat of cattle, goat, horse and sheep 0.01
>
> Meat byproducts (except liver) of cattle, goat, horse
>
> and sheep 0.01

Additionally, HED has determined that a tolerance is required for the
combined free and conjugated residues of cyproconazole
\[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1*H*-1,2,4-triazole-1-ethanol\]
and its metabolite M36
\[δ-(4-chlorophenyl)-β,δ-dihydroxy-γ-methyl-1H-1,2,4-triazole-1-hexenoic
acid\] in or on the following commodity:

> Milk 0.02

and that tolerances are required for the combined free and conjugated
residues of cyproconazole
\[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1*H*-1,2,4-triazole-1-ethanol\]
and its metabolite M14
\[2-(4-chlorophenyl)-3-cyclopropyl-1-\[1,2,4\]triazol-1-yl-butane-2,3-diol\]
in or on the following commodities:

> Liver of cattle, goat, horse, and sheep 0.50
>
> Hog liver 0.01

Registration of these tolerances should be made conditionally until the
remaining residue chemistry deficiencies described in Section 9.0 are
satisfied.

**Note to RD:** The preferred chemical name for cyproconazole is
"α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1*H*-1,2,4-triazole-1-ethanol."
40 CFR §180.485(a) should be revised to use this terminology. Also, the
time-limited tolerance established for soybean seed under 40 CFR
§180.485(b) should be deleted once a tolerance is established in section
(a).

[]{#__RefHeading___Toc182970172 .anchor}**2.0 Ingredient Profile**

Cyproconazole is a broad-spectrum triazole fungicide (Group 3) that is a
mixture of two distereoisomers (2RS,3RS:2RS,3SR; \~1:1). Cyproconazole
acts by inhibiting sterol biosynthesis in fungi. It is effective for the
control of several plant diseases, such as yellow Sigatoka
(*Mycosphaerella musicola*) and black Sigatoka (*Mycosphaerella
fijiensis* var. *difformis*) in bananas, early leaf spot (*Cercospora
arachidicola*) and stem rot (*Sclerotitum rolfsii*) in peanuts, and rust
(*Puccinia spp.*) and powdery mildew (*Erysiphe spp.*) in wheat and
soybean.

Cyproconazole is currently registered to Syngenta Crop Protection for
use on greenhouse- and field-grown roses, and as a wood preservative.
The wood preservative products are labeled for industrial and commercial
use only. The use on turf is no longer being supported. Aside from a
Section 18 Emergency Exemption for use on soybeans, there are currently
no food/feed uses for cyproconazole in the U.S. A permanent tolerance is
established for the residues of cyproconazole,
(2RS,3RS)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1*H*-1,2,4-triazol-1-yl)butan-2-ol,
on imported green coffee beans at 0.1 ppm \[40 CFR §180.485(a)\], and a
temporary tolerance, set to expire on 12/31/09, is established for
cyproconazole in/on soybean seed at 0.10 ppm.

[]{#__RefHeading___Toc182970173 .anchor}**2.1 Cyproconazole Structure
and Nomenclature**

[]{.mark}

+-------------------+--------------------------------------------------+
| **Table 2.1a.     |                                                  |
| Cyproconazole     |                                                  |
| Nomenclature**.   |                                                  |
+===================+==================================================+
| Chemical          | ![                                               |
| structure         | ](media/image2.wmf){width="2.0729166666666665in" |
|                   | height="1.4069444444444446in"}                   |
+-------------------+--------------------------------------------------+
| Common name       | Cyproconazole                                    |
+-------------------+--------------------------------------------------+
| Company           | SAN619                                           |
| experimental name |                                                  |
+-------------------+--------------------------------------------------+
| IUPAC name        | (2RS,3RS)-2-(4-chlorophenyl)-3-c                 |
|                   | yclopropyl-1-(1*H*-1,2,4-triazol-1-yl)butan-2-ol |
+-------------------+--------------------------------------------------+
| CAS name          | α-(4-chlorophenyl)-α-(1                          |
|                   | -cyclopropylethyl)-1*H*-1,2,4-triazole-1-ethanol |
+-------------------+--------------------------------------------------+
| CAS registry      | 94361-06-5                                       |
| number            |                                                  |
+-------------------+--------------------------------------------------+
| End-use products  | 0.67 lb/gal SC (Quadris Xtra™ Fungicide, EPA     |
| (EP)              | Reg. No 100-1225)                                |
|                   |                                                  |
|                   | 0.83 lb/gal SC/L (Alto^®^ 100SL Fungicide; EPA   |
|                   | Reg. No. 100-1226)                               |
+-------------------+--------------------------------------------------+

+----------------------+---------------------+------------------------+
| **TABLE 2.1b.        |                     |                        |
| Physicochemical      |                     |                        |
| Properties of        |                     |                        |
| Cyproconazole.**     |                     |                        |
+----------------------+---------------------+------------------------+
| Parameter            | Value               | Reference              |
+----------------------+---------------------+------------------------+
| Melting range        | 99-106°C            | D179678, R. Lascola,   |
|                      |                     | 9/24/91                |
+----------------------+---------------------+------------------------+
| pH at 22ºC           | 6.7 ± 0.2           |                        |
+----------------------+---------------------+------------------------+
| Bulk Density at 20ºC | 0.5 ± 0.1 g/mL      |                        |
+----------------------+---------------------+------------------------+
| Water solubility at  | 108 mg/L at pH 4.1  | MRID 46840803          |
| 25ºC                 |                     |                        |
|                      | 93 mg/L at pH 7     |                        |
|                      |                     |                        |
|                      | 109 mg/L at pH 10   |                        |
+----------------------+---------------------+------------------------+
| Solvent solubility   | n-Hexane 0.2        | D179678, R. Lascola,   |
|                      |                     | 9/24/91                |
| (g/100 mL at 25°C)   | Diisopropyl ether   |                        |
|                      | 2.2                 |                        |
|                      |                     |                        |
|                      | Toluene 10.9        |                        |
|                      |                     |                        |
|                      | Xylene 11.2         |                        |
|                      |                     |                        |
|                      | Acetone \>20        |                        |
+----------------------+---------------------+------------------------+
| Vapor pressure at    | 2.6 x 10^-5^ Pa     | MRID 46840803          |
| 25ºC                 |                     |                        |
+----------------------+---------------------+------------------------+
| Dissociation         | Compound does not   | D179678, R. Lascola,   |
| constant, pK~a~      | dissociate          | 9/24/91                |
+----------------------+---------------------+------------------------+
| Octanol/water        | 2.91 ± 0.12         |                        |
| partition            |                     |                        |
| coefficient,         |                     |                        |
| Log(K~OW~)           |                     |                        |
+----------------------+---------------------+------------------------+
| UV/visible           | Not reported        |                        |
| absorption spectrum  |                     |                        |
+----------------------+---------------------+------------------------+

[]{#__RefHeading___Toc182970174 .anchor}**2.2 Summary of Proposed and
Registered Uses**

Cyproconazole is currently registered to Syngenta Crop Protection for
use on greenhouse- and field-grown roses and as a wood preservative. All
cyproconazole uses are commercial or industrial in nature; there are no
residential uses. The use on turf is no longer supported (personal
communication with C. Grable, 10/31/07).

In the current petition, Syngenta proposes new food/feed uses for two
formulations of cyproconazole on corn (field and seed), soybeans and
wheat. One formulation is a 0.83 lb/gal soluble concentrate/liquid
(SC/L; Alto^®^ 100SL Fungicide; EPA Reg. No. 100-1226). The second
formulation is a 0.67 lb/gal SC (Quadris Xtra™ Fungicide, EPA Reg. No
100-1225); this product is a multiple-active-ingredient (MAI)
formulation, which also contains 1.67 lb/gal of azoxystrobin. The
current review pertains to issues related to cyproconazole only.
Syngenta is proposing to use these formulations for broadcast foliar
applications at up to 0.036 lb ai/A/application to corn, soybean and
wheat at the first signs of disease development. The maximum seasonal
use rate is 0.036 lb ai/A for corn and wheat and 0.072 lb ai/A for
soybeans, and the specified minimum retreatment intervals (RTIs) are 7
days for corn and 14 days for soybeans and wheat.

Aside from a Section 18 Emergency Exemption for use on soybeans, there
are currently no food/feed uses for cyproconazole in the U.S.

Table 2.2 summarizes the proposed use pattern and formulations specified
in the end-use products containing cyproconazole.

+---------------+----------+------+-------+---------+-------+--------+
| **Table 2.2.  |          |      |       |         |       |        |
| Summary of    |          |      |       |         |       |        |
| Directions    |          |      |       |         |       |        |
| for Use of    |          |      |       |         |       |        |
| Cyp           |          |      |       |         |       |        |
| roconazole.** |          |      |       |         |       |        |
+---------------+----------+------+-------+---------+-------+--------+
| Applic.       | For      | App  | Max.  | Max.    | PHI   | Use    |
| Timing, Type, | mulation | lic. | No.   | S       |       | Dire   |
| and Equip.    |          | Rate | Ap    | easonal | (     | ctions |
|               | \[EPA    |      | plic. | Applic. | days) | and    |
|               | Reg.     | (lb  | per   | Rate    |       | Li     |
|               | No.\]    | a    | S     |         |       | mitati |
|               |          | i/A) | eason | (lb     |       | ons^1^ |
|               |          |      |       | ai/A)   |       |        |
+---------------+----------+------+-------+---------+-------+--------+
| **Whea        |          |      |       |         |       |        |
| t/Triticale** |          |      |       |         |       |        |
+---------------+----------+------+-------+---------+-------+--------+
| Broadcast     | 0.83     | 0    | 2     | 0.036   | 30 -  | The    |
| foliar        | lb/gal   | .036 |       |         | grain | m      |
| a             | SC/L     |      |       |         |       | inimum |
| pplication(s) |          |      |       |         | 21 -  | RTI is |
| at Feekes     | \[10     |      |       |         | fo    | 14     |
| Stage 5-10.5  | 0-1226\] |      |       |         | rage/ | days.  |
| using ground, |          |      |       |         | hay   |        |
| air or        | 0.67     |      |       |         |       |        |
| chemigation   | lb/gal   |      |       |         |       |        |
| equipment     | SC       |      |       |         |       |        |
|               | \[100-1  |      |       |         |       |        |
|               | 225\]^2^ |      |       |         |       |        |
+---------------+----------+------+-------+---------+-------+--------+
| **Field or    |          |      |       |         |       |        |
| Seed Corn**   |          |      |       |         |       |        |
+---------------+----------+------+-------+---------+-------+--------+
| Broadcast     | 0.83     | 0    | 2     | 0.036   | 30 -  | The    |
| foliar        | lb/gal   | .036 |       |         | grain | m      |
| application   | SC/L     |      |       |         |       | inimum |
| at first sign |          |      |       |         | 21 -  | RTI is |
| of disease    | \[10     |      |       |         | s     | 7      |
| using ground, | 0-1226\] |      |       |         | ilage | days.  |
| air or        |          |      |       |         |       |        |
| chemigation   | 0.67     |      |       |         |       |        |
| equipment     | lb/gal   |      |       |         |       |        |
|               | SC       |      |       |         |       |        |
|               | \[100-1  |      |       |         |       |        |
|               | 225\]^2^ |      |       |         |       |        |
+---------------+----------+------+-------+---------+-------+--------+
| **Soybean**   |          |      |       |         |       |        |
+---------------+----------+------+-------+---------+-------+--------+
| Broadcast     | 0.83     | 0    | 2     | 0.072   | 30 -  | The    |
| foliar        | lb/gal   | .036 |       |         | seed  | m      |
| application   | SC/L     |      |       |         |       | inimum |
| prior to      |          |      |       |         |       | RTI is |
| disease using | \[10     |      |       |         |       | 14     |
| ground, air   | 0-1226\] |      |       |         |       | days.  |
| or            |          |      |       |         |       | Do not |
| chemigation   | 0.67     |      |       |         |       | graze  |
| equipment     | lb/gal   |      |       |         |       | forage |
|               | SC       |      |       |         |       | within |
|               | \[100-1  |      |       |         |       | 14     |
|               | 225\]^2^ |      |       |         |       | days   |
|               |          |      |       |         |       | of     |
|               |          |      |       |         |       | applic |
|               |          |      |       |         |       | ation. |
+---------------+----------+------+-------+---------+-------+--------+

^1^ Both labels specify the following rotational crop restrictions: no
PBI for corn, soybean and wheat; a 60-day PBI for leafy vegetables and
cereal grains other than wheat; and a 365-day PBI for all other crops.

^2^ This MAI formulation also contains azoxystrobin at 1.67 lb/gal.

[]{#__RefHeading___Toc182970175 .anchor}**3.0 Hazard Assessment**

References:

Memo, P. Terse, TXR 0053768, 11/17/2005.

Toxicology Endpoint Selection Document, L. Taylor *et. Al.,* HED Doc.
No. 013148,

06/18/1997.

Cyproconazole was moderately acutely toxic by the oral, dermal and
inhalation routes (Toxicity Category III). It was neither an eye nor
dermal irritant (Toxicity Category IV). Cyproconazole did not cause
dermal sensitization in the guinea pig.

The critical toxicological effects in mammals appeared to be indicative
of hepatotoxicity. These included elevated LDH and AST, increased liver
weight (relative and absolute), vacuolation, fatty changes,
hepatocytomegaly, hypertrophy and single cell necrosis. Adenomas and
carcinomas were only observed in mice. Hepatotoxicity was observed in
rats, mice and dogs; all of these species appeared to be equally
sensitive to cyproconazole toxicity. The chemical has been classified by
The Cancer Peer Review Committee as "Not Likely to be Carcinogenic to
Humans", based on the weight of evidence that supports a non-genotoxic
mitogenic mode of action for cyproconazole. Except for one of three *in
vitro* chromosomal-aberration assays, cyproconazole exhibited a negative
response in all other genotoxicity screening assays. Thus, it appears
that cyproconazole is not genotoxic.

The chemical is a developmental toxicant. Rabbits appeared to be more
sensitive for developmental effects than the rat. Cyproconazole produced
increased incidences of malformed fetuses and litters with malformed
fetuses (hydrocephale and kidney agenesis) at doses lower than the doses
that produced maternal toxicity in rabbit. Cyproconazole increased the
incidences of supernumerary ribs in rats at the same doses at which
maternal adverse effects were observed. There was no evidence of
reproductive toxicity in the 2-generation reproduction toxicity study.
The maternal toxicity in a 2-generation reproduction study was
manifested as fatty changes and increased lipid storage in the liver. No
offspring toxicity was observed at any doses tested in the 2-generation
reproduction study.

The dermal-penetration study indicated that for cyproconazole, the
percent absorbed increased with duration of exposure and decreased with
dose. The quantity absorbed increased with dose and duration of
exposure. At the 10-hour exposure time point, 11% of the low dose was
absorbed.

[]{#__RefHeading___Toc182970176 .anchor}**3.1 Hazard and Dose-Response
Assessment**

[]{#__RefHeading___Toc182970177 .anchor}**3.2 Absorption, Distribution,
Metabolism and Excretion in Rats**

Cyproconazole was almost completely absorbed in males (84%) and females
(100%). The majority of the total administered dose (96.5%) was
recovered in the feces (56.3%) and urine (40.2%). It is extensively
metabolized; diastereomers A & B of parent + 13 metabolites were
identified and isolated; 35 metabolites were detected; metabolic
profiles for urine, feces and bile were similar; major metabolic
reactions include oxidative elimination of triazole ring; hydroxylation
of the C bearing CH~3~ group; oxidation of CH~3~ group to carbinol and
further oxidation to carboxylic acid; rapid excretion occurred with the
majority of the total administered dose appearing in feces (biliary
excretion). Three days after final dosing, radioactivity was almost
completely excreted. The calculated half-life for the depletion of
radioactivity (assuming mono-phasic first-order kinetics) from the
tissues ranged from one to three days. The greater persistence and
longer half-life of radioactivity in blood compared to plasma indicated
some partitioning of radioactivity into the red blood cells. The highest
concentrations of radioactivity were observed in the liver (1.37 ppm
cyproconazole equivalents), adrenals (0.93 ppm), lungs (0.56 ppm), fat
(0.49 ppm), kidneys (0.25 ppm), pancreas, (0.22 ppm), and ovaries (0.16
ppm) seven days after the start of dosing. The results also indicated a
potential for accumulation in the liver during long-term studies.
[]{#__RefHeading___Toc182970178 .anchor}

**3.3 FQPA Considerations**

[]{#__RefHeading___Toc182970179 .anchor}**3.3.1 Adequacy of the Toxicity
Database**

The toxicology database for cyproconazole is adequate. The following
acceptable studies are available:

One developmental toxicity study in rats

Two developmental toxicity studies in rabbits

One 2-generation reproduction study in rats

[]{#__RefHeading___Toc182970180 .anchor}**3.3.2 Evidence of
Neurotoxicity**

There is not a concern for neurotoxicity resulting from exposure to
cyproconazole. Acute and subchronic neurotoxicity studies were not
performed. Based on the available data (clinical signs and
neuropathology) from multiple studies, the chemical is not considered to
be neurotoxic.

[]{#__RefHeading___Toc182970181 .anchor}**3.3.3 Developmental Toxicity
Studies**

[]{#__RefHeading___Toc182970182 .anchor}**3.3.3.1 Developmental Toxicity
Study in the New Zealand White Rabbit**

In a developmental toxicity study (MRID 42175401), cyproconazole (95%
a.i. Batch \# 8507)) was administered to pregnant New Zealand White
rabbits (18/dose) in 1% aqueous methyl cellulose by gavage at dose
levels of 0, 2, 10, or 50 mg/kg bw/day from days 6 through 18 of
gestation.

Maternal toxicity as indicated by decreased body weight gain and food
consumption was observed at the high dose level. The pregnancy rate was
88.9% in the control, low-, and mid-dose groups and 77.8% in the high
dose group. The number of litters with viable young was 16, 11, 14, and
10 for the control, low , mid , and high dose groups, respectively.
There was no effect noted on the numbers of implants or live fetuses per
doe, on the number of resorptions or fetal deaths, and overall mean
fetal weight and mean fetal weight/sex were comparable among the groups.
Pre- and post-implantation losses were comparable among the groups.

There was an increased incidence of total external/visceral or skeletal
malformations at the high dose level, which was statistically
significant when compared to the concurrent control group. The incidence
in external/visceral and skeletal variations was increased in a
dose-related manner in some instances. It is concluded that the highest
dose level resulted in a slight increase in the incidence of several
malformations and variations. This is based on the facts that (1)
several of the malformations were not observed in either the concurrent
control or historical control data; (2) each of these malformations
occurred in more than one fetus and in more than one litter; (3) the
malformation, malrotated hindlimbs, was also observed at the mid-dose
but at a lower incidence than in the high dose group (dose-related); (4)
of the twenty three skeletal malformations observed in the study, all
but 4 were observed only at the high dose level \[one control fetus had
one malformation, one mid-dose fetus displayed 3 malformations, and one
additional mid dose fetus displayed 1 malformation (2 different
litters)\]; and (5) the mid and high dose fetuses displayed more
malformations/variations per fetus than the low-dose, concurrent, and
historical control groups. Also to be considered are the facts that (1)
the high-dose had the highest number of non-pregnant does and, were
these does to have been pregnant, the number of fetal findings might
have been greater for this group; and (2) both the mid- and high dose
groups had fewer fetuses/litter than the low-dose and control groups
\[5.O and 5.5 vs 6.9 and 6.4, respectively).

The maternal NOAEL was 10 mg/kg, the LOAEL was 50 mg/kg, based on
decreased body-weight gains and food consumption.

The developmental toxicity NOAEL was 2 mg/kg, the LOAEL was 10 mg/kg,
based on the increased incidence of malformed fetuses and litters with
malformed fetuses.

This developmental toxicity study is classified acceptable/Guideline and
satisfy the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in the rabbit.

[]{#__RefHeading___Toc182970183 .anchor}**3.3.3.2 Developmental Toxicity
Study in the Chinchilla Rabbit**

In a developmental toxicity study (MRID 40607720), SAN 619F (95.6 % a.i.
Lot \# 8507)) was administered to pregnant Chinchilla rabbits (16/group)
in 4% aqueous methyl cellulose by gavage at dose levels of 0, 2, 10, or
50 mg/kg bw/day from days 6 through 18 of gestation.

Evidence of maternal toxicity included reduced body weight gain (-26%)
during treatment and decreased food consumption during the initial phase
of treatment, both at 50 mg/kg. However, corrected body weight changes
between groups were comparable indicating maternal changes in body
weight gain could be due to increased resorptions.

Developmental toxicity, observed at 50 mg/kg, was evident from the
decreased number of live fetuses/dam and an increased incidence of
non-ossification in certain forelimb and hindlimb digits. Evidence of
Developmental toxicity at dosages of 10 and 50 mg/kg was indicated by an
increased incidence of embryonic and fetal resorptions.

Evidence of developmental toxicity included hydrocephalus internus,
observed in 1 fetus at each dosage level, and agenesia of the left
kidney and ureter in 1 high-dose fetus. The incidence of hydrocephalus
internus was 0.85, 0.83 and 0.93 for the low-, mid- and high-dose
fetuses and 0.08 for the historical control incidence. Hydrocephaly was
also seen at 2 dosage levels in a developmental toxicity study in rats
with this test material, however, this anomaly did not occur in the
concurrent controls of either study. In the another developmental
toxicity study in New Zealand White rabbits, Hydrocephaly was not seen.

The maternal NOAEL was 10 mg/kg, the LOAEL was 50 mg/kg, based on
decreased body-weight gains and food consumption.

Developmental toxicity NOAEL was not attained; Developmental LOAEL was 2
mg/kg, based on incidence of hydrocephalus internus.

This developmental toxicity study is classified Unacceptable/Guideline
and does not satisfy the guideline requirement for a developmental
toxicity study (OPPTS 870.3700; OECD 414) in the rabbit because: 1) a
NOAEL for developmental toxicity apparently was not attained and 2) the
concentrations of test material were not within the acceptable range (±
15% of nominal concentration) for the mid- and high dose suspensions
immediately after preparation.

[]{#__RefHeading___Toc182970184 .anchor}**3.3.3.3 Developmental Toxicity
Study in Rats**

In a developmental toxicity study (MRID 40607721), SAN 619F (95% a.i.
Lot \# 8507)) was administered to pregnant Wistar/Han rats (25/dose) in
4% aqueous methyl cellulose by gavage at dose levels of 0, 6, 12, 24 or
48 mg/kg bw/day from days 6 through 15 of gestation.

Evidence of maternal toxicity included inhibited body weight gain
(11.4%) during treatment at dosage levels of 12 mg/kg and above and
decreased body weight and food consumption among females in the 24 and
48 mg/kg dosage groups. These differences in maternal body weights could
have been influenced by treatment-related intrauterine effects (e.g.,
increased number of resorptions, decreased fetal weight). Evidence of
fetal toxicity was apparent from observed dose-related increases in the
number of litters with supernumerary ribs at dosages 12 mg/kg and above.
Developmental toxicity was apparent at 24 and 48 mg/kg from the
following observations: decreased total number of fetuses/dam, decreased
number of live fetuses/dam, increased percentage and number of fetal
resorptions, decreased body weight and incomplete ossification in
phalangeal nuclei and the absence of ossification in calcanea. There was
evidence of developmental toxicity in the 24 and 48 mg/kg groups.
Hydrocephaly was observed in 1 fetus in the 24 mg/kg and 2 fetuses in
the 48 mg/kg groups. Cleft palate was observed in 2 fetuses in the 48
mg/kg group.

The maternal NOAEL was 6 mg/kg, the LOAEL at 12 mg/kg based on decreased
body weight gain during treatment. The developmental toxicity NOAEL was
6 mg/kg, the LOAEL at 12 mg/kg based on increased incidence of
supernumerary ribs.

This developmental toxicity study is classified acceptable/Guideline and
satisfy the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in the rat.

[]{#__RefHeading___Toc182970185 .anchor}**3.3.4 Reproductive Toxicity**

In a 2-generation reproduction study (MRID 40607723) cyproconazole
(purity, 95.6% a.i.; lot \# 8507) was administered to groups of 26/sex
KFM-Wistar albino rats/dose, in the diet, at concentrations of 0, 4, 20,
or 120 ppm (F0, M/F: 0, 0.28/0.33, 1.39/1.67, 8.29/9.88 mg/kg/day,
respectively) during the pre-mating (10 wks and 12 wks, for the F0 and
F1 generation, respectively), mating, pregnancy and lactation periods.

Two of the reproductive parameters investigated in parental animals were
affected by treatment in F0 animals only: the duration of gestation at
the mid- and high doses was increased and a lower number of implantation
sites was seen in high-dose females, both in comparison to respective
concurrent control values. However, the HED/Peer Review committee (TXR
\# 0053466, Nov 15, 1993) concluded that the effects noted (increased
gestation length and litter size) were not treatment related. Evidence
of liver toxicity was seen in high dose F0 males (increased lipid
storage and relative weight) and females (increased relative weight).

Parameters examined among the offspring which showed treatment-related
effects included decreased litter sizes in both the F1 and F2 high-dose
groups and the F1 mid-dose group during the early phase of lactation
(litters were standardized at day 4 post partum), decreased live birth
index in the high-dose F1 offspring and decreased viability index in the
high-dose F1 and F2 offspring. However, the HED/Peer Review committee
(TXR \# 0053466, Nov 15, 1993) concluded that the effects noted (litter
size) were not treatment related.

The parental LOAEL for the systemic toxicity is 120 ppm ( 8.29
mg/kg/day), based on liver effects ((increased lipid storage and
relative weight). The parental NOAEL for systemic toxicity is 20 ppm
(1.39 mg/kg/day).

The offspring toxicity NOAEL is \> 120 ppm ( 8.29 mg/kg/day), LOAEL is
not established.

The reproductive toxicity NOAEL is \> 120 ppm ( 8.29 mg/kg/day), LOAEL
is not established.

This study is classified Acceptable/Guideline and satisfies the
guideline requirement (It was noted that although dose levels were not
adequate, study need not be repeated since similar effects (increased
resorptions, decreased litter size) were observed in the rat
developmental study at dose levels of 24 and 48 mg/kg and a NOAEL for
these effects was established in that study.

[]{#__RefHeading___Toc182970186 .anchor}**3.3.5 Pre- and Post-Natal
Toxicity**

1.  []{#__RefHeading___Toc182970187 .anchor}**Determination of
    Susceptibility**

There is no quantitative or qualitative evidence of increased
susceptibility of rats fetuses to cyproconazole in utero exposure in
developmental toxicity study in rats. There is no quantitative or
qualitative evidence of increased susceptibility of rats fetuses
following pre/post-natal exposure to cyproconazole in a 2-generation
reproduction study in rats. In the developmental toxicity study in rats,
maternal (decreased body weight gain) and fetal toxicity (increased
incidence of supernumerary ribs) was observed at the same dose (NOAEL=6
mg/kg/day. In this study, hydrocephaly was observed in 1 fetus in the 24
mg/kg and 2 fetuses in the 48 mg/kg groups. Cleft palate was observed in
2 fetuses in the 48 mg/kg group. In the 2-generation reproduction study
in rats, no offspring toxicity was observed including highest dose
tested and in the presence of maternal toxicity. Therefore, it is
concluded that there is no evidence of increased susceptibility of rats
fetuses to pre/post natal exposure to cyproconazole.

There is evidence of increased susceptibility for cyproconazole from *in
utero* exposure in rabbits. Cyproconazole produced developmental
toxicity at doses lower than the doses that produced maternal toxicity
in two developmental toxicity studies in rabbits.

Cyproconazole was evaluated by the HED Developmental and Reproductive
Toxicity Peer Review Committee on July 21, 1993. The deliberations of
the Committee are detailed in the memorandum dated November 15, 1993.
The Committee concluded that developmental toxicity was induced
following cyproconazole exposure in rats and rabbits by the oral route
and established the NOAELs and LOAELs (as discussed above).
Hydrocephalus and cleft palate were observed in the rat study at higher
doses (24 and 48 mg/kg/day) than the dose that produced marginal
maternal toxicity. (12 mg/kg/day). These findings were not observed in
the concurrent control animals. The incidence of these observations in
the treated animals exceeded the values reported in the historical
control data. There is a well defined NOAEL for the developmental
toxicity of cyproconazole in the rat of 6 mg/kg/day.

Hydrocephalus was also observed in the cyproconazole Chinchilla rabbit
developmental toxicity study in one fetus of each treatment group (not
including control). The incidence was 0.85, 0.83, and 0.93% for the low,
mid, and high dose fetuses and 0.09% for the historical control. While
the hydrocephaly does appear to be treatment related, a dose response
relationship does not exist for this finding. Therefore, in the
Chinchilla rabbit developmental toxicity study a NOAEL was not achieved.
The LOAEL is \< 2.0 mg/kg/day. The available hazard database for the
other triazole fungicides does not identify hydrocephaly as a
developmental outcome or concern.

When side by side comparison of the developmental toxicity studies was
performed, it was noted that hydrocephaly was seen in the rat and the
Chinchilla rabbit study when 4% CMC was used as the vehicle. However,
when 1% CMC was used as the vehicle in the NZW rabbit study hydrocephaly
was not observed. The influence of CMC concentration in the induction of
hydrocephaly in these studies is unknown.

The cyproconazole hazard database contains a second developmental
toxicity study conducted in New Zealand White rabbits which is the
preferred strain. In the second study, the exact same doses were
evaluated (i.e., 0, 2, 10, or 50 mg/kg/day) and hydrocephaly was not
observed. However, the New Zealand White rabbits treated with
cyproconazole did exhibit an increased incidence of malformed fetuses
and litters with malformed fetuses. Malrotated hindlimbs were observed
at the mid and high dose levels in the main study, and at the high dose
in the range-finding study. This malformation was not observed in the
concurrent or relevant historical control data. The New Zealand White
rabbit study does have a well defined NOAEL of 2 mg/kg/day for
developmental toxicity.

[]{#__RefHeading___Toc182970188 .anchor}**3.3.5.2 Degree of Concern**

There is no evidence of increased susceptibility in the developmental
study in rats or in the two-generation reproduction study in rat. There
is no concern for the increased susceptibility in the NZW rabbit study
since clear NOAELs/LOAELs were established for maternal and
developmental toxicities and malformations were observed at a doses
higher than the dose that produced marginal maternal toxicity. The
concern is low for the increased susceptibility in the Chinchilla rabbit
study since the incidences of hydrocephaly were low, there was no dose
response, high concentration of the vehicle (CMC) used, and the
hydrocephaly was not seen at the same doses in the New Zealand White
strain of rabbit. Therefore, there is no residual uncertainty for pre-
and/or post natal toxicity.

[]{#__RefHeading___Toc182970189 .anchor}**3.3.6 Recommendation for a
Developmental Neurotoxicity Toxicity (DNT) Study**

Acute and subchronic neurotoxicity studies were not performed for
cyproconazole. The liver appears to be the primary target organ for
cyproconazole. Based on the available data (clinical signs and
neuropathology) from multiple studies, the chemical is not considered to
be neurotoxic. However, cyproconazole produced hydrocephaly in one fetus
in each treatment group in the Chinchilla rabbit developmental toxicity
study \[the finding was observed in one fetus at 2 mg/kg/day (lowest
dose tested, LDT)\]. Cyproconazole did not produce hydrocephaly in the
NZW rabbit. Hydrocephaly was observed in the cyproconazole rat
developmental toxicity study at 24 and 48 mg/kg/day. In the rat
developmental toxicity study, there was a well defined NOAEL of 6
mg/kg/day for hydrocephaly. Therefore, the Chinchilla rabbit appears to
be the most sensitive species/strain.

Because the doses are well characterized at which hydrocephaly was
observed in the developmental toxicity study in the rat, a developmental
neurotoxicity study in this species will not provide additional
toxicological data. Although hydrocephaly was also observed in the
chinchilla at lower doses than in the rat, DNT studies are performed
only in the rat. Therefore, a DNT study is not required for
cyproconazole.

[]{#__RefHeading___Toc182970190 .anchor}**3.4 FQPA Safety Factor**

The cyproconazole risk assessment team evaluated the quality of the
hazard and exposure data and determined that based on the hazard and
exposure data, the FQPA SF is reduced to 1X. In terms of hazard, there
are low concerns and no residual uncertainties with regard to pre-
and/or post-natal toxicity. The recommendation is based on the
following:

-   The acute dietary food exposure assessment utilizes proposed
    tolerance-level residues and 100% CT information for all
    commodities. The chronic dietary food exposure estimate is
    conservative since it assumed average residues based on field-trial
    data (maximum application rate; minimum pre-harvest interval; frozen
    immediately after harvest) and assumed that 100% of the imported
    coffee was treated By using these screening-level assessments, acute
    and chronic exposures/risks will not be underestimated.

-   The dietary drinking water assessment (Tier 1 estimates) utilizes
    values generated by models and associated modeling parameters which
    are designed to provide conservative, health-protective, high-end
    estimates of water concentrations.

-   There are no residential uses.

    []{#__RefHeading___Toc182970191 .anchor}**3.5 Hazard Identification
    and Endpoint Selection**

    []{#__RefHeading___Toc182970192 .anchor}**3.5.1 Acute Dietary
    Endpoint**

The acute dietary endpoint for child bearing females (females 13+years
old) was determined from the developmental toxicity in New Zealand white
rabbits; LOAEL = 10 mg/kg/day. The NOAEL is 2 mg/kg/day. An UF of 100X
(10-fold for interspecies extrapolation and 10-fold for intra species
variability) was applied to the NOAEL of 2 mg/kg/day to derive the aRfD.
The FQPA safety factor of 1X is applicable for acute dietary risk
assessment. Therefore, the aPAD is 0.02 mg/kg.

Note: In the previous section 18 risk assessment (Memo, G. Kramer,
D318617, 9/27/2005), the dose and endpoint selected for acute dietary
risk assessment was based on the study in chinchilla rabbits described
above with a total FQPA SF of 300. The FQPA SF of 3X was applied for the
use of LOAEL instead of the NOAEL. Up on detailed review of the
cyproconazole toxicological database for this action, RAB1 toxicologists
concluded that the developmental toxicity in New Zealand white rabbits
is more appropriate for this exposure scenario (details provided above
under section 3.3.5.1 Determination of Susceptibility).

The aRfD for the general population, including infants and children, was
not established since an endpoint of concern attributable to a single
dose was not identified.

[]{#__RefHeading___Toc182970193 .anchor}**3.5.2 Chronic Dietary
Endpoint**

The cRfD of 0.01 mg/kg/day was determined on the basis of the chronic
oral-toxicity study in dogs. The LOAEL of 3.2 mg/kg/day is based on
liver effects (P450 induction in females and histopathology, laminar
eosinophilic intrahepatocytic bodies in males). This study provided the
lowest NOAEL (1.0 mg/kg/day) in the database (most sensitive endpoint)
and also provides the most protective limits for human effects. In
addition, hepatotoxicity was seen in rats, mice and dog; all of these
species were appeared to be equally sensitive to cyproconazole toxicity
with very close NOAELs (range between 1-2 mg/kg/day). An UF of 100X
(10-fold for interspecies extrapolation and 10-fold for intra species
variability) was applied to the NOAEL of 1 mg/kg/day to derive the cRfD.

[]{#__RefHeading___Toc182970194 .anchor}**3.5.3 Short- and
Intermediate-Term Incidental Oral Endpoints**

Endpoints for these scenarios are based on a 90-day oral rat study;
LOAEL = 27.3 mg/kg/day based on decreased body weight gain in males and
increased liver weight in females (NOAEL = 1.5 mg/kg/day). This endpoint
is appropriate for the route, duration of exposure (1-30 days) and
population of concern (infants and children). The subchronic dog study
was not considered for these scenarios because the NOAEL from the
subchronic dog study (0.8 mg/kg/day) appears to be artificially lower
than the NOAEL of the chronic dog study (1.0 mg/kg/day) and subchronic
rat study (1.5 mg/kg/day) due to dose-spread effect.

HED's LOC for cyproconazole residential incidental oral exposure is 100
(i.e., MOE greater than 100 is not of concern to HED). The level of
concern is based on a 10X UF to account for interspecies extrapolation
to humans from the animal test species and 10X UF to account for
intra-species sensitivity.

[]{#__RefHeading___Toc182970195 .anchor}**3.5.4 Short and
Intermediate-Term Dermal and Inhalation Endpoints**

Endpoints for these scenarios were determined from the developmental
toxicity study in New Zealand white rabbits; LOAEL = 10 mg/kg/day. The
NOAEL is 2 mg/kg/day. The endpoint is appropriate for the duration of
exposure. Since oral studies were selected for dermal exposure
assessment, a dermal-penetration factor of 11% (based on a
dermal-penetration study in rats) should be used. Since oral NOAELs were
selected for inhalation exposure assessment, an inhalation-absorption
factor of 100% oral equivalent should be used.

HED's LOC for cyproconazole residential incidental oral exposure is 100
(i.e., MOE greater than 100 is not of concern to HED). The level of
concern is based on a 10X UF to account for interspecies extrapolation
to humans from the animal test species and 10X UF to account for
intra-species sensitivity.

[]{#__RefHeading___Toc182970196 .anchor}**3.5.5 Long-Term Dermal and
Inhalation Endpoints**

Endpoints for these scenarios are based on the chronic oral toxicity
study in dog; LOAEL = 3.2 mg/kg/day based on liver effects (P450
induction in females and histopathology, laminar eosinophilic
intra-hepatocytic bodies in males) (NOAEL = 1.0 mg/kg/day). The endpoint
is appropriate for the duration of exposure (\> 6 months).

Since oral studies were selected for dermal exposure assessment, a
dermal-penetration factor of 11% (based on a dermal-penetration study in
rats) should be used. Since oral NOAELs were selected for inhalation
exposure assessment, an inhalation-absorption factor of 100% oral
equivalent should be used. The LOC for residential exposure is for MOEs
= 100 and for occupational exposure is for MOEs =100.

HED's LOC for cyproconazole residential incidental oral exposure is 100
(i.e., MOE greater than 100 is not of concern to HED). The level of
concern is based on a 10X UF to account for interspecies extrapolation
to humans from the animal test species and 10X UF to account for
intra-species sensitivity.

[]{#__RefHeading___Toc182970197 .anchor}**3.5.6 Carcinogenicity**

Cyproconazole has been classified by the Cancer Peer Review Committee as
Not Likely to be Carcinogenic to Humans (Report in Process; W. Greear,
Meeting date: 8/22/2007, TXR 054777). The decision was based on the
weight of evidence that supports a non-genotoxic mitogenic mode of
action for cyproconazole.

Note: Previously, cyproconazole was considered a carcinogen (TXR 052586,
06/03/2004). HED has since re-evaluated cyproconazole with respect to
carcinogenicity based on toxicity studies submitted by the registrant
describing cyproconazole's mechanistic mode of action. The Cancer Peer
Review Committee re-evaluated the studies and concluded that
cyproconazole is not likely to be carcinogenic to humans at doses that
do not perturb the liver in rats. Further, HED concluded that the cRfD
of 0.01 mg/kg/day is low enough to be protective of any liver effects.

+-------------+-------------+----------------+------------------------+
| **Table     |             |                |                        |
| 3.5.        |             |                |                        |
| Summary of  |             |                |                        |
| To          |             |                |                        |
| xicological |             |                |                        |
| Dose and    |             |                |                        |
| Endpoints   |             |                |                        |
| for         |             |                |                        |
| Cy          |             |                |                        |
| proconazole |             |                |                        |
| Used in     |             |                |                        |
| Human Risk  |             |                |                        |
| As          |             |                |                        |
| sessment.** |             |                |                        |
+=============+=============+================+========================+
| *           | **Dose Used | **Special FQPA | **Study and            |
| *Exposure** | in Risk     | SF\* and Level | Toxicological          |
|             | Assessment, | of Concern for | Effects**              |
| *           | UF**        | Risk           |                        |
| *Scenario** |             | Assessment**   |                        |
+-------------+-------------+----------------+------------------------+
| Acute       | Not         | None           | An endpoint of concern |
| Dietary     | applicable  |                | attributable to a      |
| (general    |             |                | single dose for        |
| population) |             |                | general population was |
|             |             |                | not identified.        |
+-------------+-------------+----------------+------------------------+
| Acute       | NOAEL =2    | FQPA SF = 1X   | Developmental toxicity |
| Dietary     | mg/kg/day   |                | -- New Zealand white   |
| (Females    |             | **aPAD** =     | rabbits;               |
| 13+)        | UF = 100X   |                |                        |
|             |             | [acute         | LOAEL = 10 mg/kg/day   |
|             | **Acute     | Rf             | based on increased     |
|             | RfD** =     | D]{.underline} | incidence of malformed |
|             | 0.02 mg/kg  |                | fetuses and litters    |
|             |             | FQPA SF        | with malformed         |
|             |             |                | fetuses.               |
|             |             | = **0.02**     |                        |
|             |             | mg/kg          |                        |
+-------------+-------------+----------------+------------------------+
| Chronic     | NOAEL=      | FQPA SF =      | Chronic oral           |
| Dietary     | **1.0**     | **1X**         | toxicity - dog;        |
|             | mg/kg/day   |                |                        |
| (All        |             | **cPAD** =     | LOAEL = 3.2 mg/kg/day  |
| p           | UF =        |                | based on liver effects |
| opulations) | **100X**    | [chronic       | (P450 induction in     |
|             |             | Rf             | females and            |
|             | **Chronic   | D]{.underline} | histopathology,        |
|             | RfD** =     |                | laminar eosinophilic   |
|             |             | FQPA SF        | intrahepatocytic       |
|             | **0.01**    |                | bodies in males).      |
|             | mg/kg/day   | = **0.01**     |                        |
|             |             | mg/kg/day      |                        |
+-------------+-------------+----------------+------------------------+
| Short-Term  | NOAEL=      | Residential    | 90-day oral toxicity - |
|             | **1.5**     | LOC for MOE =  | rat;                   |
| Incidental  | mg/kg/day   | 100            |                        |
| Oral (1-30  |             |                | LOAEL = 27.3 mg/kg/day |
| days)       |             | Occupational   | based on decreased     |
|             |             | LOC for MOE =  | body weight gain in    |
|             |             | 100            | males and increased    |
|             |             |                | liver weight in        |
|             |             |                | females.               |
+-------------+-------------+----------------+------------------------+
| Interm      |             |                |                        |
| ediate-Term |             |                |                        |
|             |             |                |                        |
| Incidental  |             |                |                        |
| Oral (1- 6  |             |                |                        |
| months)     |             |                |                        |
+-------------+-------------+----------------+------------------------+
| Short-Term  | NOAEL       | Residential    | Developmental toxicity |
| Dermal (1   | =**2**      | LOC for MOE =  | -- New Zealand white   |
| to 30 days) | mg/kg/day   | 100            | rabbits;               |
|             |             |                |                        |
|             | (dermal     | Occupational   | LOAEL = 10 mg/kg/day   |
|             | -absorption | LOC for MOE =  | based on increased     |
|             | rate =      | 100            | incidence of malformed |
|             | **11**%)    |                | fetuses and litters    |
|             |             |                | with malformed         |
|             |             |                | fetuses.               |
+-------------+-------------+----------------+------------------------+
| Interm      |             |                |                        |
| ediate-Term |             |                |                        |
|             |             |                |                        |
| Dermal (1   |             |                |                        |
| to 6        |             |                |                        |
| months)     |             |                |                        |
+-------------+-------------+----------------+------------------------+
| Long-Term   | NOAEL=      | Residential    | Chronic oral           |
| Dermal (\>6 | **1.0**     | LOC for MOE =  | toxicity - dog;        |
| months)     | mg/kg/day   | 100            |                        |
|             |             |                | LOAEL = 3.2 mg/kg/day  |
|             | (dermal     | Occupational   | based on liver effects |
|             | -absorption | LOC for MOE =  | (P450 induction in     |
|             | rate =      | 100            | females and            |
|             | **11**%)    |                | histopathology,        |
|             |             |                | laminar eosinophilic   |
|             |             |                | intrahepatocytic       |
|             |             |                | bodies in males).      |
+-------------+-------------+----------------+------------------------+
| Short-Term  | NOAEL       | Residential    | Developmental toxicity |
| Inhalation  | =**2**      | LOC for MOE =  | -- New Zealand white   |
| (1 to 30    | mg/kg/day   | 100;           | rabbits;               |
| days)       |             |                |                        |
|             | (           | Occupational   | LOAEL = 10 mg/kg/day   |
|             | inhalation- | LOC for MOE =  | based on increased     |
|             | absorption  | 100            | incidence of malformed |
|             | rate = 100% |                | fetuses and litters    |
|             | oral        |                | with malformed         |
|             | equivalent) |                | fetuses.               |
+-------------+-------------+----------------+------------------------+
| Interm      |             |                |                        |
| ediate-Term |             |                |                        |
| Inhalation  |             |                |                        |
| (1 to 6     |             |                |                        |
| months)     |             |                |                        |
+-------------+-------------+----------------+------------------------+
| Long-Term   | NOAEL=      | Residential    | Chronic oral           |
| Inhalation  | **1.0**     | LOC for MOE =  | toxicity - dog;        |
| (\>6        | mg/kg/day   | 100;           |                        |
| months)     |             |                | LOAEL = 3.2 mg/kg/day  |
|             | (           | Occupational   | based on liver effects |
|             | inhalation- | LOC for MOE =  | (P450 induction in     |
|             | absorption  | 100            | females and            |
|             | rate = 100% |                | histopathology,        |
|             | oral        |                | laminar eosinophilic   |
|             | equivalent) |                | intrahepatocytic       |
|             |             |                | bodies in males).      |
+-------------+-------------+----------------+------------------------+
| Cancer      | "Not Likely |                |                        |
|             | to be       |                |                        |
|             | C           |                |                        |
|             | arcinogenic |                |                        |
|             | to Humans." |                |                        |
+-------------+-------------+----------------+------------------------+

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL =
no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect
level, PAD = population-adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable.

[]{#__RefHeading___Toc182970198 .anchor}**3.6 Endocrine Disruption**

EPA is required under the Federal Food, Drug and Cosmetic Act (FFDCA),
as amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate. Following 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.

[]{#__RefHeading___Toc182970199 .anchor}**4.0 Dietary Exposure/Risk
Characterization**

References:

Residue Chemistry Summary - D349906, G. Kramer, 27-FEB-2008

Dietary Exposure - D349907, M. Sahafeyan, 28-FEB-2008

Estimated Drinking Water Concentrations & Environmental Degradation -
D343771, J. Hetrick, 11-SEP-2007

[]{#__RefHeading___Toc182970200 .anchor}**4.1 Pesticide Metabolism and
Environmental Degradation**

[]{#__RefHeading___Toc182970201 .anchor}**4.1.1 Metabolism in Primary
Crops**

The nature of cyproconazole residues in plants is adequately understood
for purposes of this petition, provided that questions are resolved
pertaining to the stability of ^14^C-residues in an earlier wheat
metabolism study using \[triazole-^14^C\]cyproconazole. Plant metabolism
data are available from studies using \[^14^C\]cyproconazole on coffee,
apples, grapes, and wheat. Although several of the studies are not fully
acceptable, their results have been relatively consistent with respect
to the major residues identified in plants. The metabolism of
cyproconazole in plants involves (i) hydroxylation of the methyl- and
cyclopropyl-substituted carbon to form Metabolites M9/M14; (ii)
oxidation of the methyl group to form Metabolites M11/M18; (iii)
elimination of the cyclopropyl-substituted carbon to form the benzylic
alcohol (M15) and further oxidation to the ketone (M16); (iv)
hydroxylation of the cyclopropyl ring and the phenyl ring; (v)
conjugation of parent and hydroxylated metabolites to form various
glycosides; and (vi) oxidative elimination of the triazole ring and its
subsequent conversion to triazole alanine.

[]{#__RefHeading___Toc182970202 .anchor}**4.1.2 Metabolism in Rotational
Crops**

Although the confined rotational crop study contained numerous
deficiencies, the available data suggest that the primary route of
metabolism for cyproconazole in rotated crops involves hydroxylation of
either the carbon bearing the cyclopropyl group (Metabolites M9/M14) or
hydroxylation of the methyl group (Metabolites M11/M18). These primary
metabolites and parent also appeared to form conjugates. Although the
data are tentative, the metabolism of cyproconazole in rotational crops
appears to be similar to primary crops. The study also indicates that
residues of parent may occur at levels \>0.01 ppm in rotated crops
planted up to 90 days following applications totaling 0.089 lb
ai/A/season (1.2X the maximum seasonal rate for soybeans).

[]{#__RefHeading___Toc182970203 .anchor}**4.1.3 Metabolism in
Livestock**

The nature of cyproconazole residues in livestock is also adequately
understood for purposes of this petition, provided that the outstanding
deficiencies related to the goat metabolism study are adequately
resolved. The submitted poultry metabolism study is adequate. Although
incomplete, the available data indicate that the metabolism of
cyproconazole is similar in ruminants and poultry. The major routes of
metabolism involved either hydroxylation of the carbon bearing the
cyclopropyl group to form M9 and M14 or elimination of the
methyl-cyclopropyl side chain (M16) followed by reduction (M15).
Hydroxylation of the methyl group (M11 and M18) was also a major route
of metabolism, as was opening and modification of the cyclopropyl ring
(M21, M36, M56, M57, and M59). The data indicate that there is only
limited cleavage of the triazole ring and that the majority of residues
retain the intact phenyl and triazole rings. See Appendix B for the
proposed metabolic pathway in laying hens.

[]{#__RefHeading___Toc182970204 .anchor}**4.1.4 Analytical Methodology**

An adequate gas chromatograph/nitrogen-phosphorus detection (GC/NPD)
method is available for enforcing tolerances of cyproconazole (free and
conjugated) on plant commodities (Method AM-8022-0994-3). An improved
version of this method is also available, which includes mass-selective
detection (MSD). As the extraction and purification procedures for the
two methods are identical, a copy of Method AM-0842-0790-0 will be
forwarded to the Food and Drug Administration (FDA) for inclusion in the
Pesticide Analytical Method Volume II (PAM II), as it is superior to the
current enforcement method. In the current petition, the GC/MSD method
(Method AM-0842-0790-0) was used to collect data on cyproconazole
residues in corn, soybean and wheat commodities. In addition, a liquid
chromatography with tandem mass spectrometry (LC-MS/MS) method (Morse
Method #Meth-160) was used in the corn, soybean, and wheat field trials
and processing studies to collect data on residues of triazole, TA and
TAA in plant commodities. Both of these methods were adequately
validated in conjunction with the field trials and processing studies.
The method limit of quantitation (LOQ) is 0.01 ppm for cyproconazole and
each of the triazole residues.

For enforcing the proposed tolerances on livestock commodities, Syngenta
provided a copy of a LC-MS/MS method (Syngenta Method RAM 499/01) for
determining free and conjugated cyproconazole in milk, eggs and
livestock tissues. For this method, free and conjugated cyproconazole
residues are extracted with acetonitrile (ACN):water and hydrolyzed
using either concentrated ammonia (eggs and tissues) or 2M HCl (milk).
Cyproconazole residues are then determined by LC-MS/MS using external
standards. The method LOQ is 0.01 ppm for cyproconazole in each
livestock commodity. Method RAM 499/01 was used for collecting
cyproconazole residue data in the submitted cattle and poultry feeding
studies, and was adequately validated in conjunction with these studies.
The method has also undergone a successful ILV trial and was
radiovalidated using samples from a goat dosed with
\[^14^C\]cyproconazole. A copy of Method RAM 499/01 will be forwarded to
the Analytical Chemistry Branch (ACB) for evaluation as an enforcement
method. As M14 in ruminant liver and M36 in milk need to be included in
the tolerance expression, enforcement methods will be required for these
residues. HED thus requests that the petitioner submits ILVs of the
HPLC/MS method for Metabolite M14 in liver and the high-performance
liquid chromatography/ultraviolet (HPLC/UV) method for M36 in milk.
Radiovalidation data should also be submitted. Once the ILVs and
radiovalidation data are submitted, the methods will be forwarded to ACB
for evaluation as enforcement methods.

[]{#__RefHeading___Toc182970205 .anchor}**4.1.5 Environmental
Degradation**

Probable cyproconazole dissipation pathways are microbial-mediated
degradation, leaching, surface water runoff, and spray drift.
Cyproconazole is stable to hydrolysis and photodegradation. It slowly
degrades in aerobic soil (t~1/2~=329 days) and aerobic/anaerobic aquatic
environments (t~1/2~= 2,895 days). Degradation products include
2-amino-3-(1-*H*-1,1,2,4-triazol-tyl) propanoic acid and CO~2~. Triazole
acetic acid, triazole aniline and triazole were not identified as
environmental degradation products of cyproconazole.

[]{#__RefHeading___Toc182970206 .anchor}**4.1.6 Comparative Metabolic
Profile**

The metabolism of cyproconazole in plants and livestock involves (i)
hydroxylation of the methyl- and cyclopropyl-substituted carbon to form
Metabolites M9/M14; (ii) oxidation of the methyl group to form
Metabolites M11/M18; (iii) elimination of the cyclopropyl-substituted
carbon to form the benzylic alcohol (M15) and further oxidation to the
ketone (M16). Further metabolism of cyproconazole in plants involves (i)
hydroxylation of the cyclopropyl ring and the phenyl ring; (ii)
conjugation of parent and hydroxylated metabolites to form various
glycosides; and (iii) oxidative elimination of the triazole ring and its
subsequent conversion to triazole alanine. Further metabolism of
cyproconazole in livestock involves opening and modification of the
cyclopropyl ring (M21, M36, M56, M57, and M59). In rats, cyproconazole
is extensively metabolized; parent + 13 metabolites were identified and
isolated; 35 metabolites were detected; metabolic profiles for urine,
feces and bile were similar; major metabolic reactions include oxidative
elimination of triazole ring; hydroxylation of the C bearing CH~3~ group
(M9/M14); oxidation of CH~3~ group to carbinol and further oxidation to
carboxylic acid; rapid excretion occurred with the majority of the total
administered dose appearing in feces (biliary excretion). The primary
residue in urine and feces was the parent compound and a metabolite
identified as M9/M14 (a diol metabolite of cyproconazole).

[]{#__RefHeading___Toc182970207 .anchor}**4.1.7 Toxicity Profile of
Major Metabolites and Degradates**

Rat metabolism studies indicate that urine was found to contain at least
21 metabolite fractions by two-dimensional TLC (thin layer
chromatography). Feces were found to contain at least 13 metabolite
fractions by two- dimensional TLC. The primary residue in urine and
feces was the parent compound and a metabolite identified as NOA 421153
(a diol metabolite of cyproconazole). Toxicity data are only available
on Metabolite M-36. M-36 is not acutely toxic by the oral route of
exposure. In 4-week subchronic toxicity studies in rats, the only toxic
effects were attributed to malnutrition. M-36 was not mutagenic in a
bacterial reverse mutation (Ames) test. It is unlikely that
cyproconazole metabolites are more toxic than the parent compound since
they would probably be conjugated and/or hydroxylated (polar) products
which are likely to be excreted rapidly.

+-------+------------+---------------+---------------------------------+
| **    |            |               |                                 |
| Table |            |               |                                 |
| 4     |            |               |                                 |
| .1.7. |            |               |                                 |
| Tox   |            |               |                                 |
| icity |            |               |                                 |
| Pr    |            |               |                                 |
| ofile |            |               |                                 |
| of    |            |               |                                 |
| Cyp   |            |               |                                 |
| rocon |            |               |                                 |
| azole |            |               |                                 |
| Meta  |            |               |                                 |
| bolit |            |               |                                 |
| es.** |            |               |                                 |
+=======+============+===============+=================================+
| *     | **Study    | **MRID No.    | **Results**                     |
| *Guid | Type**     | (year)/       |                                 |
| eline |            | C             |                                 |
| No.** |            | lassification |                                 |
|       |            | /Doses**      |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | Acute oral | 43674701      | LD~50~ = 2054 mg/kg in males    |
| .1100 | toxicity   | (1992)        | and females                     |
|       |            |               |                                 |
|       | (rat)      | Accepta       |                                 |
|       |            | ble/guideline |                                 |
|       |            |               |                                 |
|       |            | M-36          |                                 |
|       |            | Metabolite    |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | Acute oral | 43674732      | LD~50~ \> 2000 mg/kg in males   |
| .1100 | toxicity   | (1995)        | and females                     |
|       |            |               |                                 |
|       | (mouse)    | Accepta       |                                 |
|       |            | ble/guideline |                                 |
|       |            |               |                                 |
|       |            | M-36          |                                 |
|       |            | Metabolite    |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | 4-Week     | 43674702      | NOAEL = 2800 ppm (366           |
| .3100 | oral       | (1994)        | mg/kg/day)                      |
|       | toxicity   |               |                                 |
|       | (rat)      | S             | LOAEL was not determined.       |
|       |            | upplementary/ |                                 |
|       |            | non-guideline |                                 |
|       |            |               |                                 |
|       |            | 0, 20, 200,   |                                 |
|       |            | 800 or 2800   |                                 |
|       |            | ppm           |                                 |
|       |            |               |                                 |
|       |            | 0, 2.5, 25,   |                                 |
|       |            | 99 and 366    |                                 |
|       |            | mg/kg/d       |                                 |
|       |            |               |                                 |
|       |            | M-36          |                                 |
|       |            | Metabolite    |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | 4-Week     | 43674703      | NOAEL = 1500 ppm (M/F: 155/176  |
| .3100 | oral       | (1995)        | mg/kg/day)                      |
|       | toxicity   |               |                                 |
|       | (rat)      | S             | LOAEL = 5000 ppm (M/F: 527/528  |
|       |            | upplementary/ | mg/kg/day) base on malnutrition |
|       |            | non-guideline | as indicated by various         |
|       |            |               | changes; i.e., decreased food   |
|       |            | 0, 1500, 5000 | efficiency and body weight      |
|       |            | or 20000 ppm  | gains in females, clinical      |
|       |            |               | chemistry changes, decreased    |
|       |            | M: 0, 155,    | organ weights, small seminal    |
|       |            | 527 and 2008  | vesicles, uteri and thymus, and |
|       |            | mg/kg/d       | microscopic lesions in most     |
|       |            |               | organs examined.                |
|       |            | F: 0, 176,    |                                 |
|       |            | 528 and 2126  |                                 |
|       |            | mg/kg/d       |                                 |
|       |            |               |                                 |
|       |            | M-36          |                                 |
|       |            | Metabolite    |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | Bacterial  | 43692601      | Negative                        |
| .5100 | Reverse    | (1990)        |                                 |
|       |            | Accepta       |                                 |
|       | Mutation   | ble/guideline |                                 |
|       | Test       |               |                                 |
|       |            | 8-5000        |                                 |
|       |            | μg/plate (+/- |                                 |
|       |            | S9)           |                                 |
|       |            |               |                                 |
|       |            | 312.5-5000    |                                 |
|       |            | μg/plate (+/- |                                 |
|       |            | S9)           |                                 |
|       |            |               |                                 |
|       |            | M-36          |                                 |
|       |            | Metabolite    |                                 |
+-------+------------+---------------+---------------------------------+

8.  []{#__RefHeading___Toc182970208 .anchor}**Pesticide Metabolites and
    Degradates of Concern**

*Plants*

Cyproconazole (free and conjugated) was the only significant (\>10%)
residue identified in the plant metabolism studies (other than the
triazole-related metabolites). HED has also determined that
1,2,4-triazole, TA and TAA are also potential residues of concern in
plants and livestock for all triazole fungicides. However, these
triazole-related residues will not be regulated for specific triazole
pesticides, but will be evaluated for the entire class of triazole
compounds. HED has recently completed a comprehensive risk assessment
considering triazole, TA and TAA based on established and proposed uses
of triazole fungicides as of September 2005 (DP# 322215, M. Doherty *et
al.*, 2/7/06). Along with other uses, this risk assessment considered
the use of cyproconazole on soybeans and the use of related triazole
fungicides on wheat and corn. Triazole-related residues from the
application of cyproconazole to the subject crops will not be
sufficiently different from those used in the previous risk assessment.
Therefore, a separate risk assessment for these triazole-related
residues will not be required for the current petition.

*Livestock*

The available toxicity data for M36 (the major metabolite in milk) show
that the metabolite is less acutely toxic than the parent. However, as
the metabolite is closely related to the parent and no data addressing
chronic toxicity are available, the M36 metabolite is considered as
toxic as the parent in this risk assessment. As there are no toxicity
data for M14 and M15, they are considered as toxic as the parent. These
metabolites will thus be included in the tolerance expression for
tissues in which they comprise a significant portion of the toxic
residue (i.e., M36 in milk, M14 in ruminant liver, and M14 + M15 in
poultry commodities).

*Water*

As no major environmental degradates were identified, the residue of
concern in the risk assessment for drinking water is cyproconazole only.

  -------------------------------------------------------------------------
  **Table 4.1.8.                                       
  Summary of                                           
  Metabolites and                                      
  Degradates to                                        
  be included in                                       
  the Risk                                             
  Assessment and                                       
  Tolerance                                            
  Expression.**                                        
  --------------- --------------- -------------------- --------------------
  Matrix                          Residues included in Residues included in
                                  Risk Assessment      Tolerance Expression

  Plants          Primary Crops   Cyproconazole (free  Cyproconazole (free
                                  and conjugated)      and conjugated)

                  Rotational      Cyproconazole (free  Not Applicable
                  Crops           and conjugated)      

  Livestock       Ruminant, milk  Cyproconazole (free  Cyproconazole (free
                                  and conjugated) +    and conjugated) +
                                  M36                  M36

                  Ruminant, liver Cyproconazole (free  Cyproconazole (free
                                  and conjugated) +    and conjugated) +
                                  M14                  M14

                  Ruminant, meat, Cyproconazole (free  Cyproconazole (free
                  meat byproducts and conjugated)      and conjugated)
                  (except liver),                      
                  and fat                              

                  Poultry         Cyproconazole (free  Cyproconazole (free
                                  and conjugated) +    and conjugated) +
                                  M14 and M15          M14 and M15

  Drinking Water                  Cyproconazole        Not Applicable
  -------------------------------------------------------------------------

[]{#__RefHeading___Toc182970209 .anchor}**4.1.9 Drinking Water Residue
Profile**

Probable cyproconazole dissipation pathways are microbial-mediated
degradation, leaching, surface water runoff, and spray drift.
Cyproconazole is stable to hydrolysis and photodegradation. It slowly
degrades in aerobic soil (t~1/2~=329 days) and aerobic/anaerobic aquatic
environments (t~1/2~= 2,895 days). Degradation products include
2-amino-3-(1-H-1,1,2,4-triazol-tyl) propanoic acid and CO~2~. TAA, TA
and triazole were not identified as environmental degradation products
of cyproconazole. Cyproconazole is moderately mobile in soil (FAO
Mobility Classification,
[http://www.fao.org](http://www.fao.org/)/DOCREP/003
/X2570E/X2570E06.htm).

The drinking water assessment for parent cyproconazole is based on Tier
I modeling. Tier I FIRST modeling indicates that PCA-corrected
cyproconazole concentrations in surface source drinking water are not
expected to exceed 1.14 µg/L for the annual peak concentration and 0.11
µg/L for the annual concentration. Tier I SCI-GROW modeling indicates
the peak and chronic cyproconazole concentration in shallow groundwater
is not expected to exceed 0.05 µg/L.

The degradation products 1,2,4-triazole and triazole conjugates (*i.e.*
TA and TAA) are not addressed in this assessment. Although cyproconazole
is a triazole fungicide, laboratory environmental fate studies do not
show formation of 1,2,4-triazole and triazole conjugates (i.e., TA and
TAA) in soil or aquatic environments. Additionally, the drinking water
assessment for 1,2,4-triazole and triazole conjugates was conducted for
the group of triazole fungicides (D320682).

  ------------------------------------------------------------------------
  **Table 4.1.9. Summary of                         
  Estimated Surface Water                           
  and Groundwater                                   
  Concentrations for                                
  Cyproconazole.**                                  
  -------------------------- ---------------------- ----------------------
                             **Cyproconazole *per   
                             se***                  

                             **Surface Water Conc., **Groundwater Conc.,
                             ppb^a^**               ppb ^b^**

  Acute                      1.14                   0.05

  Chronic (non-cancer)       0.11                   0.05
  ------------------------------------------------------------------------

^a^ From the FIRST (Version 1.1, 12/12/05) model. Input parameters are
based on 0.036 lbs a.i./acre per application with a 14 day minimum
interval between applications and two applications per season
(soybeans). The PCA factor was 0.83.

^b^ From the SCI-GROW model assuming a maximum seasonal use rate of
0.036 lbs ai/A, a K~oc~ of 364 L/kg-OC, and a half-life of 228.64 days.

[]{#__RefHeading___Toc182970210 .anchor}**4.1.10 Food Residue Profile**

Adequate numbers of field corn, soybean and wheat field trials were
conducted in the appropriate regions at 1x the maximum use rates.
Although soybean forage and hay samples were not collected in four of
the soybean trials, sufficient residue data are available on forage and
hay to establish tolerances on these livestock feedstuffs. The available
data also support the use of low-volume applications on corn, soybeans
and wheat. In addition, storage stability data for triazole-related
residues are required to support the triazole, TA and TAA residue data
from the field trials.

In the corn field trials conducted at the 1x rate, cyproconazole
residues were \<0.01-0.44 ppm in/on forage harvested at 19-22 days after
treatment (DAT), and \<0.01-1.50 ppm in/on stover harvested at 27-31
DAT. Residues were \<0.01 ppm in/on all grain samples harvested at 27-31
DAT, including grain from applications at a 5x rate. Average free and
conjugated cyproconazole residues were 0.12 ppm on forage, 0.31 ppm on
stover, and \<0.01 ppm on grain. The residue decline trials indicated
that cyproconazole residues declined slightly in forage from 0 to 28
DAT, but remained relative steady in stover from 7 to 38 DAT.

In the soybean field trials conducted at the 1x rate, cyproconazole
residues were 0.05-0.82 ppm in/on forage and 0.07-1.90 ppm in/on hay
harvested at 14-15 DAT following the first application. Residues were
\<0.01-0.047 ppm in/on mature seeds harvested at 27-31 DAT following the
second application. Average residues were 0.35 ppm on forage, 0.61 ppm
on hay and 0.02 ppm on seeds. Data from the three residue decline trials
showed that cyproconazole residues declined on forage and hay from 0 to
14 DAT, but remained relatively constant on seeds from 9 to 37 DAT.

In the wheat field trials conducted at the 1x rate, free and conjugated
cyproconazole residues were \<0.01-0.70 ppm in/on forage and \<0.01-1.32
ppm in/on hay harvested at 19-23 DAT. At maturity (28-35 DAT),
cyproconazole residues were \<0.01-0.77 ppm in/on straw and \<0.01-0.03
ppm in/on grain. Average cyproconazole residues were 0.17 ppm on forage,
0.31 ppm on hay, 0.22 ppm on straw and 0.01 ppm on grain. In the residue
decline trials, cyproconazole residues were shown to decline at longer
post-treatment intervals on forage, hay and straw, but decline could not
be determined for grain, as all samples had residues \<LOQ.

Adequate field corn, soybean and wheat processing studies are also
available depicting the potential for concentration of cyproconazole
residues in processed commodities. These processing studies also
provided data on triazole, TA and TAA residues in processed fractions;
however, storage stability data for triazole-related residues are
required to support these data.

For cyproconazole, residues in corn grain and all processed fractions
were \<LOQ following a 5x application to field corn; however, the study
did indicate that there was the potential for at least at 5.8x
concentration in aspirated grain fractions (AGF) derived from corn. For
soybeans, cyproconazole residues concentrated on average by 14x in
soybean AGF and 1.6x in refined oil, but did not concentrate in soybean
meal (0.7x) or hulls (0.8x). For wheat grain, two processing studies are
available. In the most recent wheat processing study, cyproconazole
residues concentrated on average by 32x in AGF, 1.8x in bran, 2.8x in
shorts, and 3.6x in germ, but did not concentrate substantially in
either flour (0.8x) or middlings (1.1x). In the earlier wheat grain
processing study, cyproconazole residues were also shown to concentrate
in wheat grain AGF (220x) and bran (1.2x). Considering data from both
wheat studies, the processing factors for wheat are 126x for AGF, 3.6x
for wheat milled byproducts, and \<1x for flour.

In one cattle feeding study, dairy cows were dosed orally via capsule
once a day for 29-30 days with cyproconazole at levels equivalent to
2.4, 6.9 and 22.3 ppm in the diet (1.5x, 4.3x, and 14x the MDB). In an
earlier cattle feeding study, dairy cows were dosed orally twice a day
for 35-38 days using feed fortified with cyproconazole at 1, 3, 10, and
30 ppm (0.6x, 1.9x, 6.3x and 19x the MDB). With regards to cyproconazole
residues, the results from the two feeding studies are similar. In both
studies, cyproconazole residues were quantifiable (\>0.01 ppm) in liver
samples from all dosing levels (0.6x-19x the MDB), and the
concentrations in liver were dose dependent. Cyproconazole residues were
also detected at ≥0.01 ppm in kidneys and fat from dosing levels
equivalent to 4.3x-19x the MDB, but were \<0.01 ppm in kidney and fat
from dosing levels equivalent to 0.6x-1.9x. For muscle, cyproconazole
residues were \<0.01 ppm in samples from all dose groups up to 19x the
MDB, and quantifiable residues in milk (\>0.01 ppm) were detected only
in samples from the highest dose groups (14x and 19x MDB).

Using residue data from the 1.5x and 1.9x dose groups, the maximum
expected cyproconazole residues in cattle commodities at 1x the MDB
would be \<0.01 ppm in kidney, muscle, fat and milk and 0.053-0.115 ppm
in liver. Although quantifiable residues are only expected in liver at a
1x feeding level, quantifiable residues (≥0.01 ppm) were detected in
milk, kidneys and fat at the 14x and 19x dose levels in both studies;
therefore, tolerances will be required for these commodities at the
method LOQ. However, a separate tolerance for meat is not required as
cyproconazole residues were \<0.01 ppm at dosing levels equivalent to
14x and 19x the MBD. The levels of Metabolites M36 and M14 at a 1x
feeding level were calculated using the maximum residue values from the
3-ppm dose group (1.9x MDB). At a 1x feeding level, residues of
Metabolite M36 in milk are estimated to be 0.0132 ppm, and residues of
Metabolite M14 in liver are estimated to be 0.289 ppm. Thus, the
appropriate tolerance level for cyproconazole plus M14 in ruminant liver
is 0.50 ppm and for cyproconazole plus M36 in milk is 0.02 ppm.

The dosing levels in the cattle feeding studies are equivalent to
16x-476x the MDB for swine. Using the residue data from the cattle
feeding study, cyproconazole residues would be \<0.01 ppm in all hog
commodities at a feeding level equivalent to 1x the MDB, and residues
would only be quantifiable in liver (0.02-0.06 ppm) at 10x the MDB.
Therefore, tolerances are not required for hog fat and meat, and the
tolerance for hog liver should be set at 0.01 ppm.

In the poultry feeding study, laying hens were dosed orally for 29 days
with cyproconazole in the feed at actual concentrations of 0.12, 0.45
and 1.87 ppm (1.6x, 6x, and 25x the MDB for poultry). Residues of
cyproconazole were \<0.01 ppm in all samples of eggs and tissues from
the 25x dose group. The data from the poultry feeding study indicate
that quantifiable residues of cyproconazole are unlikely to occur in
eggs or poultry at 10x the MDB. In addition, data from the feeding study
and hen metabolism study also indicate that the other residues of
concern in poultry (M14, M15, triazole, TA and TAA) will also be \<LOQ
at 10x the MDB. Therefore, tolerances are not required for poultry
commodities \[40 CFR 180.6(a)(3)\]. However, if in the future, proposed
new uses result in an increase in the MDB, then a new poultry feeding
study which includes data for Metabolites M14 and M15 may be required.

Adequate storage stability data are available indicating that
cyproconazole is stable under frozen storage conditions for up to 27-40
months in a variety of plant matrices, including grapes, raisins, stone
fruits, peanuts (forage, hay, nutmeats and hulls, meal, oil and
soapstock), and wheat forage, grain and hay. Adequate data are also
available indicating that cyproconazole is stable in frozen milk and
cattle tissues for 9-12 months, Metabolite M14 is stable in frozen
kidney and liver for up to 20 months, and Metabolite 21a is stable in
frozen milk for up to 12 months. However, Metabolite M36 was shown to
decline by approximately 40% in frozen milk over 12 months of storage.
For cyproconazole and Metabolites M14, M21a, and M36, these data
adequately support the sample storage conditions and intervals from the
submitted field trials, processing studies, and feeding studies.
However, no data are available to support the stability of the
triazole-related residues (triazole, TA and TAA) in plant and livestock
commodities.

Adequate data are available from a limited field rotational crop study
reflecting a 60-day PBI. In the two limited field trials, free and
conjugated cyproconazole residues in the representative rotational crops
from the 60-day PBI were \<0.01 ppm in/on all samples of spinach leaves,
radish roots, and wheat forage, hay, straw and grain; however, two out
of four samples of radish tops had cyproconazole residues of 0.010-0.012
ppm. These data support the proposed rotational crop restrictions, which
allow for the immediate replanting of corn, soybean and wheat and
specify a 60-day PBI for leafy vegetables and cereal grains other than
wheat, and a 365-day PBI for all other crops.

A summary of the recommended tolerances for the current petition are
listed in Section 9.1. The petitioner should submit a revised Section F
reflecting the recommended tolerances and commodity definitions
presented in Section 9.1.

The Agency's *Guidance for Setting Pesticide Tolerances Based on Field
Trial Data* was utilized for determining appropriate tolerance levels
for corn forage and stover, soybean forage and hay, and wheat forage,
hay and straw were determined using the tolerance harmonization
spreadsheet, as residue levels of cyproconazole in these commodities
were generally above the method LOQ. However, the recommended tolerance
levels of corn grain, soybean seed and wheat grain were based on the
maximum observed residues levels, as \>50% of the samples for these
commodities had residues ≤LOQ.

Based on highest-average field trial (HAFT) residues of cyproconazole
for corn grain (\<0.01 ppm), soybean seeds (0.045 ppm) and wheat grain
(0.02 ppm) from the field trials and the available processing data,
separate tolerances for cyproconazole are not required for any corn
grain processed fractions, soybean meal and hulls, or wheat flour.
However, separate tolerances are required for soybean oil, wheat milled
byproducts and AGF. Based on a 1.6x processing factor and HAFT residues
at 0.045 ppm, the maximum expected residues in soybean oil would be
0.072 ppm. Based on the 3.6x processing factor for wheat germ and HAFT
residues at 0.02 ppm, the maximum expected residues in wheat milled
byproducts would be 0.072 ppm. These data will support separate
tolerances for cyproconazole residues at 0.1 ppm in soybean oil and
wheat milled byproducts.

Based on the various concentration factors for AGF from corn (5.8x),
soybeans (14x) and wheat (126x), and their respective HAFT residues, the
maximum expected cyproconazole residues are \<0.06 ppm in corn grain
AGF, 0.63 ppm in soybean AGF, and 2.52 ppm in wheat grain AGF.
Therefore, the tolerance for AGF should be set at 2.5 ppm based on the
wheat grain data.

[]{#__RefHeading___Toc182970211 .anchor}**4.1.11 International Residue
Limits**

There are no established or proposed Canadian or Codex maximum residue
limits (MRLs) for cyproconazole on food or feed crops. Mexico has
established tolerances for cyproconazole at 0.05 ppm in barley and wheat
grain, which is equivalent to the recommended U.S. tolerance for wheat
grain. Therefore, there are generally no questions about the
compatibility of the proposed tolerances with international tolerances.
However, HED notes that Japan has established numerous tolerances for
cyproconazole, including MRLs on wheat (0.2 ppm), corn (0.1 ppm), and
soybeans (0.05 ppm).

[]{#__RefHeading___Toc182970212 .anchor}**4.2 Dietary Exposure and
Risk**

Cyproconazole acute and chronic dietary exposure assessments were
conducted using the DEEM-FCID™, Version 2.03 which incorporates
consumption data from USDA's Continuing Surveys of Food Intakes by
Individuals (CSFII), 1994-1996 and 1998. The 1994-96, 98 data are based
on the reported consumption of more than 20,000 individuals over two
non-consecutive survey days. Foods "as consumed" (e.g., apple pie) are
linked to EPA-defined food commodities (e.g., apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA. For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events. Based on analysis of the 1994-96, 98
CSFII consumption data, which took into account dietary patterns and
survey respondents, HED concluded that it is most appropriate to report
risk for the following population subgroups: the general U.S.
population, all infants (\<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis. The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or "matched" in multiple random
pairings with residue values and then summed in a probabilistic
assessment. The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e*.*, those
who reported eating the relevant commodities as well as those who did
not) basis. In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis. However, for Tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

For chronic dietary exposure assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate. The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure. Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD. This procedure is performed for each
population subgroup.

As stated above, for acute and chronic assessments, HED is concerned
when dietary risk exceeds 100% of the PAD. The DEEM-FCID™ analyses
estimate the dietary exposure of the U.S. population and various
population subgroups. The result of the acute dietary exposure estimate
is for females 13-49 years old as an endpoint of concern attributable to
a single dose for general population was not identified. The results of
the chronic dietary exposure estimates reported in Table 4.2 are for the
general U.S. population, all infants (\<1 year old), children 1-2,
children 3-5, children 6-12, youth 13-19, females 13-49, adults 20-49,
and adults 50+ years.

The acute and chronic analyses assumed tolerance-level residues, 100% CT
information, and DEEM default processing factors. Therefore, these
analyses were considered conservative and could be further refined if
needed through the use of anticipated residues for all commodities,
percent market share data for the proposed commodities, percent of crop
treated data for registered commodities, and/or empirical processing
factors.

[]{#__RefHeading___Toc182970213 .anchor}**4.2.1 Acute Dietary Risk
Characterization (Females 13-49 years old)**

The acute (food + water) exposure risk estimate for females 13-49 years
old was 3% aPAD at the 95^th^ percentile of the exposure distribution,
and is not of concern to HED.

[]{#__RefHeading___Toc182970214 .anchor}**4.2.2 Chronic Dietary Risk
Characterization**

The chronic (food + water) exposure estimates were \<100% cPAD for U.S.
general population (4% cPAD) and all population sub-groups; the most
highly exposed population subgroup was children 1-2 years old with 13%
cPAD. Therefore, the chronic dietary exposure to cyproconazole is not of
concern to HED.

+-----------------+---------+-------+---------+-----------------------+
| **Table 4.2.2.  |         |       |         |                       |
| Dietary         |         |       |         |                       |
| Exposure and    |         |       |         |                       |
| Risk for        |         |       |         |                       |
| C               |         |       |         |                       |
| yproconazole.** |         |       |         |                       |
+=================+=========+=======+=========+=======================+
| Population      | Acute   |       | Chronic |                       |
| Subgroup        | Die     |       | Dietary |                       |
|                 | tary^1^ |       |         |                       |
|                 |         |       |         |                       |
|                 | (95     |       |         |                       |
|                 | Perc    |       |         |                       |
|                 | entile) |       |         |                       |
+-----------------+---------+-------+---------+-----------------------+
|                 | Dietary | \%    | Dietary | \% cPAD\*             |
|                 |         | a     | E       |                       |
|                 | E       | PAD\* | xposure |                       |
|                 | xposure |       |         |                       |
|                 | (mg/    |       | (mg/    |                       |
|                 | kg/day) |       | kg/day) |                       |
+-----------------+---------+-------+---------+-----------------------+
| General U.S.    | N/A     |       | 0       | 3.8                   |
| Population      |         |       | .000376 |                       |
+-----------------+---------+-------+---------+-----------------------+
| All Infants (\< |         |       | 0       | 4.8                   |
| 1 year old)     |         |       | .000480 |                       |
+-----------------+---------+-------+---------+-----------------------+
| Children 1-2    |         |       | 0       | 13                    |
| years old       |         |       | .001264 |                       |
+-----------------+---------+-------+---------+-----------------------+
| Children 3-5    |         |       | 0       | 10                    |
| years old       |         |       | .001015 |                       |
+-----------------+---------+-------+---------+-----------------------+
| Children 6-12   |         |       | 0       | 6.6                   |
| years old       |         |       | .000663 |                       |
+-----------------+---------+-------+---------+-----------------------+
| Youth 13-19     |         |       | 0       | 3.6                   |
| years old       |         |       | .000356 |                       |
+-----------------+---------+-------+---------+-----------------------+
| Adults 20-49    |         |       | 0       | 2.7                   |
| years old       |         |       | .000265 |                       |
+-----------------+---------+-------+---------+-----------------------+
| Adults 50+      |         |       | 0       | 2.3                   |
| years old       |         |       | .000229 |                       |
+-----------------+---------+-------+---------+-----------------------+
| Females 13-49   | 0       | 2.9   | 0       | 2.6                   |
| years old       | .000585 |       | .000261 |                       |
+-----------------+---------+-------+---------+-----------------------+

^1^ Acute toxicity endpoint was determined only for females 13-49 years
old.

[]{#__RefHeading___Toc182970215 .anchor}**5.0 Residential
(Non-Occupational) Risk**

There are no existing or proposed residential uses for cyproconazole.
All turf uses have been withdrawn. Therefore, a residential assessment
was not necessary.

[]{#__RefHeading___Toc182970216 .anchor}**6.0 Aggregate Risk
Assessments**

Acute and chronic aggregate risks were assessed based on dietary
exposure from food and drinking water sources. Since there are no
residential uses, short- and intermediate-term aggregate risks were not
assessed. Cancer aggregate risk was not assessed since a cancer risk
assessment is not needed.

HED has also determined that 1,2,4-triazole, TA and TAA are also
potential residues of concern in plants and livestock for all triazole
fungicides. However, these triazole-related residues will not be
regulated for specific triazole pesticides, but will be evaluated for
the entire class of triazole compounds. HED has recently completed a
comprehensive risk assessments considering 1,2,4-triazole and TA + TAA
based on established and proposed uses of triazole fungicides. These
risk assessments were last updated in October 2007 (DP#: 341803 and DP#:
344298, M. Sahafeyan, 10/30/07; note: separate memorandums). Along with
other uses, these risk assessments considered the use of cyproconazole
on soybeans and the use of related triazole fungicides on wheat and
corn. Triazole-related residues from the application of cyproconazole to
the subject crops will not be sufficiently different from those used in
the in the previous risk assessment. Therefore, a separate risk
assessment for these triazole-related residues will not be required for
the current petition.

[]{#__RefHeading___Toc182970217 .anchor}**6.1 Acute Aggregate Risk**

No acute residential exposures are expected. Since the acute dietary
assessment included food and water only, the exposures in Table 4.2.2
represent aggregate exposures. The Tier 1 acute dietary analysis (food
and water) resulted in an exposure estimate for females 13-49 years old
of 3% aPAD (Table 4.2.2). The resulting risk estimate for females 13-49
years old is thus not of concern to HED. An acute endpoint of concern
was not identified for the general population including infants and
children.

[]{#__RefHeading___Toc182970218 .anchor}**6.2 Chronic Aggregate Risk**

No chronic residential exposures are expected. Since the chronic dietary
assessment included food and water only, the exposures in Table 5.2
represent aggregate exposures. The chronic (food + water) exposure
estimates were \<100% cPAD for U.S. general population (4% cPAD) and all
population sub-groups; the most highly exposed population subgroup was
children 1-2 years old with 13% cPAD. Therefore, the chronic dietary
exposure to cyproconazole is not of concern to HED.

7.  []{#__RefHeading___Toc182970219 .anchor}**Cumulative Risk
    Characterization**

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding for cyproconazole and any other
substance, and cyproconazole does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, EPA has not assumed that cyproconazole does
not have a common mechanism of toxicity with other substances. For
information regarding EPA's efforts to determine which chemicals have a
common mechanism of toxicity and to evaluate the cumulative effects of
such chemicals, see the policy statements released by EPA's Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA's website at
[[http://www.epa.gov/pesticides/cumulative/.]{.underline}](http://www.epa.gov/pesticides/cumulative/.)

[]{#__RefHeading___Toc182970220 .anchor}**8.0 Occupational Risk
Assessment**

Reference: Memo, K. Lowe, D330711, 9/06/2007.

Based on the proposed uses in/on corn, soybean and wheat, occupational
exposure is expected. The use pattern for the proposed uses is described
below in Table 8.0.

+-----+-----+-------+------+-------+------+--------------------------+
| *   |     |       |      |       |      |                          |
| *Ta |     |       |      |       |      |                          |
| ble |     |       |      |       |      |                          |
| 8   |     |       |      |       |      |                          |
| .0. |     |       |      |       |      |                          |
| Pr  |     |       |      |       |      |                          |
| opo |     |       |      |       |      |                          |
| sed |     |       |      |       |      |                          |
| Use |     |       |      |       |      |                          |
| Pa  |     |       |      |       |      |                          |
| tte |     |       |      |       |      |                          |
| rns |     |       |      |       |      |                          |
| and |     |       |      |       |      |                          |
| For |     |       |      |       |      |                          |
| mul |     |       |      |       |      |                          |
| ati |     |       |      |       |      |                          |
| ons |     |       |      |       |      |                          |
| for |     |       |      |       |      |                          |
| C   |     |       |      |       |      |                          |
| ypr |     |       |      |       |      |                          |
| oco |     |       |      |       |      |                          |
| naz |     |       |      |       |      |                          |
| ole |     |       |      |       |      |                          |
| .** |     |       |      |       |      |                          |
+=====+=====+=======+======+=======+======+==========================+
| P   | For | Use   | App  | A     | Area | Timing of Application    |
| rod | mul | Sites | lica | pplic | Tre  | and Restrictions         |
| uct | a-t |       | tion | ation | ated |                          |
| ^a^ | ion |       | R    | Equi  |      |                          |
|     |     |       | ates | pment |      |                          |
|     |     |       | (lb  |       |      |                          |
|     |     |       | a    |       |      |                          |
|     |     |       | i/A) |       |      |                          |
+-----+-----+-------+------+-------+------+--------------------------+
| A   | Liq | Corn  | 0    | A     | 1200 | Apply when disease first |
| lto | uid | (incl | .036 | erial | a    | appears;                 |
| ^®^ |     | uding |      |       | cres |                          |
| 100 |     | f     |      | Groun |      | Re-apply every 7-14      |
| SL  |     | ield, |      | dboom | 200  | days;                    |
|     |     | po    |      |       | a    |                          |
| and |     | pcorn |      | C     | cres | 2 applications/season;   |
|     |     | and   |      | hemig |      | 30 days PHI; 24 hours    |
| Q   |     | seed  |      | ation | 350  | REI                      |
| uad |     | corn) |      |       | a    |                          |
| ris |     |       |      |       | cres |                          |
| X   |     |       |      |       |      |                          |
| tra |     |       |      |       |      |                          |
| ^®^ |     |       |      |       |      |                          |
+-----+-----+-------+------+-------+------+--------------------------+
|     |     | Wheat |      |       |      | For early suppression:   |
|     |     |       |      |       |      | apply in spring at       |
|     |     |       |      |       |      | approx Feekes Stage 5;   |
|     |     |       |      |       |      | for control of leaf      |
|     |     |       |      |       |      | diseases: apply between  |
|     |     |       |      |       |      | Feekes Stage 8 and       |
|     |     |       |      |       |      | 10.5.1;                  |
|     |     |       |      |       |      |                          |
|     |     |       |      |       |      | Re-apply every 14 days;  |
|     |     |       |      |       |      | 30 days PHI; 24 hours    |
|     |     |       |      |       |      | REI                      |
+-----+-----+-------+------+-------+------+--------------------------+
|     |     | Soy   |      |       |      | For rust: application    |
|     |     | beans |      |       |      | timing should be R1      |
|     |     |       |      |       |      | (beginning flowering,    |
|     |     |       |      |       |      | approx 50 days after     |
|     |     |       |      |       |      | planting) up to R6 stage |
|     |     |       |      |       |      | (seed development); for  |
|     |     |       |      |       |      | other diseases: begin    |
|     |     |       |      |       |      | before disease           |
|     |     |       |      |       |      | development;             |
|     |     |       |      |       |      |                          |
|     |     |       |      |       |      | Re-apply every 14-28     |
|     |     |       |      |       |      | days; 30 days PHI; 24    |
|     |     |       |      |       |      | hours REI                |
+-----+-----+-------+------+-------+------+--------------------------+

a Quadris Xtra^®^ contains 18.2% azoxystrobin (1.67 lb ai/gal) and 7.3%
cyproconazole (0.67 lb ai/gal); Alto^®^ 100 SL contains 8.9%
cyproconazole (0.83 lb ai/gal).

[]{#__RefHeading___Toc182970221 .anchor}**8.1 Occupational Handler Risk
Assessment**

There is potential for occupational handler exposure from the proposed
uses on agricultural crops. It is anticipated that the following
scenarios could result in handler exposure: mixer/loaders for aerial,
chemigation, or groundboom applications of liquids, applicators using
aerial or groundboom equipment, and flaggers for aerial applications.
Based upon the proposed use pattern, HED expects the *most highly*
exposed occupational pesticide handlers are likely to be:

\(1\) mixing/loading liquids for aerial applications (PHED); and

\(2\) applying sprays via aerial equipment (PHED).

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers. The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED
(August, 1998). For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for "baseline," that is, for
workers wearing a single layer of work clothing consisting of a
long-sleeved shirt, long pants, shoes plus socks and no protective
gloves, as well as for "baseline" and the use of protective gloves or
other PPE as might be necessary. The proposed product label involved in
this assessment directs applicators and other handlers to wear a
long-sleeved shirt and long pants; chemical-resistant gloves made of any
waterproof material such as polyvinyl chloride, nitrile rubber or butyl
rubber; and shoes plus socks.

*Exposure Duration*

HED believes most exposure durations will be short-term (1 - 30 days).
However, the ExpoSAC maintains it is possible for commercial applicators
to be exposed to intermediate-term exposure durations (1-6 months). In
addition, the short- and intermediate-term toxicological endpoints are
the same; therefore, the estimates of risk for short-term duration
exposures are protective of those for intermediate-term duration
exposures. Long-term exposures are not expected; therefore, a long-term
assessment was not conducted.

*Risk Calculations*

Since an oral study was selected for the short- and intermediate-term
assessments, an 11% dermal-absorption factor was applied and a 100%
inhalation-absorption factor was applied. A body weight of 60 kg was
used since the endpoints were from a developmental toxicity study with
fetal effects. The dermal and inhalation MOEs were combined for the
occupational handler risk assessments because the toxicity endpoints for
the dermal and inhalation routes of exposure are based on the same
toxicological effects.

Daily dermal or inhalation handler exposures are estimated for each
applicable handler task using the following formula:

Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x
Application Rate (lbs ai/gallon) x Amount Handled (gal/day)

Where:

> Daily Exposure = Amount (mg ai/day) deposited on the surface of the
> skin that is available for dermal absorption or amount inhaled that is
> available for inhalation absorption;
>
> Unit Exposure = Unit exposure value (mg ai/lb ai) derived from August
> 1998 PHED data or from ORETF data;
>
> Application Rate = Normalized application rate (lb ai/gal); and

Daily Area Treated = Normalized amount handled (gal/day).

The daily dermal or inhalation dose is calculated by normalizing the
daily exposure by body weight and adjusting, if necessary, with an
appropriate dermal or inhalation absorption factor using the following
formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100) / Body Weight (kg)

Where:

> Average Daily Dose = Absorbed dose received from exposure to a
> pesticide in a given scenario (mg ai/kg bw/day);
>
> Daily Exposure = Amount (mg ai/day) deposited on the surface of the
> skin that is available for dermal absorption or amount inhaled that is
> available for inhalation absorption;
>
> Absorption Factor = A measure of the amount of chemical that crosses a
> biological boundary such as the skin or lungs (% of the total
> available absorbed); and
>
> Body Weight = Body weight determined to represent the population of
> interest in a risk assessment (kg).

Non-cancer dermal and inhalation risks for each applicable handler
scenario are calculated using a MOE, which is a ratio of the NOAEL to
the daily dose. All MOE values were calculated using the formula below:

MOE= NOAEL or LOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

A total MOE was calculated because the dermal and inhalation
toxicological endpoints of concern are based on the same adverse
effects. The total MOE values were calculated using the formula below:

Number range CHAPTERTotal MOE = NOAEL or LOAEL / (Dermal dose +
Inhalation Dose)

Table 8.1 presents the exposure/risks for short and intermediate-term
dermal and inhalation exposures at baseline, and with additional PPE.
The combined dermal and inhalation exposure risks for mixer/loaders are
not of concern (i.e., MOEs\>100), **provided the mixer/loaders wear
protective gloves as directed on the label.**

HED has no data to assess exposures to pilots using open cockpits. The
only data available is for exposure to pilots in enclosed cockpits.
Therefore, risks to pilots are assessed using the engineering control
(enclosed cockpits) and baseline attire (long-sleeve shirt, long pants,
shoes, and socks); pilots are not required to wear protective gloves.
With this level of protection, there are no risks of concern for
applicators.

+------+----+-----+------------+-----------+-----------+--------------+
| **T  |    |     |            |           |           |              |
| able |    |     |            |           |           |              |
| 8.1. |    |     |            |           |           |              |
| C    |    |     |            |           |           |              |
| ypro |    |     |            |           |           |              |
| cona |    |     |            |           |           |              |
| zole |    |     |            |           |           |              |
| Occu |    |     |            |           |           |              |
| pati |    |     |            |           |           |              |
| onal |    |     |            |           |           |              |
| N    |    |     |            |           |           |              |
| onca |    |     |            |           |           |              |
| ncer |    |     |            |           |           |              |
| De   |    |     |            |           |           |              |
| rmal |    |     |            |           |           |              |
| and  |    |     |            |           |           |              |
| In   |    |     |            |           |           |              |
| hala |    |     |            |           |           |              |
| tion |    |     |            |           |           |              |
| E    |    |     |            |           |           |              |
| xpos |    |     |            |           |           |              |
| ures |    |     |            |           |           |              |
| and  |    |     |            |           |           |              |
| Risk |    |     |            |           |           |              |
| s.** |    |     |            |           |           |              |
+======+====+=====+============+===========+===========+==============+
| Crop | A  | A   | Dermal and | Doses     | MOEs^h^   | Combined     |
| or   | pp | rea | Inhalation | (mg/k     |           | MOEs^i^      |
| Ta   | Ra | T   | Unit       | g/day)^g^ |           |              |
| rget | te | rea | Exposures  |           |           |              |
|      | (  | ted |            |           |           |              |
|      | lb | Da  | (mg/lb ai) |           |           |              |
|      | a  | ily |            |           |           |              |
|      | i/ | (   |            |           |           |              |
|      | ac | acr |            |           |           |              |
|      | re | es) |            |           |           |              |
|      | )^ | ^b^ |            |           |           |              |
|      | a^ |     |            |           |           |              |
+------+----+-----+------------+-----------+-----------+--------------+
| *Mi  |    |     |            |           |           |              |
| xing |    |     |            |           |           |              |
| /Loa |    |     |            |           |           |              |
| ding |    |     |            |           |           |              |
| Li   |    |     |            |           |           |              |
| quid |    |     |            |           |           |              |
| Conc |    |     |            |           |           |              |
| entr |    |     |            |           |           |              |
| ates |    |     |            |           |           |              |
| for  |    |     |            |           |           |              |
| Ae   |    |     |            |           |           |              |
| rial |    |     |            |           |           |              |
| A    |    |     |            |           |           |              |
| ppli |    |     |            |           |           |              |
| cati |    |     |            |           |           |              |
| ons* |    |     |            |           |           |              |
+------+----+-----+------------+-----------+-----------+--------------+
| c    | 0  | 1   | [Dermal]{. | [D        | [D        | Baseline     |
| orn, | .0 | 200 | underline} | ermal]{.u | ermal]{.u | Dermal and   |
| soyb | 36 |     |            | nderline} | nderline} | Inhalation:  |
| ean, |    |     | Ba         |           |           | **8.7**      |
| w    |    |     | seline^c^: | Baseline: | Baseline: |              |
| heat |    |     | 2.9        | 0.23      | **8.7**   | PPE -- SL    |
|      |    |     |            |           |           | w/gloves +   |
|      |    |     | SL         | SL        | SL        | Baseline     |
|      |    |     | w/         | w/gloves: | w/gloves: | Inhalation:  |
|      |    |     | gloves^d^: | 0.0018    | 1,100     | 740          |
|      |    |     | 0.023      |           |           |              |
+------+----+-----+------------+-----------+-----------+--------------+
|      |    |     | [Inh       | [Inhal    | [Inhal    |              |
|      |    |     | alation]{. | ation]{.u | ation]{.u |              |
|      |    |     | underline} | nderline} | nderline} |              |
|      |    |     |            |           |           |              |
|      |    |     | Ba         | Baseline: | Baseline: |              |
|      |    |     | seline^e^: | 0.00086   | 2,300     |              |
|      |    |     | 0.0012     |           |           |              |
+------+----+-----+------------+-----------+-----------+--------------+
| *    |    |     |            |           |           |              |
| Appl |    |     |            |           |           |              |
| ying |    |     |            |           |           |              |
| Sp   |    |     |            |           |           |              |
| rays |    |     |            |           |           |              |
| via  |    |     |            |           |           |              |
| Ae   |    |     |            |           |           |              |
| rial |    |     |            |           |           |              |
| Eq   |    |     |            |           |           |              |
| uipm |    |     |            |           |           |              |
| ent* |    |     |            |           |           |              |
+------+----+-----+------------+-----------+-----------+--------------+
| c    | 0  | 1   | [Dermal]{. | [D        | [D        | Engineering  |
| orn, | .0 | 200 | underline} | ermal]{.u | ermal]{.u | control      |
| soyb | 36 |     |            | nderline} | nderline} | Dermal +     |
| ean, |    |     | E          |           |           | Inhalation:  |
| w    |    |     | ngineering | En        | En        | 4,500        |
| heat |    |     | c          | gineering | gineering |              |
|      |    |     | ontrol^f^: | control:  | control:  |              |
|      |    |     | 0.005      | 0.0004    | 5,100     |              |
+------+----+-----+------------+-----------+-----------+--------------+
|      |    |     | [Inh       | [Inhal    | [Inhal    |              |
|      |    |     | alation]{. | ation]{.u | ation]{.u |              |
|      |    |     | underline} | nderline} | nderline} |              |
|      |    |     |            |           |           |              |
|      |    |     | E          | En        | En        |              |
|      |    |     | ngineering | gineering | gineering |              |
|      |    |     | control:   | control:  | control:  |              |
|      |    |     | 0.000068   | 0.000049  | 41,000    |              |
+------+----+-----+------------+-----------+-----------+--------------+

a Application rates are the maximum application rates determined from
proposed labels for cyproconazole.

b Amount handled per day values are HED estimates of acres treated per
day based on Exposure SAC SOP #9 "Standard Values for Daily Acres
Treated in Agriculture," industry sources, and HED estimates.

c Baseline Dermal: Long-sleeve shirt, long pants, and no gloves.

d Dermal SL w/gloves: Single layer plus chemical-resistant gloves.

e Baseline Inhalation: no respirator.

f Engineering control: enclosed cockpit.

g Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x %Absorption (11% dermal and 100% inhalation)
/ Body weight (60 kg).

h MOE = NOAEL/Dose; where the short- and intermediate-term dermal and
inhalation NOAEL = 2 mg/kg/day.

i Combined MOEs =NOAEL / (Dermal + Inhalation Exposure).

[]{#__RefHeading___Toc182970222 .anchor}**8.2 Occupational
Post-application Exposure**

Following cyproconazole application to corn, wheat and soybean,
occupational exposure is possible. Post-application activities may
include scouting, maneuvering irrigation equipment, hand weeding and
hand harvesting.

Since no post-application data were submitted in support of this
registration action, exposures during post-application activities were
estimated using dermal TCs from the TC Policy Number 3.1: Agricultural
TCs, August 2000, summarized in Table 8.2.1 below and the following
assumptions:

Assumptions:

-   Application Rate = 0.036 lb ai/A

-   Exposure Duration = 8 hours per day

-   Body Weight = 60 kg

-   Dermal Absorption = 11%

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

  ------------------------------------------------------------------------------
  **Table 8.2.1.                                         
  Post-application                                       
  Activities and                                         
  Dermal TCs.**                                          
  ------------------ ---------------- ------------------ -----------------------
  Proposed Crops     Policy Crop      TCs (cm^2^/hr)     Activities
                     Group Category                      

  Soybeans and Wheat Field / row      100                Hand weeding, scouting
                     crop, low /                         
                     medium                              

                                      1500               Scouting, irrigation

  Corn               Field / row      400                Scouting
                     crop, tall                          

                                      1000               Irrigation, scouting

                                      17,000             Hand harvesting
  ------------------------------------------------------------------------------

The information in this table is based on proprietary and
non-proprietary data.

Daily dermal exposures were calculated on each post-application day
after application using the following equation:

*DE~(t)~ (mg/day) = (TR~(t)~ (µg/cm^2^) x TC (cm^2^/hr) x Hr/Day)/1000
(µg/mg)*

Where:

> DE(t) = Daily exposure or amount deposited on the surface of the skin
> at time (t) attributable for activity in a previously treated area,
> also referred to as potential dose (mg ai/day);

TR(t) = Transferable residues that can be dislodgeable foliar residue at
time "t" (µg/cm^2^);

TC = Transfer Coefficient (cm^2^/hour); and

Hr/day = Exposure duration meant to represent a typical workday (hours).

Note that the (TR~(t)~) input may represent levels on the day of
application in the case of short-term risk calculations. Once daily
exposures are calculated, the calculation of daily absorbed dose and the
resulting MOEs use the same algorithms that are described above for the
handler exposures. These calculations are completed for each day or
appropriate block of time after application.

Risks are not of concern (i.e., MOE\>100) on day 0 (REI = 12 hours) for
all post-application activities. Table 8.2.2 presents a summary of
occupational post-application risks associated with use of
cyproconazole.

+-----------+--------+--------------------------+--------+-----------+
| **Table   |        |                          |        |           |
| 8.2.2.    |        |                          |        |           |
| Summary   |        |                          |        |           |
| of        |        |                          |        |           |
| Occ       |        |                          |        |           |
| upational |        |                          |        |           |
| Post-ap   |        |                          |        |           |
| plication |        |                          |        |           |
| Risks for |        |                          |        |           |
| Cyproco   |        |                          |        |           |
| nazole.** |        |                          |        |           |
+===========+========+==========================+========+===========+
| Crop      | Appli  | Transfer Coefficient     | Day    | MOE at    |
| Grouping  | cation | (µg/cm^2^)               | after  | Day 0     |
|           | rate   |                          | Appli  |           |
|           |        |                          | cation | (Level of |
|           | (lb    |                          |        | Concern = |
|           | ai     |                          |        | 300)      |
|           | /acre) |                          |        |           |
+-----------+--------+--------------------------+--------+-----------+
| Soybean,  | 0.036  | 100 (Hand weeding,       | 0 (12  | 17,000    |
| Wheat     |        | scouting)                | hours) |           |
+-----------+--------+--------------------------+--------+-----------+
|           |        | 1500 (Scouting,          |        | 1,100     |
|           |        | irrigation)              |        |           |
+-----------+--------+--------------------------+--------+-----------+
| Corn      |        | 400 (Scouting)           |        | 4,200     |
+-----------+--------+--------------------------+--------+-----------+
|           |        | 1000 (Irrigation,        |        | 1,700     |
|           |        | scouting)                |        |           |
+-----------+--------+--------------------------+--------+-----------+
|           |        | 17,000 (Hand harvesting, |        | 99        |
|           |        | Detasseling)             |        |           |
+-----------+--------+--------------------------+--------+-----------+
|           |        |                          | 1 day  | 110       |
+-----------+--------+--------------------------+--------+-----------+

[]{#__RefHeading___Toc182970223 .anchor}

**8.3 REI**

Cyproconazole is classified in Toxicity Category III for acute dermal,
acute oral, and acute inhalation. It is classified in Toxicity Category
IV for primary eye irritation and primary skin irritation and it is not
a dermal sensitizer. Therefore, the Worker Protection Standard (WPS)
interim REI of 12 hours is adequate to protect agricultural workers from
post-application exposures to cyproconazole from soybeans, wheat and
corn.

[]{#__RefHeading___Toc182970224 .anchor}**9.0 Data Needs and Label
Recommendations**

[]{#__RefHeading___Toc182970225 .anchor}**9.1** Number range
CHAPTER**Regulatory Recommendations and Residue Chemistry Deficiencies**

Provided the petitioner submits revised Sections B and F and ILVs of the
HPLC/MS method for Metabolite M14 in liver and the HPLC/UV method for
M36 in milk, HED concludes that the residue chemistry database is
sufficient for conditional registration and establishment of permanent
tolerances for free and conjugated residues of cyproconazole
\[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1*H*-1,2,4-triazole-1-ethanol\]
in or on the following commodities:

> Aspirated Grain Fractions 2.5
>
> Corn, field, forage 0.60
>
> Corn, field, grain 0.01
>
> Corn, field, stover 1.2
>
> Soybean, seed 0.05
>
> Soybean, forage 1.0
>
> Soybean hay 3.0
>
> Soybean, oil 0.10
>
> Wheat, forage 0.80
>
> Wheat, hay 1.3
>
> Wheat, straw 0.90
>
> Wheat, grain 0.05
>
> Wheat, grain, milled byproducts 0.10
>
> Fat of cattle, goat, horse and sheep 0.01
>
> Meat byproducts (except liver) of cattle, goat, horse
>
> and sheep 0.01

Additionally, HED has determined that a tolerance is required for the
combined free and conjugated residues of cyproconazole
\[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1*H*-1,2,4-triazole-1-ethanol\]
and its metabolite M36
\[δ-(4-chlorophenyl)-β,δ-dihydroxy-γ-methyl-1*H*-1,2,4-triazole-1-hexenoic
acid\] in or on the following commodity:

> Milk 0.02

and that tolerances are required for the combined free and conjugated
residues of cyproconazole
\[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1*H*-1,2,4-triazole-1-ethanol\]
and its metabolite M14
\[2-(4-chlorophenyl)-3-cyclopropyl-1-\[1,2,4\]triazol-1-yl-butane-2,3-diol\]
in or on the following commodities:

> Liver of cattle, goat, horse, and sheep 0.50
>
> Hog liver 0.01

*Residue Chemistry Deficiencies*

[860.1200 Directions for Use]{.underline}

• The field trial data support only a single application to soybeans
prior to harvest of forage or hay. The use directions for soybean should
be amended to allow for only one application at up to 0.036 lb ai/A,
prior to the harvest or grazing of forage or hay.

[860.1300 Nature of the Residue - Plants]{.underline}

• To upgrade the existing wheat metabolism study to adequate, data are
required supporting the stability of ^14^C-residues during the
analytical phase of the study.

[860.1300 Nature of the Residue - Livestock]{.underline}

• To upgrade the goat metabolism study to adequate, the deficiencies
previously cited in the goat metabolism study must be resolved (see
D217295, G. Kramer, 6/14/96).

[860.1340 Residue Analytical Methods]{.underline}

• Method AM-0842-0790-0 for determining cyproconazole in plant
commodities is an improved version of the current enforcement, which
allows for use of either NPD or MSD. As this method is superior to the
current enforcement method, it will be forward to FDA to either replace
or supplement the existing tolerance enforcement method for plant
commodities.

• The LC-MS/MS method (Syngenta Method RAM 499/01) for determining
cyproconazole in livestock commodities has undergone a successful ILV
trial and radiovalidation trial. Therefore, a copy of the method will be
forwarded to ACB for evaluation as an enforcement method.

-   As M14 in liver and M36 in milk need to be included in the tolerance
    expression, enforcement methods will be required for these residues.
    HED thus requests that the petitioner submits ILVs of the HPLC/MS
    method for Metabolite M14 in liver and the HPLC/UV method for M36 in
    milk. Radiovalidation data should also be submitted. Once the ILVs
    and radiovalidation data are submitted, the methods will be
    forwarded to ACB for evaluation as enforcement methods.

[]{.mark}

[860.1380 Storage Stability]{.underline}

[]{.mark}

• Storage stability data for triazole, TA, TAA in plant raw agricultural
commodity (RAC) and processed fractions and in livestock commodities are
required in order to support the available data on triazole-related
residues in the submitted field trials, processing studies and feeding
studies. However, storage stability data for these compounds has been
requested as part of the Human-Health Aggregate Risk Assessment for
1,2,4-T, TA and TAA (M. Doherty, *et al.,* 2/7/06). Submission of the
data requested in the 2/7/06 document will satisfy storage stability
data requirement for the subject petitions.

[]{.mark}

[860.1850 Confined Accumulation in Rotational Crops]{.underline}

[]{.mark}

• Although the submitted confined rotational crop study was considered
acceptable for purposes of this petition, the study contained numerous
deficiencies and can not be upgraded. Therefore, a new confined study
may be required for any future uses of cyproconazole resulting in
seasonal use rates above 0.072 lb ai/A in rotated crops.

[860.1900 Field Accumulation in Rotational Crops]{.underline}

• Although the interim 60-day data from the limited field rotational
crop trials are adequate and support the proposed label restrictions for
rotated crop, the final results from the limited field trials should be
submitted once they are available.

[]{.mark}

[860.1550 Proposed Tolerances]{.underline}

The petitioner is requested to submit a revised Section F specifying the
following:

-   The revised tolerances and commodity definitions summarized above.

**Note to RD:** The preferred chemical name for cyproconazole is
"α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1*H*-1,2,4-triazole-1-ethanol."
40 CFR §180.485(a) should be revised to use this terminology. Also, the
time-limited tolerance established for soybean seed under 40 CFR
§180.485(b) should be deleted once a tolerance is established in section
(a).

[]{#__RefHeading___Toc182970226 .anchor}**Appendix A**

+---------+-------------------------+---------------------+-----------+
| **Table |                         |                     |           |
| A.1.    |                         |                     |           |
| Acute   |                         |                     |           |
| T       |                         |                     |           |
| oxicity |                         |                     |           |
| of      |                         |                     |           |
| Cy      |                         |                     |           |
| procona |                         |                     |           |
| zole.** |                         |                     |           |
+=========+=========================+=====================+===========+
| Gu      | Study Type              | Results             | Toxicity  |
| ideline |                         |                     | Category  |
| No.     |                         |                     |           |
+---------+-------------------------+---------------------+-----------+
| 8       | Acute Oral (rat)        | M: 1020 mg/kg F:    | III       |
| 70.1100 |                         | 1330 mg/kg          |           |
|         |                         |                     |           |
| (81-1)  |                         |                     |           |
+---------+-------------------------+---------------------+-----------+
| 8       | M-36 metabolite, Acute  | MRID-43674701,      | III       |
| 70.1100 | Oral (rat)              | \>2000 mg/kg        |           |
|         |                         |                     |           |
| (81-1)  |                         |                     |           |
+---------+-------------------------+---------------------+-----------+
| 8       | M-36 metabolite, Acute  | MRID-43674732       | III       |
| 70.1100 | Oral (mouse)            | \>2000 mg/kg        |           |
|         |                         |                     |           |
| (81-1)  |                         |                     |           |
+---------+-------------------------+---------------------+-----------+
| 8       | Acute Dermal (rabbit)   | LD50 \> 2000 mg/kg  | III       |
| 70.1200 |                         |                     |           |
|         |                         |                     |           |
| (81-2)  |                         |                     |           |
+---------+-------------------------+---------------------+-----------+
| 8       | Acute Inhalation (rat)  | LC50 \> 5.6 mg/L    | III       |
| 70.1300 |                         |                     |           |
|         |                         |                     |           |
| (81-3)  |                         |                     |           |
+---------+-------------------------+---------------------+-----------+
| 8       | Primary Eye Irritation  | Not an eye irritant | IV        |
| 70.2400 | (rabbit)                |                     |           |
|         |                         |                     |           |
| (81-4)  |                         |                     |           |
+---------+-------------------------+---------------------+-----------+
| 8       | Primary Skin Irritation | Not a dermal        | IV        |
| 70.2500 | (rabbit)                | irritant            |           |
|         |                         |                     |           |
| (81-5 ) |                         |                     |           |
+---------+-------------------------+---------------------+-----------+
| 87.2600 | Dermal Sensitization    | Not a dermal        | N/A       |
|         | (guinea pig)            | sensitizer          |           |
| (81-6)  |                         |                     |           |
+---------+-------------------------+---------------------+-----------+

[]{.mark}

+-------+------------+---------------+---------------------------------+
| **    |            |               |                                 |
| Table |            |               |                                 |
| A.2.  |            |               |                                 |
| S     |            |               |                                 |
| ubchr |            |               |                                 |
| onic, |            |               |                                 |
| Chr   |            |               |                                 |
| onic, |            |               |                                 |
| and   |            |               |                                 |
| Other |            |               |                                 |
| Tox   |            |               |                                 |
| icity |            |               |                                 |
| Pr    |            |               |                                 |
| ofile |            |               |                                 |
| of    |            |               |                                 |
| C     |            |               |                                 |
| yproc |            |               |                                 |
| onazo |            |               |                                 |
| le.** |            |               |                                 |
+=======+============+===============+=================================+
| *     | **Study    | **MRID No.    | **Results**                     |
| *Guid | Type**     | (year)/       |                                 |
| eline |            | C             |                                 |
| No.** |            | lassification |                                 |
|       |            | /Doses**      |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | 28-Day     | 40624305      | NOAEL= 5 mg/kg/day              |
| .3050 | oral - rat | (1986)        |                                 |
|       |            |               | LOAEL = 15 mg/kg/day, based on  |
|       |            | Acceptable/   | elevated LDH, increased liver   |
|       |            | non-guideline | weight (relative and absolute)  |
|       |            | 0, 10,        | and liver vacuolation.          |
|       |            | 30,100, 300   |                                 |
|       |            | and 1000 ppm  |                                 |
|       |            |               |                                 |
|       |            | 0, 0.5, 1.5,  |                                 |
|       |            | 5.0, 15, 50   |                                 |
|       |            | mg/kg/d       |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | 90-Day     | 40607718      | NOAEL = 20 ppm (1 mg/kg/day)    |
| .3100 | oral       | (1986)        |                                 |
|       | toxicity   |               | LOAEL = 80 ppm (4 mg/kg/day)    |
|       | (rat)      | Accepta       | based on 1) lack of a dose      |
|       |            | ble/guideline | response relationship, 2) lack  |
|       |            |               | of correlation with             |
|       |            | 0, 20. 80 or  | histopathological or organ      |
|       |            | 320 ppm       | weight changes, 3) because      |
|       |            |               | similar changes were not seen   |
|       |            | 0, 1, 4 and   | in male and female rats fed the |
|       |            | 16 mg/kg/d    | same level (20 ppm) of SAN619F  |
|       |            |               | in a chronic/carcinogenicity    |
|       |            |               | study (MRID No. 41164701), and  |
|       |            |               | 4) because the creatinine,      |
|       |            |               | sodium, and calcium values      |
|       |            |               | observed in the 90-day study    |
|       |            |               | were within the range of        |
|       |            |               | baseline values for these       |
|       |            |               | parameters in several strains   |
|       |            |               | of rats of this age.            |
+-------+------------+---------------+---------------------------------+
| 870   | 90-Day     | 43078601      | NOAEL = 20 ppm (1.5/2.0         |
| .3100 | oral       | (1993)        | mg/kg/day in males/females)     |
|       | toxicity   |               |                                 |
|       | (rat)      | Acceptable/   | LOAEL = 350 ppm (27.3/35.4      |
|       |            | supplementary | mg/kg/day in males/females),    |
|       |            |               | based on decreased body weight  |
|       |            | 0, 20, 350,   | gain in males and increased     |
|       |            | 700, or 1400  | liver weights in females.       |
|       |            | ppm           |                                 |
|       |            |               |                                 |
|       |            | M/F: 0/0,     |                                 |
|       |            | 1.4/1.6,      |                                 |
|       |            | 24.7/29.6,    |                                 |
|       |            | 52.8/57.3,    |                                 |
|       |            | and           |                                 |
|       |            |               |                                 |
|       |            | 106.8/118.1   |                                 |
|       |            | mg/kg/d       |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | 90-Day     | 46950013      | NOAEL = 15 ppm (2.2 and 3.2     |
| .3100 | oral       | (1987)        | mg/kg bw/day in males and       |
|       | toxicity   |               | females)                        |
|       | (mouse)    | Acceptable/   |                                 |
|       |            | non-guideline | LOAEL = 300 ppm (43.8 and 70.2  |
|       |            |               | mg/kg bw/day in males and       |
|       |            | 0, 5, 15,     | females), based on decreased    |
|       |            | 300, or 600   | body weight gain in both sexes  |
|       |            | ppm M: 0,     | and evidence of liver effects   |
|       |            | 0.7, 2.2,     | (increased liver weight in both |
|       |            | 43.8, or 88.7 | sexes, periacinar hepatocytic   |
|       |            | mg/kg bw/d    | eosinophilia in males, and      |
|       |            |               | single cell hepatocyte necrosis |
|       |            | F: 0, 1.0,    | in both sexes).                 |
|       |            | 3.2, 70.2, or |                                 |
|       |            | 128.2         |                                 |
|       |            | mg/kg bw/d    |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | 90-Day     | 40607719      | NOAEL = 0.8 mg/kg/day           |
| .3150 | oral       | (1986)        |                                 |
|       | toxicity   |               | LOAEL = 4.0 mg/kg/day, based on |
|       | (dog)      | Accepta       | increased absolute liver weight |
|       |            | ble/guideline | & hepatocytomegaly.             |
|       |            |               |                                 |
|       |            | 0, 20, 100,   |                                 |
|       |            | 500           |                                 |
|       |            |               |                                 |
|       |            | 0, 0.8. 4.0   |                                 |
|       |            | and 20.0      |                                 |
|       |            | mg/kg         |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | 21/28-Day  | 40624306      | NOAEL = 250 mg/kg/day           |
| .3200 | dermal     | (1988)        |                                 |
|       | toxicity   |               | LOAEL 1250 mg/kg/day, based on  |
|       | (rat)      | Accepta       | decreased body weight gain and  |
|       |            | ble/guideline | food consumption (M), increased |
|       |            |               | AST (males), creatinine         |
|       |            | 0, 50, 250,   | (females), cholesterol (both    |
|       |            | 1250 mg/kg/d  | sexes).                         |
+-------+------------+---------------+---------------------------------+
| 870.  | Prenatal   | 40607721      | Maternal NOAEL = 6 mg/kg/day    |
| 3700a | dev        | (1985)        |                                 |
|       | elopmental |               | Maternal LOAEL = 12 mg/kg/day,  |
|       | in (rat)   | Accepta       | based on decreased BWG during   |
|       |            | ble/guideline | dosing                          |
|       |            |               |                                 |
|       |            | 0, 6. 12, 24, | Developmental NOAEL = 6         |
|       |            | 48 mg/kg/d    | mg/kg/day                       |
|       |            |               |                                 |
|       |            |               | Developmental LOAEL = 12        |
|       |            |               | mg/kg/day, based on increased   |
|       |            |               | incidence of supernumerary      |
|       |            |               | ribs, malformations             |
|       |            |               | \[hydrocephaly\] at 24 & 48     |
|       |            |               | mg/kg/day and cleft palate at   |
|       |            |               | 48 mg/kg/day.                   |
+-------+------------+---------------+---------------------------------+
| 870.  | Prenatal   | 42175401      | Maternal NOAEL = 10 mg/kg/day   |
| 3700b | dev        | (1991),       |                                 |
|       | elopmental |               | Maternal LOAEL = 50 mg/kg/day,  |
|       | in         | Accepta       | based on decreased body weight  |
|       | (rabbit)   | ble/guideline | gain.                           |
|       |            |               |                                 |
|       |            | 0, 2, 10, 50  | Developmental NOAEL. = 2        |
|       |            | mg/kg/d       | mg/kg/day                       |
|       |            |               |                                 |
|       |            |               | Developmental LOAEL = 10        |
|       |            |               | mg/kg/day, based on increased   |
|       |            |               | incidence of malformed fetuses  |
|       |            |               | & litters with malformed        |
|       |            |               | fetuses.                        |
+-------+------------+---------------+---------------------------------+
| 870.  | Prenatal   | 40607720      | Maternal NOAEL = 10 mg/kg/day   |
| 3700b | dev        | (1986)        |                                 |
|       | elopmental |               | Maternal LOAEL = 50 mg/kg/day,  |
|       | in         | Accepta       | based on inhibited BWG during   |
|       | (rabbit)   | ble/guideline | treatment.                      |
|       |            |               |                                 |
|       |            | 0, 2, 10, 50  | Developmental NOAEL \< 2        |
|       |            | mg/kg/d       | mg/kg/day                       |
|       |            |               |                                 |
|       |            |               | Developmental LOAEL = 2         |
|       |            |               | mg/kg/day, based on incidence   |
|       |            |               | of hydrocephalus internus.      |
+-------+------------+---------------+---------------------------------+
| 870   | Re         | 4067723       | Parental NOAEL = 20 ppm (1.7    |
| .3800 | production | (1987)        | mg/kg/day)                      |
|       | and        |               |                                 |
|       | fertility  | Accepta       | Parental LOAEL = 120 ppm        |
|       | effects    | ble/guideline | (10.6mg/kg/day), based on liver |
|       |            |               | effects.                        |
|       | (rat)      | 0, 4, 20, 120 |                                 |
|       |            | ppm           | Reproductive toxicity NOAEL =   |
|       |            |               | 120 ppm (10.6 mg/kg/day),       |
|       |            | 0, 0.4, 1.7   | although gestation length was   |
|       |            | or 10.6       | slightly increased and litter   |
|       |            | mg/kg/d       | size were decreased, the        |
|       |            |               | changes are not considered      |
|       |            |               | treatment-related.              |
|       |            |               |                                 |
|       |            |               | Reproductive LOAEL was not      |
|       |            |               | determined.                     |
+-------+------------+---------------+---------------------------------+
| 870.  | Chronic    | 41212901      | NOAEL = 30 ppm (1.0 mg/kg/day)  |
| 4100b | toxicity   | (1988)        |                                 |
|       |            |               | LOAEL = 100 ppm (3.2            |
|       | (dog)      | Accepta       | mg/kg/day), based on liver      |
|       |            | ble/guideline | effects (P450 induction in      |
|       |            |               | females and histopathology,     |
|       |            | 0, 30, 100,   | laminar eosinophilic            |
|       |            | and 350 ppm   | intrahepatocytic bodies in      |
|       |            | M/F: 0/0,     | males).                         |
|       |            | 1.0/1.0,      |                                 |
|       |            | 3.2/3.2, and  |                                 |
|       |            | 12. 1/12.6    |                                 |
|       |            | mg/kg/d)      |                                 |
+-------+------------+---------------+---------------------------------+
| 870.  | Carci      | 4             | NOAEL = M/F: 1.8/2.6 mg/kg/day  |
| 4200b | nogenicity | 1147201(1989) |                                 |
|       | (mouse)    |               | LOAEL = M/F: 13.2/17.7          |
| .     |            | Accepta       | mg/kg/day, based on increased   |
|       |            | ble/guideline | incidence of hepatocytic        |
|       |            |               | single-cell necrosis; increased |
|       |            | 0, 5, 15,     | incidence of hepatocellular     |
|       |            | 100,200 ppm   | adenomas and carcinomas         |
|       |            | M/F:          |                                 |
|       |            | 0/0.69/1.03,  |                                 |
|       |            | 1.84/2.56,    |                                 |
|       |            | 13.17/17.65,  |                                 |
|       |            | or            |                                 |
|       |            | 27.85/36.30   |                                 |
|       |            | mg/kg/d       |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | Combined   | 41164701      | NOAEL = 50 ppm (2.2 mg/kg/day)  |
| .4300 | Chronic    | (1988)        |                                 |
|       |            |               | LOAEL = 350 ppm (15.6           |
|       | Toxi       | Accepta       | mg/kg/day), based on decreased  |
|       | city/Carci | ble/guideline | body weight and increased       |
|       | nogenicity |               | incidence of fatty infiltration |
|       | (rat)      | 0, 20, 50 or  | in liver (M). Dosing was        |
|       |            | 350 ppm       | inadequate in females.          |
|       |            |               |                                 |
|       |            | M/F: 0/0,     |                                 |
|       |            | 1.0/1.2,      |                                 |
|       |            | 2.2/2/7 and   |                                 |
|       |            | 15.6/21.8     |                                 |
|       |            | mg/kg/d       |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | Bacterial  | 40607725      | Negative.                       |
| .5100 | Reverse    | (1986)        |                                 |
|       |            |               |                                 |
|       | Mutation   | Accepta       |                                 |
|       | Test       | ble/guideline |                                 |
|       |            |               |                                 |
|       |            | 0, 1,5, 10,   |                                 |
|       |            | 100, 500,     |                                 |
|       |            | 1000 ug/plate |                                 |
|       |            | w/wt rat S9   |                                 |
|       |            | mix           |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | Bacterial  | 40624307      | Negative.                       |
| .5100 | Reverse    | (1985)        |                                 |
|       |            |               |                                 |
|       | Mutation   | Unaccepta     |                                 |
|       | Test       | ble/guideline |                                 |
|       |            |               |                                 |
|       |            | 0, 10, 100,   |                                 |
|       |            | 250, 400, 500 |                                 |
|       |            | or 550        |                                 |
|       |            | ug/plate w/wt |                                 |
|       |            | rat S9 mix    |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | *In Vitro* | 40607726      | Negative.                       |
| .5300 | Gene       | (1985)        |                                 |
|       | Mutation   |               |                                 |
|       | assay in   | Accepta       |                                 |
|       | Chinese    | ble/guideline |                                 |
|       | Hamster    |               |                                 |
|       | Ovary      | 0, 20, 50,    |                                 |
|       | cells      | 100 or 200    |                                 |
|       |            | ug/mL w/wt    |                                 |
|       |            | S9.           |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | *In Vitro* | 41757801      | Can not be interpreted.         |
| .5375 | Mammalian  | (1990)        |                                 |
|       | C          |               |                                 |
|       | hromosomal | Unaccepta     |                                 |
|       | Aberration | ble/guideline |                                 |
|       |            |               |                                 |
|       |            | 60.1, 100.0,  |                                 |
|       |            | 150.0 or 200  |                                 |
|       |            | ug/mL wt S9;  |                                 |
|       |            | 45.0, 59.9,   |                                 |
|       |            | 99.9 or 150.0 |                                 |
|       |            | w S9.         |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | *In Vitro* | 46950019      | Negative.                       |
| .5375 | Mammalian  | (1995)        |                                 |
|       | C          |               |                                 |
|       | hromosomal | Accepta       |                                 |
|       | Aberration | ble/guideline |                                 |
|       |            |               |                                 |
|       |            | 0, 50, 100,   |                                 |
|       |            | 200 or 400    |                                 |
|       |            | µg/mL without |                                 |
|       |            | S9            |                                 |
|       |            |               |                                 |
|       |            | 0, 25, 50,    |                                 |
|       |            | 100 or 200    |                                 |
|       |            | µg/mL with    |                                 |
|       |            | metabolic     |                                 |
|       |            |               |                                 |
|       |            | 0, 50, 100,   |                                 |
|       |            | 200 or 400    |                                 |
|       |            | µg/mL without |                                 |
|       |            | S9            |                                 |
|       |            |               |                                 |
|       |            | 0, 100, 200,  |                                 |
|       |            | 400 or 800    |                                 |
|       |            | µg/mL with    |                                 |
|       |            | metabolic     |                                 |
|       |            | activation    |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | *In Vitro* | 41757701      | Positive w/wt S9.               |
| .5375 | Mammalian  | (1988)        |                                 |
|       | C          |               |                                 |
|       | hromosomal | Unaccepta     |                                 |
|       | Aberration | ble/guideline |                                 |
|       |            |               |                                 |
|       |            | 100, 150 or   |                                 |
|       |            | 200 ug/mL wt  |                                 |
|       |            | S9; 100, 150, |                                 |
|       |            | 200 or 250 w  |                                 |
|       |            | S9.           |                                 |
+-------+------------+---------------+---------------------------------+
| 870.  | *In Vivo*  | 40607728      | Negative.                       |
| 5395  | Mammalian  | (1984)        |                                 |
|       | Cyto       |               |                                 |
|       | genetics - | Accepta       |                                 |
|       | E          | ble/guideline |                                 |
|       | rythrocyte |               |                                 |
|       | Mi         | 0, 16.7,      |                                 |
|       | cronucleus | 55.7, 167     |                                 |
|       | Assay in   | mg/kg         |                                 |
|       | Mice       |               |                                 |
+-------+------------+---------------+---------------------------------+
|       | Cell       | 40607724      | Negative.                       |
|       | Tran       | (1985)        |                                 |
|       | sformation |               |                                 |
|       |            | Acceptable    |                                 |
|       |            |               |                                 |
|       |            | 0, 20, 50,    |                                 |
|       |            | 100 or 200    |                                 |
|       |            | ug//mL w/wt   |                                 |
|       |            | S9 (assumed)  |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | Rodent     | 41961401      | Negative.                       |
| .5450 | Dominant   | (1991)        |                                 |
|       | Lethal     |               |                                 |
|       |            | Accepta       |                                 |
|       |            | ble/guideline |                                 |
|       |            |               |                                 |
|       |            | 20, 40 or 80  |                                 |
|       |            | mg/kg/d       |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | U          | 40607729      | Can't be evaluated.             |
| .5550 | nscheduled | (1988)        |                                 |
|       | DNA        |               |                                 |
|       |            | Unaccepta     |                                 |
|       | Synthesis  | ble/guideline |                                 |
|       | in         |               |                                 |
|       | Mammalian  | 0.15,0.5,     |                                 |
|       |            | 1.5, 5, 15,   |                                 |
|       | Cells in   | 50, 100, 150  |                                 |
|       | Culture    | ug//mL        |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | U          | 40607727      | Can't be evaluated.             |
| .5550 | nscheduled | (1985)        |                                 |
|       | DNA        |               |                                 |
|       |            | Unaccepta     |                                 |
|       | Synthesis  | ble/guideline |                                 |
|       | in         |               |                                 |
|       | Mammalian  | 0.15,0.5,     |                                 |
|       |            | 1.5, 5, 15,   |                                 |
|       | Cells in   | 50, 100, 150  |                                 |
|       | Culture    | ug//mL        |                                 |
+-------+------------+---------------+---------------------------------+
| 870   | Metabolism | 41701901      | Absorption, distribution,       |
| .7485 | and        | (1987)        | excretion and blood kinetics    |
|       | pharma     |               | were examined. Almost           |
|       | cokinetics | Accepta       | completely absorbed in males    |
|       |            | ble/guideline | (84%) and females (106%),       |
|       | (rat)      |               | extensively metabolized;        |
|       |            | oral -        | diastereomers A & B of parent + |
|       |            | 10mg/kg , 910 | 13 metabolites identified &     |
|       |            | mg/kg x       | isolated; 35 metabolites        |
|       |            |               | detected; metabolic profiles    |
|       |            | 14 days;      | for urine, feces, bile similar; |
|       |            |               | major metabolic reactions       |
|       |            | iv - 10 and   | include oxidative elimination   |
|       |            | 130 mg/kg     | of triazole ring; hydroxylation |
|       |            |               | of C bearing CH3 group;         |
|       |            |               | oxidation of CH3 group to       |
|       |            |               | carbinol & further to oxidation |
|       |            |               | carboxylic acid; rapid          |
|       |            |               | excretion with majority         |
|       |            |               | appearing in feces \[biliary    |
|       |            |               | excretion\]; residual '4C found |
|       |            |               | within renal fat, adrenals,     |
|       |            |               | liver; potential liver          |
|       |            |               | accumulation in long-term       |
|       |            |               | studies.                        |
+-------+------------+---------------+---------------------------------+
| 870   | Metabolism | 46152903      | The majority of the total       |
| .7485 | and        | (2003)        | administered dose (96.5%) was   |
|       | pharma     |               | recovered in the feces (56.3%)  |
|       | cokinetics | 0.5 mg/kg.    | and urine                       |
|       |            | Animals were  |                                 |
|       | (rat)      |               | (40.2%).                        |
|       |            | dosed with    |                                 |
|       |            | the           | The highest blood levels were   |
|       |            | radioactive   | found ten days after the start  |
|       |            | test          | of dosing (0.08 ppm SAN 619F    |
|       |            | substance     | equivalents). Three days after  |
|       |            | daily for up  | the final dosing, radioactivity |
|       |            | to 14 days    | was almost completely excreted. |
|       |            |               | The calculated half-life for    |
|       |            |               | the depletion of radioactivity  |
|       |            |               | (assuming mono-phasic           |
|       |            |               | first-order kinetics) from the  |
|       |            |               | tissues ranged from one to      |
|       |            |               | three days. The greater         |
|       |            |               | persistence and longer          |
|       |            |               | half-life of radioactivity in   |
|       |            |               | blood compared to plasma        |
|       |            |               | indicated some partitioning of  |
|       |            |               | radioactivity into the red      |
|       |            |               | blood cells. The highest        |
|       |            |               | concentrations of radioactivity |
|       |            |               | were observed in the liver      |
|       |            |               | (1.37 ppm SAN 619F              |
|       |            |               | equivalents), adrenals (0.93    |
|       |            |               | ppm), lungs (0.56 ppm), fat     |
|       |            |               | (0.49 ppm), kidneys (0.25 ppm), |
|       |            |               | pancreas, (0.22 ppm), and       |
|       |            |               | ovaries (0.16 ppm) seven days   |
|       |            |               | after the start of dosing.      |
|       |            |               |                                 |
|       |            |               | Urine was found to contain at   |
|       |            |               | least 21 metabolite fractions   |
|       |            |               | by two-dimensional TLC.         |
|       |            |               | Individual fractions were       |
|       |            |               | detected in similar proportions |
|       |            |               | on Days 0-1, 6-7, and 13-14.    |
|       |            |               | The combined urinary metabolite |
|       |            |               | fractions accounted for         |
|       |            |               | 20.8-41.0% of the daily         |
|       |            |               | administered doses.             |
+-------+------------+---------------+---------------------------------+
| 870   | Dermal     | 43 173701     | At dose levels of 2.5, 15, and  |
| .7600 | p          | (1993),       | 120 .ig/cm2 cyproconazole, the  |
|       | enetration |               | percent absorbed \[0.87-7.69,   |
|       | (rat)      | Accepta       | 0.59-11.88, and 0.92-0.89,      |
|       |            | ble/guideline | respectively\] increased with   |
|       |            |               | duration of exposure and        |
|       |            | 0, 2.5 15 and | decreased with dose. The        |
|       |            | 120 ug/cm2    | quantity absorbed increased     |
|       |            | for 0.5,      | with dose and duration of       |
|       |            |               | exposure. At the 10-hour        |
|       |            | 1,2,4 10,24   | exposure time point, 10.8 1% of |
|       |            | hr            | the low dose was absorbed.      |
|       |            |               |                                 |
|       |            |               | \% absorbed = 11% for 10 hours  |
+-------+------------+---------------+---------------------------------+

**Cyproconazole Toxicology Executive Summaries**

Reference: Memo, P. Terse, TXR No. 0053768, 11/17/2005.

**1) Developmental Toxicity Study in New Zealand Rabbits MRID 42175401**

In a developmental toxicity study (MRID 42175401), cyproconazole (95%
a.i. Batch \# 8507)) was administered to pregnant New Zealand White
rabbits (18/dose) in 1% aqueous methyl cellulose by gavage at dose
levels of 0, 2, 10, or 50 mg/kg bw/day from days 6 through 18 of
gestation.

Maternal toxicity as indicated by decreased body‑weight gain and food
consumption was observed at the high‑dose level. The pregnancy rate was
88.9% in the control, low-, and mid-dose groups and 77.8% in the
high‑dose group. The number of litters with viable young was 16, 11, 14,
and 10 for the control, low‑, mid‑, and high‑dose groups, respectively.
There was no effect noted on the numbers of implants or live fetuses per
doe, on the number of resorptions or fetal deaths, and overall mean
fetal weight and mean fetal weight/sex were comparable among the groups.
Pre- and post-implantation losses were comparable among the groups.

There was an increased incidence of total external/visceral or skeletal
malformations at the high‑dose level, which was statistically
significant when compared to the concurrent control group. The incidence
in external/visceral and skeletal variations was increased in a
dose-related manner in some instances. It is concluded that the highest
dose level resulted in a slight increase in the incidence of several
malformations and variations. This is based on the facts that (1)
several of the malformations were not observed in either the concurrent
control or historical control data; (2) each of these malformations
occurred in more than one fetus and in more than one litter; (3) the
malformation, malrotated hindlimbs, was also observed at the mid-dose
but at a lower incidence than in the high‑dose group (dose-related); (4)
of the twenty‑three skeletal malformations observed in the study, all
but 4 were observed only at the high‑dose level \[one control fetus had
one malformation, one mid-dose fetus displayed 3 malformations, and one
additional mid‑dose fetus displayed 1 malformation (2 different
litters)\]; and (5) the mid‑ and high‑dose fetuses displayed more
malformations/variations per fetus than the low-dose, concurrent, and
historical control groups. Also to be considered are the facts that (1)
the high-dose had the highest number of non-pregnant does and, were
these does to have been pregnant, the number of fetal findings might
have been greater for this group; and (2) both the mid- and high‑dose
groups had fewer fetuses/litter than the low-dose and control groups
\[5.O and 5.5 vs 6.9 and 6.4, respectively).

**The maternal NOAEL was 10 mg/kg/day, the LOAEL was 50 mg/kg/day, based
on decreased body-weight gains and food consumption.**

**The developmental toxicity NOAEL was 2 mg/kg/day, the LOAEL was 10
mg/kg/day, based on the increased incidence of malformed fetuses and
litters with malformed fetuses.**

This developmental toxicity study is classified **acceptable/Guideline**
and satisfy the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in the rabbit.

This study provided the basis for the dose and endpoint selected for
acute dietary and short- and intermediate-term dermal and inhalation
assessment.

**2) Chronic Toxicity Study in Beagle Dogs MRID 41212901**

In a chronic toxicity study (MRID 41212901), cyproconazole (95% a.i.)
was administered through diet to 4 beagle dogs/sex/dose at
concentrations of 0, 30, 100 or 350 ppm \[equivalent to 0, 1.0, 3.2, or
12.1 9 (males); 12.6 (females) mg/kg/day, respectively\] for 52 weeks.

The results indicated liver as a target organ of toxicity. Absolute and
relative liver weights were increased in the high dose animals of both
sexes compared to controls but statistical significance was attained
only in the males. Elevated alkaline phosphatase and ALT levels (males),
decreased total protein, albumin and cholesterol levels were observed in
high dose animals. Relative kidney weight was increased significantly in
both the low and high dose females but there was no dose dependence.
Statistically significant increases were observed in cytochrome P450 in
both sexes of the high dose and in the mid dose females. Glutathione
S-transferase (GST) values in the mid and high dose females were
significantly and dose dependently decreased. Laminar eosinophilic
intrahepatocytic bodies were observed in all high dose males, one mid
dose male and two high dose females.

**Under the conditions of this study, the LOAEL for cyproconazole in
beagle dogs is 3.2 mg/kg/day (100ppm), based on liver effects \[P450
induction and GST inhibition in females and histopathology (laminar
eosinophilic intrahepatocytic bodies in male)\]. The NOAEL is 1.0
mg/kg/day (30 ppm).**

This chronic study in the dog is **Acceptable/Guideline** and satisfies
the guideline requirement for a chronic oral study \[OPPTS 870.4100,
OECD 452\] in dog.

This study provided the basis for the dose and endpoint selected for
chronic dietary, long-term dermal and inhalation assessment.

**3) Subchronic Oral Toxicity Study in Rats MRID 46152901**

In a subchronic oral toxicity study (MRID 46152901), SAN 619 A
(Cyproconazole, 95.5% a.i., Batch \# Charge 8507) was administered to 15
Wistar rats/sex/dose in the diet at dose levels of 0, 20, 350, 700, or
1400 ppm (equivalent to 0/0, 1.4/1.6, 24.7/29.6, 52.8/57.3, and
106.8/118.1 mg/kg/day in males/females) for 13 weeks. Five rats/sex/dose
were subjected to neuropathological examination, and also evaluated in
the functional observational battery, and for the assessment of motor
activity.

No treatment-related effect was observed on survival, clinical signs,
the functional observational battery, food consumption ratios, water
consumption, the eyes, gross pathology or neuropathology.

At [\>]{.underline}350 ppm, absolute and relative to body liver weights
were increased (p[\<]{.underline}0.05) by 13-55% in the both sexes.
Increased incidences of liver fatty change in males and liver
hypertrophy in both sexes were observed. Increased incidences of thyroid
gland follicular hypertrophy were noted in both sexes. Pituitary gland
distal lobe hypertrophy was observed in the males. Additionally,
relative to body spleen weights were decreased (p[\<]{.underline}0.05)
in the females by 14-25%, compared to controls.

Systemically, body weights and cumulative body weight gains were
decreased (p[\<]{.underline}0.01) throughout treatment in the
[\>]{.underline}700 ppm males and 1400 ppm females. Food consumption was
reduced (p[\<]{.underline}0.01) in the 1400 ppm males during Weeks 1-7
and 11-13, and overall mean food consumption (calculated by reviewers)
was also decreased. Motor activity was decreased (p[\<]{.underline}0.05)
in the 1400 ppm males at Week 13 in total distance, number of movements,
and movement times.

Additional effects were observed on the liver. Increased
(p[\<]{.underline}0.001) gamma-glutamyl transpeptidase was observed in
the 1400 ppm males and the [\>]{.underline}700 ppm females. Additional
differences (p[\<]{.underline}0.01) noted at 1400 ppm included increased
alanine aminotransferase and aspartate aminotransferase in the males,
decreased triglycerides in the males, and increased cholesterol and
globulin in the females.

Increased (p[\<]{.underline}0.05) leukocytes were observed in the
[\>]{.underline}700 ppm groups. Several types of leukocytes were
increased in number (g/l) in the 700 and/or 1400 ppm groups, including
neutrophils, lymphocytes, monocytes, and large unstained cells. Urinary
leukocyte levels were increased (p[\<]{.underline}0.05) in the 1400 ppm
males.

In addition to the increase in relative to body spleen weight, spleen
congestion was also observed in the [\>]{.underline}700 ppm females.
Additionally, a decreased incidence of extramedullary hematopoiesis in
the spleen was noted in the 1400 ppm group.

Increased incidences of the following microscopic lesions were also
observed: (i) fatty change in the adrenal cortex in [\>]{.underline}700
ppm males; (ii) single cell necrosis in the adrenal gland cortex in
[\>]{.underline}700 ppm females; (iii) ceroid deposition in the adrenal
gland cortex in [\>]{.underline}700 ppm females; and (iv) renal
hemosiderosis in the 1400 ppm males and [\>]{.underline}700 ppm females.

**The LOAEL is 350 ppm (equivalent to 24.7/29.6 mg/kg/day in
males/females), based on increased liver weight and increased incidence
of liver hypertrophy in both sexes and increased incidence of liver
fatty change in males. The NOAEL is 20 ppm (equivalent to 1.4/1.6
mg/kg/day in males/females).**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirements (OPPTS 870.3100a; OECD 408) for a subchronic oral
toxicity study in the rat.

This study provided the basis for the dose and endpoint selected for
short- and intermediate-term incidental oral risk assessment.

**4) 21-Day Dermal Toxicity Study in New Zealand White Rabbits MRID
43968317**

In a 21-day dermal toxicity study (MRID 43968317), SAN 619 F 320 SC 412
DP Formulation (29.4% a.i.; Batch #: 6616-01) was applied as supplied to
the shaved intact skin of 5 New Zealand White rabbits/sex/dose at dose
levels of 0, 100, 300, or 1000 mg/kg bw/day (limit dose), 6 hours/day
for at least 21 consecutive days. Dermal irritation was evaluated daily
using the Draize method.

No compound-related effects on mortality, clinical signs, body weight,
body weight gain, food consumption, organ weights, or gross pathology
were observed.

At 1000 mg/kg/day, dermal irritation characterized by slight to well
defined erythema and edema with sloughing was observed in both sexes.
Histopathological effects observed in the treated skin in both sexes
included: (i) trace to minimal diffuse acanthosis; (ii) trace to minimal
diffuse inflammatory cells in the superficial dermis; and (iii) minimal
diffuse hyperkeratosis. The dermal effects were transient in the males
(occurring between Days 5-15) and only slight erythema was observed in
3/5 females from Day 15 to the end of the study.

**The systemic LOAEL was not observed. The systemic NOAEL is 1000
mg/kg/day (limit dose).**

**The dermal LOAEL was established at 1000 mg/kg/day (limit dose) based
on erythema, edema, sloughing and histopathological effects (acanthosis,
inflammatory cells infiltration, and hyperkeratosis) in both sexes. The
dermal NOAEL is 300 mg/kg/day.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement (OPPTS 870.3200; OECD 410) for a 21-day dermal
toxicity study in rabbits.

**5) Dermal Penetration Study in Human and Rat Skin MRID 44883301**

In a non-guideline study (MRID 44883301), the penetration rate of
\[^14^C\]-cyproconazole through human and rat skin was assessed *in
vitro*. \[^14^C\]-Cyproconazole (\>98% radiochemical purity, batch \#
900919) was mixed with SAN 1414 F 360 SL 001 BS (6.41% w/w
cyproconazole, 300 g/L didecyldimethylammonium chloride) to a final
nominal radioactive concentration of 1 μCi/18 mg, at nominal doses of
0.641, 0.01, or 0.0012 mg a.i./cm^2^. The doses approximated exposure to
the undiluted commercial formulation and to the dilute aqueous spray
used in the field. The formulated test substance was applied to excised
rat skin or human skin (1.77 cm^2^/sample) mounted in an *in vitro*
dermal penetration cell to compare the rates of dermal penetration. Ten
samples of each type of tissue were treated and results from the first
five were reported. The integrity of the skin was first tested using
tritiated water, and then penetration of the test formulations was
measured at 0, 1, 2, 4, 6, 10, and 24 h following application to the
skin samples.

The rate of penetration of \[^14^C\]-cyproconazole following dermal
application of SAN 1414 F 360 SL 001 BS was greater through rat skin
than through human skin. The rate of penetration of the undiluted
formulation through rat skin was 12.30 μg/cm^2^/h, compared to 0.501
μg/cm^2^/h for human skin. As the dilution factor increased, the rate of
penetration decreased, and the permeability coefficients increased.

Recovery of radioactivity from the isolated rat and human skin samples
was \>90% of the applied dose for all formulations. The amount of
radioactivity found in the receptor fluid was greater for rat skin
(32.39-72.40% of the applied dose) than for human skin (1.32-49.22% of
the applied dose), reflecting the greater permeability of rat skin
compared to human skin. This percentage increased with increasing
dilution for both species.

For rat skin, the percentage of radioactivity recovered in the surface
wash (8.88-16.47% of the applied dose) was less than that recovered in
the skin sample (17.45-50.78% of the applied dose). Conversely, for
human skin, the percentage of radioactivity recovered in the surface
wash (35.52-66.42% of the applied dose) was greater than that recovered
in the skin sample (22.54-27.44% of the applied dose).

This study is classified as **acceptable/non-guideline**.

**6) *In Vivo* Bone Marrow Chromosome Aberration Assay MRID 46152902**

In an *in vivo* bone marrow chromosome aberration assay (MRID 46152902),
5 CD1 mice/sex/dose/sampling time were treated once via oral gavage (10
mL/kg) with SAN 619 A (Cyproconazole; 95.5% a.i., Batch #: CHARGE 8507)
in Arachis oil at doses of 0, 50, 100, or 200 mg/kg. Bone marrow cells
were harvested at 16, 24, or 48 hours after treatment in the 0 and 200
mg/kg groups, and after 24 hours in the 50 and 100 mg/kg treatment
groups and the positive controls (cyclophosphamide; 64 mg/kg).

No mortalities were observed. Signs of toxicity (hyperactivity, ataxia,
piloerection, hunched posture, and decreased body weight) were observed
at 200 mg/kg, and to a lesser degree at 100 mg/kg. Although there was no
indication of bone marrow toxicity (decreased mitotic index), the
animals received the maximum tolerated dose (MTD). No treatment-related
increases in the percent of aberrant cells (including or excluding gaps)
were observed at any dose or sampling time compared to concurrent
controls. The positive control induced the appropriate response. **There
was no evidence of chromosome aberration induced over background.**

This study is classified as **acceptable/guideline** and satisfies the
guideline requirement (OPPTS 870.5385; OECD 475) for *in vivo*
cytogenetic mutagenicity data.

In a rat metabolism study (MRID 46152903, 46622801),
\[Phenyl-U-^14^C\]-SAN 619F (cyproconazole; Batch \# ILA-117.1; 95.9%
radiochemical purity) in 2/2/1 polyethylene glycol/ethanol/water (v/v)
was administered to female HanBrl: WIST (SPF) rats by gavage at a
nominal dose level of 0.5 mg/kg. Animals were dosed with the radioactive
test substance daily for up to 14 days, and groups of four rats were
killed 1, 7, 14, or 20 days after the first administration. The
distribution of radioactivity between tissues was determined in all
subgroups. Radioactivity in the urine, feces, and blood was measured,
and identification of metabolites in the urine and feces was determined
in the subgroup of rats killed 20 days after the first administration.

Recovery of \[Phenyl-U-^14^C\]-SAN 619F was 97.1% of the total
administered dose seven days after administration of the last dose. The
majority of the total administered dose (96.5%) was recovered in the
feces (56.3%) and urine (40.2%). The cage wash accounted for 0.19%,
while the carcass/tissues retained [\<]{.underline}0.42% of the total
administered dose.

Blood kinetics showed increasing residue values with ongoing
administrations, peaking at approximately 0.075 ppm SAN 619F equivalents
within eight days after the start of dosing. The highest blood levels
were found ten days after the start of dosing (0.08 ppm SAN 619F
equivalents). After administration of the final dose, blood residues
declined rapidly, with a depletion half-life of approximately 40 h.

During the dosing period, a steady state in terms of excretion was
reached approximately four days after the first administration.
Thereafter, the amount of daily excretion remained nearly constant until
the end of dosing, accounting for approximately 40% of the daily dose
for urine and 55% of the daily dose for feces. Three days after the
final dosing, radioactivity was almost completely excreted.

The levels of radioactivity reached plateau levels by seven days after
the start of dosing, and decreased rapidly once dosing ceased. The
calculated half-life for the depletion of radioactivity (assuming
mono-phasic first-order kinetics) from the tissues ranged from one to
three days. The greater persistence and longer half-life of
radioactivity in blood compared to plasma indicated some partitioning of
radioactivity into the red blood cells. The highest concentrations of
radioactivity were observed in the liver (1.37 ppm SAN 619F
equivalents), adrenals (0.93 ppm), lungs (0.56 ppm), fat (0.49 ppm),
kidneys (0.25 ppm), pancreas, (0.22 ppm), and ovaries (0.16 ppm) seven
days after the start of dosing. All other tissues had concentrations of
radioactivity that were comparable to or below the concentrations in
blood throughout the time course.

Urine was found to contain at least 21 metabolite fractions by
two-dimensional TLC. Individual fractions were detected in similar
proportions on Days 0-1, 6-7, and 13-14. The combined urinary metabolite
fractions accounted for 20.8-41.0% of the daily administered doses.

More than 92.5% of the radioactivity was extractable from feces,
accounting for 25.6-56.3% of the administered daily dose. Feces were
found to contain at least 13 metabolite fractions by two-dimensional
TLC. The combined fecal metabolite fractions accounted for 23.7-52.5% of
the administered daily dose, while non-extractable radioactivity
accounted for 1.9-3.8% of the daily dose. Two of the fractions
(Fractions 9 and 10) were identified as unmetabolized parent, and
Fraction 6 was identified as NOA 421153 (a diol metabolite of SAN 619F).

This metabolism study in the rat is classified **acceptable/guideline**
and does satisfy the guideline requirement for a Tier 1 metabolism study
\[OPPTS 870.7485, OPP 85-1\] in rats.

In a non-guideline study (MRID 46152909.), 5 CD-1 (Crl:CD^®^-1 (ICR) BR)
mice/sex/dose were exposed to SAN 619 A (Cyproconazole; 97.4% a.i.; Lot
#: MU 809073) daily in the diet at concentrations of 0, 50, 100 or 200
ppm (equivalent to 0/0, 9.0/12.7, 16.7/21.5, and 24.8/29.5 mg/kg/day
\[M/F\], respectively) for 14 days. An additional group of 5 mice/sex
was treated with phenobarbitone, a known potent hepatic enzyme inducer.
On Day 15, all animals were killed and the livers of all animals were
either processed or frozen. The hepatic 100x*g* supernatant, microsomal
fraction, and cytosolic fraction were obtained by standard differential
centrifugation, and protein contents, microsomal cytochrome P450
content, enzyme activities, and immunoblot analysis for isozyme-specific
cytochrome P450 expression were determined. The purpose of this study
was to examine whether repeated administration of SAN 619 A caused
induction of enzymes in the liver and to compare induction to
phenobarbitone.

No effects of treatment were observed on mortality, clinical
observations, body weights, food consumption, gross pathology, or
carcass weight. Relative (to body) liver weights were increased
(p[\<]{.underline}0.05) in both sexes at [\>]{.underline}100 ppm.
Absolute liver weights were increased (p[\<]{.underline}0.001) in the
200 ppm males and the [\>]{.underline}100 ppm females. At
[\>]{.underline}50 ppm, an increased incidence of centrilobular and
midzonal hepatocellular hypertrophy in both sexes was observed with a
dose-dependent increase in severity. In both sexes, hypertrophy was
frequently associated with centrilobular cytoplasmic vacuolation and
hepatocellular necrosis. At 200 ppm, an increase in the incidence of
mitotic activity was observed. These liver weight and histopathological
changes were similar to those observed in phenobarbitone-treated
animals.

Hepatic microsomal protein content in females and cytochrome P450
content in both sexes were increased at [\>]{.underline}50 ppm. Except
for an additional increase in the protein content in the 100x*g*
supernatant in phenobarbitone-treated females, similar effects on
protein content were observed between mice treated with SAN 619 A and
phenobarbitone. At [\>]{.underline}50 ppm, hepatic 7-pentoxyresorufin
O-depentylation (PROD), 7-benzyloxyresorufin O-debenzylation (BROD),
coumarin 7-hydroxylation (COH) activities were increased
(p[\<]{.underline}0.05) in both sexes. Microsomal epoxide hydrolase (EH)
and glutathione S-transferases (GST) activities were increased
(p[\<]{.underline}0.05) in males at 200 ppm and [\>]{.underline}50 ppm,
respectively. In females, EH and GST activities were both increased (p
[\<]{.underline}0.01) at [\>]{.underline}100 ppm. Additionally in
females, 7-Methoxyresorufin O-demethylation (MROD) and 7-ethoxyresorufin
O-deethylation (EROD) were increased (p≤0.001) at ≥50 ppm. Slight
increases (p≤0.05) in lauric acid 11- and 12-hydroxylation activities
were also observed in females at [\>]{.underline}50 ppm. The
determination of regio- and stereoselective hydroxylation of
testosterone demonstrated an increase in total oxidation rates of
testosterone for both sexes of SAN 619 A-treated mice. Oxidation at all
positions, except the 1α position in males, contributed to this
increase. The expression of CYP 1A2, CYP 3A, and two protein bands for
CYP 2B, as determined by immunoblot analysis, was increased in both
sexes of SAN 619 A-treated mice at [\>]{.underline}50 ppm. In females,
expression of one of two protein bands for CYP 4A was slightly decreased
at ≥100 ppm.

The induction of enzyme activities and cytochrome P450 enzyme expression
were similar to those observed for phenobarbitone. In
phenobarbitone-treated mice, increases (p≤0.01) were also observed in
activities for UDP-glucuronosyltransferase in both sexes and MROD, EROD,
and lauric acid 11-hydroxylation in males, but increased lauric acid
12-hydroxylation activity was not observed in phenobarbitone-treated
females. Additionally, peroxisomal fatty acid oxidation was slightly
decreased (p≤0.01) in phenobarbitone-treated males. The profile of
testosterone metabolism in phenobarbitone-treated mice was similar to
that observed for mice treated with 200 ppm SAN 619 A. However,
oxidation at the 16α position in females and the 6α position in both
sexes was more potent, and conversion to androstenedione in both sexes
was less potent when compared to SAN 619 A-treated mice. The expression
of CYP 1A2 in phenobarbitone-treated females, was considerably higher in
than that observed at 200 ppm in SAN 619 A-treated mice. Additionally,
decreased expression of both protein bands identified by the antibody
for CYP 4A were observed in both sexes of phenobarbitone-treated mice,
but not SAN 619 A-treated mice.

In summary, these results demonstrate an increase in isozyme-specific
cytochrome P450 activities (CYP 2B, CYP 2D, and CYP 3A families, CYP
2A4/5, and CYP 2A12 in both sexes and CYP 1A1/2, 2E1, and 4A in females)
and expression (CYP 1A2, CYP 3A, and CYP 2B), and increased phase II
enzyme activities (EH and GST in both sexes and lauric acid 11- and
12-hydroxylation in females).

The submitted study is classified as **acceptable/non-guideline**.

**7) 13-Week feeding Study in Beagle Dogs MRID 40607719**

In a 13 Week feeding study (MRID 40607719), cyproconazole (95.6% a.i.)
was administered through diet to 4 beagle dogs/sex/dose at
concentrations of 0, 20, 100 or 500 ppm (approximately 0, 0.8, 4.0, or
20 mg/kg/day) for 13 weeks.

Changes associated with treatment observed in both sexes administered
the highest dietary level, included "slack muscle tone", inhibited body
weight gain, increased platelet counts, decreased: bilirubin, total
cholesterol, HDL-cholesterol, triglycerides, total protein and albumin
and increased alkaline phosphatase and gamma glutamyl transferase.
Decreased food consumption was seen in high dose males. Increased
absolute and relative liver weights and increased relative kidney
weights were noted for high dose males and females; relative brain
weights were increased in high dose females. Histopathologic evidence of
liver toxicity in high dose males and females included hepatocytomegaly,
degeneration of single hepatocytes and cytoplasmic inclusions. Evidence
of liver effects in mid dose dogs was increased absolute liver weights
in males and hepatocytomegaly in males and females. However, these
effects were considered adaptive changes.

**Under the conditions of this study, the LOAEL for cyproconazole in
beagle dogs is 20.0 mg/kg/day (500 ppm), based on "slack muscle tone",
inhibited body weight gain, liver effects (increased alkaline
phosphatase and gamma glutamyl transferase) and histopathologic
evidences (hepatocytomegaly, degeneration of single hepatocytes and
cytoplasmic inclusions). The NOAEL is 4.0 mg/kg/day (100 ppm).**

This subchronic study in the dog is **Acceptable/Guideline** and
satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3150; OECD 409) in non-rodent.

**8) Developmental Toxicity Study in Chinchilla Rabbits MRID 40607720**

In a developmental toxicity study (MRID 40607720), SAN 619F (95.6 % a.i.
Lot \# 8507)) was administered to pregnant Chinchilla rabbits (16/group)
in 4% aqueous methyl cellulose by gavage at dose levels of 0, 2, 10, or
50 mg/kg bw/day from days 6 through 18 of gestation.

Evidence of maternal toxicity included reduced body weight gain (-26%)
during treatment and decreased food consumption during the initial phase
of treatment, both at 50 mg/kg. However, corrected body weight changes
between groups were comparable indicating maternal changes in body
weight gain could be due to increased resorptions.

Developmental toxicity, observed at 50 mg/kg, was evident from the
decreased number of live fetuses/dam and an increased incidence of
non-ossification in certain forelimb and hindlimb digits. Evidence of
Developmental toxicity at dosages of 10 and 50 mg/kg was indicated by an
increased incidence of embryonic and fetal resorptions.

Evidence of developmental toxicity included hydrocephalus internus,
observed in 1 fetus at each dosage level, and agenesia of the left
kidney and ureter in 1 high-dose fetus. The incidence of hydrocephalus
internus was 0.85, 0.83 and 0.93 for the low-, mid- and high-dose
fetuses and 0.08 for the historical control incidence. Hydrocephaly was
also seen at 2 dosage levels in a developmental toxicity study in rats
with this test material, however, this anomaly did not occur in the
concurrent controls of either study. In the another developmental
toxicity study in New Zealand White rabbits, Hydrocephaly was not seen.

**The maternal NOAEL was 10 mg/kg, the LOAEL was 50 mg/kg, based on
decreased body-weight gains and food consumption.**

**Developmental toxicity NOAEL was not attained; Developmental LOAEL was
2 mg/kg, based on incidence of hydrocephalus internus.**

This developmental toxicity study is classified
**Unacceptable/Guideline** and does not satisfy the guideline
requirement for a developmental toxicity study (OPPTS 870.3700; OECD
414) in the rabbit because: 1) a NOAEL for developmental toxicity
apparently was not attained and 2) the concentrations of test material
were not within the acceptable range (± 15% of nominal concentration)
for the mid- and high dose suspensions immediately after preparation.

In a developmental toxicity study (MRID 40607721), SAN 619F (95% a.i.
Lot \# 8507)) was administered to pregnant Wistar/Han rats (25/dose) in
4% aqueous methyl cellulose by gavage at dose levels of 0, 6, 12, 24 or
48 mg/kg bw/day from days 6 through 15 of gestation.

Evidence of maternal toxicity included inhibited body weight gain
(11.4%) during treatment at dosage levels of 12 mg/kg and above and
decreased body weight and food consumption among females in the 24 and
48 mg/kg dosage groups. These differences in maternal body weights could
have been influenced by treatment-related intrauterine effects (e.g.,
increased number of resorptions, decreased fetal weight). Evidence of
fetal toxicity was apparent from observed dose-related increases in the
number of litters with supernumerary ribs at dosages 12 mg/kg and above.
Developmental toxicity was apparent at 24 and 48 mg/kg from the
following observations: decreased total number of fetuses/dam, decreased
number of live fetuses/dam, increased percentage and number of fetal
resorptions, decreased body weight and incomplete ossification in
phalangeal nuclei and the absence of ossification in calcanea. There was
evidence of developmental toxicity in the 24 and 48 mg/kg groups.
Hydrocephaly was observed in 1 fetus in the 24 mg/kg and 2 fetuses in
the 48 mg/kg groups. Cleft palate was observed in 2 fetuses in the 48
mg/kg group.

**The maternal NOAEL was 6 mg/kg, the LOAEL at 12 mg/kg based on
decreased body weight gain during treatment. The developmental toxicity
NOAEL was 6 mg/kg, the LOAEL at 12 mg/kg based on increased incidence of
supernumerary ribs.**

This developmental toxicity study is classified **acceptable/Guideline**
and satisfies the guideline requirement for a developmental toxicity
study (OPPTS 870.3700; OECD 414) in the rat.

**9) Two-Generation Reproductive Toxicity Study in Rats MRID 40607723**

In a 2-generation reproduction study (MRID 40607723) cyproconazole
(purity, 95.6% a.i.; lot \# 8507) was administered to groups of 26/sex
KFM-Wistar albino rats/dose, in the diet, at concentrations of 0, 4, 20,
or 120 ppm (F0, M/F: 0, 0.28/0.33, 1.39/1.67, 8.29/9.88 mg/kg/day,
respectively) during the pre-mating (10 wks and 12 wks, for the F0 and
F1 generation, respectively), mating, pregnancy and lactation periods.

Two of the reproductive parameters investigated in parental animals were
affected by treatment in F0 animals only: the duration of gestation at
the mid- and high doses was increased and a lower number of implantation
sites was seen in high-dose females, both in comparison to respective
concurrent control values. However, the HED/Peer Review committee (TXR
\# 0053466, Nov 15, 1993) concluded that the effects noted (increased
gestation length and litter size) were not treatment related. Evidence
of liver toxicity was seen in high dose F0 males (increased lipid
storage and relative weight) and females (increased relative weight).

Parameters examined among the offspring which showed treatment-related
effects included decreased litter sizes in both the F1 and F2 high-dose
groups and the F1 mid-dose group during the early phase of lactation
(litters were standardized at day 4 post partum), decreased live birth
index in the high-dose F1 offspring and decreased viability index in the
high-dose F1 and F2 offspring. However, the HED/Peer Review committee
(TXR \# 0053466, Nov 15, 1993) concluded that the effects noted (litter
size) were not treatment related.

**The parental LOAEL for the systemic toxicity is 120 ppm (8.29
mg/kg/day), based on liver effects ((increased lipid storage and
relative weight). The parental NOAEL for systemic toxicity is 20 ppm
(1.39 mg/kg/day).**

**The offspring toxicity NOAEL is \> 120 ppm (8.29 mg/kg/day), LOAEL is
not established.**

**The reproductive toxicity NOAEL is \> 120 ppm (8.29 mg/kg/day), LOAEL
is not established.**

This study is classified **Acceptable/Guideline** and satisfies the
guideline requirement (It was noted that although dose levels were not
adequate, study need not be repeated since similar effects (increased
resorptions, decreased litter size) were observed in the rat
developmental study at dose levels of 24 and 48 mg/kg and a NOAEL for
these effects was established in that study.

[]{#__RefHeading___Toc182970227 .anchor}**Appendix B**

  ------------------------------------------------------------------------
  **Nomenclature of   
  Triazole-related    
  Metabolites.**      
  ------------------- ----------------------------------------------------
  Compound            ![](media/image3.wmf){width="0.6201388888888889in"
                      height="0.5534722222222223in"}

  Common name (Abbr)  1,2,4-Triazole (Triazole)

  Chemical Name       1*H*-1,2,4-Triazole

  CAS registry number 288-88-0

  Compound            ![](media/image4.wmf){width="1.5298611111111111in"
                      height="0.8493055555555555in"}

  Common name (Abbr)  Triazole alanine (TA)

  Chemical Name       α-amino-1*H*-1,2,4-triazole-1-proanoic acid

  CAS registry number 114419-45-3

  Compound            ![](media/image5.wmf){width="1.3493055555555555in"
                      height="0.5993055555555555in"}

  Common name (Abbr)  Triazole Acetic Acid (TAA)

  Chemical Name       1*H*-1,2,4-Triazole-1-Acetic acid

  CAS registry number 28711-29-7
  ------------------------------------------------------------------------

**Proposed Metabolic Profile of Cyproconazole in Laying Hens.**

![](media/image6.wmf){width="6.639583333333333in"
height="7.854166666666667in"}