UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

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  TOC \o "1-4" \h \z \u  

  HYPERLINK \l "_Toc182970171"  1.0	Executive Summary	  PAGEREF
_Toc182970171 \h  5  

  HYPERLINK \l "_Toc182970172"  2.0	Ingredient Profile	  PAGEREF
_Toc182970172 \h  10  

  HYPERLINK \l "_Toc182970173"  2.1	Cyproconazole Structure and
Nomenclature	  PAGEREF _Toc182970173 \h  11  

  HYPERLINK \l "_Toc182970174"  2.2	Summary of Proposed and Registered
Uses	  PAGEREF _Toc182970174 \h  11  

  HYPERLINK \l "_Toc182970175"  3.0	Hazard Assessment	  PAGEREF
_Toc182970175 \h  12  

  HYPERLINK \l "_Toc182970176"  3.1	Hazard and Dose-Response Assessment	
 PAGEREF _Toc182970176 \h  13  

  HYPERLINK \l "_Toc182970177"  3.2	Absorption, Distribution, Metabolism
and Excretion in Rats	  PAGEREF _Toc182970177 \h  13  

  HYPERLINK \l "_Toc182970178"  3.3	 FQPA Considerations	  PAGEREF
_Toc182970178 \h  14  

  HYPERLINK \l "_Toc182970179"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc182970179 \h  14  

  HYPERLINK \l "_Toc182970180"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc182970180 \h  14  

  HYPERLINK \l "_Toc182970181"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc182970181 \h  14  

  HYPERLINK \l "_Toc182970182"  3.3.3.1	 Developmental Toxicity Study in
the New Zealand White Rabbit	  PAGEREF _Toc182970182 \h  14  

  HYPERLINK \l "_Toc182970183"  3.3.3.2	 Developmental Toxicity Study in
the Chinchilla Rabbit	  PAGEREF _Toc182970183 \h  15  

  HYPERLINK \l "_Toc182970184"  3.3.3.3	 Developmental Toxicity Study in
Rats	  PAGEREF _Toc182970184 \h  16  

  HYPERLINK \l "_Toc182970185"  3.3.4	Reproductive Toxicity	  PAGEREF
_Toc182970185 \h  17  

  HYPERLINK \l "_Toc182970186"  3.3.5	Pre- and Post-Natal Toxicity	 
PAGEREF _Toc182970186 \h  17  

  HYPERLINK \l "_Toc182970187"  3.3.5.1	Determination of Susceptibility	
 PAGEREF _Toc182970187 \h  17  

  HYPERLINK \l "_Toc182970188"  3.3.5.2	Degree of Concern	  PAGEREF
_Toc182970188 \h  18  

  HYPERLINK \l "_Toc182970189"  3.3.6	Recommendation for a Developmental
Neurotoxicity Toxicity (DNT) Study	  PAGEREF _Toc182970189 \h  18  

  HYPERLINK \l "_Toc182970190"  3.4	FQPA Safety Factor	  PAGEREF
_Toc182970190 \h  19  

  HYPERLINK \l "_Toc182970191"  3.5	Hazard Identification and Endpoint
Selection	  PAGEREF _Toc182970191 \h  19  

  HYPERLINK \l "_Toc182970192"  3.5.1	Acute Dietary Endpoint	  PAGEREF
_Toc182970192 \h  19  

  HYPERLINK \l "_Toc182970193"  3.5.2	Chronic Dietary Endpoint	  PAGEREF
_Toc182970193 \h  20  

  HYPERLINK \l "_Toc182970194"  3.5.3	Short- and Intermediate-Term
Incidental Oral Endpoints	  PAGEREF _Toc182970194 \h  20  

  HYPERLINK \l "_Toc182970195"  3.5.4	Short and Intermediate-Term Dermal
and Inhalation Endpoints	  PAGEREF _Toc182970195 \h  20  

  HYPERLINK \l "_Toc182970196"  3.5.5	Long-Term Dermal and Inhalation
Endpoints	  PAGEREF _Toc182970196 \h  21  

  HYPERLINK \l "_Toc182970197"  3.5.6	Carcinogenicity	  PAGEREF
_Toc182970197 \h  21  

  HYPERLINK \l "_Toc182970198"  3.6	Endocrine Disruption	  PAGEREF
_Toc182970198 \h  23  

  HYPERLINK \l "_Toc182970199"  4.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc182970199 \h  23  

  HYPERLINK \l "_Toc182970200"  4.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc182970200 \h  23  

  HYPERLINK \l "_Toc182970201"  4.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc182970201 \h  24  

  HYPERLINK \l "_Toc182970202"  4.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc182970202 \h  24  

  HYPERLINK \l "_Toc182970203"  4.1.3	Metabolism in Livestock	  PAGEREF
_Toc182970203 \h  24  

  HYPERLINK \l "_Toc182970204"  4.1.4	Analytical Methodology	  PAGEREF
_Toc182970204 \h  24  

  HYPERLINK \l "_Toc182970205"  4.1.5	Environmental Degradation	 
PAGEREF _Toc182970205 \h  25  

  HYPERLINK \l "_Toc182970206"  4.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc182970206 \h  25  

  HYPERLINK \l "_Toc182970207"  4.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc182970207 \h  26  

  HYPERLINK \l "_Toc182970208"  4.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc182970208 \h  27  

  HYPERLINK \l "_Toc182970209"  4.1.9	Drinking Water Residue Profile	 
PAGEREF _Toc182970209 \h  28  

  HYPERLINK \l "_Toc182970210"  4.1.10	Food Residue Profile	  PAGEREF
_Toc182970210 \h  29  

  HYPERLINK \l "_Toc182970211"  4.1.11	International Residue Limits	 
PAGEREF _Toc182970211 \h  32  

  HYPERLINK \l "_Toc182970212"  4.2	Dietary Exposure and Risk	  PAGEREF
_Toc182970212 \h  32  

  HYPERLINK \l "_Toc182970213"  4.2.1	Acute Dietary Risk
Characterization (Females 13-49 years old)	  PAGEREF _Toc182970213 \h 
33  

  HYPERLINK \l "_Toc182970214"  4.2.2	Chronic Dietary Risk
Characterization	  PAGEREF _Toc182970214 \h  34  

  HYPERLINK \l "_Toc182970215"  5.0	Residential (Non-Occupational) Risk	
 PAGEREF _Toc182970215 \h  34  

  HYPERLINK \l "_Toc182970216"  6.0	Aggregate Risk Assessments	  PAGEREF
_Toc182970216 \h  34  

  HYPERLINK \l "_Toc182970217"  6.1	Acute Aggregate Risk	  PAGEREF
_Toc182970217 \h  35  

  HYPERLINK \l "_Toc182970218"  6.2	Chronic Aggregate Risk	  PAGEREF
_Toc182970218 \h  35  

  HYPERLINK \l "_Toc182970219"  7.0	Cumulative Risk Characterization	 
PAGEREF _Toc182970219 \h  35  

  HYPERLINK \l "_Toc182970220"  8.0	Occupational Risk Assessment	 
PAGEREF _Toc182970220 \h  35  

  HYPERLINK \l "_Toc182970221"  8.1	Occupational Handler Risk Assessment
  PAGEREF _Toc182970221 \h  36  

  HYPERLINK \l "_Toc182970222"  8.2	Occupational Post-application
Exposure	  PAGEREF _Toc182970222 \h  40  

  HYPERLINK \l "_Toc182970223"  8.3	REI	  PAGEREF _Toc182970223 \h  41  

  HYPERLINK \l "_Toc182970224"  9.0	Data Needs and Label Recommendations
  PAGEREF _Toc182970224 \h  41  

  HYPERLINK \l "_Toc182970225"  9.1	Regulatory Recommendations and
Residue Chemistry Deficiencies	  PAGEREF _Toc182970225 \h  41  

  HYPERLINK \l "_Toc182970226"  Appendix A	  PAGEREF _Toc182970226 \h 
45  

  HYPERLINK \l "_Toc182970227"  Appendix B	  PAGEREF _Toc182970227 \h 
61  

 

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-(1H-1,2,4-triazol-1-yl)buta
n-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 95th 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 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 95th 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. 

  SEQ CHAPTER \h \r 1 Regulatory Recommendations and Residue Chemistry
Deficiencies

cyproconazole
[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1H-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 

cyproconazole
[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1H-1,2,4-triazole-1-ethanol
] and its metabolite M36
[δ-(4-chlorophenyl)-β,δ-dihydroxy-γ-methyl-1H-1,2,4-triazole-1-hexen
oic 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)-1H-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.

α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1H-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).

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-(1H-1,2,4-triazol-1-yl)buta
n-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.

2.1	Cyproconazole Structure and Nomenclature

Table 2.1a.  Cyproconazole Nomenclature.

Chemical structure	

Common name	Cyproconazole

Company experimental name	SAN619

IUPAC name
(2RS,3RS)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)buta
n-2-ol

CAS name
α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1H-1,2,4-triazole-1-ethanol

CAS registry number	94361-06-5

End-use products (EP)	0.67 lb/gal SC (Quadris Xtra™ Fungicide, EPA
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 25ºC	108 mg/L at pH 4.1

93 mg/L at pH 7

109 mg/L at pH 10	MRID 46840803

Solvent solubility

(g/100 mL at 25°C)	n-Hexane	0.2

Diisopropyl ether	2.2

Toluene	10.9

Xylene	11.2

Acetone	>20	D179678, R. Lascola, 9/24/91

Vapor pressure at 25ºC	2.6 x 10-5 Pa 	MRID 46840803

Dissociation constant, pKa	Compound does not dissociate	D179678, R.
Lascola, 9/24/91

Octanol/water partition coefficient, Log(KOW)	2.91 ± 0.12

	UV/visible absorption spectrum	Not reported

	

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).  

 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 Cyproconazole.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate

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

(lb ai/A)	PHI

(days)	Use Directions and Limitations1

Wheat/Triticale

Broadcast foliar application(s) at Feekes Stage 5-10.5 using ground, air
or chemigation equipment	0.83 lb/gal SC/L

[100-1226]

0.67 lb/gal SC [100-1225]2	0.036	2	0.036	30 - grain

21 - forage/ hay	The minimum RTI is 14 days.

Field or Seed Corn

Broadcast foliar application at first sign of disease using ground, air
or chemigation equipment	0.83 lb/gal SC/L

[100-1226]

0.67 lb/gal SC [100-1225]2	0.036	2	0.036	30 - grain

21 - silage	The minimum RTI is 7 days.

Soybean

Broadcast foliar application prior to disease using ground, air or
chemigation equipment	0.83 lb/gal SC/L

[100-1226]

0.67 lb/gal SC [100-1225]2	0.036	2	0.072	30 - seed	The minimum RTI is 14
days.  Do not graze forage within 14 days of application.

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.

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.

3.1	Hazard and Dose-Response Assessment

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 CH3 group; oxidation of CH3 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. 



3.3		FQPA Considerations

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

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.

3.3.3	Developmental Toxicity Studies

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. In a teratogenicity study in
rabbit (MRID  42175401), cyproconazole (purity 94.8%) was administered
by gavage to 18 inseminated New Zealand white rabbits/group once daily
from day 6 to 18 post-coitus at dose levels of 2, 10, and 50 mg
cyproconazole per kg body weight/day (vehicle was 1% carboxymethyl
cellulose).  Dose selection was based upon a range-finding study with
dose levels of 0, 2, 10, and 50 mg/kg/day.  Does were sacrificed on day
28 of gestation, dissected, and examined macroscopically for
pathological changes.  The ovaries and uteri of each doe were removed,
and the number corpora lutea in each ovary and the number and position
of implantations [as live fetuses, early resorptions, late resorptions,
and dead fetuses] were determined.

Maternal Toxicity

The number of pregnant does was decreased at the high dose; two does
aborted in both the low- and high-dose groups; one doe in both the mid-
and high-dose groups died; and three low-dose, one mid-dose, and one
high-dose does had 100% intrauterine deaths, leaving 16, 11, 14, and 10
does with viable fetuses in the control, low-, mid-, and high-dose
groups, respectively.  The NOAEL for maternal toxicity was 10 mg/kg/day;
the LOAEL was 50 mg/kg/, based on decreased body-weight gains.

Developmental Toxicity

There was an increase in total skeletal or external/visceral
malformations at the high dose when compared to the concurrent control
group.  Although the incidence of malformations at the mid dose was low,
one of the malformations (malrotated hindlimbs) observed at this dose
was not listed in the concurrent or historical control data, and it was
observed at the high dose at a higher incidence than at the mid dose. 

In summary, the highest dose resulted in a slight increase in the
incidence of several malformations and variations.  This is based on the
fact 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 and at a lower incidence than in the high-dose group (dose
related); (4) of the 23 skeletal malformations observed in the study,
all but four were observed only at the high-dose level [control fetus
had one malformation, one mid-dose fetus displayed three malformations,
and one additional mid-dose fetus displayed one malformation (two
different litters)); (5) the mid- and high-dose fetuses displayed more
malformations and/or variations per fetus than the low dose, concurrent,
and historical control groups; and (6) both the mid- and high-dose
groups had fewer fetuses/litter than the low-dose and control groups
[5.5 vs 6.9 and 6.4, respectively).  The NOAEL for developmental
toxicity 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.

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.In a teratogenicity study in rabbits (MRID
40607720), cyproconazole (purity 95.6%) was administered by gavage to
sixteen Chinchilla rabbits [Kfm: CHIN, Hybrids, SPF (specific pathogen
free)]/group on days 6 through 18 of gestation at 0, 2, 10, or 50
mg/kg/day (vehicle:  distilled water with 4% CMC).  Dose selection was
based upon a range-finding study with dose levels of 0, 1, 4, 12, or 40
mg/kg/day.  Does were sacrificed on day 28 of gestation; postmortem
examination included a macroscopic inspection of all internal organs,
and each uterus was examined for contents, position of each fetus, and
number of corpora lutea.  Fetuses were sexed, weighed, and examined for
external abnormalities.  All fetuses were dissected for body cavity
(thorax, abdomen, and pelvis) examination and the organs were examined
for abnormalities.  The skin was removed from the crania of all fetuses
in order to examine for ossification.  Following fixation, heads were
cross-sectioned and the cephalic viscera were examined.  The trunk of
each fetus was stained and examined for skeletal abnormalities.

Maternal Toxicity

Initially, the mean body weight of the 50 mg/kg/day does was 6% lower
than the control throughout most of the study (on day 28, it was reduced
to 10.7%).  No additional decrease in body weight occurred, but the
decrement established during dosing was maintained until sacrifice. 
During treatment (days 6-19), the body-weight gain of the 50 mg/kg/day
group was 37.6% of the controls.  The mean weight gain in the 50
mg/kg/day treatment group before and immediately after treatment
exceeded that of the control.  As such, these results were interpreted
as possibly treatment-related.  Food consumption in the 50 mg/kg/day
group was significantly reduced (- 26.9% of control) during the initial
phase of treatment on days 6-11.  The NOAEL for maternal toxicity was 10
mg/kg/day (equivocal).  The LOAEL was 50 mg/kg/day, based on decreased
body-weight gain during dosing.

Developmental Toxicity

Developmental effects considered related to treatment include: 
decreased total number of fetuses alive and dead/doe (50 mg/kg/day),
decreased number of live fetuses/doe (50 mg/kg/day), and increased
resorptions (10 and 50 mg/kg/day).  Additional findings included an
increased incidence of reduced ossification of the fifth digit of the
forelimbs and fourth digit of the hindlimbs (50 mg/kg/day). 
Hydrocephalus internus was observed in one fetus at each treatment level
(1/118, 1/120, 1/107 vs 3/3202 for historical 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 incidence.  Therefore, the NOAEL for
developmental toxicity was set at <2 mg/kg/day, the LOAEL was 2
mg/kg/day.

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.

In a teratogenicity study in rats (MRID 40607721), cyproconazole (purity
95.6%) was administered as a suspension by gavage to sperm-positive
Wistar/HAN (Kfm: WEST, outbred, apr quality) female rats at dose levels
of 0 (vehicle: distilled water with 4% carboxymethylcellulose sodium
salt, 99.5%), 6, 12, 24, and 48 mg/kg on days 6 through 15 of gestation.
 Dose selection was based upon a range-finding study in which the dose
levels were 0, 7.5, 30, 75, and 120 mg/kg/day.  There were 25 rats per
group.  Dams were sacrificed on day 21 of gestation; postmortem
examination included a macroscopic inspection of all internal organs,
and each uterus was examined for contents, position of each fetus, and
number of corpora lutea.  Fetuses were sexed, weighed, examined for
external abnormalities; one third of the live fetuses were examined for
visceral malformations (Wilson technique); the remaining two thirds were
stained for evaluation of skeletal malformations (modified Dawson
technique).

Maternal Toxicity

Body-weight gain was decreased (treatment related) during the dosing
period.  Maternal food consumption was significantly reduced at 24 and
48 mg/kg/day during the treatment period.  The NOAEL for maternal
toxicity was 6 mg/kg/day.  The LOAEL was 12 mg/kg/day, based on
decreased body-weight gain during dosing.

Developmental Toxicity

Pregnancy rate, number of corpora lutea/dam, and number of
implantations/per dam were comparable among the groups.  The number of
fetuses (live and dead)/dam and number of live fetuses/dam were
decreased at the two highest dose levels (dose related).  The number of
resorptions (early, late, and total) was increased at the two highest
dose levels (dose related), although statistical significance was
attained only for total resorptions.  There was a dose-related increase
in postimplantation loss at the two highest dose levels, but statistical
significance was not attained.  One runt was observed in each of the
treatment groups; historical control data list no runts in 6292 vehicle
control fetuses.  Hydrocephaly was observed in 1 fetus at 24 mg/kg/day
and in 2 fetuses/2 litters at 48 mg/kg/day; historical control data list
one vehicle control fetus (out of 6292) displaying this malformation. 
Cleft palate was observed in two fetuses/two litters at the highest dose
level only; historical control data list no vehicle controls with cleft
palate.  There was a dose-related increase in the incidence of
supernumerary ribs, although statistical significance was attained only
at the 24 and 48 mg/kg/day dose levels.  Additionally, decreased
ossification (or an increase in the % of fetuses with an absence of
ossification) of phalangeal nuclei (fore-, hindlimb) & calcanea was
observed at the 24 and 48 mg/kg/day dose levels.  Neither of these
findings was reported in the historical control data.  Mean fetal body
weight was decreased (equally) at the two highest dose levels, compared
to the control value.

The NOAEL for developmental toxicity is 6 mg/kg/day.  The LOAEL for this
study was considered to be 12 mg/kg/day, based on the increased
incidence of supernumerary ribs.

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. In a two-generation
reproduction study in rats (MRID 40607723), technical cyproconazole
(purity 95.6%) was administered to 26 male and 26 female F0 and F1
KFM-Wistar rats per group for 10 and 12 weeks, respectively, during the
premating period via the diet at 0, 4, 20, or 120 ppm (0, 0.4, 1.7 or
10.6 mg/kg/day).  Treatment of the males was continued for three weeks
after termination of mating, and the dams were treated until necropsy
(post-weaning).

Systemic Toxicity 

There were no deaths among the parental animals in either generation and
body weight and food consumption were comparable among the groups/sex
for each generation.  Males at the high-dose level displayed an
increased incidence of fatty change in the liver (73.1%) compared to the
control (38.5%), which was characterized as mainly macrovesicular lipid
storage in hepatocytes of zones 3 and 2; the severity was increased at
all dose levels (1.8, 1.9, 1.8, at the low, mid, and high dose,
respectively) compared to the control (1.6), but there was no dose
response.  High-dose F1 males displayed a slight increase (58%) in the
incidence of lipid storage in the liver compared to the control value
(42%).  Liver weight was increased in both sexes of the F1 generation at
the high dose level compared to the control values, but statistical
significance was attained only for the increased relative liver weight
in males.  No other macro- or microscopic changes were observed in
either the F0 or F1 parental rats.  The systemic NOAEL was set at 20 ppm
(1.7 mg/kg), based on liver effects at 10.6 mg/kg/day.

Reproductive Toxicity

Although gestation length was slightly increased and litter size
decreased, these changes were not considered to be treatment related. 
The reproductive NOAEL was >120 ppm (10.6 mg/kg).

3.3.5	Pre- and Post-Natal Toxicity

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 that were
marginally maternally 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.  No
treatment related reproductive effects were reported in the 2-generation
rat reproduction study; therefore there is no evidence of evidence of
concern for postnatal susceptibility for cyproconazole.

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. 

 

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
concern is nolow 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. 
TSimilarly, 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.

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.

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.

3.5	Hazard Identification and Endpoint Selection

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 SUF 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).  HED has since
re-evaluated the suitability of the chinchilla rabbit study as the basis
for the acute RfD for females 13+ years old based on the comments
provided by the registrant.  Specifically, upon evaluation of the
chinchilla rabbit development study, HED concluded that the
developmental toxicity study in New Zealand white rabbits is more
appropriate for assessment of acute dietary risk to females 13+ years
old.    

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.

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.
 

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.

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.

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.

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 Toxicological Dose and Endpoints for
Cyproconazole Used in Human Risk Assessment.



Exposure

Scenario	

Dose Used in Risk Assessment, UF 	Special FQPA SF* and Level of Concern
for Risk Assessment	

Study and Toxicological Effects

Acute Dietary (general population)	Not applicable	None	An endpoint of
concern attributable to a single dose for general population was not
identified. 

Acute Dietary (Females 13+)	NOAEL =2 mg/kg/day 

UF = 100X

Acute RfD =  0.02 mg/kg 	FQPA SF = 1X

aPAD =

acute RfD

 FQPA SF

= 0.02 mg/kg	Developmental toxicity – New Zealand white rabbits;

LOAEL = 10 mg/kg/day based on increased incidence of malformed fetuses
and litters with malformed fetuses. 

Chronic Dietary

(All populations)	NOAEL= 1.0 mg/kg/day

UF = 100X

Chronic RfD = 

0.01 mg/kg/day

	FQPA SF =  1X

cPAD = 

chronic RfD

 FQPA SF

= 0.01 mg/kg/day	Chronic oral toxicity - dog;

LOAEL = 3.2 mg/kg/day based on liver effects (P450 induction in females
and histopathology, laminar eosinophilic intrahepatocytic bodies in
males).

Short-Term 

Incidental Oral (1-30 days)	NOAEL= 1.5 mg/kg/day

	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	90-day oral toxicity - rat;

LOAEL = 27.3 mg/kg/day based on decreased body weight gain in males and
increased liver weight in females.



Intermediate-Term 

Incidental Oral (1- 6 months)



	Short-Term Dermal (1 to 30 days)	NOAEL =2 mg/kg/day 

(dermal-absorption rate = 11%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100

	Developmental toxicity – New Zealand white rabbits;

LOAEL = 10 mg/kg/day based on increased incidence of malformed fetuses
and litters with malformed fetuses.

Intermediate-Term

Dermal (1 to 6 months)



	Long-Term Dermal (>6 months)	NOAEL= 1.0 mg/kg/day

(dermal-absorption rate = 11%)

	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Chronic oral toxicity - dog;

LOAEL = 3.2 mg/kg/day based on liver effects (P450 induction in females
and histopathology, laminar eosinophilic intrahepatocytic bodies in
males).

Short-Term Inhalation (1 to 30 days)	NOAEL =2 mg/kg/day 

(inhalation- absorption rate = 100% oral equivalent)	Residential LOC for
MOE = 100;

Occupational LOC for MOE = 100

	Developmental toxicity – New Zealand white rabbits;

LOAEL = 10 mg/kg/day based on  increased incidence of malformed fetuses
and litters with malformed fetuses.

Intermediate-Term Inhalation (1 to 6 months)



	Long-Term Inhalation (>6 months)	NOAEL= 1.0 mg/kg/day

(inhalation- absorption rate = 100% oral equivalent)

	Residential LOC for MOE = 100;

Occupational LOC for MOE = 100	Chronic oral toxicity - dog;

LOAEL = 3.2 mg/kg/day based on liver effects (P450 induction in females
and histopathology, laminar eosinophilic intrahepatocytic bodies in
males).

Cancer	 “Not Likely to be Carcinogenic 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. 

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.

4.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	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

4.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1 
Pesticide Metabolism and Environmental Degradation 

4.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	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 14C-residues in an earlier wheat
metabolism study using [triazole-14C]cyproconazole.  Plant metabolism
data are available from studies using [14C]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.  

4.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	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).

4.1.3	Metabolism in Livestock  TC \l3 "5.1.3	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.

4.1.4	Analytical Methodology  TC \l3 "5.1.4	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 [14C]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.

4.1.5	Environmental Degradation TC \l3 "5.1.5	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 (t1/2=329 days) and aerobic/anaerobic aquatic
environments (t1/2= 2,895 days).  Degradation products include
2-amino-3-(1-H-1,1,2,4-triazol-tyl) propanoic acid and CO2.  Triazole
acetic acid, triazole aniline and triazole were not identified as
environmental degradation products of cyproconazole.  

4.1.6	Comparative Metabolic Profile TC \l3 "5.1.6	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 CH3 group
(M9/M14); oxidation of CH3 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).  

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.  Toxicity Profile of Cyproconazole Metabolites.

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

870.1100	Acute oral toxicity 

(rat)	43674701 (1992)

Acceptable/guideline

M-36 Metabolite	LD50 = 2054 mg/kg in males and females

870.1100	Acute oral toxicity 

(mouse)	43674732 (1995)

Acceptable/guideline

M-36 Metabolite	LD50 > 2000 mg/kg in males and females

870.3100

	4-Week oral toxicity (rat)	43674702 (1994)

Supplementary/non-guideline

0, 20, 200, 800 or 2800 ppm

0, 2.5, 25, 99 and 366 mg/kg/d

M-36 Metabolite	NOAEL  = 2800 ppm (366 mg/kg/day)

LOAEL was not determined.  

870.3100

	4-Week oral toxicity (rat)	43674703 (1995)

Supplementary/non-guideline

0, 1500, 5000 or 20000 ppm

M: 0, 155, 527 and 2008 mg/kg/d

F: 0, 176, 528 and 2126 mg/kg/d

M-36 Metabolite	NOAEL  = 1500 ppm (M/F: 155/176 mg/kg/day)

LOAEL  = 5000 ppm (M/F:  527/528 mg/kg/day) base on malnutrition as
indicated by various changes; i.e., decreased food efficiency and body
weight gains in females, clinical chemistry changes, decreased organ
weights, small seminal vesicles, uteri and thymus, and microscopic
lesions in most organs examined. 

870.5100

	Bacterial Reverse

Mutation Test	43692601 (1990)         Acceptable/guideline

8-5000 μg/plate (+/- S9)

312.5-5000 μg/plate (+/- S9)

M-36 Metabolite	Negative



Pesticide Metabolites and Degradates of Concern

 TC \l3 "5.1.8	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 Risk Assessment	Residues included in
Tolerance Expression

Plants

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

	Rotational Crops	Cyproconazole (free and conjugated)	Not Applicable

Livestock

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

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

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

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

Drinking Water

	Cyproconazole	Not Applicable



4.1.9	Drinking Water Residue Profile TC \l3 "5.1.9	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 (t1/2=329 days) and aerobic/anaerobic aquatic
environments (t1/2= 2,895 days).  Degradation products include
2-amino-3-(1-H-1,1,2,4-triazol-tyl) propanoic acid and CO2. TAA, TA and
triazole were not identified as environmental degradation products of
cyproconazole.  Cyproconazole is moderately mobile in soil (FAO Mobility
Classification,   HYPERLINK "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., ppba	Groundwater Conc., 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 Koc of 364 L/kg-OC, and a half-life of 228.64 days.

4.1.10	Food Residue Profile  TC \l3 "5.1.10	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.

 ≤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.

4.1.11	International Residue Limits TC \l3 "5.1.11	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).

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.

0% 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.

   

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 95th percentile of the exposure distribution, and
is not of concern to HED. 

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 Cyproconazole.

Population Subgroup	Acute Dietary1

(95 Percentile)	Chronic Dietary

	Dietary

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

(mg/kg/day)	% cPAD*

General U.S. Population	N/A

	0.000376	3.8

All Infants (< 1 year old)

0.000480	4.8

Children 1-2 years old

0.001264	13

Children 3-5 years old

0.001015	10

Children 6-12 years old

0.000663	6.6

Youth 13-19 years old

0.000356	3.6

Adults 20-49 years old

0.000265	2.7

Adults 50+ years old

0.000229	2.3

Females 13-49 years old	0.000585	2.9	0.000261	2.6

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

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.

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.

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.

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. 

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   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

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.

Table 8.0.  Proposed Use Patterns and Formulations for Cyproconazole.

Producta	Formula-tion	Use Sites	Application Rates (lb ai/A)	Application
Equipment	Area Treated 	Timing of Application and Restrictions

Alto® 100 SL

and 

Quadris Xtra®	Liquid	Corn (including field, popcorn and seed corn)
0.036 	Aerial

Groundboom

Chemigation	1200 acres

200 acres

350 acres	Apply when disease first appears; 

Re-apply every 7-14 days; 

2 applications/season; 30 days PHI; 24 hours REI



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



Soybeans



For rust:  application 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).

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:

  SEQ CHAPTER \h \r 1 Total 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.



Table 8.1.  Cyproconazole Occupational Noncancer Dermal and Inhalation
Exposures and Risks.

Crop or Target	App Rate (lb ai/acre)a	Area Treated Daily (acres)b	Dermal
and Inhalation Unit Exposures 

(mg/lb ai)	Doses (mg/kg/day)g	MOEsh	Combined MOEsi

Mixing/Loading Liquid Concentrates for Aerial Applications

corn, soybean, wheat	0.036	1200	Dermal

Baselinec: 2.9

SL w/glovesd: 0.023	Dermal

Baseline: 0.23

SL w/gloves: 0.0018	Dermal

Baseline: 8.7

SL w/gloves: 1,100	Baseline Dermal and Inhalation: 8.7

PPE – SL w/gloves + Baseline Inhalation:  740



	Inhalation

Baselinee: 0.0012	Inhalation

Baseline:  0.00086	Inhalation

Baseline:  2,300

	Applying Sprays via Aerial Equipment

corn, soybean, wheat	0.036	1200	Dermal

Engineering controlf: 0.005	Dermal

Engineering control: 0.0004	Dermal

Engineering control: 5,100	Engineering control Dermal + Inhalation:
4,500



	Inhalation

Engineering control: 0.000068	Inhalation

Engineering control:  0.000049	Inhalation

Engineering control:  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).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 Group Category	TCs (cm2/hr)	Activities

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



1500 	Scouting, irrigation

Corn	Field / row crop, tall	400 	Scouting



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/cm2) x TC (cm2/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/cm2);

	TC	=	Transfer Coefficient (cm2/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 Occupational Post-application Risks for
Cyproconazole.

Crop Grouping	Application rate

(lb ai/acre)	Transfer Coefficient (µg/cm2)	Day after Application	MOE at
Day 0

(Level of Concern = 300)

Soybean, Wheat	0.036	100 (Hand weeding, scouting)	0 (12 hours)	17,000



1500 (Scouting, irrigation)

1,100

Corn

400 (Scouting)

4,200



1000 (Irrigation, scouting)

1,700



17,000 (Hand harvesting, Detasseling)

99



	1 day	110



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.  

9.0	Data Needs and Label Recommendations

9.1	  SEQ CHAPTER \h \r 1 Regulatory Recommendations and Residue
Chemistry Deficiencies

cyproconazole
[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1H-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 

cyproconazole
[α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1H-1,2,4-triazole-1-ethanol
] and its metabolite M36
[δ-(4-chlorophenyl)-β,δ-dihydroxy-γ-methyl-1H-1,2,4-triazole-1-hexen
oic 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)-1H-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

	•	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

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

860.1300 Nature of the Residue - Livestock

	•	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

	•	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.

860.1380 Storage Stability

	•	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.

860.1850 Confined Accumulation in Rotational Crops

	•	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

	•	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.

860.1550 Proposed Tolerances

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

The revised tolerances and commodity definitions summarized above.

α-(4-chlorophenyl)-α-(1-cyclopropylethyl)-1H-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).

Appendix A

Table A.1.  Acute Toxicity of Cyproconazole.

Guideline No.	Study Type	Results	Toxicity Category

870.1100 

(81-1)	Acute Oral (rat)	M: 1020 mg/kg F: 1330 mg/kg	III

870.1100 

(81-1)	M-36 metabolite, Acute Oral (rat)	MRID-43674701, >2000 mg/kg	III

870.1100 

(81-1)	M-36 metabolite, Acute Oral (mouse)	MRID-43674732 >2000 mg/kg	III

870.1200 

(81-2)	Acute Dermal (rabbit)	LD50 > 2000 mg/kg	III

870.1300 

(81-3)	Acute Inhalation (rat)	LC50 > 5.6 mg/L	III

870.2400 

(81-4)	Primary Eye Irritation (rabbit)	Not an eye irritant	IV

870.2500 

(81-5 )	Primary Skin Irritation (rabbit)	Not a dermal irritant	IV

87.2600 

(81-6)	Dermal Sensitization (guinea pig)	Not a dermal sensitizer	N/A



Table A.2.  Subchronic, Chronic, and Other Toxicity Profile of
Cyproconazole.

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

870.3050	28-Day oral - rat	40624305 (1986)

Acceptable/non-guideline 0, 10, 30,100, 300 and 1000 ppm 

0, 0.5, 1.5, 5.0, 15, 50 mg/kg/d	NOAEL= 5 mg/kg/day

LOAEL = 15 mg/kg/day, based on elevated LDH, increased liver weight
(relative and absolute) and liver vacuolation.

870.3100

	90-Day oral toxicity (rat)	40607718 (1986)

Acceptable/guideline

0, 20. 80 or 320 ppm

0, 1, 4 and 16 mg/kg/d	NOAEL = 20 ppm (1 mg/kg/day)

LOAEL = 80 ppm (4 mg/kg/day) based on 1) lack of a dose response
relationship, 2) lack of correlation with histopathological or organ
weight changes, 3) because similar changes were not seen in male and
female rats fed the 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.

870.3100

	90-Day oral toxicity (rat)	43078601 (1993)

Acceptable/supplementary 

0, 20, 350, 700, or 1400 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	NOAEL = 20 ppm (1.5/2.0 mg/kg/day in males/females)

LOAEL = 350 ppm (27.3/35.4 mg/kg/day in males/females), based on
decreased body weight gain in males and increased liver weights in
females.

870.3100

	90-Day oral toxicity (mouse)	46950013 (1987)

Acceptable/non-guideline 

0, 5, 15, 300, or 600 ppm M: 0, 0.7, 2.2, 43.8, or 88.7 mg/kg bw/d 

F: 0, 1.0, 3.2, 70.2, or 128.2 mg/kg bw/d 	NOAEL = 15 ppm (2.2 and 3.2
mg/kg bw/day in males and females)

LOAEL = 300 ppm (43.8 and 70.2 mg/kg bw/day in males and females), based
on decreased body weight gain in both sexes and evidence of liver
effects (increased liver weight in both sexes, periacinar hepatocytic
eosinophilia in males, and single cell hepatocyte necrosis in both
sexes).  

870.3150

	90-Day oral toxicity (dog)	40607719 (1986)

Acceptable/guideline 

0, 20, 100, 500 

0, 0.8. 4.0 and 20.0 mg/kg	NOAEL = 0.8 mg/kg/day

LOAEL = 4.0 mg/kg/day, based on increased absolute liver weight &
hepatocytomegaly. 

870.3200

	21/28-Day dermal toxicity (rat)	40624306 (1988)

Acceptable/guideline 

0, 50, 250, 1250 mg/kg/d 	NOAEL = 250 mg/kg/day

LOAEL 1250 mg/kg/day, based on decreased body weight gain and food
consumption (M), increased AST (males), creatinine (females),
cholesterol (both sexes).

870.3700a

	Prenatal developmental in (rat)	40607721 (1985)

Acceptable/guideline

0, 6. 12, 24, 48 mg/kg/d

	Maternal NOAEL = 6 mg/kg/day

Maternal LOAEL = 12 mg/kg/day, based on decreased BWG during dosing

Developmental NOAEL = 6 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.

870.3700b

	Prenatal developmental in (rabbit)	42175401 (1991),

Acceptable/guideline

0, 2, 10, 50 mg/kg/d

	Maternal NOAEL = 10 mg/kg/day

Maternal LOAEL = 50 mg/kg/day, based on decreased body weight gain.

Developmental NOAEL. = 2 mg/kg/day

Developmental LOAEL = 10 mg/kg/day, based on increased incidence of
malformed fetuses & litters with malformed fetuses.

870.3700b

	Prenatal developmental in (rabbit)	40607720 (1986)

Acceptable/guideline

0, 2, 10, 50 mg/kg/d

	Maternal NOAEL = 10 mg/kg/day

Maternal LOAEL = 50 mg/kg/day, based on inhibited BWG during treatment.

Developmental NOAEL < 2 mg/kg/day

Developmental LOAEL = 2 mg/kg/day, based on incidence of hydrocephalus
internus.

870.3800

	Reproduction and fertility effects

(rat)	4067723 (1987)

Acceptable/guideline

0, 4, 20, 120 ppm 

0, 0.4, 1.7 or 10.6 mg/kg/d

	Parental NOAEL = 20 ppm (1.7 mg/kg/day)

Parental LOAEL = 120 ppm (10.6mg/kg/day), based on liver effects.

Reproductive toxicity NOAEL = 120 ppm (10.6 mg/kg/day), although
gestation length was slightly increased and litter size were decreased,
the changes are not considered treatment-related.

Reproductive LOAEL was not determined.

870.4100b

	Chronic toxicity

(dog)	41212901 (1988)

Acceptable/guideline

0, 30, 100, and 350 ppm M/F: 0/0, 1.0/1.0, 3.2/3.2, and 12. 1/12.6
mg/kg/d)	NOAEL = 30 ppm (1.0 mg/kg/day)

LOAEL = 100 ppm (3.2 mg/kg/day), based on liver effects (P450 induction
in females and histopathology, laminar eosinophilic intrahepatocytic
bodies in males).

870.4200b 

.	Carcinogenicity (mouse)

	41147201(1989)

Acceptable/guideline

0, 5, 15, 100,200 ppm M/F: 0/0.69/1.03, 1.84/2.56, 13.17/17.65, or
27.85/36.30 mg/kg/d	NOAEL = M/F: 1.8/2.6 mg/kg/day

LOAEL = M/F: 13.2/17.7 mg/kg/day, based on increased incidence of
hepatocytic single-cell necrosis; increased incidence of hepatocellular
adenomas and carcinomas

870.4300 

	Combined Chronic

Toxicity/Carcinogenicity (rat)	41164701 (1988)

Acceptable/guideline

0, 20, 50 or 350 ppm

M/F: 0/0, 1.0/1.2, 2.2/2/7 and 15.6/21.8 mg/kg/d 	NOAEL = 50 ppm (2.2
mg/kg/day)

LOAEL = 350 ppm (15.6 mg/kg/day), based on decreased body weight and
increased incidence of fatty infiltration in liver (M).  Dosing was
inadequate in females.

870.5100	Bacterial Reverse

Mutation Test	40607725 (1986)

Acceptable/guideline

0, 1,5, 10, 100, 500, 1000 ug/plate w/wt rat S9 mix	Negative.

870.5100	Bacterial Reverse

Mutation Test	40624307 (1985)

Unacceptable/guideline

0, 10, 100, 250, 400, 500 or 550 ug/plate w/wt rat S9 mix	Negative.

870.5300	In Vitro Gene Mutation assay in Chinese Hamster Ovary cells
40607726 (1985)

Acceptable/guideline

0, 20, 50, 100 or 200 ug/mL w/wt S9.	Negative.

870.5375	In Vitro Mammalian Chromosomal Aberration	41757801 (1990)

Unacceptable/guideline

60.1, 100.0, 150.0 or 200 ug/mL wt S9; 45.0, 59.9, 99.9 or 150.0 w S9.
Can not be interpreted.

870.5375	In Vitro Mammalian Chromosomal Aberration	46950019 (1995)

Acceptable/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	Negative.

870.5375	In Vitro Mammalian Chromosomal Aberration	41757701 (1988)

Unacceptable/guideline

100, 150 or 200 ug/mL wt S9; 100, 150, 200 or 250   w S9.	Positive w/wt
S9. 

870.5395 	In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus
Assay in Mice	40607728 (1984)

Acceptable/guideline

0, 16.7, 55.7, 167 mg/kg

	Negative.

	Cell Transformation	40607724 (1985)

Acceptable

0, 20, 50, 100 or 200 ug//mL w/wt S9 (assumed)	Negative.

870.5450	Rodent Dominant Lethal	41961401 (1991)

Acceptable/guideline

20, 40 or 80 mg/kg/d	Negative.

870.5550	Unscheduled DNA

Synthesis in Mammalian

Cells in Culture	40607729 (1988)

Unacceptable/guideline

0.15,0.5, 1.5, 5, 15, 50, 100, 150 ug//mL 	Can’t be evaluated.

870.5550	Unscheduled DNA

Synthesis in Mammalian

Cells in Culture	40607727 (1985)

Unacceptable/guideline

0.15,0.5, 1.5, 5, 15, 50, 100, 150 ug//mL 	Can’t be evaluated.

870.7485

	Metabolism and pharmacokinetics

(rat)

	41701901 (1987)

Acceptable/guideline

oral - 10mg/kg , 910 mg/kg x

14 days;

iv - 10 and 130 mg/kg

	Absorption, distribution, excretion and blood kinetics were examined.
Almost completely absorbed in males (84%) and females (106%),
extensively metabolized; diastereomers A & B of parent + 13 metabolites
identified & isolated; 35 metabolites detected; metabolic profiles for
urine, feces, bile similar; major metabolic reactions include oxidative
elimination 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.



870.7485	Metabolism and pharmacokinetics

(rat)

	46152903 (2003)

0.5 mg/kg. Animals were

dosed with the radioactive test substance daily for up to 14 days	The
majority of the total administered dose (96.5%) was recovered in the
feces (56.3%) and urine

(40.2%).

The highest blood levels were found ten days after the start of dosing
(0.08 ppm SAN 619F equivalents). Three days after the 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 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.

870.7600	Dermal penetration (rat)	43 173701 (1993),

Acceptable/guideline

0, 2.5 15 and 120 ug/cm2 for 0.5,

1,2,4 10,24 hr	At dose levels of 2.5, 15, and 120 .ig/cm2 cyproconazole,
the percent absorbed [0.87-7.69, 0.59-11.88, and 0.92-0.89,
respectively] 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, 10.8 1% of 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 >350 ppm, absolute and relative to body liver weights were increased
(p<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<0.05) in the females by 14-25%, compared to controls.  

Systemically, body weights and cumulative body weight gains were
decreased (p<0.01) throughout treatment in the >700 ppm males and 1400
ppm females.  Food consumption was reduced (p<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<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<0.001)
gamma-glutamyl transpeptidase was observed in the 1400 ppm males and the
>700 ppm females.  Additional differences (p<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<0.05) leukocytes were observed in the >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<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 >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 >700 ppm males; (ii)
single cell necrosis in the adrenal gland cortex in >700 ppm females;
(iii) ceroid deposition in the adrenal gland cortex in >700 ppm females;
and (iv) renal hemosiderosis in the 1400 ppm males and >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
[14C]-cyproconazole through human and rat skin was assessed in vitro. 
[14C]-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./cm2.  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 cm2/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 [14C]-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/cm2/h, compared to 0.501
μg/cm2/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-14C]-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-14C]-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 <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 100xg 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<0.05)
in both sexes at >100 ppm.  Absolute liver weights were increased
(p<0.001) in the 200 ppm males and the >100 ppm females.  At >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.

ed 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 >50 ppm.  In
females, expression of one of two protein bands for CYP 4A was slightly
decreased at (100 ppm. 

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.  

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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. 

Appendix B

Nomenclature of Triazole-related Metabolites.

Compound	

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

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

CAS registry number	288-88-0

Compound	

Common name (Abbr)	Triazole alanine (TA)

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

CAS registry number	114419-45-3

Compound	

Common name (Abbr)	Triazole Acetic Acid (TAA)

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

CAS registry number	28711-29-7





Proposed Metabolic Profile of Cyproconazole in Laying Hens.

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