Document ID: EPA-HQ-OPP-2007-0226-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-09T04:00Z

FQPA NOTICE OF FILING

<COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (7/1/2006)>

<EPA Registration Division contact: [Tawanda Spears, PM Team 22]>

 

<INSTRUCTIONS:  Please utilize this outline in preparing tolerance
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<TEMPLATE:>

<[Chemtura USA Corporation]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Chemtura USA Corporation], [199 Benson Road, Middlebury, CT 06749]
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.>

<	X 1. by establishing a tolerance for residues of>

<	[Ipconazole
(2-[(4-chlorophenyl)methyl]-5-(1-methylethyl)-1-(1H-1,2,4-triazole-1-ylm
ethyl)cyclopentanol)] [from the treatment of seed prior to planting in
or on the raw agricultural commodities as follows:  cereal grains
(except rice), group 15;  forage, fodder and straw of cereal grains
(except rice), group 16; cotton; peanut; soybean , and dry pea & bean
(shelled) at 0. 01 ppm ] The registrant has field residue data in the
petition for barley, wheat, corn, cotton, peanut and soybean. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d)(2) of the FDDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.>

<A. Residue Chemistry>

<	1. Plant metabolism [The nature of the residues of ipconazole in wheat
and soybeans grown from seeds treated with ipconazole is adequately
understood.  The major residues found are triazolylalanine,
triazolylpyruvate and triazolylacetic acid.  Minor metabolites include
tert-hydroxy-isopropyl-ipconazole and hydroxy-ipconazole-glycoside.].>

<	2. Analytical method. [Analytical methods have been developed,
validated (including radiovalidation), and independently validated for
the determination of ipconazole, triazolylalanine, triazolylacetic acid,
and triazolylpyruvate in wheat forage, hay, straw, and grain, and in
corn forage, cobs, and straw using liquid chromatography-tandem mass
spectrometry (LC-MS/MS). The limit of quantitation of 0.01 ppm for each
analyte in each matrix was determined as the lowest level validated.
Analytical methods have also been validated and independently validated
in peanut nutmeat for the determination of ipconazole, triazolylalanine,
triazolylacetic acid, triazolylpyruvate, and triazole in peanut nutmeat
using LC-MS/MS, with a limit of quantitation of 0.01 ppm for ipconazole,
and 0.025 ppm for its metabolites. ]

>

<	3. Magnitude of residues. [A crop residue program has been completed
for ipconazole in the major growing areas of the US for:

Cereal grains (except rice) – Chemtura is proposing a crop group
tolerance of 0.01 ppm in cereal grains, except rice, based on field
trials in barley, wheat, and corn at the exaggerated rate of 5X in which
no quantifiable residues of ipconazole were found in the RACs at a limit
of quantitation of 0.01 ppm.

Cotton – Chemtura is proposing a tolerance of 0.01 ppm, based on field
trials at the exaggerated rate of 5X in which no quantifiable residues
of ipconazole were found at a limit of quantitation of 0.01 ppm.

Peanut – Chemtura is proposing a tolerance of 0.01 ppm on peanut
nutmeat, based on field trials at the exaggerated rate of 5X in which no
quantifiable residues of ipconazole were found at a limit of
quantitation of 0.01 ppm. A label restriction will be applied to peanut
hay.

Soybean - Chemtura is proposing soybean and  subgroup  6-C (dried
shelled pea and beans) tolerances of 0.01 ppm, based on field trials on
soybeans at the exaggerated rate of 5X in which no quantifiable residues
of ipconazole were found in the RACs at a limit of quantitation of 0.01
ppm. ]

>

<B. Toxicological Profile>

<	1. Acute toxicity.  [Ipconazole Technical and Ipconazole formulations
(Crusoe® MD, Ipconazole 3.8FS and Ipconazole/Thiram 10/350 FS) have
low acute oral, dermal, and inhalation toxicity in laboratory animals. 
The oral LD50 in rats is greater than 5 g /kg for Crusoe MD and the
Ipconazole/Thiram formulation.  The oral LD50 in rats for Ipconazole 3.8
FS is 5.3 g/kg for males and 3.7 g/kg for females.  The oral LD50 is 1.3
g/kg for male rats and 0.89 g/kg in female rats for the technical
material.  The oral LD50 for ipconazole technical in male mice is 0.53
g/kg and 0.47 for female rats.  The dermal LD50 in rats of Ipconazole
Technical is greater than 2 g/kg.  The dermal LD50 in rats for Crusoe
MD, Ipconazole 3.8 FS and Ipconazole/Thiram formulations are all greater
than 5 g/kg.   The 4 hour inhalation LC50 in rat for Ipconazole
Technical and Crusoe MD are greater than 1.88 and 2.07 mg/l,
respectively.  The 4 hour inhalation LC50 in rats for the
Ipconazole/Thiram formulation is greater than 2.04 mg/l and greater than
2.59 mg/L for Ipconazole 3.8 FS.  In the eye irritation studies, Crusoe
MD, Ipconazole 3.8FS, Ipconazole/Thiram formulation and Ipconazole
Technical were all mildly irritating to rabbit eyes.  Crusoe MD,
Ipconazole 3.8FS and Ipconazole/Thiram formulations were found to be
slightly irritating to the skin of rabbits.  Ipconazole Technical was
found to be non-irritating to the skin of rabbits.  Ipconazole Technical
and Ipconazole formulations were non-sensitizing on the skin of guinea
pigs.]>

<	2. Genotoxicty. [Ipconazole Technical was evaluated and found to be
negative in the Ames Reverse Mutation, CHO HGPRT Mammalian mutation,
Bacillus subtilis DNA Repair, Chinese Hamster Lung Chromosome Aberration
and Mouse Micronucleus assays.]>

<	3. Reproductive and developmental toxicity. [Rabbit Teratology Study: 
Ipconazole was evaluated in a rabbit teratology study as dose levels of
0, 2, 10 and 50 mg/kg/day.  At the 50 mg/kg/day, there was a tendency
for reduction of maternal body weight gain and food consumption during
dosing.  A tendency for reduction of fetal body weights and placental
weights was seen at the high dose (50 mg/kg/day) when compared to the
concurrent controls.  There was no increase in fetal variations or
malformations at any dosage level.  The NOEL for maternal and
developmental toxicity was 10 mg/kg/day  

Rat Teratology Study:  Ipconazole was evaluated in a teratology study
with the Sprague Dawley rat at dose levels of 0, 3, 10 and 30 mg/kg/day.
 At the 30 mg/kg/day dose level, there was a statistically significant
reduction in maternal body weight gain and food consumption during
dosing.  There was a statistically significant reduction in fetal body
weights at the high dose level (30/mg/kg/day) with an increase in the
incidence of visceral and/or skeletal variations.  There was no increase
in fetal malformations at any dose level.  The NOEL for maternal and
developmental toxicity was 10 mg/kg/day

Rat Reproduction Study: [Ipconazole was evaluated through dietary
administration to two successive generations of Han Wistar rats at 0,
30, 100 or 300 ppm.  The no-observed-adverse-effect-level (NOAEL) for
the reproductive performance of the F0 and F1 adults was 300 ppm. The
NOAEL for the general toxicity of the F0 and F1 females was 100 ppm, in
view of minor but statistically significant reductions in bodyweight
gain during gestation and food consumption during gestation and
lactation. The NOAEL for the growth of the offspring was 100 ppm, in
view of reduced weight gain seen among F1males at 300 ppm, but was 300
ppm for the survival and general condition of the F1 and F2 offspring. ]

>

<	4. Subchronic toxicity. [Thirteen Week Rat Feeding Study:  Ipconazole
was fed to male and female Fischer-344 rats for thirteen weeks at
dietary concentrations of 30, 120, 500 and 2000 ppm. At the 500 and 2000
ppm dosage levels, there was a reduction in body weight gain and food
consumption.  Effects were seen on numerous clinical chemistry
parameters at 500 and 2000 ppm.  Histopathological effects observed at
500 and 2000 ppm include erosion, hyperplasia, and hyperkeratosis of the
stomach, hyperkeratosis of the esophagus and hepatocellular swelling. 
The 500 ppm dose group had an increase in liver and salivary gland
weight.  Effects at 2000 ppm included a decrease in red blood cell
concentration and hepatocellular hyperplasia.  No treatment related
effects were seen on neurobehavior in a standard Functional Observation
Battery conducted at weeks 8 and 13.  No effects were seen on
neuropathology.  The NOAEL for subchronic toxicity in rats was 120 ppm
(7.22 mg/kg/day). 

Thirteen Week Dog Feeding Study:  Ipconazole was fed to male and female
Beagle dogs for thirteen weeks at dietary concentrations of 2, 10 and 40
mg/kg/day.  The target organs were identified as the liver and eyes
(lens).  At dosage levels of 10 and 40 mg/kg/day there was a lens fiber
anomaly in males as well as clinical signs that were attributable to the
irritant potential of ipconazole presented by reddening of gums, ears,
muzzle, eyes and neck.  Liver weights were increased at 40 mg/kg/day and
centrilobular hepatocellular hypertrophy and bile duct proliferation
were seen.  The NOAEL for subchronic toxicity in dogs was 2 mg/kg/day).
]>

<

	5. Chronic toxicity. [Dog Chronic Feeding Study: Ipconazole was
administered in capsules to male and female Beagle dogs for one year at
concentrations of 1.5, 5 and 20 mg/kg/day.  At 5 or 20 mg/kg/day there
was reddening of the skin and at 20 mg/kg/day there was some
non-specific toxicity in two females and the target organs were
identified as the liver, eyes (lens) and adrenal.  Ipconazole exerts its
antifungal action by the inhibition of sterol synthesis.  The NOAEL for
chronic toxicity in dogs 1.5 mg/kg/day.

Rat Chronic Feeding/Oncogenicity Study: The chronic toxic and
carcinogenic potential of ipconazole, when administered to male and
female HsdBrl Han:Wist (Han Wistar) rats, via the diet, was assessed
over a period of 52 and 104 weeks.  The initial concentrations given to
these groups were 0, 30, 80, 200 or 300 ppm but, following advice from
the US EPA, the dietary concentrations given to females in the 200 and
300 ppm groups were reduced to 120 and 200 ppm, respectively, from
Week 2.  Treatment caused only an initial non-specific toxic response
at 300 ppm.  The histopathological examination did not reveal any
neoplastic or non-neoplastic change.  The no-observed-adverse-effect
level (NOAEL) was concluded to be 300 ppm in the males (equivalent to
an overall mean achieved dosage of 13.3 mg/kg/day) and 200 ppm in the
females (equivalent to an overall mean achieved dosage of
12.6 mg/kg/day) 

Mouse Oncogenicity Study: Ipconazole was not oncogenic when administered
in the diet to CD-1 mice for eighteen months at concentrations of 15,
175 or 350 ppm .  Treatment related effects included reduced body
weight gain in females at 350 ppm.  There were treatment-related
non-neoplastic findings in the liver of animals given 175 or 350 ppm
and in the stomach of females given these dietary concentrations, though
there was no evidence of treatment-related neoplastic change. 
Consequently, the no-observed-adverse-effect level (NOAEL) in this study
was concluded to be 15 ppm (equivalent to an overall mean achieved
dosage of 1.9 mg/kg/day in males and 2.3 mg/kg/day in females).]>

<	6. Animal metabolism.  [ Pharmacokinetic parameters] in the rat. 
Following single oral doses of [14C-benzyl methylene]ipconazole or
[14C-triazole]ipconazole at levels of 2 and 100 mg/kg, greater than 90%
of the radioactivity was eliminated in urine and feces within 72 hours. 
Excretion was mainly via the feces and was higher in male rats than in
females.  Urinary excretion was higher in females than in males. 
Excretion and retention of radioactivity during 0 – 120 hours after
the final dose following administration of 14 consecutive daily oral
doses of 14C-[benzyl methylene]ipconazole was also investigated and
excretion was rapid with greater than 90% of the dose excreted within 48
hours after the final dose.  There were no substantial differences in
excretion patterns between single and repeat low level oral doses.  In
bile duct-cannulated rats, absorption was higher at the low dose
compared to the high dose and higher in male rats than in females.  Bile
was an important route of excretion.  After administration of
[14C-benzyl methylene]ipconazole at 2 mg/kg, no major differences in
pharmacokinetic parameters were observed between the sexes apart from
Tmax, which occurred later in male rats.  After administration of
[14C-triazole]ipconazole, lower Cmax and AUC parameters were observed
for females relative to males.  There were no sex differences in the
time taken to reach Cmax or the terminal half life.  Following the
administration of single oral doses of 100 mg/kg [14C-benzyl]ipconazole,
both Cmax and AUC increased in comparison to the 2 mg/kg dose. After 14
consecutive daily doses of [14C-benzyl methylene]ipconazole at 2 mg/kg,
exposure was higher in males than in females.  Tmax occurred at 1 hour
for both sexes which was earlier in males than after a single dose.  The
terminal half life of radioactivity was longer after repeated oral doses
indicating that changes in clearance and/or volume of distribution of
radioactivity occurred during repeated dosing.  In all cases, T1/2 was
shorter for plasma than whole blood, indicating a transfer of
radioactivity into red blood cells.  After repeated oral daily dosing,
the whole blood to plasma ratio was increased by approximately two fold
thus indicating an increased distribution of radioactivity into the red
blood cells.] 

>

<	7. Metabolite toxicology. [Metabolites from the goat metabolism study
essentially matched those produced in the rat.  In addition to triazole,
intact ipconazole metabolites were characterized as further oxidized and
conjugated.  In addition, cyclization occurred to produce both
hemiacetals and lactones.  In plants, intact ipconazole metabolites were
also found in the rat.  In addition to intact metabolites, wheat and
soybean produced triazole conjugates – triazolylalanine,
triazolylpyruvic acid and triazolylacetic acid.  Although not produced
in the rat, triazolylalanine, triazolylacetic acid, and by inference,
triazolylpyruvic acid, have been evaluated in a recent human health risk
assessment for triazole-derived fungicides (EPA, Memorandum entitled,
“1,2,4-Triazole, Triazole Alanine, Triazole Acetic Acid: Human Health
Aggregate Risk Assessment in Support of Reregistration and Registration
Actions for Triazole-derviative Fungicide Compounds”, dated February
7, 2006. In this risk assessment, it was assumed that triazole
conjugates were all toxicologically equivalent to triazolylalanine. It
was concluded that the risk from these metabolites was below HED’s
level of concern.] 

>

<8. Endocrine disruption. [There are no known reported adverse
reproductive or developmental effects in domestic animals or wildlife as
a result of exposure to this chemical. A standard battery of required
toxicity tests have been conducted on ipconazole. No effects were seen
in the reproduction or teratology studies to indicate that ipconazole
has an effect on the endocrine system.] 

	9. Toxicology Endpoints (special sensitivities).  [The following are
the toxicology endpoints for the exposure assessments:    

a) Acute Endpoint: An acute reference dose (RfD) is not necessary for
ipconazole.  An acute dietary RfD for females 13-50 years of age and the
general population, including infants and children, was not selected
because an acute oral endpoint attributed to a single-dose exposure
could not be identified in any of the studies in the toxicological
database, including developmental and maternal toxicity in the
developmental toxicity studies.

b) Short-term Endpoint: The endpoint for acute dermal exposure is based
on the NOEL of 150 mg/kg/day from the 21-day dermal toxicity study in
rats. Use of a 100-fold safety factor, a margin of exposure (MOE) of
100, is appropriate. 

c) Intermediate Endpoint: An intermediate exposure endpoint is not
required. Residential exposure is not expected and Ipconazole is not
used on turf.

d) Chronic Endpoint: Chronic Endpoint. The endpoint for chronic exposure
is based upon the NOEL of 1.5 mg/kg/day which was obtained in the
chronic dog feeding studies.  The RfD for chronic effects is 0.015
mg/kg/day using a 100-fold safety factor. 

The need for an additional safety factor for infants and children has
been evaluated. Ipconazole was not carcinogenic in rodents and did not
produce reproductive effects in rats or developmental toxicity in rats
and rabbits. These data indicate that children would not be more
sensitive to dietary ipconazole than the general population, therefore,
a chronic RfD of 0.015 mg/kg/day, which is sufficient to protect the
general population, would provide adequate protection to infants and
children. Therefore, the application of an additional 10X safety factor
is not necessary.

Due to the general inaccessibility of agricultural use sites to children
and given the low mammalian dermal and inhalation toxicity of Crusoe MD,
Ipconazole 3.8 FS and Ipconazole/Thiram formulation, both exposure and
risk to children will be insignificant.]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [Based on dietary, drinking water, and
non-occupational exposure assessments, there is reasonable certainty of
no harm to the US population, any population subgroup, or infants and
children from chronic exposure to ipconazole.]>

<	i. Food. [Chronic dietary exposures were estimated utilizing the
Dietary Exposure Evaluation Model software with Food Commodity Intake
Database (DEEM-FCID) version 2.16.  Results from residue trials indicate
that ipconazole tolerances should be set at the limit of quantification
for the analytical method (0.01 ppm) for cotton, peanuts, soybeans, dry
shelled peas and beans (Group 6C) and cereal grains (except rice).  All
crops were assumed to be 100% treated and default processing factors of
1.89 for peanut butter and 1.5 for corn syrup were incorporated into the
residue file.  For the general US population, the estimated chronic
dietary exposure is 0.3% of the cPAD.  The most highly exposed
subpopulation, children aged 3-5, has an estimated total ipconazole
exposure equal to 0.8% of the cPAD. The total chronic dietary exposure
associated with proposed uses of ipconazole has been demonstrated to be
less than the cPAD (0.015 mg/kg/d) and are therefore not of concern. It
is important to remember that this assessment is quite conservative
because it includes tolerance level residues and 100% crop treated in
all proposed crops. ]>

<	ii. Drinking Food. [Exposure to ipconazole and potential residues in
drinking water is expected to be negligible. The maximum application
rate for Ipconazole on an area basis is that for wheat at 0.00223 lb
ai/A.  This value is derived from an application rate on seed of 2.5 g
ai/100 kg seed and a planting rate of 100 kg seed per hectare.  Surface
and ground water impacts from such a low rate seed treatment use are
expected to be negligible.  Screening level water modeling using
SCI-GROW for ground water and FIRST for surface water demonstrate that
the annual concentration in ground water is 0.0002 ppb in ground water
and 0.024 ppb in surface water.  At these very low concentrations,
exposures from drinking water will be negligible for all subpopulations.
 Therefore, it is not necessary to include potential residues in
drinking water for this assessment.  This is consistent with EPA
practice, which generally does not include estimates of residues in
drinking water for seed treatment uses. ]>

<	2. Non-dietary exposure. [Food uses described in this petition are
strictly agricultural, and will not add to any residential non-dietary
exposure that may exist.]>

<D. Cumulative Effects>

<	[Ipconazole is a member of the triazole-containing class of
pesticides. Although conazoles act similarly in plants (fungi) by
inhibiting ergosterol biosynthesis, there is no relationship in their
mechanism of toxicity in mammals. There is no evidence to indicate that
conazoles share a common mechanism of toxicity and EPA is not following
a cumulative risk approach based on a common mechanism of toxicity.]>

<E. Safety Determination>

<	1. U.S. population. [Chronic Risk.  The chronic Population Adjusted
Dose (cPAD) of  0.015 mg/kg bw/day was based on the NOAEL of 1.5
mg/kg/day from the 1 year dog study and a 100x uncertainty factor and a
1x FQPA safety factor.  The chronic dietary exposure to the U.S.
population (total) was 0.000047 mg/kg/day or 0.3% of the cPAD.]>

			

<	2. Infants and children. [Chronic Risk.  The chronic dietary exposure
to infants was 0.000055 mg/kg bw/day, and was 0.4% of the cPAD.  The
chronic dietary exposure to children 3-5 yrs, the most sensitive group,
was 0.000113 and was 0.8% of the cPAD. Therefore, chronic aggregate
exposure from ipconazole is not expected to exceed the cPAD.]>

<F. International Tolerances>

<	[No CODEX or other international MRLs or tolerances have been
established for the requested uses.  Ipconazole is currently registered
in Japan as a seed treatment on rice and wheat.  Registrations also
exist in Argentina on wheat, barley, corn and peanuts and in Uruguay on
wheat and barley.]>