Document ID: EPA-HQ-OPP-2011-0053-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-03-29T04:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (7/1/2007)>

<EPA Registration Division contact: [insert name and telephone number
with area code]>

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.>

<TEMPLATE:>

<[Bayer CropScience]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Bayer CropScience], [P.O. Box 12014, 2 T.W. Alexander Drive, Research
Triangle Park, NC 27709] 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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	[Prothioconazole,
2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl-2-hydroxypropyl]-1,2-dihydr
o-3H-1,2,4-triazole-3-thione and its desthio metabolite] in or on the
raw or processed agricultural commodity [rice, grain] at [0.25] parts
per million (ppm), [rice, hulls] at [1.0] parts per million (ppm),
[alfalfa, forage and alfalfa, hay] at [0.02] parts per million (ppm) and
[potato, tuber] at [0.02] parts per million (ppm).  

Bayer CropScience is also proposing use of the currently established
tolerances for residues of Prothioconazole,
2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl-2-hydroxypropyl]-1,2-dihydr
o-3H-1,2,4-triazole-3-thione and its desthio metabolite, in or on the
raw agricultural commodity [pea and bean, dried shelled, except soybean,
subgroup 6C],  [soybean, forage], [soybean, hay], [soybean, seed] to
support the use of prothioconazole as a seed treatment on these crops.
Bayer CropScience is also proposing that the above proposed tolerances
on rice, based on foliar data, also support the use of prothioconazole
as a seed treatment on rice.

EPA has determined that the petition contains data or information
regarding the elements set forth in section 408 (d)(2) of  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. [In plants, the metabolism of prothioconazole is
adequately understood for purposes of establishing these proposed
tolerances. Prothioconazole was extensively metabolized in plants with
the major residue found in all crops (wheat, peanuts and sugar beets)
being JAU6476-desthio with smaller amounts of various isomers of
JAU6476-hydroxy-desthio, and their conjugates also being found.
Triazolylalanine, triazolylhydroxypropionic acid, and triazolylacetic
acid, metabolites common to the triazole-derivative class of fungicides,
were also found. Based on the above data the residues of concern in
plants are prothioconazole and its metabolite JAU6476-desthio. The risk
assessment for the common metabolites arising from the
triazole-derivative fungicides is being addressed by the US Triazole
Task Force.  In large animals, the nature of residues is also adequately
understood for purposes of establishing the proposed tolerances. The
residues of concern in edible tissues and milk are prothioconazole, its
metabolites JAU6476-desthio, JAU6476-4-hydroxy, and their conjugates
that can be converted to these three compounds by acid hydrolysis.]>

<	2. Analytical method. [The analytical method for determining residues
of concern in plants extracts residues of prothioconazole and
JAU6476-desthio and converts the prothioconazole  to JAU6476-desthio and
JAU6476-sulfonic acid. Following addition of internal standards the
sample extracts are analyzed by LC/MS/MS. Radiovalidation and
independent laboratory validation have shown that the method adequately
quantifies prothioconazole residues in treated commodities. The
validated LOQ for total prothioconazole-derived residues in rice grain
was 0.02 ppm. The validated LOQs were 0.01 ppm for 1H-1,2,4-triazole and
0.05 pm for the triazole conjugates for grain. The analytical method for
analysis of large animal tissues includes extraction of the residues of
concern, followed by addition of an internal standard to the extract.
The extract is then hydrolyzed to release conjugates, partitioned and
analyzed by LC/MS/MS as prothioconazole, JAU6476-desthio and
JAU6476-4-hydroxy. The method for analysis of milk eliminated the
initial extraction step in the tissue method.]

>

<	3. Magnitude of residues. [A total of 16 field trials (14 harvest and
2 decline) were conducted as part of the supervised crop field trial
study for rice to measure the prothioconazole derived residues in/on
rice following two foliar spray applications of JAU6476 480 SC at a
target rate of 0.18 lb ai/acre/application (0.20 kg ai/ha/application),
with a 13 to 16 day spray interval. Rice grain and straw were collected
from each treated plot with PHIs ranging from 40 to 67 days. At two
locations additional samples were taken to determine residue decline.
The average prothioconazole derived residue was 0.03 ppm in/on rice
grain with a maximum residue of 0.22 ppm. Results of the rice processing
study indicated that prothioconazole residues concentrated in rice hulls
(4.4X), but not in polished grain or bran. Residues of 1H-1,2,4-triazole
were less than the LOQ (<0.01 ppm) in/on rice grain. Maximum residues of
the triazole conjugates were 0.571 ppm (rice grain).

The maximum storage interval of crop samples from harvest to analysis
for total prothioconazole-derived residues was 1240 days (40.8 months).
The degree of loss of prothioconazole-derived residues and
prothioconazole-desthio residues is not expected to exceed 30% after
40.8 months in rice samples.

For alfalfa, results from a TRR study indicate a no residue situation.
The TRR in alfalfa forage from three successive cuttings from plants
grown from seed treated with [triazole-3,5-14C] prothioconazole at a
target rate of 5 g a.i./100 kg seed and 15 g a.i./100 kg seed loading
was <0.005 ppm. The TRR in alfalfa hay from the second and third
cuttings from plants grown from seed treated with [triazole-3,5-14C]
prothioconazole at both application rates was also <0.005 ppm. Although
the TRR in alfalfa hay from the first cutting was not measured, the
percent dry matter for forage from the first cutting was measured and
when adjusted to reflect the typical percent dry matter in alfalfa hay
(89%)5 the net residues in alfalfa hay at both treatment levels are
<0.005 ppm.

For potato, results from a TRR study indicate a no residue situation for
components of the residue definition. Potato seed, treated with
[triazole-UL-14C] prothioconazole at a rate of 0.36 g ai/100 kg seed
(3.7 ppm; 1.02X the target rate of 0.36 g ai/100 kg seed), was planted
and potato was grown to maturity.  The potato raw agricultural commodity
(RAC) of tubers was collected at harvest time.  The total radioactive
residue (TRR) in the tubers was 0.0061 ppm.  The residues in tubers were
extracted and characterized.  Mainly highly polar degradation products
were found in potato; only very small amounts (5% or <0.001 ppm) of the
components of the residue definition were detected.]

>

<B. Toxicological Profile>

<	1. Acute toxicity.  [Prothioconazole exhibits very low acute oral,
dermal and inhalation toxicity. The acute oral LD50 for prothioconazole
in rats was >6200 mg/kg/day while the dermal LD50 was >2000 mg/kg/day
and the four-hour rat inhalation LC50 >4990 mg/m3. Prothioconazole was
not irritating to the eye or skin of rabbits and did not cause skin
sensitization in guinea pigs.>]

<	2. Genotoxicty. [Prothioconazole is not mutagenic. Slightly positive
and equivocal responses seen in in vitro cytogenetic and UDS assays were
negative in in vivo tests.]>

<	3. Reproductive and developmental toxicity. [Prothioconazole is not
considered a  primary reproductive toxicant in a two-Generation rat
reproduction study. The NOAEL for parental toxicity as well as the NOAEL
for reproductive and neonatal effects is 95.6 mg/kg bw/day. In the rat
oral developmental toxicity study the fetal NOAEL was 500 mg/kg bw/day
and the maternal NOAEL was 80 mg/kg bw/day. A dose level of 1000 mg/kg
bw/day administered to the rat by the dermal route does not elicit
developmental toxicity. In the rabbit, prothioconazole does not produce
developmental toxicity at dose levels exceeding the maximum tolerated
dose. Thus, prothioconazole is not teratogenic in either the rat or
rabbit.]>

<	4. Subchronic toxicity. [90-day feeding studies conducted in rats,
mice, and dogs showed the liver and/or kidney to be the target organs. 
In these subchronic studies NOAELs were established at 100 mg/kg/day for
the rat and 25 mg/kg/day for the mouse and dog.]>

<	5. Chronic toxicity. [Prothioconazole is not carcinogenic in either
the rat or the mouse even at dose levels in the rat exceeding the
maximum tolerated dose. The liver and kidney are target organs of
prothioconazole for non-neoplastic toxicity in the rat, mouse and dog.
The lowest NOAEL established on the basis of long-term toxicity studies
is 5 mg/kg bw/day in the rat chronic toxicity/carcinogenicity study and
the dog 52-week toxicity study.]>

<	6. Animal metabolism. [Metabolism and pharmacokinetic studies in the
rat demonstrate that prothioconazole is rapidly absorbed, metabolized
and eliminated. The primary metabolites included JAU6476-desthio, as
well as S- and O-glucuronides of prothioconazole.]>

<	7. Metabolite toxicology. [The major metabolite of prothioconazole in
the rat, plants and large animals is JAU6476-desthio. Therefore, a
comprehensive evaluation of the mammalian toxicity of JAU6476-desthio
has been performed.  

The acute oral, dermal, and inhalation toxicity of JAU6476-desthio in
the rat is low (LD50 values: 2806/2506mg/kg [male/female], >5000mg/kg,
4-hour LC50: >5077mg/m3, respectively). It is non-irritating to skin and
only very slightly irritating to eyes and has no cutaneous sensitizing
potential by topical application.

The short and long-term oral toxicity of JAU6476-desthio has been
investigated by dietary administration in the rat, mouse and dog. The
common target organ in all 3 species is the liver. Secondary effects on
the thyroid in the rat and dog were associated with increased hepatic
enzyme induction. In the long term studies, 52 weeks in the rat and 30
weeks in the dog, the NOAEL for the rat and the dog were 1.1 and 10.1
mg/kg bw/day, respectively. JAU6476-desthio is not carcinogenic in
either the rat or the mouse. The NOAEL selected for human risk
assessment is 1.1 mg/kg bw/day established in the combined chronic
toxicity and carcinogenicity study in the rat.

JAU6476-desthio was negative for mutagenicity and genotoxicity in all in
vitro and in vivo studies both with and without metabolic activation.

In a two-generation reproduction study the maternal NOAEL was 2.7 mg/kg
bw/day and the NOAEL for reproductive and neonatal effects 10.0 mg/kg
bw/day. The main targets at the highest dose were dystocia (probably
secondary to hepatic toxicity), decreased pup viability, growth
retardation and low incidence of cleft palates.

In the developmental toxicity studies cleft palates were seen in the rat
and rabbit at the highest dose levels and supernumerary ribs in the rat
at lower dose levels. The oral NOAEL is 1 mg/kg bw/day in the rat and 2
mg/kg/day in the rabbit.

A developmental neurotoxicity study (DNT) in rats was conducted with
JAU6476-desthio as the anticipated dietary exposure is mainly to
JAU6476-desthio and not the parent. No evidence of neurotoxicity was
seen in this study, including no compound-related effects involving
neurobehavioral tests and neuropathology.  Compound-related effects were
limited to overt toxicity and developmental effects which were
consistent with effects seen in other developmental toxicity studies.
The overall NOAEL was 3.6 mg/kg bw/day.]>

<	8. Endocrine disruption. [The toxicology database for prothioconazole
is current and complete.  Studies in this database include evaluation of
the potential effects on carcinogenic, reproduction and development
effects including an evaluation of the pathology of the endocrine organs
following short- or long-term exposure. Prothioconazole is considered
not to have primary endocrine effects.]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [An aggregate risk assessment was conducted for
all registered uses on barley; dried beans and peas (Crop Group 6C);
canola; peanuts; wheat; triticale; soybeans; and sugar beets; the
pending petition requesting tolerances be established on the cereal
grain crop group 15 and 16 (except sweet corn, sorghum, and rice) and
sweet corn; and this proposed petition requesting tolerances on rice,
alfalfa and potato. In actuality, rice and potato do not contribute to
the dietary burden since the TRR studies show a no residue situation. 

The acute toxicity endpoint used in the acute assessment was the NOAEL
of 2.0 mg/kg/day from the prothioconazole-desthio rabbit developmental
toxicity study as described in the Agency’s HED risk assessment
memorandum on prothioconazole dated January 5, 2009. No acute endpoint
was identified for the general U.S. population; Females, 13-49 years of
age, was the only population subgroup to be included in the acute
assessment. Application of a 100x uncertainty factor results in an acute
reference dose (aRfD) of 0.02 mg/kg/day. The chronic reference dose
(cRfD) of 0.01 mg/kg/day results from application of a 100x uncertainty
factor to the NOAEL of 1.1 mg/kg/day from the rat chronic\oncogenicity
prothioconazole-desthio toxicity study. 

The acute and chronic dietary assessments for combined food and water
exposure show 7.33% utilization of the aRfD by females 13-49 years and
9.0% utilization of the cRfD by the most sensitive subgroup, all
infants.  Results from the dietary exposure assessments demonstrate a
reasonable certainty that no harm to the overall U.S. population or any
population subgroup will result from the use of prothioconazole on the
above crops.]>

<	i. Food. [An acute, Tier 2 dietary (food only) risk assessment was
conducted. For the population subgroup females 13-49 years old, the
acute analysis indicates an exposure of 0.57% of the aRfD at the 95th
percentile. Results from a chronic, Tier 2 dietary (food only) risk
assessment show that the most highly exposed population subgroup is
children 1 to 2 years with an exposure equal to 1.4% of the cRfD
followed by all infants at 0.9%. Chronic exposure to the overall U.S.
population is 0.6% of the cRfD.]>

<	ii. Drinking water. [No monitoring data are available for residues of
prothioconazole in drinking water, and EPA has established no health
advisory levels or maximum contaminant levels for residues of
prothioconazole in drinking water. In order to address drinking water,
water was included in the dietary analysis for food. DEEM analyses were
performed using the upper bound estimates for the peanut and sugar beet
crop scenarios; the EDWC for the acute assessment is 29 ppb from the
peanut scenario and 13 ppb from the sugar beet scenario for the chronic
assessment (the estimated drinking water concentrations for the proposed
foliar use on rice were less than those used in recent acute and chronic
exposure assessments and so do not factor into the dietary assessment).
For the population subgroup females 13-49 years old, the acute analysis
results in an exposure of 6.76% of the aRfD. Results from a chronic,
Tier 2 dietary risk assessment indicate that the most highly exposed
population subgroup was all infants with an exposure equal to 8.1% of
the cRfD. Chronic exposure to the overall U.S. population is 2.5% of the
cRfD.]>

<	2. Non-dietary exposure. [Prothioconazole is not registered for
residential uses nor are any registrations pending for such uses.]>

<D. Cumulative Effects>

<	[Prothioconazole is a member of the conazole family of fungicides. The
cumulative effects of the primary common metabolites are being addressed
by the US Triazole Task Force.]>

<E. Safety Determination>

<	1. U.S. population. [In the Agency’s HED risk assessment memorandum
on prothioconazole dated October 13, 2006, it is stated that
quantification of acute risk to the general population including infants
and children is not required. Based on the conservative exposure
assumptions described above and on the completeness of the toxicity
data, it can be concluded that total food and drinking water exposure to
prothioconazole from all proposed uses will utilize 7.33% of the acute
RfD for females 13-49 years old and 3.1% of the chronic RfDs for the
overall U.S. population. EPA generally has no concerns for exposures
below 100% of the RfD, because the RfD represents the level at or below
which daily aggregate exposure over a lifetime will not pose appreciable
risks to human health.]>

<	2. Infants and children. [In the Agency’s HED risk assessment
memorandum on prothioconazole dated January 5, 2009, it is stated: 
“There are adequate data in the prothioconazole (including
metabolites) database to characterize the potential for pre-natal or
post-natal risks to infants and children: two-generation reproduction
studies in rats; developmental studies in rats and rabbits; and a
developmental neurotoxicity study in rats.  The effects seen in these
studies suggest that offspring are more susceptible: offspring effects
were seen at levels below the LOAELs for maternal toxicity and, in
general, were of comparable or greater severity compared to the effects
observed in adults.  However, the point of departure for the most
sensitive of these studies (the rabbit developmental toxicity) is lower
than that of the other studies (2 mg/kg/day), and is based on effects
observed in the fetus, not the parent.  Therefore, the offspring are
considered to be protected and there is no need to retain the 10X FQPA
factor, and it is reduced to 1X.” EPA also stated   “No acute
endpoint was identified for the general U.S. population.  Females, 13-49
years of age, was the only population subgroup included in the acute
assessment.”

 

In addition to the adequacy of the toxicity database, there are also no
uncertainties with respect to the exposure database. Both the dietary
food and water exposure assessments are conservative in nature. 
Additionally, there is no potential for residential exposure. 

In Bayer’s chronic exposure assessment, the most highly exposed
population subgroup, all infants, utilized 9.0 % of the chronic RfD. EPA
generally has no concerns for exposures below 100% of the RfD, because
the RfD represents the level at or below which daily aggregate exposure
over a lifetime will not pose appreciable risks to human health.]>

<F. International Tolerances>

<	[Codex MRLs are not yet published; however, prothioconazole was
evaluated at both the 2008 and 2009 JMPR, so CODEX MRLs should be
established in the near future.]>

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