Document ID: EPA-HQ-OPP-2009-0279-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-08-19T04:00Z

<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. by establishing a tolerance for residues of
[prothioconazole and prothioconazole-desthio] in or on the raw
agricultural commodity [grain, cereal, group 15, except sweet corn,
sorghum, and rice] at [0.35] parts per million (ppm), [forage, cereal,
group 16, except sweet corn, sorghum, and rice] at [8.0] ppm, [stover,
cereal, group 16, except sweet corn, sorghum, and rice] at [10] ppm,
[hay, cereal, group 16, except sweet corn, sorghum, and rice ] at [7.0]
ppm, [straw, cereal, group 16, except sweet corn, sorghum, and rice] at
[5.0] ppm, [corn, sweet, forage] at [7] ppm, [corn, sweet, stover] at
[8] ppm and [corn, sweet, kernel plus cob with husks removed] at [0.02]
ppm.  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
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. [Residue data on wheat and barley have
previously been submitted to the Agency under PP 4F6830. These data were
used to establish tolerances wheat and barley as published in 72 FR
11777. In addition to data on wheat and barley, additional magnitude of
residue data from foliar applications of prothioconazole on corn (field,
pop and sweet) are being submitted to support this petition. A total of
12 sweet corn field trials, 20 field corn field trials and three pop
corn field trials were conducted to measure the magnitude of
prothioconazole residues in/on corn commodities following four
applications of JAU 6476 480 SC formulation at a rate of 200 g ai/ha
with an application interval of 5-7 days. Data submitted with this
petition support the proposed tolerances for field corn, sweet corn and
pop corn commodities noted above.

Processing data other than that submitted to the Agency under PP 4F6830
are being submitted on corn grain and corn processed commodities
following exaggerated rate applications of prothioconazole to field
corn. These data show no concentration in any of the required processed
commodities. Total prothioconazole residue did concentrate in corn
aspirated grain fractions. However, the resulting residue would be less
than that already establish for wheat as published in 72 FR 11777.]

<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 is 9.7 mg/kg bw/day
and 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. [EPA is required under the 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 Screening and Testing Advisory Committee (EDSTAC),
EPA determined that there was a scientific basis for including, as part
of the program, the androgen and thyroid hormone systems, in addition to
the estrogen hormone system.  EPA also adopted EDSTAC’s recommendation
that the Program include evaluations of potential effects in wildlife. 
For pesticide chemicals, EPA will use FIFRA and, to the extent that
effects in wildlife may help determine whether a substance may have an
effect in humans, FFDCA authority to require the wildlife evaluations. 
As the science develops and resources allow, screening of additional
hormone systems may be added to the Endocrine Disruptor Screening
Program (EDSP).

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

<C. Aggregate Exposure>

<	1. Dietary exposure. [An aggregate risk assessment was conducted for
all registered and pending uses of prothioconazole including the
proposed uses on field, sweet and pop corn. 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 October 13, 2006. Application of a 1000x uncertainty factor
resulted in an acute reference dose (aRfD) of 0.002 mg/kg/day. The
chronic reference dose (cRfD) of 0.001 mg/kg/day resulted from
application of a 1000x uncertainty factor to the NOAEL of 1.1 mg/kg/day
from the rat chronic\oncogenicity prothioconazole-desthio toxicity
study. 

Results from the acute and chronic dietary exposure assessment described
below 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 and drinking water) risk
assessment was conducted. For the population subgroup females 13-49
years old, the acute analysis resulted in an exposure of 73% of the
aRfD. Results from a chronic, Tier 2 dietary (food and water) risk
assessment indicated that the most highly exposed population subgroup
was all infants with an exposure equal to 93% of the cRfD. Chronic
exposure to the overall U.S. population was 34% 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 given above.]>

<	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 [1,2,4-triazole
(1,2,4-T) and the two conjugates (TA and TAA)] were addressed in two
assessments  by EPA (one for 1,2,4-T and one for TA and TAA). Both
assessments showed acceptable dietary exposure for all of the
metabolites. ]>

<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 73% of the acute RfD
for females 13-49 years old and 34% 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 October 13, 2006, it is stated that
quantification of acute risk to the general population including infants
and children is not required. For acute exposure, the Agency used the
population subgroup females 13-49 years old. In Bayer’s acute
assessment the exposure for females 13-49 years old equaled 73% of the
acute RfD. For chronic exposure the most highly exposed population
subgroups (all infants), utilized 93% 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>

<	[There are no Codex MRLs currently established for prothioconazole.]>

 PAGE   

 PAGE   6