Document ID: EPA-HQ-OPP-2008-0327-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-06-04T04:00Z

<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] in or on the raw agricultural commodity [wheat,
forage] at [8.0] parts per million (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. [Magnitude of residue data from foliar
applications of prothioconazole on wheat are currently on file with the
EPA under MRID 46246219 from 54 field trials in the U.S. and Canada.
These data were used to establish the current tolerances for
prothioconazole on wheat forage, grain, hay, and straw at 6.0, 0.07,
4.5, and 5.0 ppm, respectively. Data submitted with this petition are
from 3 additional side-by-side trials. Residues from all trials were
within the current tolerances for all RACs except for one wheat, forage.
Although this trial gave residues in wheat forage slightly higher than
the 6.0 ppm tolerance, they were less than the 6.99 ppm highest residue
used to support the 6.0 ppm tolerance.]>

<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. [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, and wheat; the pending uses on soybeans and sugar
beets; plus the proposed increase in the tolerance for wheat forage from
6 ppm to 8 ppm. 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 30.8% of the
aRfD. Results from a chronic, Tier 2 dietary (food) risk assessment
indicated that the most highly exposed population subgroup was all
infants with an exposure equal to 27.8% of the cRfD. Chronic exposure to
the overall U.S. population was 13% 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. For the population
subgroup females 13-49 years old, the acute analysis resulted in an
exposure of 30.8% of the aRfD. Results from a chronic, Tier 2 dietary
(food) risk assessment indicated that the most highly exposed population
subgroup was all infants with an exposure equal to 27.8% of the cRfD.
Chronic exposure to the overall U.S. population was 13% 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 30.8% of the acute
RfD for females 13-49 years old and 13% 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 30.8% of the
acute RfD. For chronic exposure the most highly exposed population
subgroups (all infants), utilized 27.8% 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>

<	[Although no Codex MRLs are currently established for prothioconazole,
MRLs for prothioconazole allowing use on wheat are established in
Australia, Belgium, Canada, Czech Republic, Estonia, France, Germany,
Italy, Lithuania, Luxembourg, Netherlands, Poland, Slovakia, and
Switzerland.]>

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