Document ID: EPA-HQ-OPP-2007-1202-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-02-06T05:00Z

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

<EPA Registration Division contact: Shaja R. Brothers, (703) 308-3194>

 

INSTRUCTIONS:  

<Interregional Research Project Number 4 (IR-4) >

<PP 7E7300>

<	EPA has received a pesticide petition (PP) 7E7300 from Interregional
Research Project Number 4 (IR-4), 500 College Road East, Suite 201 W,
Princeton, NJ 05840 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 tolerances for residues of propiconazole,
1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]
methyl]-1H-1,2,4-triazole and its metabolites determined as
2,4,-dichlorobenzoic acid and expressed as parent compound in or on the
following commodities:  beet, garden, roots at 0.6 parts per million
(ppm); parsley, leaves at 13 ppm, parsley, dried leaves at 60 ppm,
coriander, fresh at 13 ppm, vegetable, leaves of root and tuber, group
at 8.0 ppm, pineapple (post harvest) at 0.9 ppm, and turnip, roots at
0.2 ppm.  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 support granting of the
petition. Additional data may be needed before EPA rules on the
petition.>

>

<A. Residue Chemistry>

<1. Plant metabolism. The metabolism of propiconazole as well as the
nature of the residues is adequately understood for purposes of the
tolerances.  Plant metabolism has been evaluated in five diverse crops,
wheat, grapes, celery, peanuts and carrots which should serve to define
the similar metabolism of propiconazole in a wide range of crops.  The
plant metabolism pathway for propiconazole is well understood.  Parent
metabolite CGA-64250 is the major compound found in crops.  Comparison
of the metabolism of propiconazole in different plant species shows that
the differences between the respective metabolic pathways to be
quantitative in nature. >

<	2. Analytical method. The metabolism data in plants and animals
suggest that analytical methods to detect either the phenyl or the
triazole ring would be appropriate for the measurement of residues. 
However, because of the natural occurrence of compounds that interfere
with the measurement of triazoles, methods designed to detect this
moiety have been proven unreliable and unacceptable.  Conversely,
conversion of phenyl moiety to 2,4-dichlorobenzoic acid (DCBA) has
proven to be satisfactory for all agricultural products analyzed to
date.  Analytical methods AG-626 and AG-454A were developed for the
determination of residues of propiconazole and its metabolites
containing the DCBA moiety.   Analytical method AG-626 has been accepted
and published by EPA as the tolerance enforcement method for crops.  The
limit of quantitation (LOQ) for the method is 0.05 ppm.

	3. Magnitude of residues. The limit of quantitation of (LOQ) for the
method in all matrices were 0.05 ppm.>

<

	i.  Garden beet.  Five beet trials (5) were conducted in Oregon, New
York, Wisconsin, Michigan, and Texas, representing NAFTA growing regions
1, 5, 6, and 12.  The number of trials and geographic representation are
adequate for garden beet.   In each trial, four applications of Tilt 3.6
EC at a rate of approximately 0.169 lb ai/A each were made, for a total
of approximately 0.676 lb ai/A.  Applications were made 10 to 15 days
apart and timed so that mature beets could be collected 14 to 16 days
after the final application.  Samples were analyzed using a procedure
adapted from the Novartis Crop Protection, Inc., method AG-626,
“Determination of Total Residues of Propiconazole in Crops as 2,
4-Dichlorobenzoic Acid Methyl Ester by Capillary Gas Chromatography”. 
Modifications were made to improve the performance of the method. 
Maximum propiconazole residues were 4.3 ppm in tops samples.  Residues
were significantly lower in root samples, with a maximum residue of 0.27
ppm.  

	ii. Turnip.   HYPERLINK  \l "_Appendix_1_FIELD" Six field trials  were
conducted for this study during the 1997 to 1998 growing season, one
each in New Jersey (  HYPERLINK  \l "_Table_B.1.3:__Trial numbers and
geo"  EPA Region 2 ), Tennessee (Region 2), Georgia (Region 2), Texas
(Region 6), Ohio (Region 5), and California (Region 10).  The number
of field trials is in accordance with OPPTS Guideline 860.1500.  In each
trial, at least four foliar applications of Tilt 3.6EC at a rate of
approximately 0.169 lb ai/A each were applied, for a total of
approximately 0.676 lb ai/A.  The applications were made 9 to 16 days
apart, and timed so that mature turnip tops and roots could be collected
approximately 14days following the last application.   HYPERLINK  \l
"_Appendix_2_Analytical_Summary Repor" Samples were analyzed  for
residues of propiconazole and its metabolites contaning the DCBA moiety
using Novartis method AG-626.  Modifications were made to improve the
performance of the method.  Maximum residues in turnip tops were 4.29
ppm.  No residues were observed in root samples above the lowest level
of method validation (0.2 ppm).  >

	

	iii. Parsley.  Four residue field trials were conducted in Texas,
California, and New Jersey.  A total of approximately 0.45 lb ai/A was
applied to the treated plots in four foliar applications of Tilt 3.6EC
at a rate of approximately 0.1125 lb ai/A each.  Mature fresh and dried
parsley was collected approximately 14 days after the final application.
 

 HYPERLINK  \l "_Appendix_2_Analytical_Summary Repor" Samples were
analyzed  for residues of propiconazole and its metabolites containing
the DCBA moiety using Novartis method AG-626.  Maximum propiconazole
residues were 6.5 ppm in fresh samples.  Residues were concentrated in
dried samples, with a maximum residue of 21 ppm

	iv. Pineapple (post- harvest).  Three residue field trials were
conducted in Hawaii (EPA Region 13). The geographic representation of
field trials is in accordance with OPPTS Guideline 860.1500.  Pineapples
were dipped in a solution of Tilt 3.6EC at approximately 0.125 lb ai/100
gal water.   Three different post-harvest treatments with Tilt 3.6E were
examined. The treatment solutions contained either: 1) no adjuvant, 2)
fruit wax at approximately 1 gal/8 gal water, or 3) fruit oil at
approximately 10 gal/100 gal water.  Following treatment, the
pineapples were allowed to dry and the crowns were removed.  Samples of
the fruit treated with Tilt 3.6E and wax were processed into edible
fresh pulp, peel, beverage juice, and process residue samples.

The method for sample analysis was derived from both the Ciba-Geigy
Corporation method AG-454B, “Determination of Total Residues of
Propiconazole in Crops as 2,4-Dichlorobenzoic Acid by Capillary Gas
Chromatography” and the Novartis Crop Protection, Inc., method AG-626,
“Determination of Total Residues of Propiconazole in Crops as
2,4-Dichlorobenzoic Acid Methyl Ester by Capillary Gas
Chromatography.”   Modifications were made to improve the performance
of the method.  

The maximum residue observed in pineapple fruit samples dipped in Tilt
3.6E alone was 4.1 ppm.  Addition of wax and oil decreased the residues
by more than 75% to a maximum residue of 0.82 ppm.  Residues in peel
samples were 0.35 ppm, while residues detected in process residue
samples were slightly higher at 0.67 ppm.  Residues in edible fresh
pulp and beverage juice samples were less than the lowest level of
method validation of 0.05 ppm.

<B. Toxicological Profile>

<1. Acute toxicity.  Propiconazole exhibits low toxicity.  Data
indicated the following:  a rat acute oral LD50 of 1,517
milligrams/kilograms (mg/kg); a rabbit acute dermal LD50 >6,000 mg/kg; a
rat inhalation LC50 >5.8 mg/liter air; minimal skin and slight eye
irritation; and nonsensitization>.

<2. Genotoxicty. Propiconazole exhibits low toxicity.  Data indicated
the following:  a rat acute oral LD50 of 1,517 milligrams/kilograms
(mg/kg); a rabbit acute dermal LD50 >6,000 mg/kg; a rat inhalation LC50
>5.8 mg/liter air; minimal skin and slight eye irritation; and
nonsensitization.>

<3. Reproductive and developmental toxicity.  In an oral teratology
study in the rabbit, a maternal no observed adverse effect level (NOAEL)
of 30 mg/kg was based on reduced food intake but without any
fetotoxicity even at the top dose of 180 mg/kg.  In an oral teratology
study in the rabbit, a maternal NOAEL of 100 mg/kg was based on
reductions in body weight gain and food consumption and a fetal NOAEL of
250 mg/kg was based on increased skeletal variations at 400 mg/kg.  In
an oral teratology study in the rat, a maternal and fetal NOAEL of 100
mg/kg was based on decreased survival, body weight gain, and food
consumption in the dams and delayed ossification in the fetuses at 300
mg/kg.  In a second teratology study in the rat, a maternal and fetal
NOAEL of 30 mg/kg was based on reductions in body weight gain and food
consumption in the dams and delayed development in the fetuses at 90 and
360/300 mg/kg.  A supplemental teratology study in the rat involving
eight times as many animals per group as usually required showed no
teratogenic potential for the compound.  A 2-generation reproduction
study in the rat showed excessive toxicity at 5,000 ppm without any
teratogenic effects.  A 2-generation reproduction study in the rat
showed no effects on reproductive or fetal parameters at any dose level.
 Postnatal growth and survival were affected at the top dose of 2,500
ppm, and parental toxicity was also evident.  The NOAEL for development
toxicity is 500 ppm.>

<4. Subchronic toxicity.  In a 21-day dermal study in the rabbit, a
NOAEL of 200 mg/kg was based on clinical signs of systemic toxicity.  In
a 28-day oral toxicity study in the rat, a NOAEL of 50 mg/kg was based
on increased liver weight. In a subchronic feeding study in the mouse, a
NOAEL of 20 ppm (3 mg/kg) was based on liver pathologic changes. In a 13
week feeding study in the male mouse, a NOAEL of 20 ppm (3 mg/kg) was
based on liver pathologic changes.  In a 90 day feeding study in rats,
the NOAEL was 240 ppm (24 mg/kg) based on a reduction in body weight
gain. In a 90 day feeding study in dogs, the NOAEL was 250 ppm (6.25
mg/kg) based on reduced food intake and stomach histologic changes.>

<5. Chronic toxicity.  In a 12-month feeding study in the dog, a NOAEL
of 50 ppm (1.25 mg/kg) was based on stomach histologic changes.  In a 24
month oncogenicity feeding study in the mouse, the NOAEL was 100 ppm (15
mg/kg).  The MTD was exceeded at 2,500 ppm in males based on decreased
survival and body weight. Increased incidence of liver tumor was seen in
these males but no evidence of carcinogenicity was seen at the next
lower dose of 500 ppm in either sex.  In a 24 month chronic
feeding/oncogenicity study in the rat, a NOAEL of 100 ppm (5 mg/kg) was
based on body weight and blood chemistry.  The MTD was 2,500 ppm based
on reduction in body weight gain and no evidence of oncogenicity was
seen.  Based on the available chronic toxicity data, Syngenta believes
the Reference dose (RfD) for propiconazole is 0.0125 mg/kg/day.  This
RfD is based on a 1 year feeding study in dogs with a NOAEL of 1.25
mg/kg/day (50 ppm) and an uncertainly factor of 100.  No additional
modifying factor for the nature of effects was judged to be necessary as
stomach mucous hyperemia was the most sensitive indicator of toxicity in
that study.

Using the Guidelines for Carcinogenic Risk Assessment published on
September 24, 1986 (51 FR 33992), the USEPA has classified propiconazole
in group C for carcinogenicity (evidence of possible carcinogenicity for
humans).  The compound was tested in 24 month studies with both rats and
mice.  The only evidence of carcinogenicity was an increase in liver
tumor incidence in male mice at a dose level that exceeded the maximum
tolerated dose (MTD).  Dosage levels in the rat study were appropriate
for identifying a cancer risk.  The Cancer Peer Review Committee
recommended the RfD approach for quantitation of human risk.  Therefore,
the RfD is deemed protective of all chronic human health effects,
including cancer.  >

<	6. Animal metabolism. Metabolism in animals is similar to plant
metabolism. In animals both the rat and the goat rapidly metabolize and
excrete propiconazole.  Neither animal retains significant amounts of
propiconazole or its metabolites in tissues.  Significant quantities of
parent or metabolites do not appear in goat’s milk.  Similar
metabolites are produced by both species, and unconjugated (phase I)
metabolites are similar in plants and animals.  The metabolism profile
supports the use of an analytical enforcement method that accounts for
combined residues of propiconazole and its metabolites that contain the
2,4-dichlorobenzoic acid (DCBA) moiety.

>

<7. Metabolite toxicology.  There are no metabolites of concerned based
on a differential metabolism between plants and animals.>

<8. Endocrine disruption. Developmental toxicity studies in rats and
rabbits and reproduction studies in rats gave no indication that
propiconazole might have any effects on endocrine function related to
development and reproduction.  The subchronic and chronic studies also
showed no evidence of a long–term effect related to the endocrine
system.  Further, due to the moderate rate of degradation of the
product, there is no risk that propiconazole may accumulate in the
environment.  In animals, propiconazole is quickly excreted and has no
tendency for accumulation in the body.  Based on these results, it is
very likely that propiconazole has no potential to interfere
specifically with the endocrine system.>

<C. Aggregate Exposure>

<	1. Dietary exposure. Tier I acute and chronic dietary exposure
evaluations were completed for propiconazole using the Dietary Exposure
Evaluation Model software with the Food Commodity Intake Database
(DEEM-FCIDTM, version 2.14) from Exponent.  Propiconazole is currently
registered on the following crops: alfalfa (inadvertent), bananas,
barley, sugar beets, berries (Crop Group 13), carrots, corn (field,
sweet and popcorn), cranberries (Section 24c), stone fruits (Crop Group
12), grasses, leaf petioles (Crop Subgroup 4B), mushrooms, tree nuts
(Crop Group 14), oats, onions (bulb and green), peanuts, peppermint,
pineapples (seed piece treatment), pistachios, rice, rye, sorghum,
soybeans, spearmint, strawberries, wheat and wild rice (Section 24c). 
Propiconazole is proposed for use in or on garden beets, parsley,
pineapples (post-harvest treatment), turnips and leaves of root and
tuber vegetables (Crop Group 2).  These exposure assessments include all
current and proposed propiconazole tolerances.  Percent of crop treated
values were conservatively estimated to be 100% for all uses and default
processing factors from DEEM™ (version 7.87) were used for processed
commodities.>

Food.   Acute Risk.  The acute dietary (food only) risk assessment was
performed for all population subgroups with an acute reference dose of
0.3 mg/kg-bw/day based on an acute no observable adverse effect level
(NOAEL) of 30 mg/kg-bw/day from an acute neurotoxicity study in rats and
an uncertainly factor of 100X.  The 100X safety factor included intra-
and inter-species variations.  No additional FQPA safety factor was
applied.  For the purpose of the aggregate risk assessment, the exposure
value was expressed in terms of margin of exposure (MOE), which was
calculated by dividing the NOAEL by the exposure for each population
subgroup.  In addition, exposure was expressed as a percent of the acute
reference dose (%aRfD).  Acute exposure to the U.S. population resulted
in a MOE of 1,699 (5.9% of the acute RfD of 0.3 mg/kg-bw/day).  Acute
exposure to the most sensitive subpopulation (children 1-2 years old)
resulted in a MOE of 826 (12.1% of the acute RfD of 0.3 mg/kg-bw/day). 
Since the benchmark MOE for this assessment is 100 and since EPA
generally has no concern for exposures below 100% of the RfD, Syngenta
believes that there is a reasonable certainty that no harm will result
from acute dietary (food) exposure to residues arising from the current
and proposed uses for propiconazole.

Chronic Risk.  The chronic dietary (food only) risk assessment was
performed for all population subgroups with a chronic reference dose of
0.1 mg/kg-bw/day based on a 24-month oncogenicity study in mice with a
NOAEL of 10 mg/kg-bw/day and an uncertainly factor of 100X.  The 100X
safety factor included intra- and interspecies variations.  No
additional FQPA safety factor was applied.  For the purpose of the
aggregate risk assessment, the exposure values were expressed in terms
of margin of exposure (MOE), which was calculated by dividing the NOAEL
by the exposure for each population subgroup.  In addition, exposure was
expressed as a percent of the reference dose (%RfD).  Chronic exposure
to the U.S. population resulted in a MOE of 1,771 (5.6% of the chronic
RfD of 0.1 mg/kg-bw/day).  Chronic exposure to the most exposed
sub-population (children 1-2 years old) resulted in a MOE of 710 (14.1%
of the chronic RfD of 0.1 mg/kg-bw/day).  Since the benchmark MOE for
this assessment is 100 and since EPA generally has no concern for
exposures below 100% of the RfD, Syngenta believes that there is a
reasonable certainty that no harm will result from chronic dietary (food
only) exposure to residues arising from all current, pending and
proposed uses for propiconazole.

Cancer Risk.  A quantitative risk assessment using a cancer endpoint was
not performed.  The chronic risk assessment is adequately protective for
cancer risk as well as other chronic effects.

nd chronic) were used in the DEEM-FCID™ analysis to estimate the
dietary exposure from drinking water.

Acute Exposure from Drinking Water.  The acute drinking water estimate
from turf uses (55.8 ppb) was incorporated directly into the dietary
exposure assessment along with the food exposure.  Acute dietary (food
and water) exposure to the U.S. population resulted in a MOE of 1,552
(6.4% of the acute RfD of 0.3 mg/kg/day).  The most exposed
sub-population was all infants (<1 year old) with a MOE of 765 (13.1% of
the acute RfD).  Based on these results, there is no concern for acute
risk from either surface or ground water from all current, pending and
proposed uses of propiconazole.

Chronic Exposure from Drinking Water.  The chronic drinking water
estimate from turf uses (21.6 ppb) was incorporated directly into the
dietary exposure assessment along with the food exposure.  Chronic
dietary (food and water) exposure to the U.S. population resulted in a
MOE of 1,639 (6.1% of the chronic RfD of 0.1 mg/kg/day).  The most
exposed sub-population was children (1-2 years old) with a MOE of 678
(14.8% of the chronic RfD).  Based on these results, there is no concern
for chronic risk from either surface or ground water from all current,
pending and proposed uses of propiconazole.

>

<	2. Non-dietary exposure. Short-term and intermediate-term risk
exposure assessments were conducted for non-dietary uses of
propiconazole since it is currently registered for residential use on
turf and for antimicrobial uses (paint and lumber).  Adult turf use
scenarios included dermal exposure for residential handlers (short-term
only) and dermal exposure from post-application scenarios (short-term
only).  For children, short-term risk assessment scenarios were run for
turf use and antimicrobial uses on lumber.  Intermediate-term risk
assessments were also run for children playing on propiconazole-treated
structures such as decks and/or play sets.  The short-term and
intermediate-term scenarios for children included both dermal exposure
and incidental oral exposure via hand to mouth and object to mouth.  The
short-term oral and dermal endpoint was 30 mg/kg/day.  The
intermediate-term oral and dermal endpoint was 10 mg/kg/day.  The
worst-case adult turf use scenario (post-application, general high
contact activities) provided a short-term MOE of 350 which is above the
EPA’s level of concern.  For post-application exposures to treated
lawns, the worst-case combined short-term MOE for children was 170 based
on dermal and non-dietary oral exposure.  For dermal and incidental oral
exposure of children playing on propiconazole-treated structures, the
combined intermediate-term MOE for children was 140.  Since the EPA’s
benchmark MOE for propiconazole is 100, the residential exposure for
both adults and children do not exceed EPA’s level of concern.

>

<D. Cumulative Effects>

<	Cumulative Exposure to Substances With a Common Mechanism of Toxicity.
 Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity”.  Propiconazole is a member of the
triazole-containing class of pesticides.  Although conazoles act
similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there
is not necessarily a relationship between this pesticidal activity and
their mechanism of toxicity in mammals.  Structural similarities do not
constitute a common mechanism of toxicity.  There is currently no
evidence to indicate that conazoles share common mechanisms of toxicity
and the EPA is not following a cumulative risk approach based on a
common mechanism of toxicity for the conazoles.>

<E. Safety Determination>

<	1. U.S. population. Using the conservative assumptions described
above, and based on the completeness and reliability of the toxicity
data, the acute aggregate (food plus water) exposure calculation for all
current, pending and proposed uses of propiconazole provided a MOE of
1,552 for the U.S. population.  The chronic aggregate exposure analysis
(food and water) showed that exposure from all current and proposed
propiconazole uses resulted in a MOE of 1,639 for the U.S. population. 
For short-term exposures, the chronic dietary (food and water) exposure
was aggregated with the residential exposure resulting in a short-term
aggregate MOE of 327 for the U.S. population.  An intermediate-term
aggregate exposure analysis (food, water and residential) was not
required for adults for residential uses of propiconazole.  Since the
worst case aggregate MOE of 327 (short-term risk) exceeds the benchmark
MOE of 100, Syngenta believes that there is a reasonable certainty that
no harm will occur to the U.S. Population from aggregate exposures
arising from all current and proposed uses for propiconazole.>

<	2. Infants and children. Using the conservative assumptions described
in the exposure section above, and based on the completeness and
reliability of the toxicity data, the acute aggregate (food plus water)
exposure calculation for all current, pending and proposed uses of
propiconazole provided a MOE of 765 for all infants <1 year old (the
most sensitive population subgroup).  The chronic aggregate exposure
analysis (food and water) showed that exposure from all current, pending
and proposed propiconazole uses resulted in a MOE of 678 for the most
sensitive population subgroup (children 1-2 years old).  A short-term
aggregate exposure analysis (food, water and residential) was determined
for small children since they represent the worst-case scenario with
both dietary (food and water) exposure and two routes of non-dietary
exposure (dermal and incidental oral) from turf residues.  For
short-term exposures, the chronic dietary (food and water) exposure was
aggregated with the residential exposure resulting in a short-term
aggregate MOE of 157 for children 1-2 years old.  An intermediate-term
aggregate exposure analysis (food, water and residential) was determined
to account for potential residues from decks and/or playsets made with
lumber treated with propiconazole (antimicrobial use).  For
intermediate-term exposures, the chronic dietary (food and water)
exposure was aggregated with the residential exposure resulting in a
short-term aggregate MOE of 116 for children 1-2 years old  Since the
worst case aggregate MOE of 116 (intermediate-term risk) exceeds the
benchmark MOE of 100, Syngenta believes that there is a reasonable
certainty that no harm will occur to infants and children from aggregate
exposure to residues arising from all current and proposed uses of
propiconazole, including anticipated dietary exposure from food, water
and all other types of non-occupational exposures.>

<F. International Tolerances>

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᐀expression includes all metabolites determined as
2,4-dichloro-benzoic acid.  In conjunction with the reregistration
process EPA intends to revise the tolerance expression to propiconazole
per se.  To the extent possible, for the present petitions, U.S.
tolerances have been numerically harmonized with Codex, Canadian and
Mexican MRLs; however, differences in use patterns and the supporting
residue data have precluded reducing many tolerances.  A summary of
Codex MRLs, Canadian MRLs and Mexican tolerances and the corresponding
U.S. tolerances for propiconazole is discusses at   HYPERLINK
"http://www.regulations.gov"  www.regulations.gov  Docket No.
EPA-HQ-OPP-2006-0347-0004; pages 53-54.>