Document ID: EPA-HQ-OPP-2008-0773-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-12-03T05:00Z

<Notice of Filing of Pesticide Petitions 8E7434 and 8E7436 

Petitioner: <Interregional Research Project No. 4 (IR-4) in cooperation
with Syngenta Crop Protection, Inc. >

>

<EPA Registration Division contact: Susan Stanton; (703) 305-5218>

<	EPA has received  pesticide petitions (PP#8E7434 and PP#8E7436) from >

<Interregional Research Project No. 4 (IR-4), 500 College Road East,
Suite 201 W, Princeton, NJ 08540, 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 180.222 by establishing tolerances for residues of
prometryn, 2,4-bis(isopropylamino)-6-methylthio-s-triazine (CAS Number
7287-19-6), in or on the raw agricultural commodities carrot at 0.7
parts per million (ppm); celeriac, roots at 0.05 ppm; celeriac, tops at
0.05 ppm; cilantro, fresh at 4.0 ppm; cilantro, dried at 15 ppm; okra at
0.05 ppm; parsley, leaves at 0.7 ppm (all the preceding in PP8E7434);
and leafy petiole subgroup 4B at 0.5 ppm (PP#8E7436).  EPA has
determined that the petitions contain 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 petitions. Additional data
may be needed before EPA rules on the petition.>

<A. Residue Chemistry>

<	1. Plant metabolism. The qualitative nature of prometryn residues in
plants is adequately understood based upon available EPA approved cotton
and celery metabolism studies.  The metabolism of prometryn involves
N-dealkylation and hydrolysis.  EPA has determined that residues of
concern in plants include parent only for tolerance setting purposes.>

<	2. Analytical method. The Pesticide Analytical Manual (PAM) lists a GC
method for determining residues in / on plants using a microcoulometric
sufur detection system that determines residues of prometryn.  No
tolerances are needed for prometryn residues in livestock commodities;
therefore, no enforcement analytical methods are needed.>

<	3. Magnitude of residues. IR-4 has submitted complete residue data for
prometryn on carrots, celeriac, cilantro, okra, parsley, and
representative crops in support of the leafy petiole subgroup 4B.>

<B. Toxicological Profile>

<	1. Acute toxicity.  The data base for acute toxicity for prometryn is
complete.  Prometryn technical is slightly to practically non-toxic for
oral (male, 1802 mg/kg; female, 2076 mg/kg), dermal (LD50 > 3170), and
inhalation (LC50 4.96 mg/L)placing it in Toxicity Category III.  It
causes mild eye irritation (Toxicity Category III) and slight dermal
irritation (Toxicity Category IV).  Prometryn is not considered a skin
sensitizer.>

<	2. Genotoxicty. In four mutagenicity studies (Ames salmonella test,
chromosomal aberration, bacterial DNA repair, and unscheduled DNA
synthesis test) prometryn was found to be negative.  There is no
evidence of a mutagenic or cytogentic effect in vivo or in vitro with
prometryn.

In the Ames test prometryn was negative for gene mutation up to cytoxic
solubility limits (100-2000 ug/plate.

In a Chromosomal aberration in vivo Chinese hamster bone marrow test,
prometryn was negative for nuclear anomalies when animals were dosed
orally up to 5000 mg/kg.

Prometryn was negative for bacterial DNA repair and gene mutation up to
precipitating levels (1000 ug/plate).

In an unscheduled DNA synthesis test, prometryn was negative in rat
hepatocytes cultured in vitro up to cytotoxic levels of 156.25 ug/ml.>

<	3. Reproductive and developmental toxicity. Developmental toxicity
studies with rats (0-250 mg/kg/day) and rabbits (0-72 mg/kg/day) showed
maternal and developmental toxicity only at the highest dose.  The
developmental NOEL was 50 mg/kg/day in rats and 12 mg/kg/day in rabbits.

A 2-generation reproduction study with rats showed effects at the
highest dose (1500 ppm; 105.6 mg/kg/day) including decreased body weight
and food consumption. The reproductive NOEL was 750 ppm or approximately
50 mg/kg/day. The results indicate that prometryn is not embryotoxic or
teratogenic in either species at maternally toxic doses.>

<	4. Subchronic toxicity. In a subchronic 28-day pilot feeding study in
mice at the highest dose (0-4500 mg/kg/day), there were pathological
findings limited to the G.I. tract along with decreased body weights. 
The NOEL was 450 mg/kg/day.  

In a 21-day dermal toxicity study in rabbits, no local or systemic
toxicity was observed at all dose levels with a NOEL of >1000
mg/kg/day.>

<	5. Chronic toxicity. In a chronic toxicity study/oncogenicity study in
mice the NOEL in females was 1,000 ppm and the LOEL was 3,000 ppm based
upon decreased body weight gain.  There were no effects observed in
males.  Prometryn was not oncogenic under the conditions of the study.

In a chronic toxicity study in dogs, the NOEL was 3.75 mg/kg/day active
ingredient with a LOEL of 37.5 mg/kg/day.  The Agency has determined
that there is “no evidence of human carcinogenic potential”.>

<	6. Animal metabolism. The metabolism of prometryn in rats and
livestock animals is adequately understood.  Data indicate that the
distribution of prometryn is greatest in the blood, followed by the
spleen and the lungs.  Prometryn is predominantly excreted in the urine
and feces with slightly higher concentrations in the urine.>

<	7. Metabolite toxicology. For risk assessment purposes, EPA has
determined that residues of concern in animals include parent only and
metabolites are toxicologically equivalent to parent prometryn.>

<	8. Endocrine disruption. There is no indication from the mammalian
toxicology database for any endocrine disrupting effect of prometryn.>

<C. Aggregate Exposure>

<	1. Dietary exposure. Dietary Exposure. Tier I acute and chronic
dietary exposure evaluations were made for prometryn using the Dietary
Exposure Evaluation Model (DEEM-FCIDTM), version 2.14 from Exponent.  In
addition to current tolerances for prometryn this exposure assessment
included proposed prometryn tolerances for uses on carrots, celeriac,
cilantro, okra, national tolerances for parsley (currently regional
tolerances only) and the leafy petioles crop subgroup 4B.  Percent of
crop treated values were conservatively estimated to be 100% for all
registered and proposed uses.  Drinking water estimates were
incorporated directly into the dietary exposure assessment using the
higher of the estimated drinking water concentrations (EDWCs) for
surface and ground water.  All consumption data for these assessments
was taken from the USDA’s Continuing Survey of Food Intake by
individuals (CSFII) with the 1994-96 consumption database and the
Supplemental CSFII children’s survey (1998) consumption database.>

<Food. Acute Exposure.  An acute reference dose of 0.12 mg/kg/day for 

the females 13-49 years subpopulation only was based on a NOAEL of 12
mg/kg/day from a rabbit developmental toxicity study and an uncertainly
factor of 100X.  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 no observable adverse effect level (NOAEL) by the exposure
for each population subgroup.  In addition, exposure was expressed as a
percent of the acute reference dose (%aRfD).  Acute (food only) exposure
to the females 13-49 years subpopulation resulted in a MOE of 13,111
(0.76% of the acute RfD of 0.12 mg/kg/day).  Since the benchmark MOE for
this assessment was 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 dietary (food)
exposure to residues arising from the current and proposed uses for
prometryn.

Chronic Exposure.  The prometryn chronic dietary (food only) risk
assessment  was performed for all population subgroups with a chronic
reference dose of 0.04 mg/kg/day based on a chronic feeding study in
dogs with a no observable adverse effect level (NOAEL) of 3.75 mg/kg/day
and an uncertainty factor of 100X.  The 100X safety factor includes
intra- and inter-species variations.  No additional FQPA safety factor
was applied.  For the purpose of 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 (food only) exposure to the U.S.
population resulted in a MOE of 9,528 (1.0% of the chronic RfD of 0.04
mg/kg/day).  The most exposed sub-population was children (3-5 years
old) with a MOE of 4, 216 (2.4% of the chronic RfD of 0.04 mg/kd/day).
Since the benchmark MOE for this assessment was 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 dietary (food only) exposure to residues arising from the current
and proposed tolerances for prometryn.

Cancer.  Prometryn has been classified as a Group E chemical (no
evidence of human carcinogenic potential).  Therefore, no cancer risk
assessment was performed for prometryn.>

<	ii. Drinking Food. The EPA uses the screening models FIRST to estimate
potential surface water concentrations and the screening model SCI-GROW
to estimate potential ground water concentrations.  None of these models
includes consideration of the impact that processing (mixing, dilution,
or treatment) would have on the removal of pesticides from the water
source prior to distribution as drinking water.  The primary use of
these models by the Agency at this stage is to provide a conservative
approximation of the Estimated Drinking Water Concentrations (EDWCs) of
specific pesticides in drinking water.  Syngenta used the Tier 1 FIRST
and SCI-GROW to model prometryn concentrations in drinking water based
on current and proposed uses.  Surface water was the driver with a peak
day EDWC of 439.5 ppb (acute) and an annual average EDWC of 207.1 ppb
(chronic).

Acute Exposure from Drinking Water:  The acute EDWC of 439.5 ppb
(surface water) was used to calculate the acute drinking water exposure
values for females 13-49 years old (the only acute population subgroup
of concern).  Acute drinking water estimates were incorporated directly
into the DEEM-FCID™ software along with current and proposed crop
tolerances.  Acute exposure (food and water) to females 13-49 years old
resulted in a MOE of 576 (17.3% of the aRfD of 0.12 mg/kg/day).  Since
the benchmark MOE for this assessment was 100 and since the 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 and drinking water) exposure to residues
arising from all current and proposed uses of prometryn.

 Water.  The chronic EDWC of 207.1 ppb (ground water) was used to
calculate the chronic drinking water exposure values for the U.S.
Population and population subgroups.  Chronic drinking water estimates
were incorporated directly into the DEEM-FCID™ software along with
current and proposed crop tolerances.  Chronic exposure (food and water)
to the U.S. population resulted in a MOE of 859 (11.6% of the chronic
RfD of 0.04 mg/kg/day).  The most exposed sub-population was all infants
(<1 year old) with a MOE of 262 (38.2% of the chronic RfD of 0.04
mg/kg/day).  Since the benchmark MOE for this assessment was 100 and
since the 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 and drinking water) exposure to
residues arising from all current and proposed uses of prometryn.>

<	2. Non-dietary exposure. Prometryn is not currently registered for
residential use such as turf and ornamentals.  Therefore there is no
expectation of non-occupational residential exposures.>

<D. Cumulative Effects>

<	Cumulative Exposure to Substances with a Common Mechanism of Toxicity.
 Prometryn is a member of the triazine class of pesticides.  Other
members of this class include atrazine, simazine, cyanazine, prometron,
propazine, metribuzin, hexazinone, ametryn, terbutrne, dipropetryn and
ethiozin.  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”.  EPA does not have, at this time,
available data to determine whether prometryn has a common mechanism of
toxicity with other substances or how to include this pesticide in a
cumulative risk assessment.  For the purposes of this tolerance action,
the EPA has not assumed that prometryn has a common mechanism of
toxicity with other substances.>

<E. Safety Determination>

<	1. U.S. population. The chronic dietary exposure analysis (food plus
water) showed that exposure from all established and proposed prometryn
tolerances would result in a MOE of 788 (12.7% of the chronic RfD) for
the general U.S. population.  An acute dietary exposure analysis was not
required for the general U.S. population, however exposure from all
established and proposed prometryn tolerances would result in a MOE of
552 (18.1% of the acute RfD) for females 13-49 years old (the only acute
population of concern).  Based on the completeness and reliability of
the toxicity data supporting these petitions, Syngenta believes that
there is a reasonable certainty that no harm will result from aggregate
exposure to residues arising from all current and proposed prometryn
tolerances, including anticipated dietary exposure from food, water, and
all other types of non-occupational exposures.>

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lation subgroup, all infants <1 year old.  Since the worst-case chronic
aggregate MOE of 252 exceeds the benchmark MOE of 100, Syngenta believes
that there is a reasonable certainty that no harm will result from
aggregate exposure to residues arising from all current and proposed
prometryn uses, including anticipated dietary exposure from food, water,
and all other types of non-occupational exposures.>

<F. International Tolerances>

<	There are no Codex or Mexican MRLs established for residues of
prometryn in plant or animal commodities.  A Canadian MRL of 0.1 ppm for
carrots has been established for prometryn.>