Document ID: EPA-HQ-OPP-2016-0495-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-11-30T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

Interregional Research Project No. 4 (IR-4) in cooperation with Syngenta
Crop Protection, LLC

PP #6E8492

	EPA has received a pesticide petition (6E8492) from Interregional
Research Project No. 4 (IR-4) IR-4 Project Headquarters, Rutgers, The
State University of NJ, 500 College Road East, Suite 201 W, Princeton,
NJ 08540 in cooperation with Syngenta Crop Protection, LLC, P.O. Box
18300, Greensboro NC 27419 requesting, 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 
prometryn in or on the raw agricultural commodity sesame, seed at 0.05
parts per million (ppm); sesame, oil at 0.12 ppm; leaf petiole vegetable
subgroup 22B at 0.5 ppm; fennel, Florence at 0.5 ppm; celtuce at 0.5
ppm; Swiss chard at 0.5 ppm; and cottonseed subgroup 20C at 0.25 ppm. 
Upon the approval of the aforementioned tolerances, IR-4 proposes to
remove the established tolerances for residues of prometryn, including
its metabolites and degradates in or on the leaf petioles subgroup 4B at
0.5 ppm and cotton, undelinted seed at 0.25 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. The qualitative nature of prometryn residues in
plants has been characterized based upon EPA approved cotton, celery and
carrot metabolism studies.  The major metabolic pathway involves
oxidative elimination, N-dealkylation and oxidative deamination, leading
to multiple minor products.  Characterization of the residues indicates
the biotransformation of prometryn is qualitatively similar in all three
crops.

	2. Analytical method. Syngenta has developed and validated a gas
chromatography analytical method for enforcement purposes.  The method
determines residues of prometryn in/on plants using a microcoulometric
sulfur detection system.  This method has been submitted to the EPA and
is in the Pesticide Analytical Manual (PAM).

	3. Magnitude of residues. Complete residue data to support the
requested tolerances have been submitted with this petition.

B. Toxicological Profile

	1. Acute toxicity.  The database for acute toxicity of prometryn is
considered complete.  Prometryn technical is slightly to practically
non-toxic (Toxicity Category III) by the oral, dermal and inhalation
routes.  It causes mild eye irritation (Toxicity Category III) and
slight dermal irritation (Toxicity Category IV).  Prometryn is not
considered a skin sensitizer.

	2. Genotoxicity. 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 cytogenetic effect in vivo or in vitro with
prometryn.

	3. Reproductive and developmental toxicity. In developmental toxicity
studies with rats and rabbits, maternal and developmental toxicity was
observed only at the highest doses tested (rats 250 mg/kg/day, rabbits
72 mg/kg/day).  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), with a
reproductive NOEL of 750 ppm or approximately 50 mg/kg/day.  The results
indicate that prometryn is not embryotoxic or teratogenic in the species
tested at maternally toxic doses.

	4. Subchronic toxicity. In a subchronic 28-day feeding study in mice at
the highest dose tested (4500 mg/kg/day), there were pathological
findings limited to the G.I. tract along with decreased body weights. 
The NOAEL 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 NOAEL of >1,000 mg/kg/day.

	5. Chronic toxicity. Studies with prometryn have shown no significant
chronic toxicity in either rats, mice or dogs.  In a chronic toxicity
study/oncogenicity study in mice the NOAEL in females was 1,000 ppm and
the LOAEL 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.  The lowest chronic toxicity endpoints were
observed in the chronic toxicity study in dogs, with a NOAEL of 3.75
mg/kg/day and a LOAEL of 37.5 mg/kg/day.  The EPA has determined that,
for prometryn, there is no evidence of human carcinogenic potential.

	6. Animal metabolism. The metabolism of prometryn in rats 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 and enforcement purposes,
EPA has determined that residues of concern include parent prometryn
only.

	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. Tier I acute and chronic dietary exposure
evaluations were made for prometryn using the Dietary Exposure
Evaluation Model (DEEM-FCID™ Version 4.02) from EPA and consumption
data from the USDA NHANES “What We Eat in America” survey,
2005-2010.  In addition to current uses, these aggregate assessments
included estimated prometryn tolerances for a proposed IR-4 use on
sesame as well as a proposed regrouping on Crop Group 22B. The Tier I
assessments incorporated tolerance values for all crops.  All processing
factors used DEEMTM Version 7.87 defaults.  Percent of crop treated
(%CT) 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.

	i. Food. Acute Exposure:  An acute reference dose of 0.12 mg/kg/day for
females 13-49 years old was based on a no observed adverse effect level
(NOAEL) of 12 mg/kg/day from a developmental toxicity study in rabbits
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 NOAEL by the exposure for each subpopulation.
 In addition, exposure was expressed as a percent of the acute reference
dose (aRfD).  Acute (food only) exposure to females 13-49 years old
resulted in an MOE of 26,284 or 0.4% of the aRfD (Benchmark MOE = 100;
aRfD = 0.12 mg/kg/day).  

Chronic Exposure.  The prometryn chronic dietary (food only) risk
assessment was performed for all subpopulations with a chronic reference
dose of 0.04 mg/kg/day based on a chronic feeding study in dogs with a
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 subpopulation.  In addition, exposure was expressed as
a percent of the chronic reference dose (cRfD).  Chronic (food only)
exposure to the U.S. population resulted in an MOE of 30,392 or 0.3% of
the cRfD (Benchmark MOE = 100; cRfD = 0.04 mg/kg/day).  The most exposed
subpopulation was infants <1 year old, with an MOE of 7,191 or 1.3% of
the cRfD (Benchmark MOE = 100; cRfD = 0.04 mg/kg/day).  

Cancer.  Prometryn has been classified as a Group E chemical (no
evidence of human carcinogenic potential).  Therefore, a cancer risk
assessment was not performed for prometryn.

	ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs)
of prometryn were determined using Tier l screening models, SCI-GROW
which estimates pesticide concentration in ground water and FIRST which
estimates pesticide concentration in surface water.  EDWCs of prometryn
from the currently registered uses plus the proposed sesame use were
determined.   Based on the SCI-GROW modeling, the highest groundwater
EDWC for prometryn is 21.8 ppb (acute and chronic) based on the
currently registered use on cotton.  Based on the FIRST modeling, the
cotton use provided the highest surface water EDWCs of 486.0 ppb for
acute and 183.7 ppb for chronic.  No Percent Cropped Area (PCA)
adjustments were applied to surface water EDWCs. Since the surface water
EDWCs exceed the ground water EDWC, the surface water values were used
for risk assessment purposes and will be considered protective for any
ground water exposure concerns.  

Acute Exposure from Drinking Water.  The acute surface water EDWC of
486.0 ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the acute drinking water
exposures.  Exposure contributions at the 95.0%-ile of exposures were
determined by taking the difference between the aggregate (food +
drinking water) exposures and the food (alone) exposures for each
population subgroup.  Acute drinking water exposure to females 13-49
years old resulted in an MOE of 474 (21.1% of the acute RfD of 0.12
mg/kg-bw/day).  

Chronic Exposure from Drinking Water.  The chronic surface water EDWC of
183.7 ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the chronic drinking water
exposures.  Chronic drinking water exposure to the U.S. population
resulted in a MOE of 1,010 (9.3% of the chronic RfD of 0.04
mg/kg-bw/day).  Chronic drinking water exposure to the most exposed
sub-population (infants, <1 year old) resulted in a MOE of 270 (34.7% of
the chronic RfD of 0.04 mg/kg-bw/day).

	2. Non-dietary exposure. Residential exposure assessments were
performed for prometryn to evaluate exposures resulting from off-site
drift of agricultural products into residential areas.  Incidental
exposure to consumers from spray drift from non-residential uses were
not included in the aggregate consumer risk; this approach agrees with
the EPA’s current policy and practice.

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, terbutryn, 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. An acute dietary exposure analysis was not required
for the general U.S. population, however exposure from all current and
proposed prometryn uses would result in an MOE of 465 or 21.5% of the
aRfD for females 13-49 years old (Benchmark MOE = 100; aRfD = 0.12
mg/kg/day).  The chronic dietary exposure analysis (food plus water)
showed that exposure from all current and proposed prometryn uses for
the general U.S. population would result in an MOE of 978 or 9.6% of the
cRfD (Benchmark MOE = 100; cRfD = 0.04 mg/kg/day).

	2. Infants and children. There are no acute dietary exposure concerns
from prometryn for infants and children.  The chronic dietary exposure
analysis (food plus water) showed that exposure from all current and
proposed prometryn uses for all infants <1 year old would result in a
MOE of 260 or 36.0% of the cRfD (Benchmark MOE = 100; cRfD = 0.04
mg/kg/day).

F. International Tolerances

	There are no Codex MRLs established for residues of prometryn in plant
or animal commodities.

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