Document ID: EPA-HQ-OPP-2005-0477-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-01-04T05:00Z

COMPANY NOTICE OF FILING OF PESTICIDE PETITION TO ESTABLISH PERMANENT
DICLORMID TOLERANCES ON CORN COMMODITIES  

EPA Registration Division contact: Susan Stanton (7505P), 703-305-5218

	EPA has received a pesticide petition (PP 9E7517 ) from Dow
AgroSciences LLC, 9330 Zionsville Road – Indianapolis, IN  46268
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 permanent tolerance for residues of acetamide,
2,2-dichloro-N,N-di-2-propenyl- (dichlormid) CAS Reg. No. 37764–25–3
in or on the raw agricultural commodities Corn, field, forage; Corn,
field, grain; Corn, field, stover; Corn, pop, grain; Corn, pop, stover;
Corn, sweet, forage; Corn, sweet, kernel plus cob with husks removed and
Corn, sweet, stover at 0.05 parts per million (ppm).  Dichlormid
(R-25788) is an herbicide safener that is used in the Dow AgroSciences
LLC (DAS) acetochlor product line that is used for the control of
grasses and broadleaf weeds in field corn, pop corn and sweet corn. 
Currently, time-limited tolerances on corn commodities are established. 
Initially on March 27, 2000 (65 FR 16143) (FRL-6498-7), EPA established
time-limited tolerances under 40 CFR 180.469 for residues of dichlormid
in or on field corn (forage, grain, stover), pop corn (grain, stover) at
0.05 ppm with an expiration date of March 27, 2002.  Time-limited
tolerances on corn commodities have been reestablished in 2002 (67 FR
51102) (FRL-7192-5); in 2005 (70 FRL-76697-76699) and on July 29, 2009,
(74 FR 37621 (FRL-8422-2) EPA extended the time-limited tolerances for
residues on field corn (forage, grain, stover); pop corn (grain,
stover); and sweet corn (forage, kernel plus cob with husks removed,
stover) with an expiration/revocation date of December 31, 2010.  In
2010 EPA ARIA responded to DAS Petition 9E7517 (Memorandum, Dichlormid. 
Petition for the Use on Corn.  Response to Registrant’s Comments,
D372259, March 31, 2010) and recommended the establishment of permanent
tolerances for dichlormid on field corn, sweet corn and popcorn
commodities.

Prior to the conversion of the time-limited tolerances to permanent
tolerances, several data gaps were identified in the 2005 EPA Human
Health assessment (Hanson, D321928) and these were addressed in a
summary report by Kaminski (MRID 47448101, June 12, 2008).  EPA’s
requirements for additional residue chemistry data (D318075, D. Rate,
Sept 14, 2005) were addressed in DAS response (Kaminski, MRID 47628301,
November 24, 2008) and upon review EPA stated no additional MOR studies
were required to support the existing tolerances (W. T. Drew, DP366892,
August 11, 2009).  In addition, new information for physical properties
(MRIDs 47916901 and 47916902, 2009), and an immunotoxicity study (MRID
48102801, 2010) have recently been submitted.  In 2010, several
additional toxicity studies were reported acceptable, (D369088, April
2010).  And per D372259, March 31, 2010, EPA ARIA recommended the
establishment of permanent tolerances for dichlormid in corn.  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 nature of the residue in plants is adequately
understood based on a study depicting the metabolism of dichlormid in
corn plants.  The request for additional metabolite information in the
2005 EPA Human Health review (D321928) has been addressed by Kaminski
(MRID 47448101, June 12, 2008).  The metabolism of dichlormid in corn is
extensive and occurs via two metabolite pathways.  In one pathway,
dichlormid is a de-chlorinated and oxidized to generate N,N-diallyl
glycolamide.  An alternative pathway is the loss of an allyl group
followed by oxidation to form dichloroacetic acid.  There is also
extensive incorporation into natural constituents.  Per the EPA 2010
memo (D372259, March 2010), EPA ARIA and HED concluded the previously
submitted plant metabolism study is adequate that dichlormid is the
residue of concern for tolerance setting purposes.

	2. Analytical method.  An adequate enforcement method for residues of
dichlormid in corn has been developed (MRID 44960101) and validated by
the Analytical Chemical Laboratory (ACL) of EPA (Memo, D199230, G.
Kramer, 08/29/94).  Analysis is carried out using gas chromatography
with nitrogen selective thermionic detection.  A revised method was
resubmitted to the EPA on 10/29/99.

	3. Magnitude of residues.  Field trial information in field corn (MRID
46353807, 47628301) and sweet corn (DAS report BJK042403pkm, May 2003)
with dichlormid have been previously submitted and reviewed.  In 2005,
EPA confirmed that the field trial data residue levels of dichlormid are
< 0.01 ppm, but the appropriate tolerance level is 0.05 ppm for all corn
RACs based on the enforcement methods’ LOQ of 0.05 ppm (EPA, D321928,
2005).  Per the EPA 2010 memo (D372259, March 2010), the EPA has
determined that the residue chemistry database is adequate to
established tolerances of 0.05 parts per million (ppm) based on the
enforcement method LOQ for all corn commodities.

B. Toxicological Profile  The toxicity database is adequate for the
establishment of permanent tolerances in corn.  Per the EPA 2010 memo
(D369088, April 2010), several new studies have been reviewed and found
acceptable, with the exception of the subchronic neurotoxicity study
which was technically listed as unacceptable according to the
guidelines.  However a repeat of that study at higher doses to establish
a LOAEL value would not change the regulatory risk assessment endpoints
for dichlormid.

	1. Acute toxicity.  Dichlormid has low acute toxicity, causes mild
ocular irritation, severe skin irritation, and is mild skin sensitizer
(MRID 44606401, 44606402, 44606403, 44606404, 42807902, 44606405).  The
NOAEL for acute neurotoxicity was 1,500 mg dichlormid/kg (MRID
46353805).  EPA has previously established an acute RfD of 0.10
mg/kg/day based on the maternal NOAEL of 10 mg/kg bw/day in the rat
developmental toxicity study (EPA, D321928, 2005).

	2. Genotoxicity.  Dichlormid was not mutagenic via in vitro assays
including the Salmonella/microsome (Ames) assay, and the human
lymphocyte cytogenetic assay (both assays with and without metabolic
activation (MRID 41561404, 41561407).  In the L5178Y mouse lymphoma
assay, small increases in mutant frequency were observed only at
cytotoxic concentrations, and were not considered to be significant
(MRID 41561405).  In vivo, dichlormid was negative in the mouse
micronucleus test and in the rat unscheduled DNA synthesis assay, when
tested at the maximum tolerated dose (MRID 41561403, 44606409,
41561408).

	3. Reproductive and developmental toxicity.  In a multi-generation
reproduction study in rats, the NOAEL for reproductive toxicity was
greater than 500 ppm (48.5 mg/kg bw/day), the highest dose tested (MRID
46353801).  In rats, the NOAEL for developmental toxicity was 40 mg/kg
bw/day and the LOAEL was 160 mg/kg bw/day based on marginally increased
skeletal anomalies (MRID 44606408).  The developmental NOAEL for rabbits
was 30 mg/kg/day and the LOAEL was 180 mg/kg bw/day based on a small
increase in post-implantation loss, an increased number of early
resorptions, a decreased number of fetuses per litter and evidence of
fetotoxicity- all observed in the presence of maternal toxicity at the
same dose-level (MRID 44606407).

In assessing the potential for additional sensitivity of infants and
children to residues of dichlormid, data from developmental toxicity
studies in the rat and rabbit have been considered.  The developmental
toxicity studies are designed to evaluate adverse effects on the
developing organism resulting from maternal pesticide exposure during
gestation.  There was not evidence to suggest that dichlormid was a
selective developmental toxicant in either the rat or rabbit.  In rats,
there was no risk below maternally toxic doses as the NOAEL for
developmental effects was 40 mg/kg bw/day, compared to the maternal
NOAEL of 10 mg/kg bw/day.  In the rabbit developmental toxicity study,
the NOAEL for both maternal and developmental effects was 30 mg/kg
bw/day.  EPA has previously concluded that the 10X FQPA safety factor
should be retained in part due to an incomplete database, and in part
due to the qualitative evidence of increased susceptibility demonstrated
following in utero exposure in the prenatal developmental toxicity in
rabbits.  It should be noted that in the rabbit developmental toxicity
study, the LOAEL for both maternal and developmental toxicity was 180
mg/kg bw/day.  The effects on resorptions at this dose were observed in
the presence of substantial maternal toxicity as evidenced by clinical
toxicity, reduced feed consumption (up to 48% lower than controls), and
body weight loss (-3.8g during the treatment period compared with an
average weight gain in controls of 272g).  Also, a multi-generation
study has been completed (MRID 46353801).  In 2005, EPA noted that the
data gap for FQPA considerations had been addressed, but that metabolism
studies were still needed to reassess reduction of the FQPA factor (EPA,
D321928, 2005).  In 2010 (D372259, March 2010), EPA reviewed and
accepted the repeat Oral Dose rat metabolism study (MRID 46366001) and
the biotransformation,tissue distribution and extraction studies (MRID
46353802, 46353803).  Thus, Dow AgroSciences believes that the current
10X FQPA safety factor should be reduced to 1X in the future.  For
expediency of this petition; however, the previously established FQPA
factor of 10X will be retained for the risk assessment.

	4. Subchronic toxicity.  In a 90-day dietary toxicity study in dogs,
the NOAEL was 5 mg/kg bw/day while in rats the 90-day dietary NOAEL was
20 ppm (1.4 and 1.6 mg/kg bw/day in males and females respectively)
(MRID 41419401, 44606461). In a 14-week rat inhalation study, the NOAEL
was 2.0 mg/m3 (MRID 00155678).  In a subchronic rat neurotoxicity study,
there was no evidence of neurotoxicity at 750 ppm (55.4 mg/kg bw/day for
males, 61.2 mg/kg bw/day for females), the highest dose-level tested
(MRID 46353806).  Due to the lack of an established LOAEL this study has
technically been listed as unacceptable according to the guidelines;
however, a repeat of this study at higher doses to establish a LOAEL
would not change the regulatory risk assessment endpoints for
dichlormid.  In a functional immunotoxicity study in female rats, there
was no evidence of immunotoxicity at 1000 ppm (85.9 mg/kg bw/day), the
highest dose tested (MRID 48102801).  This immunotoxicity study has
recently been reviewed and found acceptable by the EPA, per the August
24, 2010 DER D378513.

	5. Chronic toxicity.  The NOAEL in the two-year rat chronic study was
100 ppm (6.5 and 7.5 mg/kg bw/day for males and females, respectively)
(MRID 44529402).  In an 18-month oncogenicity study, the NOAEL was 50
ppm (7.0 and 9.2 mg/kg/day for males and females, respectively) (MRID
44529401).  It was concluded, there was no evidence of oncogenicity
associated with dichlormid treatment in rats or mice.  Based on
available chronic toxicity data, the cRfD for dichlormid was previously
established as 0.017 mg/kg bw/day based on the 90-day feeding studies in
dogs with a NOAEL of 5 mg/kg bw/day along with a UF of 300 (EPA,
D321928, 2005).  The data gaps have now been filled (MRID 46353805,
46353806, 46366001, 46353802, 46353803, 46353801, 48102801), and Dow
AgroSciences LLC; therefore, proposes that the currently applied 300X UF
should be reduced in the future and a revised uncertainty factor of 100X
UF be applied to the previous POD resulting in a revised cRfD of 0.05
mg/kg/day.  For this petition, however, the previously established cRFD
of 0.017 mg/kg/day will be used.

	6. Animal metabolism.  Dichlormid was well absorbed, extensively
metabolized and eliminated mainly in the urine within 24 hours.  A
significant proportion of the dose, up to 11%, was exhaled as CO2 (MRID
46353803).  Per the 2010 memo (D372259, March 2010), the EPA has
determined that the previously submitted livestock metabolism study is
adequate for the current use on corn and that no livestock tolerances
are required for use in corn.

	7. Metabolite toxicology.  No unique plant or soil metabolites have
been identified that warrant a separate toxicological assessment.

	8. Endocrine disruption.  There is no indication in the dichlormid
toxicology database of adverse effects associated with endocrine
disrupter activity.

C. Aggregate Exposure

re Evaluation Model™ (DEEM-FCID, ver. 2.16, Exponent, Inc.,
Washington, DC-20036) software was employed.  DEEM contains food
consumption data as reported by respondents in the USDA Continuing
Surveys of Food Intake by Individuals (CSFII) conducted in 1994-1996 and
1998 and food translation to RACs, as indicated by EPA/USDA FCID recipe
set as of August, 2002.

	i. Food.  This Tier-I assessment considers residues at tolerance levels
of 0.05 ppm for all consumed corn commodities at 100% crop treated (CT),
it also includes the DEEM 7.81 default processing factor of 1.5 for corn
syrup.  These results are conservative (health protective) risk
estimates.  Refinements such as use of percent crop-treated information
and/or anticipated residue values would yield lower estimates of dietary
exposure.

	ii. Drinking water.  The previous EPA estimates of potential drinking
water exposures have been directly incorporated in the DEEM-FCID into
the food categories “water, direct, all sources” and “water,
indirect, all sources.”  Per the EPA 2005 Human Health Assessment of
dichlormid (D321928), drinking water estimate concentrations were
calculated for groundwater using Screening Concentration in Groundwater
(SCI-GROW, modeling, and surface water estimate concentrations were
calculated using Generic Estimated environmental Concentration (GENEEC)
modeling.  These models provide a coarse screen for assessing whether a
pesticide is likely to be present in drinking water at concentrations
which would exceed human health levels of concern.  For acute exposure,
the maximum estimated concentration of dichlormid in surface and ground
water concentration was 27.3 and 0.046 ppb, respectively.  For chronic
exposure, the estimated concentration of dichlormid in surface and
ground water concentration was 8.98 and 0.046 ppb, respectively.

	2. Non-dietary exposure.  The general population is not expected to be
exposed to dichlormid through non-dietary routes, because dichlormid is
used only on agricultural crops, and is not used in or around the home.

D. Cumulative Effects

	The potential for cumulative effects of dichlormid and other substances
that have a common mechanism of toxicity have been considered.  There is
no reliable information to suggest that dichlormid has any toxic effects
that arise from toxic mechanisms common to other substances.  Therefore,
a consideration of common mechanism and cumulative effects with other
substances is not appropriate for dichlormid.

E. Safety Determination

	1. U.S. population

i. Chronic Risk.  Using the conservative exposure assumptions described
earlier, and based on the completeness and reliability of the toxicity
data base for dichlormid, the food and water chronic exposure estimate
for the general U.S. population is 0.000294 mg/kg/day or 1.7% of the
cRfD.  The most highly exposed subgroup are infants (<1 year) with an
estimated food and water exposure of 0.000758 mg/kg/day or 44.6% of the
cPAD.

ii. Acute Risk.  Modeled acute exposures from DEEM for food and water at
the 95th percentile were 0.001568 mg/kg/day, or 1.57% of the aRfD for
the general population.  The most highly exposed subgroup are infants
(<1 year) with an estimated food and water acute exposure of 0.005998
mg/kg/day, or 60% of the aPAD.

All population subgroups have shown potential Tier-I (worst-case)
exposure below 100% of the PAD.  EPA generally has no concern for
exposures below 100% of the PAD, thus there is a reasonable certainty
that no harm will result from aggregate exposure to dichlormid residues.

	2. Infants and children.  Per the preceding discussion and based on the
recent reviews of several additional toxicity studies, Dow AgroSciences
LLC maintains that an additional FQPA 10X as well as the previous 3X
chronic database uncertainty factors are no longer warranted for the
safety of infants and children.  Reliable data support the appropriate
use of a 100-fold uncertainty factor (MOE) to account for interspecies
extrapolation and intraspecies variability.  However, for the expediency
of this petition, the previously established PAD values were used along
with the conservative exposure assumptions in food and water.  Estimates
indicate the highest potentially exposed subpopulation of infants does
not have an aggregate exposure to dichlormid above the PAD.  Therefore,
based on the completeness and reliability of the toxicity data base and
the conservative exposure assessment, Dow AgroSciences LLC concludes
that there is a reasonable certainty that no harm will result to infants
and children from aggregate exposure to dichlormid residues.

F. International Tolerances

	There is neither a Codex proposal nor Canadian or Mexican limits for
residues of dichlormid in corn commodities.

 PAGE   

 PAGE   6