COMPANY NOTICE OF FILING OF PESTICIDE PETITION TO ESTABLISH

PERMANENT DI CL ORMID TOLERANCES ON CORN COMMODITIES EPA Registration Division contact: Susan Stanton (7505P) , 703 - 305 - 5 218 EPA has received a pesticide petition ( PP 9E7517 ) from Dow AgroScie nces LLC , 9330 Zionsville R oad

– 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 commodit ies Corn, field, forage ; Corn, field, grain; Corn, field, stover; Corn, pop, grain; Corn, p op, stover; Corn, sweet, forage; Corn, sweet, kernel plus cob with husks removed and Corn, sweet, stover at 0.05 parts per million (ppm) . Dichlor mid (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 weed s in field corn, pop corn and sweet corn. Currentl y , time
- limited tolerances on corn commodities are established . Initially

o n March 27, 2000 (65 FR 16143) (FRL
- 6498 - 7), EPA established time
- limited tolerances under 40 CFR 18 0. 469 for residues of dichlor mid 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 - 7 6699) 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, Dich l ormid. 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, s everal 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 ph ys ical properties (MRIDs 47916901 and 47916902, 2009), and an immunotoxicity stu dy (MRID 48102801, 2010) have recently been submitted. In2010, s everal additional toxicity studies were reported acceptable, (D369088, April 2010) . And per D372259, March 31, 2010, EPA ARIA recommended the establishment of permanent tolerances for dichl ormid 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 the2

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. T he nature of the residue in plants is adequatel y understood based on a study depicting the metabolism of dich lormid in corn plants. The r equest for additional metabolite information in the 2005 EPA Human Health review (D321928) has been addressed b y Kaminski (MRID 47448101, June 12, 2008). The metabolism of dichlormid in corn is extensive and occurs via two met abolite pathway s. In one pathway , dichlormid is a de
- chlorinated and oxidized to generate N,N
- diall ylglycolamide. An alternative pathway

is the loss of an all ylgroup 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 conclud ed the previously

submitted plant metabolism study is adequate that dichlormid is the residue of concern for tolerance setting purposes. 2. Analytical me thod. An adequate enforcement method for residues of dichlormid in corn has been developed (MRID 44960101) and validated b y the Analy tical Chemical Laboratory (ACL) of EPA (Memo, D199230, G. Kramer, 08/29/ 94) . Analy sis is carried out using gas chromatogr aph y with nitrogen selective thermionic detection. A revised method was resubmitted to the EPA on 10/29/99. 3. Magnitude of residues. F ield trial information in field corn (MRID 46353807 , 47628301 ) and sweet corn (DAS report BJK042403pkm, May 2003) with dichlormid have been previousl y 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 tolerance s of 0.05 parts per million (ppm) based on the enforcement method L OQ for all co rn commodities . B. Toxicological Profile T he toxicity database is adequate for the establishment of permanent tolerances in corn. Per the EPA 2010 memo (D3 69088 , April 2010), several new studies have been reviewed and found acceptable, with the exceptio n of the subchronic neurotoxicity

study which was technically listed as unacceptab le according to the guidelines. H owever a repeat of th at study at higher doses to establish a LOAEL value would not change the regulatory risk assessment endpoints for dichl ormid . 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 1,5 00 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 developmental3

toxicity study (EPA, D321928, 2005) . 2. Genotoxicity. Dichlormid was not mutageni c via in vitro assay s including the Salmonella/microsome (Ames) assay , and the human ly mphocy te cy togenetic assay

(both assay s with and without metabolic activation (MRID 41561404, 41561407). In the L5178Y mouse l ymphoma assay , small increases in mutant f requency were observed only at cy totoxic concentrations, and were not cons idered to be significant (MRID 41561405). In vivo , dichlormid was negative in the mouse micronucleus test and in the rat unscheduled DNA s ynthesis assay, when tested at the maximum tolerated do se (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 L OAEL was 160 mg/kg bw/day based on marginall y 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 earl y 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. Inrats, there was no risk below maternall y 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 10 X FQPA safet y 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 pren atal 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 b y 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 b een 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 (D 372259, 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 10 X F QPA safet y factor should be reduced to 1X in the future . For expediency of this petition ;4

however, the previousl y established FQPA factor of 10X will be retained for the risk assessment . 4. Subchronic toxicity. In a 90 - day dietary toxicity study in do gs, 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 respectivel y) (MRID 41419401, 44606461). In a 14
- week rat inhalation study, the NOAEL was 2.0 mg/m 3 (MRID 00155678). In a sub chronic 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 hi ghest dose
- level tested (MRID 46353806). Due to the lack of an established L OAEL this study has technica lly

been listed as unacceptable according to the guidelines; however , a repeat of this study at higher doses to establish a L OAEL would not change the regulatory risk assessment endpoints for dichlormid . Ina 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 tox icity. The NOAEL in the two
- ye ar rat chronic study was 100 ppm (6.5 and 7.5 mg/kg bw/day for males and females, respectivel y) (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, respectiv ely) (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 previousl y established as 0.0 17 mg/kg bw/day

based o n 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 ga ps have now been filled (MRID 46353805, 46353806, 46366001, 46353802, 46353803, 46353801, 48102801) , and Dow AgroSciences LLC ; ther efore , proposes that the currently applied 3 00 X UF should be reduced in the future and a revised uncertaint y factor of 100 X UF be applied to the previous POD resulting in a revised cRfD of 0.05 mg/kg/day . For this petition , however, the previously establi shed 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 CO 2 (MRID 4635380 3). P er 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 sep arate toxicological assessment. 8. Endocrine disruption . There is no indication in the dichlormid toxicology database of adverse effects associated with endocrine disrupter act ivit y. C. Aggregate Exposure5
1. Dietary exposure. T he following established endpoints from the EPA 2005 Human Health Assessment of dichlormid (D321928) are used to conduct a risk assessment for chronic and acute dietary and water exposure of the U.S. p opulation subgroups to residues of dichlormid : aRfd = 0.10 mg/kg/day ; aPAD =0.010 mg/kg/day ; cRfD = 0.017 mg/kg/day and cPAD = 0.0017 mg/kg/day . The Dietary Exposure Evaluation ModelTM (DEEM
- FCID, ver. 2.1 6 , Exponent, Inc., Washington, DC
- 20036) software was emplo yed. DEEM contains food consumption data as reported by respondents in the USDA Continuing Survey s 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% cro p treated (CT), it a lso includes the DEEM 7.81 default processing factor of 1.5 for corn s yrup . 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 co ncern. For acute exposure, the maximum estimated concentration of dichlormid in surface and ground water concentration was 27.3 and 0.046 ppb , respectivel y. For chronic exposure, the estimated concentration of dichlormid in surface and ground water conce ntration was 8.98 and 0.046 ppb, respectivel y . 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 an y 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.6

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 c RfD . The most highl y exposed subgroup are infants (<1 year) with an estimated food and water exposure of 0.000 758 mg/kg/day or 44 .6% of the cPAD. ii. Acute Risk. Modeled acute exposures from DEEM for food and water at the 95 th percentile were 0.0015 68 mg/kg/day , or 1.57% of the aRfD for the general population . The most highl y 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 T ier
- 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 a dditi onal FQPA 10X as well as the previous 3X chronic database uncertainty factors are no longer warrante d for th e safet y of infants and children. R eliable data support the appropriate use of a 100
- fold uncertaint y factor (MOE) to account for interspecies extrapolation and intraspecies variability . However, for the expediency of this petition, the previously

establ ished 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 o n 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 dichlormi d residues. F. International Tolerances There is neither a C odex proposal nor Canadian or Mexican limits for residues of dichlormid in corn commodities.