Document ID: EPA-HQ-OPP-2005-0477-0011
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-03-23T04:00Z

--------------------------------------------------------------------------------

      UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                       
                                                           OFFICE OF           
                                                         PREVENTION, PESTICIDES
                                                           AND TOXIC SUBSTANCES
MEMORANDUM

Date:		3/31/10

Subject:		Dichlormid.  Petition for the Use on Corn.  Response to Registrant's Comments.

PC Code:  900497
DP Num.:  D372259
Decision No.:  419811
Registration No.: 62719-367, 62719-368, 62719-369, 62719-370, 62719-371, 62719-372, 62719-479
Petition No.:  9E7517
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  NA
Case No.:  NA
TXR No.:  NA
CAS No.:  37764-25-3
MRID No.:  474481
40 CFR:  180.469

From:		W. Cutchin, Acting Senior Branch Scientist 
		Alternative Risk Integration and Assessment (ARIA) Team
      Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)
		Registration Division (RD; 7505P)

Through:	G. Kramer, Ph.D., Senior Chemist 
      Risk Assessment Branch I (RABI)
      Health Effects Division (HED; 7509P)
      
To:		K. Liefer/P. Shah
      Inert Ingredient Assessment Branch/RD (7505C)

Executive Summary

Dichlormid, N,N-diallyl dichloroacetamide, is a herbicide safener used in pesticide formulations with the active ingredient, acetochlor, for the control of grass and broadleaf weeds.  Products containing dichlormid are conditionally registered in the U.S. to Dow AgroSciences, LLC under the trade names Surpass[TM] EC, Keystone[TM], TopNotch[TM], Surpass[TM] 20G, FulTime[TM], Surpass[TM] 7 E, and Keystone[TM] LA.  Currently, it is used in the treatment of corn (field, sweet and pop) raw agricultural commodities (RACs).  Dichlormid is an emulsifiable concentrate that was prepared by blending dichlormid with acetochlor technical.  The herbicide/safener formulations are typically applied as pre-emergence soil or early post-emergence foliar applications using broadcast ground equipment.  The herbicide/safener may be applied both in the spring and fall, but the total applied must not exceed the maximum labeled rate for corn in that type of soil.  The application must also be made within 14 days of planting when applied by conventional tillage systems and up to 40 days before planting in no-till systems.  The application rate of dichlormid ranges from 0.30-0.54 lbs ai/A.  

There were no new tolerances requested in this petition, only the conversion of time-limited tolerances to permanent tolerances.  Using the submitted studies (MRID No. 46353807 and 46353808) and previously submitted residue data on corn, ARIA indicated that there were deficiencies that would preclude the requested conversion to permanent tolerances.  ARIA recommend for an extension to the time-limited tolerances of 0.05 ppm for the use of dichlormid on field corn (forage, grain, stover), sweet corn (K+CWHR, forage and stover) and pop corn (grain, stover) pending completion of a human health risk assessment.  The registrant, Dow Agrosciences (DAS) has submitted a response to the residue chemistry deficiencies discussed in ARIA's human health risk assessment (PP#4F6950, DP# 321928, D. Rate, 11/25/05) and the associated residue chemistry assessment (PP#4F6950, DP# 318075, D. Rate, 9/14/05):

      1.  860.1300: Nature of the Residue - Plants
      The study submitted (MRID No. 46015801) for the purpose of fulfilling the Guideline 860.1300 is scientifically unacceptable and does not satisfy the requirements.  It may be upgraded if additional metabolites are identified, including unknown A, to allow a more complete characterization of the nature of the residue of dichlormid in corn.

	2.  860.1300: Nature of the Residue - Livestock
      The studies submitted (MRID No. 46015802, 46015803) for the purpose of fulfilling the Guideline 860.1300 are scientifically unacceptable and do not satisfy the requirements. The studies do not adequately define the nature of the residues or the residue(s) of concern for dichlormid.  They may be upgraded upon further identification of residues representing 10% and/or 0.05 ppm.  
	
      3.  860.1340: Residue Analytical Methods
	The requested revised method has not yet been received.
	
	4.  860.1900: Field Accumulation in Rotational Crops
      No studies in field accumulation in rotational crops have been submitted.  The registrant should submit a field accumulation in rotational crop study in accordance with OPPTS Guideline, 860.1900.

This document will only discuss the aforementioned deficiencies and the DAS responses. 

ARIA has considered the registrant's comments and determined that the previously submitted plant metabolism study is adequate.  The residue of concern for corn is parent dichlormid.  Should uses on other crops be requested, additional nature of the residue data on those commodities will be required.  

ARIA has considered the registrant's comments and determined that the previously submitted livestock metabolism study is adequate for the current use on corn.  The residue of concern for livestock is parent dichlormid.  Livestock tolerances are not required at this time; however, should additional uses on other crops be requested, the data should be reassessed if there is an increase in the livestock dietary burden.  

A copy of the proposed analytical method has been received. The method will be forwarded to FDA.

ARIA has considered the registrant's comments and determined that no field rotational crop data are required for the current uses of dichlormid.  However, additional data will be required should the registrant request higher use rates or shorter plant-back intervals (PBIs).

Regulatory Recommendations and Residue Chemistry Deficiencies

For the purpose of establishing permanent tolerances for field corn (forage, grain, stover), sweet corn (forage, kernel plus cob with husks removed, stover) and pop corn (grain, stover) at 0.05 ppm, ARIA has determined that the residue chemistry database is adequate.  ARIA recommends for the requested permanent dichlormid tolerances on corn

                               Commodity:			       ppm			        
		Corn, field, forage.............................      	0.05     			
		Corn, field, grain..............................     	0.05     			
		Corn, field, stover.............................  	0.05     			
		Corn, pop, grain................................  	0.05     			
		Corn, pop, stover...............................     	0.05     			
		Corn, sweet, forage.............................  	0.05     			
		Corn, sweet, kernel plus cob with husks removed..............................     	0.05     			
		Corn, sweet, stover.............................  	0.05     			

Since a human health risk assessment has been completed at these levels (PP#4F6950, DP# 321928, D. Rate, 11/25/05) and the risks to all populations of interest through all modes of exposure to dichlormid were found not to be of concern to the Agency, an updated risk assessment is not required.
 
Note:  The tolerance expression for dichlormid residues needs to be updated to reflect current Agency policy:  "Tolerances are established for residues of dichlromid, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only dichlormid (2,2-dichloro-N,N-di-2-propenylacetamide) in or on the following commodities:"

Detailed Discussion

860.1300: Nature of the Residue  -  Plants

EPA Comment:  The studies submitted (MRID No. 46015801) for the purpose of fulfilling the Guideline 860.1300 is scientifically unacceptable and does not satisfy the requirements.  It may be upgraded if additional metabolites are identified, including unknown A, to allow a more complete characterization of the nature of the residue of dichlormid in corn.

DAS Response  -  Plants:  Dichlormid (N,N-diallyl-2,2-dichloroacetamide)is a 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.  The current label for these products allows for either pre-emergent soil applications or early post-emergent foliar applications to corn that is up to 11" tall at rates not to exceed 0.54 lb/A (0.61 kg/ha) for the safener.

As part of the registration package for acetochlor, a crop metabolism study was run in which 14C dichlormid was applied to separate plots of corn (Dichlormid Metabolism in Corn, MRID No. 46015801) as either a pre-emergent or post-emergent treatment at rates that were nominally equivalent to either 1X or 10X the critical GAP rate.  Initial review of the study report by the Toxicology and Hazard Assessment Group at Oak Ridge National Laboratory (Task order No. 12-2004) cited a number of potential deficiencies and resulted in the study being classified as "Unacceptable/Guideline and does not satisfy OPPTS 860.1300, but is upgradeable if additional metabolites are identified, including Unknown A, to allow more complete characterization of the nature of the residue of dichlormid in corn".  In arriving at this conclusion, it did not appear that the review took into account that the total radioactive residue (TRR) in all but one of the three possible raw agricultural commodities (forage, grain and stover) from plants treated either pre- or post-emergent at the 1X rate were less than 0.010 mg/kg and that the TRR in the one exception (post-emergent corn stover) was only 0.011 mg/kg.  Based on the current OECD guideline for crop metabolism studies, no residue characterization work was technically required due to the fact that all 1X residues were at or below the 0.01 mg/kg trigger level.  In spite of that, extensive characterization work was done with the 10X samples and it was the results from these analyses that were actually evaluated.  Unfortunately, even in these samples the residues were relatively low (from 0.045 mg/kg in grain to 0.272 mg/kg in stover) and the amount of actual identification work that could be done (or, in all cases, which even needed to be done) was limited to those components that were chromatographic matches with the available references standards.  Thus it is the position of DAS that the residues in all commodities were adequately identified or characterized given the low levels at which they were observed and that the status of this study should be upgraded to Acceptable.

While keeping the preceding positions in mind, responses to the individual deficiencies or issues that were cited in the DER are as follow:

EPA Comment:  "No explanation was provided of why Metabolite A (designated in the report as Unknown A) was not identified since it represented >10% of the TRR in young forage and stover." (Page 16, Section II, part 3 - Identification of Metabolites; and page 18, Section IV - Study Deficiencies)

DAS Response:  Unknown A was observed in three samples - 10X pre-emergence forage (15% TRR; 0.016 mg/kg); 10X pre-emergence stover (14% TRR; 0.024 mg/kg); and 1OX post-emergence stover (16.6% TRR; 0.045 mg/kg).  It was noted that the residue level of this component in the forage sample was mistakenly cited as being 0.16 mg/kg at several places in the DER.  The correct value is 10-fold less or 0.016 mg/kg.

Even at the 10X treatment rate used in this study, levels of Metabolite A were below the trigger level requiring identification in all three samples in which it was found.  In addition, this fraction also exhibited characteristics that would have made isolation and cleanup for identification purposes very difficult.

First, this was a highly polar component that could only be extracted from crop samples using polar solvent such as acetonitrile and acetonitrile/water.  Crop extracts using these solvents typically have high levels of co-extractants that need to be removed before an unknown component can be successfully identified by spectroscopic means such as LC/MS or NMR.  Such cleanup would have been difficult with this unknown fraction since it could not be readily partitioned into organic solvents, it often chromatographed poorly on silica TLC plates (see Figures 33, 34 and 35 of the study report), and it could not be retained on C18 SPE cartridges.

The aqueous soluble nature of this fraction and the fact that it often did not chromatograph well on silica TLC systems suggested that it could represent some type of conjugate.  Enzyme hydrolysis using driselase did not appear to result in any significant reduction in the level at which this component was observed in the fraction that was hydrolyzed.  There did appear to be a significant reduction, however, following an acid hydrolysis step (reflux in 2M HCl) with there being a corresponding increase in the levels of several other unidentified fractions in the TLC chromatogram.  This result suggested that this material could represent a mixture of conjugates of two or more metabolites.

These results indicate that Metabolite A was most likely multi-component in nature and may have represented a mixture of highly polar conjugates, none of which were present at high enough levels that warranted identification.  Based then on the work that has already been done, DAS feels that this residue component has been adequately characterized and that no additional work is necessary.

EPA Comment:  "This metabolism study did not provide sufficient information to establish the residues of concern for dichlormid in corn because only a small fraction of the TRR (<12%) was identified in each matrix." (Page 17, Section II, part 5 - Residues of Concern for Dichlormid)

DAS Response:  While it is true that only a small percentage of the TRR was identified during the course of this study, the two metabolites that were identified (N,N-diallyl glycolamide and dichloroacetic acid) confirmed the presence of two metabolic pathways that were responsible for dc-chlorination and de-alkylation of the parent molecule.  The nearly complete absence of the parent molecule in any of the samples that were analyzed indicates that residues of dichlormid following application were rapidly and almost completely metabolized by the treated crop.  The extent of the metabolism that occurred is highlighted by two other observations from the data.  The first was the absence of any sizeable, individual residue component in any of the sample extracts.  The largest single component was the material referred to as Unknown A which represented a maximum of 16.6% of the TRR in stover.  As indicated in the preceding response, this fraction itself was suspected of being multi-component in nature.  The second observation that served as an indication that extensive metabolism had taken place was the work that confirmed that the radioactive residues that were observed in the control grain samples represented radioactivity that had actually been incorporated into the starch fraction of the grain.  The source of the radioactivity that was incorporated into the starch fraction was understood to be from the 14C dichlormid treated pots that were maintained in the same greenhouse and could only have been form by liberation from the labeled test material.  If there was sufficient 14C02 generated that it could be taken up by the control plants that were located some distance away from the treated plants, it only stands to reason that even more would be taken up by the treated plants themselves.  Thus significant portions of the TRR most likely represented radioactivity that had been incorporated into a variety of natural products that could not be readily identified.

Given the preceding observations, DAS feels that it has been adequately demonstrated that dichlormid is rapidly and extensively metabolized by corn and that there are no significant metabolite residues present that would need to be included in the residue definition for either risk assessment or enforcement purposes.  This in conjunction with the low total residues observed following a typical application (the total residues would be <0.010 mg/kg) confirms that the current proposed residue definition of only dichlormid itself is adequate and that no further work is needed in order to determine if there are additional residues of concern.

EPA Comment:  "It is unclear why two ethyl acetate aqueous fractions having 0.109 and
0.115 mg/kg residues were not subjected to TLC." (Page 16, Section II, part 3 - Identification of Metabolites)

DAS Response:  The "two" aqueous fractions referred to were from the pooled acetonitrile, acetonitrile/water and acetone extracts of 10X post-emergence stover that together represented 48.2% (0.130 mg/kg) of the sample TRR (see pages 48 and 49 of the study report along with Figure 19).  This pooled extract was initially characterized by TLC in solvent system 7 with sample chromatograms shown in Figures 35 and 37 of the report.  Results of this analysis showed the presence of Metabolite 01(5.3% TRR) and Unknown A (16.6% TRR), while the remainder of the residue was highly polar in nature and remained at or near the origin of the TLC plate.  Following the initial analysis of this pooled fraction, a subsample was subjected to a partitioning step at pH 7 with ethyl acetate.  The spent aqueous fraction from this step was the spent aqueous fractions referred to in the DER as containing 0.109 mg/kg.  This spent aqueous fraction was not subjected to TLC but was further partitioned at pH 2 and pH 10 with ethyl acetate and the spent aqueous fraction from these steps subjected to a C18 SPE cleanup step.  The major fraction from the SPE step (it contained approximately 90% of the radioactivity in the sample) was then analyzed by TLC (see autoradiogram in Figure 38).

A second sub-sample from the pooled acetonitrile/acetonitrile-water/acetone extracts was subjected to enzyme hydrolysis using driselase and the sample then partitioned with ethyl acetate at pH 7.  The spent aqueous from this step was the one referred to in the DER as containing 0.115 mg/kg.  As above, this aqueous fraction was not subjected to TLC analysis at that time but was further extracted at pH 2 and 10 and the spent aqueous again subjected to a C18 SPE cleanup step.  The major fraction from the SPE work (again it contained approximately 90% of the radioactivity in the sample) was then analyzed by TLC (see the autoradiogram in Figure 39).

Thus while it is true that the two aqueous fractions referred to in the DER were not analyzed per se by TLC, both were subjected to further characterization work and the residues eventually analyzed by TLC.

EPA Comment:  "The recovery of radioactivity in young forage following extraction was unacceptably low (82%)." (Page 18, Section IV - Study Deficiencies)

DAS Response:  While the total radioactivity accounted for following extraction was slightly less than the 90% level that is targeted for in this type of work, it is not unusual to get slightly lower or sometimes higher recoveries when performing multi-step extraction procedures on low level samples such the one referred to here (0.109 mg/kg).  Extensive work was done during the study in an attempt to capture any volatile components that might have been generated during extraction with the result being that no volatile residues were observed.  Thus it was concluded that the initial combustion value may have been artificially high due to incomplete mixing of the sample after the sample preparation steps and that the actual TRR value was something closer to that seen during the extraction work.

Based on the preceding information, DAS does not feel that there was any actual loss of residues from the forage sample during extraction and that the cited low recovery should not be an issue of concern.

EPA Comment:  "The following were cited as minor deficiencies that did not likely have a significant impact on the outcome of the study." (Page 18, Section IV - Study Deficiencies)

:: Lack of information on date(s) of corn planting and soil treatment.

DAS Response:  As indicated in Table 28 of the report, the date of corn planting for both the pre-emergent and post-emergent work was 9 February 1999.  The application to the pre-emergent pots was made on 10 February 1999, while the post-emergent pots were treated on 25 February 1999.

:: The stability of samples stored frozen for >6 months was not adequately shown.

DAS Response:  Stability of the samples is addressed in Section 3.7 of the report.  Crop samples were extracted, fractionated and profiled chromatographically within six months of harvest.  Further analyses were conducted on the 10X young forage and stover samples after the 6 month period.  To demonstrate the stability of the samples, extracts that were generated on 29 November 1999 were compared chromatographically to extracts that were generated on 8 March 2000 and were shown to be the same (see Figure 46).

:: It would have been helpful if dichlormid metabolites were subjected to a confirmatory analytical method.

DAS Response:  For the low levels at which Metabolites 01 and 06 were observed (both were <0.010 mg/kg in the 10X sample), use of a confirmatory analytical method was neither warranted nor practical.

Conclusion:  ARIA and HED have considered the registrant's comments and determined that the previously submitted plant metabolism study is adequate.  The residue of concern for corn is parent dichlormid.  However, should additional uses on other crops be requested, nature of the residue data on those commodities will be required.  

860.1300: Nature of the Residue  -  Livestock

EPA Comment:  The studies submitted (MRID Nos. 46015802, 46015803) for the purpose of fulfilling the Guideline 860.1300 are scientifically unacceptable and do not satisfy the requirements.  The studies do not adequately define the nature of the residues or the residue(s) of concern for dichlormid.  They may be upgraded upon further identification of residues representing >10% and/or 0.5 ppm.

DAS Response  -  Goat:  Dichlormid (N,N-diallyl-2,2-dichloroacetamide)is a 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.  Because acetochlor is the only herbicide for which dichlormid has demonstrated safener activity and because corn is the only crop on which acetochlor is used, there are no plans to expand the use of dichlormid onto other food crops.

As a result of the use of dichlormid on corn, there is the potential for treated feedstuff items (forage, grain and stover) to be used in the diets of ruminant livestock such as beef and dairy cows.  Because of this potential use, a ruminant nature of the residue (NOR) study (The Distribution and Metabolism of [14C]-Dichlormid in the Lactating Goat, MRID No. 46015802) was conducted in which a lactating goat was dosed with 14C dichlormid for 5 consecutive days at a level equivalent to 12.88 mg/kg in the diet.  Based on data from the 14C dichlormid corn NOR study (Dichlormid Metabolism in Corn, MRID No. 46015801) in which corn was treated at a lx or 10X rate, the total radioactive residue (TRR) in grain from plots treated at the maximum label rate was less than 0.005 mg/kg and in forage and stover was in the range of 0.008-0.01 1 mg/kg.  Using these values and the percentage proportions which these items might be used in cattle diets as provided in the Table of OECD Feedstuffs, the maximum theoretical level of dichlormid related residues in the diets of ruminants would be something less than 0.010 mg/kg.  Thus the dose level used in the ruminant NOR study for dichlormid is at least a 1200-1300X exaggeration.  Given the low TRR levels observed in the milk and tissue samples from the NOR study (from a low of 0.004 mg/kg in fat to a maximum of 0.475 mg/kg in liver) despite the high feeding level that was used, it is clear that there is no reasonable expectation for detectable residues of dichlormid or its metabolites to be found in meat or milk as a result of the use of dichlormid in corn.

While it is clear from the current OECD guidelines that calculated "trigger levels" should not be used in making decisions on the extent of any characterization/identification work that should be done with the milk and tissue samples, it is also clearly indicated that "in metabolism studies in which highly exaggerated feeding levels are employed and low radioactivity results in tissues, characterization and/or identification requirements should be less stringent than when expected dietary burdens lead to significant radioactivity in animal products."  Based on this statement, DAS feels that the residues in the meat and milk samples from the dichlormid study were adequately characterized as is discussed in the responses that follow and, although the total amount of residues that were actually identified was low, it was adequately demonstrated that the residues were multi-component in nature and that no single component would be present under normal use conditions at levels that exceed 0.001 mg/kg.  Thus it is the position of DAS that no additional work is warranted at this time on this study and that the status of this study should be reclassified as Acceptable/Guidelines.

While keeping the preceding positions in mind, responses to the individual deficiencies or issues that were cited in the DER are as follow:

EPA Comment:  "A major deficiency of this study was the failure to identify sufficient metabolites to characterize the nature of the residues of dichlormid in goat milk and tissue." (page 13, Section IV  --  Study Deficiencies)

DAS Response:  While it is true that only a small portion of the residue in each milk or tissue sample was identified, results from the work that was done clearly demonstrated that the residues in each sample were multi-component in nature and that dichlormid was extensively metabolized to the point that the parent test material and its close structural metabolites represented only a small portion of any residues that were present.  Summaries demonstrating both of these facts are provided below.

For milk from either the 32 or 104-hour collections (maximum TRR of 0.122 mg/kg), approximately 80% of the total residue remained in the aqueous fraction following precipitation of the milk solids.  HPLC analysis of the milk aqueous residues following a partitioning and concentration step showed it to contain two primary components and as many as five minor components.  The two primary components were both unknowns that were poorly resolved from one another.  The smaller of the two represented approximately 15-20% of the TRR (0.018-0.020 mg/kg) and the other approximately 20-30% of the TRR (0.027-0.032 mg/kg).  None of the minor fractions which included residues that eluted in the same regions as two of the available reference standards (R305588 and R326950) represented more than 0.004 mg/kg (3.8% of the TRR).  Enzyme digestion of the milk solids resulted in the solubilization of an additional 10-12% of the TRR.  HPLC analysis of these residues showed them to consist of nine or more components, none of which represented more than 0.002 mg/kg.

For liver (0.475 mg/kg), only about 40% of the residue could be readily extracted while nearly all of the remaining residue was solubilized following enzyme digestion.  HPLC analysis showed nearly half of the readily extractable radioactivity to not be retained on the HPLC column as it eluted just after the void volume.  While this highly polar fraction contained residues representing 0.062 mg/kg, it was most likely multi-component in nature since it was not retained on the reverse phase column.  The remaining residue was a poorly resolved, multi-component mixture that eluted over about a 25-minute portion of the chromatogram.  This mixture contained at least six or more minor components, none of which represented more than 5.2% of the TRR (0.008-0.025 mg/kg).  HPLC analysis of the enzyme hydrolysate fraction showed it to contain very little of the highly polar residue that was not retained on the column but instead consisted almost entirely of the poorly resolved, multi-component mixture.  This mixture consisted of at least 10 components or fractions, none of which represented more than 9.4% of the TRR (0.044 mg/kg).  Given the nature of the chromatography, it would seem almost certain that most of the individual fractions were also multi-component in nature.

For kidney (0.186 mg/kg), approximately 50% of the TRR was readily extractable while most of the remaining residue could be solubilized by enzyme hydrolysis.  HPLC analyses of these two fractions showed similar profiles to those described for liver, although the resolution among components in the hydrolysate fraction was even poorer than that seen in liver.  With the exception of the highly polar residue that was not retained on the HPLC column, no individual component in kidney represented more than 10.2% of the TRR (0.0 19 mg/kg).

For muscle (0.056 mg/kg), approximately 75% of the residue was readily extractable and about another 20% was released by the enzyme digestion steps.  HPLC analysis of the readily extractable residues showed a similar profile to that seen for the comparable fractions from liver and kidney, with there again being a sizeable component (approximately 30% of the TRR or 0.0 17 mg/kg) that could not be retained on the HPLC column.  Unlike liver and kidney, residues in the hydrolysate fraction also consisted entirely of radioactivity that eluted at the column front.

As seen from the preceding summaries, results from this study adequately demonstrated the extent to which dichlormid is metabolized by ruminants and the multi-component nature of the resulting residue.  The data also clearly show that while most of the residue components or fractions that were observed represented less than 10% of the TRR for any given sample, those fractions that did represent larger portions of the TRR were still not present at levels in excess of 0.05 mg/kg and as such did not warrant efforts for isolation and identification.  This is especially true in light of the highly exaggerated feeding level that was used in this study and the fact that no individual component would be expected at levels even approaching 0.00 1 mg/kg under normal use conditions.

Based then on the preceding discussion, DAS feels that the residues in meat and milk have been adequately characterized, and that no additional characterization or identification is necessary.

EPA Comment:  "A major deficiency of this study was an inadequate mass balance accounting." (page 13, Section IV - Study Deficiencies)

DAS Response:  From Table 2 on page 41 of the study report, the recovery of administered radioactivity in this study was 84.4% of theory.  For a metabolism study that was designed to maximize the residue levels in the milk and edible tissues in order to allow for the delineation of the nature of the residues rather than being designed to maximize the recovery of the administered radioactivity, this level of recovery was quite good.  The level of recovery likely would have been even better had the animal voided any urine during the 24-48 hour time period since at least 10-15% of the administered dose was accounted for in each 24-hour urine sample.  No reason could be provided for the lack of a urine sample during the period cited since the animal had normal urine production both before and after this period and since it ate and drank normally throughout the entire dosing period.

While DAS understands the reasons for evaluating mass balance data in order to confirm that animals received the intended doses and perhaps to confirm that significant portions of the administered radioactivity were not lost as expired volatiles, the company feels that it was unreasonable to cite a recovery in excess of 80% as being a major study deficiency.  This is especially true in light of the fact that the data provided adequately confirmed that the desired amounts of 14C dichlormid were in the capsules that were administered to the animal and that the administered test material was readily absorbed and excreted as was demonstrated by the significant portions of the dose that were accounted for in the urine.

EPA Comment:  The Agency reviewer noted that "a schematic of a proposed metabolic pathway of dichlormid in goat matrices was not provided in the report." (page 12, Section III
- Proposed Metabolic Pathways in Goats)

DAS Response:  Based on the metabolite fractions that were tentatively identified during the study and on the belief that the extensive metabolism observed most likely resulted in the production of small carbon fragments that were reincorporated into various natural components, the following pathway is proposed:

EPA Comment:  Minor deficiencies were cited as follows: (page 13, Section IV - Study Deficiencies)

:: "Stating an incorrect number for the final collection time point (143 hours on p. 51 of MRID 46015802 but should have been approximately 120 hours)."

DAS Response:  DAS agrees that the final collection time point for the tissue samples should have been listed as approximately 120 hours instead of 143 hours.  The incorrect time point is mentioned on page 51 of the report and in the continuation of Table 9.  This is a minor inconsistency that had no effect on the study since tissue samples were collected at only one time point.
 
:: "Failure to report radioactivity levels of the fat, GI contents, blood and carcass."

DAS Response:  Total radioactive residue levels for fat were reported as 0.004 mg/kg.  The % of the administered dose that was accounted for in fat was not calculated due to the low TRR levels in fat and the fact that the total weight of fat in the animal was not know.  Levels of radioactivity in the GI contents, blood and carcass were not provided since none of these are sample types that are required to be collected and analyzed as part of a nature of residue study.

:: "Providing radioactivity in the pre-extraction samples only in a table footnote (p. 47 of MRID 46015802) with no cross reference elsewhere in the report."

DAS Response:  Total radioactivity levels in the samples prior to extraction are not shown elsewhere in the report other than the footnote in Table 7 but can be calculated, if desired, using the sample weight information provided in the extraction flow diagrams shown in Figures 3-6 and the dpm/g values for each sample as provided in Appendix 13.

:: "The goat lost weight during the two months of acclimation (59.0 kg on the day prior to first dose; 67.5 kg on the day of arrival 2 months earlier), suggesting it was under undue stress, which may have affected its metabolic profile although this was not addressed in the study report." 

DAS Response:  It is not uncommon for an animal to lose weight when maintained for an extended period at a research facility.  It is doubtful that this loss of weight was due to stress that might have affected metabolism since feed consumption was consistent throughout the study and since there was no interruption or decrease in milk production (cessation of milk production is typically one of the first signs of stress in a lactating animal and that obviously did not occur in this study).  The overall health of the animal was observed by a veterinarian throughout the study and was found to be good at all times.

:: "It would have been helpful if dichlormid metabolites were subjected to a confirmatory analytical method."

DAS Response:  DAS agrees that it would have been helpful if the dichlormid metabolites that were tentatively identified by co-chromatography with a reference standard had been subjected to a confirmatory analytical method.  Due to the nature of the samples being analyzed (either aqueous based extracts or aqueous enzyme hydrolysate solutions) and to the low levels at which the metabolites (R305 588 and R326950) were observed (with the exception of the liver hydrolysate fraction, neither metabolite was observed at levels in excess of 0.01 mg/kg), it was neither practical nor necessary to confirm the identity of these components using a second analytical technique.

DAS Response  -  Poultry:  Dichlormid (N,N-diallyl-2,2-dichloroacetamide)is a 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.  Because acetochlor is the only herbicide for which dichlormid has demonstrated safener activity and because corn is the only crop on which acetochlor is used, there are no plans to expand the use of dichlormid onto other food crops.

As a result of the use of dichlormid on corn, there is the potential for treated feedstuff items (corn grain) to be used in the diets of poultry.  Because of this potential use, a poultry nature of the residue (NOR) study (The Distribution and Metabolism of [14C]-Dichlormid in Laying Hens, MRID No. 46015803) was conducted in which 5 laying hens were dosed with 14C dichlormid for 14 consecutive days at a level equivalent to 10.0 mg/kg in the diet. Based on data from the 14C dichlormid corn NOR study (Dichlormid Metabolism in Corn, MRID No. 46015801) in which corn was treated at a 1X or 10X rate, the total radioactive residue (TRR) in grain from plots treated at the maximum label rate was 0.003 mg/kg.  Using this value and the maximum percentage proportion that corn grain might be used in poultry diets (70-80%) as provided in the Table of OECD Feedstuffs, the maximum theoretical level of dichlormid related residues in the diets of poultry would be something less than 0.003 mg/kg.  (In truth there would actually be no exposure since results from the characterization of the residues in grain from the corn NOR study showed virtually all the residue to be non-extractable in nature and suggested that it all represented radioactivity that had been incorporated into the starch fraction on the grain.)  Using the worst case dietary exposure value of 0.003 mg/kg, the dose level used in the NOR study was at least a 3300X exaggeration.  Given the TRR levels observed in the egg and tissue samples from the NOR study (from a low of 0.041 mg/kg in fat to a maximum of 0.877 mg/kg in liver), it is clear that there is no reasonable expectation for detectable residues of dichlormid or its metabolites to be found in eggs or edible tissues as a result of the use of dichlormid in corn.

While it is clear from the current OECD guidelines that calculated "trigger levels" should not be used in making decisions on the extent of any characterization/identification work that should be done with the egg or tissue samples, it is also clearly indicated that "in metabolism studies in which highly exaggerated feeding levels are employed and low radioactivity results in tissues, characterization and/or identification requirements should be less stringent than when expected dietary burdens lead to significant radioactivity in animal products".  Based on this statement, DAS feels that the residues in the meat and eggs samples from this study were adequately characterized as is discussed in the responses that follow and, although the total amount of residues that were actually identified was low, it was adequately demonstrated that the residues were multi-component in nature and that no single component would be present under normal use conditions at levels that exceed 0.001 mg/kg.  Thus it is the position of DAS that no additional work is warranted at this time on this study and that the status of this study should be reclassified as Acceptable/Guidelines.

While keeping the preceding positions in mind, responses to the individual deficiencies or issues that were cited in the DER are as follow:

EPA Comment:  "The major deficiency of this study was the failure to identify sufficient metabolites to characterize the nature of the residues of dichlormid in hen eggs and tissue." (Page 13, Section IV - Study Deficiencies)

DAS Response:  While it is true that only a small portion of the residue in each egg or tissue sample was tentatively identified, the results from this study clearly demonstrated that the residue in each sample was multi-component in nature and that dichlormid was extensively metabolized to the point that the parent test material and its recognizable metabolites represented only a small portion of any residues that were present.  The high levels of residue in each sample type that could only be solubilized by enzyme digestion steps (60-90% of the TRR in each sample) and the highly polar nature of the residues that were so released further suggested that the already small parent molecule was metabolized to the point that the portion containing the radiolabel had likely become reincorporated into endogenous natural products.

The multi-component nature of the residue in each sample type is readily demonstrated by examining the chromatograms from the analyses of the solvent extractable or enzyme solubilized radioactivity from each sample using HPLC Method 2.  (Most of the chromatograms generated using HPLC Method 1 were generally not of much use since most of the radioactivity in each sample was not retained on the column when using this elution system.)  As shown in Table 16 and Figures 24, 27 and 29 of the study report, the acetonitrile extractable residues from egg yolks and whites (these extracts contained 15.8-38.3% of the TRR in each sample) consisted of at least 4-9 different components, with several of the peaks in the egg yolk extract having retention times comparable to those of the reference standards for dichlormid (<1% of the TRR), the N-dealkylated metabolite (R326590 - 3.5% of the TRR), and two of the des-chloro metabolites (R336075 and R30558 - both <1% of the TRR).  Of the remaining unidentified fractions, only two were present at levels in excess of 0.01 mg/kg.  One was a very wide peak that eluted over a 4-5 minute span in the Day 5 yolk extract (13.4% of the TRR or 0.046 mg/kg), while the other was a better defined peak that eluted at approximately 18 minutes in both the Day 5 and Day 13 egg white extracts (each represented 3 1.9-33.2% of the TRR or 0.097-0.103 mg/kg).  While both of the 18-minute peaks in the egg white extracts gave the appearance of being a single component, both, in fact, were known to be multi-component in nature.  This was confirmed by looking at results from the analyses of these same extracts using HPLC Method 1 (see Table 14).  That analysis separated the sample residues into several distinct peaks, none of which contained more than 17.9-18.6% of the TRR (0.055-0.058 mg/kg). T hus the 18-minute peak in each of the Method 2 chromatograms had to consist of several unresolved components of which no single entity could represent more than approximately 18% of the TRR and in all likelihood represented even less.

For the residues in yolks and whites that were solubilized following enzyme digestion using pepsin and protease (55.4-77.9% of the TRR in each sample), HPLC analysis (see Figures 25, 26, 28 and 30 of the study report) showed the residues from each sample to consist of two general regions of radioactivity that either eluted in the first 3-10 minutes of each run or in the 15-30 minute portion of each run.  Within each region, the resolution between any observed peaks was generally poor (there was no base line resolution) as it consisted of peaks that eluted on top of broad general "humps" of radioactivity.  Thus as a result of the nature of the chromatography, any entry in Table 16 of the report that was referred to as an individual component (either as an unknown or as a match with one of the reference standards) was in fact a multi-component mixture.  Thus while the amount of radioactivity attributed to any given fraction was accurate, it obviously did not represent radioactivity associated with a single, unique metabolite entity.  Therefore even though it may have appeared during the initial study review that there might have been individual metabolites that were present at high enough levels to warrant identification, there were, in fact, no individual components in egg yolks or whites that needed to be pursued for this purpose.

For liver, 36.3% of the TRR was readily extractable and another 55.7% was solubilized following enzyme digestion. HPLC analysis of the readily extractable residues (see Figure 31) showed them to consist of at least 11 different components, three of which had retention times the same as the reference standards for dichlormid (0.4% of the TRR or 0.003 mg/kg), the mono N-dealkylated metabolite (R326590; 0.9% of the TRR or 0.008 mg/kg) and one of the deschloro metabolites (R305588; 0.7% of the TRR or 0.006 mg/kg).  All of the remaining fractions were present at levels representing 0.004-0.0 14 mg/kg except for a highly polar fraction that was not retained on the column (0.05 0 mg/kg) and a broad fraction that eluted over a 3-4 minute region at 30.5 minutes (5.8% of the TRR or 0.05 1 mg/kg).  Both of these fractions were assumed to be multi-component and were not further characterized.  Analysis of the enzyme solubilized residues showed them to consist of three broad fractions or peaks that each eluted over 3-4 minute portions of the chromatogram.  One of these fractions was highly polar as it was not significantly retained on the HPLC column (4 minutes; 16.6% of the TRR; 0.146 mg/kg) while another was a small, broadly tailing fraction that eluted later in the chromatogram (30 minutes; 9.9% of the TRR; 0.086 mg/kg).  Both of these fractions appeared to be multi-component in nature and thus were not further characterized.  The third fraction eluted at 23.5 minutes as a more well-defined peak (25.9% of the TRR or 0.227 mg/kg) that did not match any of the available reference standards.  While it is probable that this peak was also multi-component in nature, no work was done to verify this and LC/MS analysis of this enzyme fraction did not result in any useful structural information for this component.

For breast and thigh muscle, only about 20-25% of the TRR was readily extractable with organic solvent, while virtually all the remaining radioactivity was solubilized following enzyme digestion using pepsin.  HPLC analyses of the readily extractable residues showed them to consist of up to at least 10 different components. I n thigh muscle, two of these components eluted with the same retention times as two of the deschloro metabolites (R305588, <1% of the TRR; and R327940, <2.2% of the TRR).  All remaining components in these extracts were present at levels representing 0.001-0.013 mg/kg.  For the enzyme solubilized residues, HPLC analysis showed each to consist of two regions of poorly resolved components.  One eluted over a 5-minute portion of the chromatogram just after the column void volume while the other eluted over an approximate 10-minute region starting at about 15 minutes.  While Table 17 showed each of these extracts to consist of 3 or 4 components that represented as much as 26.6-50.3% of the TRR (0.055-0.100 mg/kg), it is clear from the chromatograms that each of these "unknowns" were multi-component in nature and that none consisted of any individual components that warranted identification.

Neither fat nor skin with adhering fat contained significant levels of residues that were readily extractable under the conditions used (8.7-1 1.5% of the TRR), while enzyme digestion using collengenase resulted in only limited solubilization of the remaining residues (28.9-42.6% of the TRR).  HPLC analyses of the respective enzyme fractions showed both to be multi-component in nature with there being poor resolution of most of the components.  No individual fraction contained residues representing more than 0.019 mg/kg.

Based on the preceding review, it is clear that the residues in the egg and edible tissue samples from this study were proven to be multi-component in nature and that neither dichlormid nor any of its closely related metabolites for which standards were available were present at significant levels in any of the samples that were analyzed.  For the many unknown fractions that were observed in the chromatograms, only a few were present at levels representing more than 0.05 mg/kg of dichlormid equivalents and evidence was provided that all but one of those was multi-component in nature and thus did not warrant identification efforts.  The only exception was a moderately polar fraction that eluted over a several minute portion of the chromatogram for the liver enzyme hydrolysate solution where it represented approximately 25% of the liver TRR (0.227 mg/kg).  While it was felt that this fraction was also most likely multi-component in nature, no data were generated to confirm this. LC/MS analysis of this extract did not result in the generation of any useful structural information for this component.  Based on the exaggerated feeding level used in this study (>3000X), even if this fraction were a single component it would not be present in the livers of poultry fed treated grain at levels even approaching 0.001 mg/kg.  Thus the data generated during this study confirmed the absence of any individual residue components at levels high enough to be included in any analytical methods that might be developed either for risk assessment or residue enforcement purposes.

EPA Comment:  "A major deficiency of this study was a failure to address the metabolic pathway of dichlormid in poultry." (Page 13, Section IV - Study Deficiencies)

DAS Response:  No metabolic pathway was provided since all structural assignments made as a part of this study were only tentative in nature (confirmatory efforts using LC/MS were not successful due to the low levels at which these components were observed).  Based on the tentative identifications made, however, two metabolic pathways were observed. O ne involved N-dealkylation of the parent test material to give R326590, while the other involved dechlorination followed by oxidation to give either the glyoxylamide (R327940) or the glycolamide (R305588) metabolites.  Given the number of other components observed during this study and the fact that the majority of the residue in each egg and tissue sample could only be solubilized following enzyme digestion, it was suspected that the molecule was further metabolized following the dechlorination step to give small fragments that were eventually reincorporated into endogenous natural products.

Based on these observations, the proposed metabolic pathway for dichlormid in poultry is shown below: 

EPA Comment:  "Minor deficiencies were cited as follows:" (page 13, Section IV - Study Deficiencies)

:: "Failure to report radioactivity levels of the fat, GI contents, blood and carcass."

DAS Response:  Total radioactive residue levels for fat were reported as 0.041 mg/kg.  The % of the administered dose that was accounted for in fat was not calculated due to the fact that the total weight of the fat in the animals was not known since all fat could not be collected at necropsy.  Levels of radioactivity in the GI contents, blood and carcasses were not provided since none of these are sample types that are required to be collected as part of a nature of residue study.

:: "Not providing radioactive recoveries of the matrices following their initial extraction."

DAS Response:  The percent of the TRR accounted for in each fraction generated during extraction and the portion of the TRR that was lost from each fraction during preparation for HPLC analysis is provided on pages 40-43 of the report and in Tables 9-12. T he actual dpm data needed to confirm the values cited in these sections are provided in the extraction flow diagrams (Figures 3-7) for Day 5 egg yolks and whites, liver, thigh muscle and skin with adhering fat.  Similar supporting data were not provided for the Day 13 egg samples, breast muscle or fat. 

:: "Some inconsistencies between various parts of MRID 46015803, such as the egg yolk extraction procedure and the skin with fat sample residue contents." 

DAS Response:  While there were some minor inconsistencies between the textual versions of the egg yolk extraction procedure and the description shown as part of the flow diagram (Figure 3) and between the textual description of the residue distribution in skin fat and the values shown in Tables 15 and 17, these differences were relatively minor and do not hinder in the overall understanding of the study.

:: "Lack of confirmation of the identity of the dichlormid metabolites by a second analytical method."

DAS Response:  DAS agrees that it would have been helpful if the identities of dichlormid and any of the metabolites that were observed could have been confirmed by a secondary method.  Unfortunately efforts to do this by means of LC/MS using extracts of egg yolks and whites and the enzyme hydrolysate solutions from liver and thigh muscle were not successful due to the low levels at which the tentatively identified components were present and to the high levels of co-extractants that were present.  Since none of these components were present at levels that exceeded 0.05 mg/kg, additional work beyond the LC/MS analyses was not deemed necessary.

:: "Lack of dates of sample processing and analysis in the main body of the text."

DAS Response:  DAS agrees that the above information was not provided in the report and is summarized below: 

                                    Repeat Extraction 	Time Before Initial
Sample 		Initial Extraction Date 	(If required) 		Extn (months)
Thigh 			1-Mar-01 			2-May-01 		4.5
Breast		 	22-Mar-01 			2-May-01 		5
Skin and fat 		22-Mar-01 						5
Abdominal fat 	22-Mar-01 						5
Liver 			22-Mar-01 			2-May-01 		5
Egg White Day 5 	10-Apr-01 						6
Egg White Day 13 	10-Apr-01 						6
Egg Yolk Day 5 	10-Apr-01 						6
Egg Yolk Day 		13 10-Apr-01 						6
Sacrifice Date: 	16-Oct-00
Egg Collection Date 	02-16 Oct00

Conclusion:  ARIA and HED have considered the registrant's comments and determined that the previously submitted livestock metabolism study is adequate for the current use on corn.  The residue of concern for livestock is parent dichlormid.  Livestock tolerances are not required at this time; however, should additional uses on other crops be requested, the data should be reassessed if there is an increase in the livestock dietary burden.  

860.1340: Residue Analytical Methods

EPA Comment:  The requested revised method has not yet been received.

DAS Response:  The requested revised method was submitted to the Agency on 29 October 1998, MRID #44960101.

Conclusion:  A copy of the proposed analytical method has been received.  The method will be forwarded to FDA.

860.1900: Field Accumulation in Rotational Crops

EPA Comment:  No studies in field accumulation in rotational crops have been submitted.  The registrant should submit a field accumulation in rotational crop study in accordance with OPPTS Guideline 860.1900.

DAS Response:  The Agency did not previously require a field accumulation in rotational crops study as a condition of approval of the time-limited tolerance.  This is a new requirement.  As a result, Dow AgroSciences is requesting a waiver.  The waiver request documents the reasons that a field accumulation in rotational crops study for the herbicide safener dichlormid is not needed in order to convert the current temporary tolerances for residues of dichlormid in corn to permanent tolerances.

Dichlormid (N, N-diallyl-dichloroacetamide) is a herbicide safener that is used solely 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. The current label for these products allows for either a pre-emergent soil application or an early post-emergent application to corn at rates not to exceed 0.56 kg/ha for the safener.

As part of the registration process to obtain approval for the use of dichlormid on corn, a metabolism study was run in corn along with additional metabolism studies in ruminants (goats) and poultry.  In addition to these studies, a confined rotational crop (CRC) study in which wheat, carrots and soybeans were planted back to 14C dichlormid treated soil at 30, 120 and 365 days after application was also conducted (The Uptake and Metabolism of 14C Dichlormid in Confined Rotational Crops; MRID 46353807).  Based on results from these studies along with residue data from a field magnitude of residue study that was conducted in corn, a temporary tolerance of 0.05 mg/kg was established for residues of dichlormid in corn grain, forage and stover.  In a Residue Chemistry Branch (RCB) response (DP Barcode D321928, 15 Nov 2005) to a DAS request that these temporary tolerances be converted to permanent tolerances, one of the reasons cited for denying the request was the absence of a field accumulation in rotational crop study that was run in accordance with OPPTS Guideline

860.1900. Based on results from the dichlormid confined rotational crop study, on the rapid dissipation of the safener and its metabolites in soil and on the restrictions for rotational crops that are already in place on the acetochlor product label, DAS feels that the request for a field accumulation rotational crop study is unwarranted.  The purpose of this document is to review the data that led to this conclusion and to request a waiver for this study requirement.

In the review summary of the CRC study that was included in the previously cited RCB response, it was concluded that "based on this confined rotational crop study, the label crop rotation restriction for all crops is one year, because (total radioactive) residues >0.01 ppm were found at 30 DAA and 120 DAA in all three rotational crops."  This conclusion was presumably the basis for the request for the field accumulation in rotational crop study since the current acetochlor product label has two limited provisions that allow for plant back intervals of less than one year.  Per the label, only corn itself can be planted back within the first 30 days after application (DAA).  Since the metabolism of dichlormid in corn has already been determined from the NOR study and since tolerances based on results from field MOR studies have already been proposed, no further discussion should be necessary to support this provision on the label.

The other noted exception to the one year rotational crop restriction is the allowance for wheat to be planted into treated fields at 120 DAA.  The acceptability of this provision is best understood by comparing results from the analyses of the 30 DAA and 120 DAA wheat samples from the CRC study.  Looking first at the 30 DAA wheat samples, TRR levels in forage, hay, stover and grain were 0.169, 0.639, 0.629 and 0.295 mg/kg, respectively.  Characterization of the residues in those commodities that are used solely as animal feed stock items (i.e., forage, hay and stover) showed the presence of only low levels of parent dichlormid (3.1% or less of the TRR) along with five metabolites that were chromatographic matches for several of the available metabolite reference standards.  Each of these metabolites was present at levels representing 0.4-9.7% of the TRR (0.003-0.028 mg/kg) in the respective samples in which they were observed and were formed as a result of either oxidative dechlorination and/or dealkylation of the amide nitrogen.  In addition to these metabolites, each sample also contained significant levels of highly polar radioactivity that could not be separated or retained by reverse phase HPLC.  There were also significant levels of radioactivity that could not be readily extracted with either organic solvent or with solvent/water mixtures and that were only released following enzyme digestion or base hydrolysis.  These latter residues were thought to represent radioactivity that was either closely associated with or actually incorporated into cell wall polysaccharides and lignin.  Based on that latter observation, it was thought that the aforementioned, polar extractable residues also most likely consisted of natural products into which the radiolabeled carbon from the 14C test material had been incorporated.

Characterization of the residues in wheat grain showed only low levels of readily extractable radioactivity (10% or less of the TRR).  As with the preceding feed stock items, significant portions of the grain residues (>60% of the TRR) were shown to consist of radioactivity that had been incorporated into natural products such as the glucose in starch and the other reducing sugars that are present in grain.  Even at this early plant back interval, no residues of dichlormid or any of the previously observed metabolites were found to-be present in wheat grain.

By the time of the 120 DAA plant back interval, TRR levels in forage, hay, straw and grain were two to four times lower than seen in the 30 DAA samples as they represented residues of 0.061, 0.155, 0.260 and 0.080 mg/kg, respectively.  Characterization of the residues in forage, hay and straw showed no parent dichlormid to be present in any of these commodities.  Four of the five metabolites seen in the 30 DAA samples were also observed at varying levels in these samples.  These included the N,N-diallyl-acetamide and N,Ndiallyl-2-hydroxyacetamide metabolites in forage (1.3-3.9% TRR; <0.00 1-0.002 mg/kg); the N,N-diallyl-2-hydroxyacetamide, N,N-diallyl-2-chloroacetamide and N-allyl-2,2-clichioroacetamide metabolites in hay (0.3-1.5% TRR; <0.001-0.002 mg/kg); and the N,N-diallyl-2-hydroxyacetamide and N-allyl-2,2-dichloroacetamide metabolites in straw (1.4- 2.1% TRR; 0.004-0.005 mg/kg).  As with the 30 DAA samples, the bulk of the remaining radioactive residues in these samples were thought to be natural product related.  Likewise analyses of the residues in the 120 DAA grain showed the total absence of any dichlormid related residues (either parent or metabolites), with at least 60-70% of the TRR again shown to be associated with the glucose in starch or with the other reducing sugars that are found in grain.

The lower TRR levels in the 120 DAA samples as compared to the 30 DAA samples and the absence of any residues of dichlormid in these same samples along with lower levels of the dichlormid related metabolites were not at all surprising given the short half-life (DT50 = 7.5 days) seen for dichlormid in the aerobic soil metabolism study (Aerobic Soil Metabolism of R25788, ICI Agricultural Product, MRID 41561412) as well as the rapid rate of mineralization of the radiolabeled test material to 14C02 (approximately 50% of the applied radioactivity within the first 30 days) as was seen in that same study.  The rapid rate of mineralization also helps to explain the high levels of incorporation of radioactivity into natural products that was seen in the CRC samples.

Based on these findings, the following conclusions can be made concerning dichlormid related residues in the forage, hay, straw and grain of wheat that is planted back into treated fields at 120 DAA:

:: Wheat grain will contain no residues of dichlormid or any of its structurally related metabolites. As such, there will be no direct human exposure to dichlormid related residues as a result of the dietary consumption of grain that is grown in accordance with this rotational crop practice.

:: No residues of unchanged parent dichlormid will be present in wheat forage, hay or straw.  While two to three structurally related metabolites of dichlormid may be present in each of these same three commodities, none of these metabolites will be present individually at levels in excess of 0.005 mg/kg.  Collectively, none of these metabolites will be present in any of the wheat commodities at levels in excess of 0.010 mg/kg.

:: Any metabolites present in these commodities will be formed as a result of dechlorination and/or N-dealkylation of the parent test material.  These metabolic alterations are same as those that were seen during the nature of the residue study that was run in the primary crop (Dichlormid Metabolism in Corn, MRID 46015801).  None of the metabolites observed in the CRC study would be expected to be any more toxic than dichlormid itself and, in most cases, may even be predicted to be somewhat less toxic.

:: Based on results from the ruminant and poultry nature of residue studies that have been run with dichlormid (The Distribution and Metabolism of 14C Dichlormid in the Lactating Goat, MRID 46015802; and The Distribution and Metabolism of 14C Dichlormid in Laying Hens, MRTD 46015803), the feeding of wheat forage, hay, straw or grain that is grown at a 120 DAA plant back interval would not result in the transference of any detectable dichlormid related residues into meat, milk or eggs.

Given the preceding information, it is evident that any dichlormid related residues that might be present in the forage, hay, straw or grain of wheat that is grown in treated fields after a 120 day plant back interval would be low and would be multi-component in nature.  No individual component would be present at levels even approaching 0.010 mg/kg and as such would pose no risk to human health as a result of the dietary consumption of either grain products or the meat, milk or eggs from animals that have consumed feed stock items grown at that same plant back interval.  In light of this evidence then, it is clear that there are no significant residues of concern for dichlormid in any of the commodities from crops that are allowed to be planted back during the first year following application of the DAS acetochlor product line that contains the herbicide safener.  Thus, DAS feels that a field accumulation in rotational crop study is unnecessary and respectively requests that this study requirement be waived. 

Conclusion:  ARIA and HED has considered the registrant's comments and determined that no field rotational crop data is required for the current uses of dichlormid.  However, additional data will be required should the registrant request higher use rates or shorter PBIs.

860.1550 Proposed Tolerances

Tolerance expressions are set in terms of the parent compound only.  However, the tolerance expression for dichlormid residues needs to be updated to reflect current Agency policy:  "Tolerances are established for residues of dichlromid, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only dichlormid (2,2-dichloro-N,N-di-2-propenylacetamide) in or on the following commodities:"  

Currently there are no international harmonization issues associated with the use of dichlormid

Table 1.  Tolerance Summary for Dichlormid.
Commodity
Established/Proposed Tolerance (ppm)
Recommended Tolerance (ppm)
Comments (correct commodity definition)
Corn, field, forage
                                     0.05
                                     0.05
                                       
Corn, field, grain
                                     0.05
                                     0.05
                                       
Corn, field, stover
                                     0.05
                                     0.05
                                       
Corn, pop, grain
                                     0.05
                                     0.05
                                       
Corn, pop, stover
                                     0.05
                                     0.05
                                       
Corn, sweet, forage
                                     0.05
                                     0.05
                                       
Corn, sweet, kernel plus cob with husks removed
                                     0.05
                                     0.05
                                       
Corn, sweet, stover
                                     0.05
                                     0.05