Document ID: EPA-HQ-OPP-2005-0477-0009
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 CHEMICAL SAFETY AND
                                                                                            POLLUTION PREVENTION
	

MEMORANDUM

Date:		01/13/2011

SUBJECT:	Dichlormid; Human Health Risk Assessment for the Purpose of Making Time-Limited Tolerances on Field Corn Commodities Permanent.  

PC Code:  900497
DP Barcode:  D385691
Decision No.:  419811
Registration No.:  62719-367, 62719-368, 62719-369, 62719-370, 62719-371, 62719-372, 62719-373
Petition No.:  NA
Regulatory Action: Section 3 Registration 
Risk Assessment Type:  Single chemical aggregate
Case No.:  NA
TXR No.:  NA
CAS No.:  37764-25-3
MRID No.:  NA
40 CFR:  180.469

FROM:	Debra Rate, Ph.D., Biologist
		Alternative Risk Integration and Assessment (ARIA) Team
		Risk Integration, Minor Use, and Emergency Response Branch (RIMUERB)
		Registration Division (RD; 7505P)
		
		
THROUGH:	Pv Shah, Branch Chief
		Inert Ingredients Assessment Branch (IIAB)/RD (7505P)
		
		
TO:		Susan Stanton
		Herbicide Branch (HB)/RD (7505P)

ARIA/RD of the Office of Pesticide Programs (OPP) is charged with re-evaluating the risk to human health that will result from converting the time-limited tolerances to permanent tolerances for the registered uses of the chemical, dichlormid (N,N-diallyl-2,2-dichloroacetamide) when used as an herbicide safener (inert ingredient) in pesticide formulations with the active ingredient, acetochlor on corn commodities.  The time-limited tolerances for dichlormid in/on corn (field, pop, and sweet) commodities were due to expire 12/30/2010.  

The risk assessment recommendations were prepared by Debra Rate (ARIA/RD).  The risk assessment incorporates new toxicology assessments prepared by Anwar Dunbar (RAB1/HED), recent residue chemistry reviews prepared by William Cutchin (ARIA/RD), and a drinking water assessment was prepared by Alex Clem (Environmental Fate and Effects Division (EFED)).  The current document reassesses the exposure and risk to human health from dichlormid resulting from the registered uses.  The most recent human health risk assessment for dichlormid was prepared by B. Hanson (DP#321928, 11/15/2005).  

I.	CONCLUSIONS

ARIA recommends that the current time-limited tolerances supporting the use of the herbicide safener, dichlormid, in/on corn, field (forage, grain, and stover), corn, pop (grain and stover), and corn, sweet (grain and stover) at 0.05 ppm (40 CFR§180.469) be converted to permanent tolerances.  

The Hazard Identification Assessment Review Committee (HIARC) previously recommended that the FQPA SF be retained at 10X for enhanced sensitivity to infants and children since there was qualitative evidence of increased susceptibility in the rabbit developmental study and data gaps (HED DOC. NO. 013614, 08/05/1999)  Based on the recent submission and evaluation of required toxicological studies and residue chemistry data, ARIA recommends that the Food Quality Protection Act (FQPA) Safety Factor (SF) be reduced from 10X (acute) and 30X (chronic) to 1X, eliminating the need for additional database uncertainty factors (UFDB).  The reviews of the recently submitted toxicological studies did not result in a lower no-observable adverse-effect level (NOAEL) or lowest-observable adverse-effect level (LOAEL) for dichlormid.  Therefore, the HIARC recommended toxicological endpoints and doses used for risk assessment remain unchanged.  

The current request does not require any change in tolerance value or use patterns.  With the submission of data and studies that fulfill the previously cited data gaps, and the recommended reduction of the FQPA SF, a new comprehensive risk assessment for dichlormid is not required at this time.  The most recent risk assessment (DP#321928, B. Hanson, 11/15/2005), is highly conservative and supports the current use patterns and tolerances.  The risk assessment indicates there is a reasonable certainty that no harm will result from aggregate exposure to dichlormid residues, including all anticipated dietary exposures from food and drinking water.  The risk assessment also indicates aggregate and occupational risks are not of concern.  

In accordance with HED's Interim Guidance on Tolerance Expressions (5/27/2009, S. Knizner), and as requested in an Agency memo (DP#372259, W. Cutchin, 03/31/2010), the tolerance expression for dichlormid should be revised to state:
      Tolerances are established for residues of dichlormid, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with 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:

An adequate enforcement method for residues of dichlormid in corn has been developed and submitted to the Agency.  Analysis is carried out using gas chromatography with nitrogen selective thermionic detection.  The limit of quantitation is 0.01 ppm.  Previously requested method modifications have been received and reviewed by the Agency, thus fulfilling this outstanding deficiency (MRID No. 44960101).

II.	ACTION REQUESTED

Dow AgroSciences, Inc., has submitted a request to convert the current time-limited tolerances for corn commodities (40 CFR§180.469) to permanent tolerances.  Data submitted by the petitioner to fulfill data gaps cited in previous risk assessments and chemistry reviews have been evaluated by the Agency.  

III.	BACKGROUND
DP#321928, B. Hanson, 11/15/2005
DP#318075, D. Rate, 09/14/2005

Dichlormid is an herbicide safener used in pesticide formulations with the active ingredient, acetochlor, for use on corn commodities to control grass and broadleaf weeds.  No new requested uses or tolerances are associated with this petition to make current time-limited tolerances permanent.

There are no existing or proposed residential uses for dichlormid, therefore the risk associated with residential exposure is below the Agency's level of concern (LOC).  Due to the data gaps cited in the previous risk assessment, the time-limited tolerances were extended, rather than made permanent in the most recent assessment (DP#321928, B. Hanson, 11/15/2005).  

The following data gaps were cited in the previous risk assessment and needed to be addressed prior to establishing permanent tolerances on the corn commodities, as requested:  

Chemistry
1.  860.1300: Nature of the Residue - Plants
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.

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.

Toxicology:
1.  Subchronic dermal and inhalation study
2.  Neurotoxicity study
3.  Metabolism studies
4.  As per revisions to the 40CFR158:
	Immunotoxicy studies
	
Due to the nature and number of data gaps and qualitative evidence of increased susceptiblilty in the rabbit developmental study, the FQPA SF was previously established at 10X for the acute assessment, and 30X for the chronic assessment.  Both FQPA SFs contribute to the highly conservative nature of the results obtained in the previous risk assessment.  

The previous risk assessment (DP#321928, B. Hanson, 11/15/2005) was highly conservative using tolerance level residues in the dietary assessment, 100% crop treated, default processing factors, and maximum use rates for determining field trial and water exposure modeling residues.  Previously, the dietary risk (food only) associated with the use of dichlormid was below the Agency's LOC.  The acute dietary risk estimates were 3.4% of the acute population-adjusted dose (aPAD) for the general U.S. population and 7.5% of the aPAD for the highest exposure group, all infants (< 1 year old).  Chronic dietary risk estimates were 6.1% of the chronic population-adjusted dose (cPAD) for the general U.S. population and 15% of the cPAD for the highest exposure group, children 3-5 years old (DP#321927, B. Hanson, 11/07/2005).  Previously, exposure and risk to drinking water was evaluated through the use of drinking water level of comparison (DWLOCs).  A DWLOC is a theoretical upper limit on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food, drinking water, and through residential uses.  A DWLOC will vary depending on the toxic endpoint, with drinking water consumption, and body weights.  Different populations will have different DWLOCs.  HED previously used DWLOCs internally in the risk assessment process as a surrogate measure of potential exposure associated with pesticide exposure through drinking water.  In the absence of monitoring data for pesticides, it was used as a point of comparison against conservative model estimates of a pesticide's concentration in water.  As calculated in the most recent human health risk assessment for dichlormid (DP#321928, B. Hanson, 11/15/2005), all DWLOCs exceeded the EFED modeled drinking water residue values provided for risk evaluation (DP#258095, A. Clem, 8/3/99). Therefore the Agency's level of concern for drinking water exposure was not exceeded.  

Since the last risk assessment was completed, studies have been reviewed that address the data gaps listed above.  The results below discuss the reviews and the impact of this data on the risk and exposure from use of dichlormid as a safener on corn (field, pop, and sweet).  

IV.	RESULTS/DISCUSSION 
DP#372259, W. Cutchin, 03/31/2010
DP#369088 and 369089, A. Dunbar, 04/07/2010
DP#378513, A. Dunbar, 08/24/2010

The Agency has recently evaluated the residue chemistry deficiencies (DP#372259, W. Cutchin, 03/31/2010) and the toxicology data gaps (DP#369088 and 369089, A. Dunbar, 04/07/2010 and DP#378513, A. Dunbar, 08/24/2010).  

Chemistry (DP#372259, W. Cutchin, 03/31/2010):
860.1300: Nature of the Residue  -  Plants:  Upon evaluation of the registrant's responses to the cited data deficiencies (above), and re-evaluation of the original studies submitted, the Agency has determined that the previously submitted plant metabolism study is adequate.  The residue of concern was determined to be the parent, dichlormid.  It was also determined that should additional uses of dichlormid on crops other than corn be requested, the nature of the residue data on those commodities will be required.  

860.1300: Nature of the Residue  -  Livestock:  Upon consideration of the registrant's comments and responses to the cited data deficiencies (above), and re-evaluation of the original submitted studies, the Agency has determined that the previously submitted livestock metabolism study is adequate for the current use on corn.  

860.1340: Residue Analytical Methods:  The requested revised method has since been received by the Agency and a copy will be forwarded to the FDA.

860.1900: Field Accumulation in Rotational Crops:  Following consideration of the registrants responses and re-evaluation of the original studies, the Agency determined that no field rotational crop data is required for the current uses of dichlormid.  However, it was also determined that additional data will be required should the registrant request higher use rates or shorter plant back intervals (PBIs).

Toxicology (DP#369088 and 369089, A. Dunbar, 04/07/2010 and DP#378513, A. Dunbar, 08/24/2010):

In response to the registrant's comments the following studies were determined to be acceptable/guideline: Subchronic Inhalation in rats (MRID No. 00155678), Acute Neurotoxicity in rats (MRID No. 46353805), and Metabolism (MRID No. 46353802 and 46353803).  The third metabolism study (MRID No. 46366001) was determined to be acceptable/non-guideline.  The final study reviewed in Agency memo (DP#369088 and 369089, A. Dunbar, 04/07/2010), Subchronic Neurotoxicity (MRID No. 46353806) was determined to be unacceptable/guideline.  The Agency also reviewed an immunotoxicity study (rat feeding) and determined that the study is acceptable/guideline (DP#378513, A. Dunbar, 08/24/2010).

All of the toxicology and residue chemistry data gaps for use on corn (field, pop, and sweet), have been fulfilled.  Uncertainty factors associated with database deficiencies can be removed.

Impact on Aggreaget Risk:
There are no existing or proposed residential uses for dichlormid, therefore aggregate risk is based on dietary exposure from food and water.  A dietary (food and water) exposure and risk assessment was performed incorporating the EDWCs (DP#258095, A. Clem, 08/03/1999) into water, direct (all sources) and water, indirect (all sources), and the HIARC determined toxicological endpoints in the Agency's dietary exposure model (DEEM-FCID(TM), Version 2.03).  Analysis using the current FQPA SFs (10X acute, 30X chronic) and appropriate toxicological endpoints (See Attachment 1) resulted in acute risk (95[th] percentile) at 16% of the aPAD for the general US population and 56% of the aPAD for the highest exposed population (All infants <1year) and chronic risk at 13% of the cPAD for the general US population and 34% of the cPAD for the highest exposed population subgroup (All infants < 1year).  Using the same residue values, appropriate toxicological endpoints and the recommended FQPA SF reduced values (1X) resulted in an acute risk (95[th] percentile) of 2% of the aPAD for the general US population and 6% of the aPAD for the highest exposed population (All infants <1 year), and <1% cPAD, for the general US population and 1% of the cPAD for the highest exposed subpopulation (All infants <1 year).  All of the dietary analyses (food and water) were well below the Agency's LOC for the general US population and all population subgroups, whether the new recommended FQPA SF was included or not.

Permanent tolerances for corn commodities are supported by the previous risk assessment, recently reviewed studies, and the new dietary analyses discussed above.  A comprehensive risk assessment for dichlormid to make current time-limited tolerances on corn commodities permanent, is not required at this time.

Occupational Exposure and Risk Associated with the Use of Dichlormid on Corn
Occupational exposures may occur via dermal and/or inhalation routes.  The HIARC has identified toxicological endpoints of concern for occupational exposure.  However, based on the use patterns for dichlormid on corn (pre-emergence soil or early post-emergence foliar applications) no potentially significant post-application or long-term exposure is expected.  Therefore, the previous occupational assessment (DP#321928, B. Hanson, 11/15/2005) is protective for the proposed use pattern.  For dichlormid, margins of exposure (MOEs) of 100 are required for handlers of agricultural crops in order for risks not to be of concern to HED.  For all previously assessed handler scenarios, short- and intermediate-term MOEs were greater than the target MOE of 100 and, therefore, risks do not exceed HED's level of concern.  Therefore, there are no risk concerns associated with the use pattern.

Attachment 1:  Toxicological Endpoints for Dichlormid.

Table 1.  Summary of Toxicological Dose and Endpoints for Dichlormid Use in Human Risk Assessment 1.

Exposure
Scenario

Dose (mg/kg/day) and Factors

FQPA SF and Endpoint for Risk Assessment

Study and Toxicological Effects

Acute Dietary
all populations including infants and children

NOAEL= 10 mg/kg
UF = 100
Acute RfD = 0.10 mg/kg/day

FQPA SF = 10
aPAD = acute RfD
FQPA SF

= 0.010 mg/kg/day

Developmental Toxicity Study - rat

Maternal LOAEL = 40 mg/kg/day based on decreased body weight gain and food consumption (most significant on days 7-10 of dosing).

Chronic Dietary
all populations

NOAEL= 6.5 mg/kg/day
UF = 100
Chronic RfD = 0.065 mg/kg/day

FQPA SF = 30
cPAD = chr RfD
FQPA SF

= 0.0022 mg/kg/day
Extra 3x UF due to data gap for the chronic toxicity study in dogs.

2-year Study  - Rat

LOAEL = 32.8 mg/kg/day (c?) based liver clinical pathology / histopathology and increased liver weight.  
Dermal Absorption
100% default; neither a dermal aborption study nor a dermal toxicity study (for extrapolation) is available in the database.
Short-Term Dermal

Oral NOAEL = 10.0

MOE = 100
Developmental toxicity Study  -  rats

Maternal LOAEL = 40 mg/kg/day based on decreased body weight gain and food consumption (most significant on days 7-10 of dosing).  This dose/endpoint/study was used for deriving the aRfD.  Dermal toxicity study is not available.  100% dermal absorption factor should be used for this risk assessment.

Intermediate- and Long-Term
(Dermal)

Oral NOAEL =  6.5

MOE = 100

2-year study - rat

LOAEL = 32.8 mg/kg/day () based on liver clinical pathology/histopathology and increased liver weight.
This dose/endpoint/study was used for deriving the cRfD.  100% dermal absorption factor should be used for this risk assessment.

Inhalation
(All Durations)

2 μg/L

14-week inhalation study

LOAEL = 19.9 μg/L based on clinical signs, increased liver and kidney weights, gross pathology and non-neoplastic histopathology.  The route of exposure in this study is appropriate for this risk assessment.

Cancer

NOAEL = 6.5

LOAEL = 32.8 mg/kg/day based on decreased BWG, decreased FE, increased liver weight, and liver histopath.
No evidence of carcinogenicity.

Feeding/
Carcinogenicity Study in rats
1 UF = uncertainty factor; FQPA SF = FQPA Safety Factor; NOAEL = no observed adverse effect level; LOAEL = lowest observed adverse effect level; PAD = population adjusted dose (a=acute, c=chronic); RfD = reference dose; LOC = level of concern; MOE = margin of exposure.