Dichlormid UNITED STA TES ENVIRONMENTA L PROTECTION AGENCY

MEMORANDUM Date : 01 / 13 / 201 1 SUBJECT: Dichlormid ; Human Health Risk Assessment for

Limited Tolerances on Field Corn Commodities Permanent PC Code: 900497 Decision No.: 419811
Petition No.: NA Risk Assessment Type: Single chemical aggregate T XR No.: NA MRID No.: NA 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

In ert Ingredients Assessment Branch (IIAB)/
TO: Susan Stanton

Herbicide Branch (HB)/ ARIA/RD of the Office of Pesticide Programs (OPP) is charged with re human h ealth that will result from converting the for the registered uses of the chemical, dichlormid used as an herbicide safener (inert ingredient) in pesticide formulations with the active ingredient, acetochlor o n corn commodities corn (field, pop, and sweet) commodities The risk assessment recommendations were prepared b y Debra Rate (ARIA/RD). The risk assessment incorporates ne w toxicology assessments prepared b y Anwar Dunbar (RAB1/HED) recent residue chemistry

reviews prepared b y William Cutchin (ARI A/RD) Human Health Risk Assessment

Page 1 of 8 UNITED STA

TES ENVIRONMENTA L PROTECTION AGENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

; Human Health Risk Assessment for the Purpose of Making Time Limited Tolerances on Field Corn Commodities Permanent
. DP Barcode: D 385691 Registration No. : 62719
- 367, 62719 62719
- 369, 62719
- 370, 62719 372, 62719
- 373 Regulatory Action: Section 3 Registration Single chemical Case No.: NA

CAS No.: 37764
- 25
- 3 40 C FR: 180. 469 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)
Branch Chief In ert Ingredients Assessment Branch (IIAB)/ RD (7505P)
Herbicide Branch (HB)/ RD (7505P) ARIA/RD of the Office of Pesticide Programs (OPP) is charged with re

- evaluating the risk to ealth that will result from converting the time

- limited tolerances to permanent tolerances 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

n 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 b y Debra Rate (ARIA/RD). The risk w toxicology

assessments prepared b y Anwar Dunbar (RAB1/HED) residue chemistry

reviews prepared b y William Cutchin (ARI A/RD) , and a DP# 385691 UNITED STA

TES ENVIRONMENTA L PROTECTION AGENCY

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

the Purpose of Making Time

367, 62719
- 368,

- 371, 62719
- Section 3 Registration

Risk Integration, Minor Use, and Emergency Response Branch (RIMUERB)

evaluating the risk to limited tolerances to permanent tolerances

dichloroacetamide) when used as an herbicide safener (inert ingredient) in pesticide formulations with the active limited tolerances for dichlormid in/on The risk assessment recommendations were prepared b y Debra Rate (ARIA/RD). The risk w toxicology

assessments prepared b y Anwar Dunbar (RAB1/HED) , , and a drinkingDichlormid Human Health Risk Assessment DP# 385691

Page 2 of 8 water assessment was prepared by Alex Clem (Environmental Fate and Effects Division (EFED)). The current d ocument 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 b y B. Hanson ( D P# 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 ( HI ARC ) previously recommended that the FQPA SF be retained at 10 X for enhanced sensitivity to infants and children since there was qualitative evidence of increased susceptibil ity 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) S afet y F actor (SF) be reduced from 10X (acute) and 30X (chronic) to 1X, eliminating the need for additional database uncertaint y factors (UF DB ). The reviews of the recentl y submitted toxicological studies did not result in a lower no

- observable adverse

- eff

ect level (NOAEL) or lowest

- observable adverse

- effect level (LOAEL) for dichlormid. Therefore, the HI ARC recommended toxicological endpoints and doses used for risk assessment remain unchanged. The current request does not require an y change in toleran ce 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 r esidues, 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/ 20 09, 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 b y measuring onl y dichlormid (2,2

- dichloro

N,N
- di

- 2
- propen yl acetamide) in or on the following commodities: An adequate enforcement method for residues of dichlormid in corn has been developed and submitted to the Agency
. Analy sis is carried out using gas chromatograph y with nitrogen selective thermionic detection. The limit of quantitation is 0.01 ppm. Previously requested method modification s have been received and reviewed b y the Agency , thus fulfilling this outstanding deficiency (MRID No. 44960101)
.Dichlormid Human Health Risk Assessment DP# 385691

Page 3 of 8 II. ACTION REQUESTED Dow AgroSciences, Inc., has submitted a request to convert the current time

- limited tolerances for corn commodities (4 0 CFR §180. 469) to permanent tolerances. Data submitted by the petitioner to fulfill data gaps cited in previous risk assessment s 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 cite d in the previous risk assessment, the time

- limited tolerances were extended, rather than made permanent in the most recent assessment ( D P# 321928 , B. Hanson , 11/15/2005). The following data gaps were cited in the previous risk assessment and need ed to b e 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. 860.130 0: Nature of the Residue

- Livestock The studies submitted (MRID No. 46015802, 46015803) for the purpose of fulfilling the Guideline 860.1300 are scientificall y unacceptable and do not satisfy the requirements. The studies do not adequatel y 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 Analy tical Methods The requested revised method has not y et been receiv ed. 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.Dichlormid Human Health Risk Assessment DP# 385691

Page 4 of 8 T oxicology : 1. S ubchronic dermal and inhalation study 2. N eurotoxicity 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 highl y conservative nature of the results obtained in the previous risk assess ment. The previous risk assessment (D P# 321928 , B. Hanson , 11/15/2005 ) was highl y 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 a cute dietary risk estimates were 3.4% of the acute po pulation

- adjusted dose (aPAD) for the general U.S. population and 7.5% of the aPAD for the highest exposure group, all infants (< 1 ye ar old). Chronic dietary risk estimates were 6.1% of the chronic population

- adjusted dose (cPAD) for the general U.S. pop ulation and 15% of the cPAD for the highest exposure group, children 3

- 5 y ears old ( DP# 321927, B. Hanson, 11/07/2005). Previously , e xposure and risk to drinking water was evaluated through the use of drinking water level of comparison (DWLOCs). A DWL OC i s 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 DWL OCs 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 ri sk assessment was completed, s tudies 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, 08/24/2010Dichlormid Human Health Risk Assessment DP# 385691

Page 5 of 8 The Agency

has recentl y 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

- evaluati on of the original studies submitted , the Agency has determined that the previously submitted plant metabolism study is adequate. The residue of concern was d e t ermined to be the parent, dichlormid. It w as also determined that shoul d 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

– Li vestock: 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: R esidue 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

- evaluati on 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 sh orter 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 (MRI D No. 46353802 and 46353803). The third metabolism study

(MRID No. 46366001) was determined to be acceptable/non

- guideline. The final study

review ed 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 acce ptable/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 wi th 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, 0 8/ 0 3/ 19 99 ) into water, direct (all sources) and water, indirect (all sources) , and the HIARC determinedDichlormid Human Health Risk Assessment DP# 385691

Page 6 of 8 toxicological endpoints in the Agency ’s dietary exposure model ( DEEM
- FCIDTM, Version 2.03 ). Analy sis u sing 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 5 6% of the aPAD for the highest exposed population ( All infants <1y ear ) 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 < 1 year). Using the same residue values , appropriate toxicological endpoints and the recommended FQPA SF redu c ed values (1X) r esulted 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 y ear), and <1% cPAD, for the general US population and 1% of the cPAD for the h ighest exposed subpopulation (All infants <1 y ear). All of the dietary anal ys es (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
. Permane nt tolerances for corn commodities are supported by the previous risk assessment , recentl y reviewed studies , and the new dietary analy ses discussed above
. A comprehensive risk assessment for dichlormid to make current time

- limited tolerances on corn commo dities 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 earl y post - emergence foliar applications) no potentially significant post

- application or long

- term e xposure 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 conc erns asso ciated with the use pattern
.Dichlormid Human Health Risk Assessment DP# 385691

Page 7 of 8 Attachment 1: Toxicological Endpoints for Dichlormid.
Table 1 . Summary of Toxicological Dose and Endpoints for Dichlorm id Use in Human Risk Assessment 1
. Exposure Scenario Dose

(m g/kg/day) and Factors FQPA SF and

Endpoint for Risk Assessment Study and Toxicological Effects

Ac ute 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/d ay 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.

Derm al Absorption 100% default; neither a dermal aborption study nor a dermal toxicity study (for

extrapolation) is available in the database. Short

- Term Derm al 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 (Derm al) 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
- we ek 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. NOAEL = 6.5 LOAEL = 32.8 Feeding/Dichlormid Human Health Risk Assessment DP# 385691

Page 8 of 8 Table 1 . Summary of Toxicological Dose and Endpoints for Dichlorm id Use in Human Risk Assessment 1
. Exposure Scenario Dose

(m g/kg/day) and Factors FQPA SF and

Endpoint for Risk Assessment Study and Toxicological Effects
Cancer mg/kg/day based on decreased BWG, decreased FE, increased liver weight, and liver histopath. No evidence of carcinogenicity. Carcinogenicity Study in rats

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