Document ID: EPA-HQ-OPP-2011-0641-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-01-27T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C. 20460
                                       

                                                  OFFICE OF CHEMICAL SAFETY AND
                                                           POLLUTION PREVENTION

DATE:		November 30, 2011	

MEMORANDUM

	SUBJECT:	Amicarbazone:  Occupational and Residential Exposure Assessment for Proposed Uses on Turf, Christmas Tree Farms, Non-Crop Areas and on Conifers in Nurseries.

PC Code:  114004
DP Barcode:  D394924
Decision No.:  441345
Registration Nos.:  66330-46
Petition Nos:  NA
Regulatory Action:  Section 3 Registration
Assessment Type:  Occupational/Residential
Case No.:  NA
TXR No.:  NA
CAS Number:  129909-90-6
MRID:  NA
40 CFR:  180.615
						
				
FROM:		Zaida Figueroa, Industrial Hygienist
		Risk Assessment Branch (RAB) II
		Health Effects Division (7509P)

THROUGH:	Richard A. Loranger, Ph.D., Branch Senior Scientist
		Risk Assessment Branch (RAB) II 
		Health Effects Division (7509P)

TO:		Michael Walsh/Kathryn Montague, RM Team 23 
		Herbicide Branch
		Registration Division (7505P)

Action Requested:

The Registration Division (RD) requested that the Health Effects Division (HED) conduct an exposure and risk assessment for proposed uses of the herbicide amicarbazone to control broadleaf weeds in residential and commercial lawns, golf course, sod farms, recreational turf, non-crop areas, Christmas tree farms and conifers in nurseries.  The proposed use pattern results in the first residential use for the active ingredient.  Note: This memorandum was reviewed by the Exposure Science Advisory Committee (ExpoSAC) on October 20, 2011. 

1.0	Executive Summary	

Amicarbazone, 4-amino-4,5-dihydro-N-(1,1-dimethylethyl)-3-(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide, is a triazolinone herbicide related to carfentrazone, flucarbazone, propoxycarbazone, and sulfentrazone.  A Section 3 registration of a dry flowable formulation is requested by Arysta LifeScience North America, LLC for use on turf (lawns, golf course, sod farms, recreational turf), ornamentals, non-crop areas, Christmas tree farms and conifers in nurseries.  Application timing includes pre-emergence and early post-emergence to control broadleaf weeds.  Amicarbazone may be applied through a variety of application methods including ground equipment, backpack, and hand held equipment.

This assessment addresses exposure and risk associated with the proposed end-use product for amicarbazone when used as directed by commercial applicators as well as residential homeowners.  There is a potential for short- and intermediate-term occupational exposure associated with handler activities (mixing, loading, and applying) as well as with postapplication activities (i.e., re-entering treated areas).  There is also a potential for short-term residential exposure to amicarbazone during handling (mixing, loading, and applying), and postapplication activities.  Chronic exposure is not expected for the proposed use patterns.

Hazard Characterization
The toxicology database is complete and adequate for purposes of this risk assessment.  Amicarbazone exhibits low acute toxicity.  The available database indicates that the major effects in mammals are general toxicity, as evidenced by decreased body weight and weight gain, and liver toxicity.  The mutagenicity battery for this chemical is complete and indicates that amicarbazone is not a mutagen.  Amicarbazone has been classified as "not likely to be a human carcinogen".  Although the acute neurotoxicity study in rats showed signs of neurotoxicity, no such effects were seen in the subchronic and developmental neurotoxicity studies.  

In the previous risk assessment for amicarbazone (K. Kosick, 8/10/2005, D288216), HED concluded there was no dermal endpoint based on the lack of systemic toxicity or local dermal irritation from a 21-day dermal toxicity study in the rat.  Using a ratio of the LOAELs from several oral studies in the rat to the NOAEL from the 21-day dermal rat study (1000 mg/kg/day), a conservative dermal absorption factor of less than 5% was estimated.  Therefore, dermal absorption is not considered to be a major route of uptake for this chemical and the dermal route of exposure was not considered for this risk assessment.  In the absence of a route-specific study for inhalation, HED selected an endpoint from the 90-day dog study for the inhalation exposure and risk assessment.  There were numerous effects observed at the LOAEL of 25 mg/kg/day (thyroid, liver, gall bladder, and blood); the NOAEL of 6.28 mg/kg/day was selected as the point of departure for inhalation risk assessment.  Since no inhalation toxicity data are available, toxicity by the inhalation route is considered to be equivalent to toxicity by the oral route of exposure.   

For the current risk assessment, HED selected an endpoint for the purpose of assessing children's incidental oral exposure on treated turf.  Only short-term (1-30 days) durations are relevant for this route of exposure.  The same subchronic oral toxicity study in the dog used for assessing inhalation exposure and risk was selected for assessing incidental oral exposure. 

FQPA and Uncertainty Factors
The database is complete with respect to pre- and post-natal toxicity and shows no evidence of increased qualitative or quantitative susceptibility.  Although neurotoxicity was observed with exposure to amicarbazone in adult animals in gavage studies, no neurotoxic effects were observed in offspring at dose levels that resulted in general systemic toxicity.  Potential immunotoxic effects were observed in the chronic dog and rat immunotoxicity studies only at doses greater than those selected for risk assessment and are therefore not of concern.  HED recommends that the special 10X FQPA safety factor be reduced to 1X.  No other database uncertainty factors are needed.  The combined uncertainty factors of 100X (10X for intraspecies variability and 10X for interspecies extrapolation) serve as the level of concern (LOC) for occupational and residential exposure and risk.  Margins of exposure (MOEs) greater than 100 are not of concern.

Residential Handler Exposure
A dermal exposure assessment was not performed for residential handlers because no dermal endpoints were selected.  Inhalation MOEs for handlers were significantly greater than the LOC of 100 (ranging from 3,600 to 220,000) and are not of concern.

Residential Postapplication Exposure 
In the absence of a dermal endpoint, oral non-dietary ingestion exposures were assessed for children (i.e. soil ingestion, and hand-/object-to-mouth).  The postapplication scenarios resulting from commercial and residential applications were assessed using the HED Draft Standard Operating Procedures (SOP's) for Residential Exposure Assessments, 2000.  Short-term hand-to-mouth (HTM), object-to-mouth (OTM) and soil ingestion scenarios resulted in MOEs ranging from 910 to 270,000, and are not of concern.  

Since the proposed uses of amicarbazone are applied only in outdoor settings and amicarbazone has a low vapor pressure (2.3 x 10[-][8] mm Hg), postapplication residential inhalation exposure and risk estimates were not quantitatively assessed. 

Summary of Residential Exposure
HED combines risk values resulting from separate exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population.  However, since a dermal endpoint was not selected, the only relevant route of exposure for adults is through the inhalation route.  Therefore, an adult combined residential exposure assessment was not conducted.  Similarly, the only relevant route of exposure for children was through the oral route, and therefore a combined residential exposure assessment was not conducted for children. 

Occupational Handler Exposure
It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data, MRID No. 44339801), and subject to the data protection provisions of FIFRA.  Default assumptions established by the Health Effects Division (HED) Science Advisory Council for Exposure were used for parameters such as body weight, acres treated and amount handled.  All occupational handler scenarios resulted in MOEs greater than the level of concern at the baseline PPE level of protection (i.e. single layer clothing and no respirator). 

Occupational Postapplication Exposure
In the absence of a dermal endpoint, a dermal postapplication exposure assessment was not conducted.  Furthermore, since the proposed uses of amicarbazone are in outdoor settings where postapplication inhalation exposures are expected to be minimal, and because amicarbazone has a low vapor pressure (2.3 x 10[-][8] mm Hg), handler inhalation exposure estimates are considered to be protective of occupational postapplication inhalation exposure scenarios.

Restricted Entry Interval
The restricted entry interval (REI) listed on proposed labels is based on the acute toxicity of the technical material.  Amicarbazone exhibits low acute toxicity and is classified as Toxicity Category III for eye irritation and Category IV for acute dermal and dermal irritation.  It is not a dermal sensitizer.  Acute toxicity Category III and IV chemicals require a 12-hour REI.  Therefore, the 12-hour REI which appears on the proposed labels is considered appropriate. 

Review of Human Research
This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; and the Outdoor Residential Exposure Task Force (ORETF) database; are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html  and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

Label Recommendations

The Registration Division (RD) should ensure the final label does not include the potential for application to Christmas trees using a mechanically pressurized handgun.  No other recommendations are needed based on HED's residential exposure and risk assessment.

2.0.	Hazard Characterization	

Amicarbazone is a triazolinone herbicide which controls broadleaf weeds by selective inhibition of acetolactase synthase, an enzyme involved in photosystem II in plants.  The available database indicates that the major effects in mammals are general toxicity, as evidenced by decreased body weight and weight gain, and liver toxicity.  Decreased body weight and weight gain were observed in studies with rats, mice and rabbits and were the most sensitive toxicological endpoints observed in many of the studies.  In the chronic dog and subchronic rat and dog studies, liver effects were seen; including increased absolute and relative liver weights, slight liver hypertrophy, dilation of sinusoids and increased liver enzymes and cholesterol/triglycerides.

2.1	Hazard Profile	

The toxicology database is complete and adequate for risk assessment.  Amicarbazone exhibits low acute toxicity.  The available database indicates that the major effects in mammals are general toxicity, as evidenced by decreased body weight and weight gain, and liver toxicity.  The mutagenicity battery for this chemical is complete and indicates that amicarbazone is not a mutagen.  Amicarbazone has been classified as "not likely to be a human carcinogen".  Although the acute neurotoxicity study in rats showed signs of neurotoxicity, no such effects were seen in the subchronic and developmental neurotoxicity studies.  

No dermal endpoint was selected for risk assessment, based on the lack of systemic toxicity or local dermal irritation in a 21-day dermal toxicity study in the rat.  Using a ratio of the LOAELs from several oral studies in the rat to the NOAEL from the 21-day dermal rat study (1000 mg/kg/day), a conservative dermal absorption factor of less than 5% was estimated.  Therefore, dermal absorption is not considered to be a major route of exposure for this chemical and the dermal route of exposure was not considered for this risk assessment.  There was no route-specific inhalation toxicity study available for endpoint selection.  Therefore, for short-term (1-30 days) and intermediate-term (1-6 months) inhalation risk assessment, the endpoint was selected from a dog subchronic oral toxicity study in which numerous toxic effects were observed at the LOAEL of 25 mg/kg/day.  These effects included thyroid, liver, gall bladder and blood toxicity.  The NOAEL for the study was 6.28 mg/kg/day, which served as the point of departure for risk assessment.  For extrapolation from oral to inhalation exposure, toxicity via the inhalation route was assumed to be equivalent to toxicity via the oral route.

2.2	FQPA and Uncertainty Factor Considerations

HED has recommended the 10x FQPA factor be reduced to 1x.  No evidence of increased quantitative or qualitative susceptibility was observed in the rat and rabbit developmental toxicity, rat reproductive toxicity or the rat developmental neurotoxicity studies.  Although neurotoxicity was observed with exposure to amicarbazone in adult animals in gavage studies, no neurotoxic effects were observed in offspring in the rat developmental neurotoxicity study at dose levels that resulted in general systemic toxicity (decreased offspring and maternal body weight).  Potential immunotoxic effects (chronic dog and rat immunotoxicity studies) were observed only at doses greater than those selected for risk assessment purposes and are therefore not of concern.

Given the completeness of the database, there are no database uncertainty factors to be retained during risk assessment, and therefore the level of concern (LOC) is a margin of exposure (MOE) of 100, based on the combined uncertainty factors of 100X (10X for interspecies extrapolation and 10X for intraspecies variability).  MOEs greater than the LOC of 100 are not of concern.

Table 1.  Acute Toxicity Profile for Amicarbazone. 
                                 Guideline No.
Study Type
MRID(s)
                                    Results
                                 Tox Category
870.1100
Acute oral - Wistar rats
                                   45121504
Males LD50 > 2050 mg/kg
Females LD50 = 1015 mg/kg
                                      III
870.1200
Acute dermal - Wistar rats
                                   45121503
LD50  > 5000 mg/kg
                                      IV
870.1300
Acute inhalation - Wistar rats
                                   45121506
LC50 > 2.030 mg/L
                                      IV
70.2400
Acute eye irritation - New Zealand white rabbit
                                   45121510
Eye irritation was present (including corneal opacity) at 24 hours, but had cleared by day 7.
                                      III
870.2500
Acute dermal irritation - New Zealand white rabbit
                                   45121509
Primary irritation indices were 0
                                      IV
870.2600
Skin sensitization - Hartley guinea pig
                                   45121628
                                   45121505
All scores during induction and challenge periods were 0.
                            Not a dermal sensitizer

Table 2.  Summary of Toxicological Doses and Endpoints for Amicarbazone for Use in Human Health Risk Assessments.
                              Exposure/ Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                     Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Incidental Oral Short-Term (1-30 days)
NOAEL= 6.28 mg/kg/day
UFA= 10x
UFH=10x
FQPA SF= 1x

Residential LOC for MOE = 100
90-Day Oral Toxicity in Dogs
LOAEL = 25 mg/kg/day based on increased thyroid vacuolization and decreased food consumption and glucose in females; increased platelets, phosphate, bile acids, absolute and relative liver weights, and lymphoid hyperplasia of the gall bladder in males; and decreased albumin and increased triglycerides, N-demethylase and O-demethylase in both sexes.
Dermal (all durations)
No systemic toxicity was observed at the limit dose.  Evidence of low dermal absorption was estimated by comparison of oral and dermal studies in the rat.
Inhalation Short-  and Intermediate-Term (1-30 days and 1-6 months, respectively)
NOAEL= 6.28 mg/kg/day

(Inhalation toxicity considered equivalent to oral toxicity)
UFA= 10x
UFH=10x
FQPA SF= 1x

Occupational/Residential LOC for MOE = 100
90-Day Oral Toxicity in Dogs
LOAEL = 25 mg/kg/day based on increased thyroid vacuolization and decreased food consumption and glucose in females; increased platelets, phosphate, bile acids, absolute and relative liver weights, and lymphoid hyperplasia of the gall bladder in males; and decreased albumin and increased triglycerides, N-demethylase and O-demethylase in both sexes.
Cancer (oral, dermal, inhalation)
Classification:  There was no treatment-related increase in tumor incidence when compared to control.  Dosing was considered adequate.  This chemical is not likely to be a carcinogen.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  MOE = margin of exposure.  LOC = level of concern.  

3.0	Proposed Use Patterns

Amicarbazone, 4-amino-4,5-dihydro-N-(1,1-dimethylethyl)-3-(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide, is a triazolinone compound proposed for the control of annual broadleaf weeds.  Amicarbazone selectively inhibits acetolactase synthase, an enzyme involved in photosystem II of plants.  Related compounds include carfentrazone, flucarbazone, propoxycarbazone, and sulfentrazone.

Arysta LifeSciences North America, LLC is currently seeking use of amicarbazone for control of broadleaf weeds in turf (i.e., lawns, sod farms, golf courses, recreational fields, etc), ornamentals, non-crop areas, Christmas tree farms and conifers in nurseries.  Amicarbazone is formulated as a 70% dry flowable powder.  It is intended for pre-emergence and post-emergence applications.  Broadcast applications are to be made with ground equipment only; spot treatments are to be made using backpacks and hand held equipment.  The product is not to be applied by aerial equipment or through irrigation systems.

Amicarbazone is available for use by commercial and professional applicators.  This herbicide works best when applied and subsequently moved into the soil by rainfall.  The personal protective equipment (PPE) for the proposed label consists of baseline clothing (i.e., long-sleeved shirt and long pants, shoes and socks) and use of chemical resistant gloves.  The proposed uses are anticipated to result in short- and intermediate-term exposure durations.  Table 3 provides a summary of the proposed uses. 

Table 3.  Proposed Products and Uses of Amicarbazone.
Product Trade Name
(EPA Reg. No.)
                                     Crops
                             Method of Application
                        Maximum Application Rates[†] 
                      Maximum Seasonal Application Rates
                       Maximum # Applications per Season
                   Use Directions and other Limitations[‡]
Amicarbazone DF Herbicide (DINAMIC
70 WDG HERBICIDE)
70% ai
(EPA Reg. No. 66330-46)
Turf, golf course, sod farms, parks and recreation areas, athletic fields, landscape plants and tree nurseries, and Christmas trees farms 
                                   Directed;
                    Broadcast using ground equipment only.
            Spot treatment using backpack and compression sprayers.
                       0.46 lb ai/A (single application)
                               (10.5 oz prod/A)
                               (0.023 lb ai/gal)
                               0.46 lbs ai/ A/yr
                         1 appl at the max appl. rate.
                   2-4 appls for turf grass at a lower rate.
                                       
                                       
                                       
12-hr REI
Application intervals from 14-21 days, but may vary depending on application rate.
Do not apply within 4 weeks of cutting or lifting sod.
Do not apply this product using aerial equipment or any irrigation system.
[†]  Max Single Application Rate = (70% ai) (1 lbsolid/16 oz) (10.5 oz/A) = 0.46 lb ai/A (1 A/20gal) = 0.023 lb ai/gal.
[‡]  Minimum Spray Volume = 20 gal/A.

Note:  The proposed label states that the maximum single application rate for turf is 10 oz prod/A.  However, for purposes of this assessment HED used the maximum single application rate of 10.5 oz prod/A based on information provided by the registrant (MRID No. 48237522).  

4.0 Residential (Non-Occupational) Exposure

4.1	Residential Handler Exposure and Risk

The Agency uses the term "Handlers" to describe those individuals who are involved in the pesticide application process.  Based on the proposed label (EPA Reg. No. 66330-46) and information provided by the registrant (MRID No. 48237522), this product is to be applied by professional applicators.  The proposed label includes occupational/commercial mixing/loading activities, PPE and REI requirements.  However, since the proposed label does not identify this product as a restricted use pesticide, a residential handler exposure assessment was performed to be protective of potential homeowner exposure.  

The following exposure scenarios and unit exposures were used to assess residential handlers for broadcast and spot treatments:

   * Mixing/Loading/Applying for Sprays with Backpack Sprayer;
   * Mixing/Loading/Applying for Sprays Using Low-Pressure Handwand; and,
   * Mixing/Loading/Applying for Sprays with Hand-Gun Sprayer (hose-end).

4.1.1	Data and Assumptions

Unit Exposures:  No chemical specific unit exposure data were provided in support of this submission; therefore, HED used data from the PHED Surrogate Exposure Guide for Residential Handlers, Version 1.1, August 1998 and the Occupational Residential Exposure Task Force (ORETF) (MRID 449722-01). 

Acres/Amount Treated:  Information regarding area treated for the various use scenarios was provided by the Science Advisory Council for Exposure Policy #12: Recommended Revisions to the Standard Operating Procedures (SOPs) for Residential Exposure Assessments.  
      
Exposure Duration:  Based on information provided in the proposed labels, residential handler exposure is anticipated to be short-term in duration.  

Body Weight:  The average adult body weight of 70 kilograms was used to assess handler exposure since the endpoints were not gender specific.

4.1.2	Residential Handler Exposure and Risk Estimates

A quantitative dermal assessment for residential handlers was not conducted since no systemic toxicity by the dermal route was seen at the limit dose in the dermal toxicity study.  Handler inhalation exposure scenarios resulted in MOEs greater than 100 and therefore are not of concern.  Handler exposure and risk estimates are summarized in Table 4.  

Table 4.  Residential Handler Exposure Estimates for Amicarbazone.
                                   Scenario
                         Inhalation Unit Exposure[a] 
                                  (mg/lb ai)
                             Application Rate [b]
                                       
                              Amount Treated [c]
                        Inhalation Dose[d] (mg/kg/day)
                              Inhalation MOE [e]
                                Mix/Load/Apply
Backpack Sprayer
(Ground Directed)
                                0.03 (Baseline)
                                    (PHED)
                                       
                                       
                                     0.023
                                   lb ai/gal
                                     5 Gal
                                   0.0000493
                                    130,000
Low Pressure Handwand 
                               1.063 (Baseline)
                                    (PHED)
                                       
                                     5 Gal
                                    0.00175
                                     3,600
Hose-end (for Handgun
Sprayer)
 (Mix your own) 
                        0.017 (Baseline) (ORETF-OMA004)
                                0.023 lb ai/gal
                                     5 Gal
                                   0.000028
                                    220,000

                                       
                                     0.46
                                    lb ai/A
                                     0.5 A
                                   0.000056
                                    110,000
a.  PHED Surrogate Exposure Guide for Residential Handlers, Version 1.1, August 1998.  Occupational Residential Exposure Task Force (ORETF) Study Data (MRID 449722-01).
b.  Application Rate = (70% ai) (1 lbsolid/16 oz) (10.5 oz/A) = 0.46 lb ai/A (1 A/20gal) = 0.023 lb ai/gal.
c.  Policy 12: Recommended Revision to the SOPs for Residential Exposure Assessment.
d.  Inhalation Dose (mg/kg/day) = Inhalation Unit Exposure (mg/lb ai) * Application Rate * Acres Treated or Amount Handled / Body Weight (70 kg).
e  Inhalation MOE = NOAEL (6.28 mg/kg/day) / Inhalation Dose (mg/kg/day).
4.2	Residential Postapplication Exposure

Amicarbazone residential postapplication scenarios include children (3 to 6 years) playing on treated turf, adults performing yard work on treated turf and adults playing golf on treated turf.  
As a result, a wide array of individuals of varying ages can potentially be exposed when they do activities in areas that have been treated.

The postapplication scenarios were assessed using the HED Draft Standard Operating Procedures (SOP's) for Residential Exposure Assessments, 2000.  Since no chemical-specific residue data were submitted for this action, postapplication exposures were assessed using default assumptions from the Residential Exposure SOPs.  

1.0.1 Inhalation Postapplication Exposure

Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for amicarbazone at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) , the low vapor pressure (2.3 x 10[-][8] mm Hg) and the proposed application rate (0.46 lb ai/A).  However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearby to pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative pos-application inhalation exposure assessment for amicarbazone.

2.0.2 Dermal Postapplication Exposure

In assessing potential dermal postapplication exposure and risk estimates, HED assumes that pesticide residues are transferred to the skin of adults/children who enter treated yards for recreation or other activities such as yard work and golfing.  However, a quantitative postapplication dermal exposure assessment was not performed for adults and children since no dermal endpoints were selected.  If dermal toxicological endpoints change in the future, HED may require a turf transferable residue (TTR) study to confirm that assessments are protective of all turf uses.  

3.0.3 Non-Dietary Ingestion (Hand-to-Mouth) Exposure

For the assessment of non-dietary ingestion (hand-to-mouth) exposure, HED assumes that pesticide residues are transferred to the skin of children playing on treated areas and are subsequently ingested as a result of hand-to-mouth transfer.

Assumptions:

   * On the day of application, it is assumed that 5% of the application rate is available on turf grass as transferable residue.
   * Oral postapplication exposure was estimated using the standard assumption for the initial fraction of residues available and assuming a 10% daily dissipation rate. 
   * The median surface area of both hands is 20 cm[2] for children.
   * It is assumed that there is a one-to-one relationship between the dislodgeable residues on the turf and on the surface area of the skin after contact.
   * The mean rate of hand-to-mouth activity is 20 times/hour for short-term exposure scenarios.
   * The saliva extraction factor is 50%.
   * The children (3-6 yrs) are assumed to weigh 15 kg.
   * Duration of exposure for children is assumed to be 2 hours per day for turf.

Equations:

TTRt = AR x F x (1-D)[t] x CF2 x CF3             

TTR	=	Turf Transferable Residue;
AR	= 	Application rate (lb ai/acre);
F	=	Fraction of ai available on turf (unitless) (0.05);
D	=	Fraction of residue that dissipates daily (unitless) (0.1);
t 	=	Postapplication day on which exposure is being assessed;
CF2	=	Weight unit conversion factor to convert the lbs ai in the application rate to ug for DFR
		value (4.54 x 10[8] ug/lb); and,
CF3	=	Area unit conversion factor to convert the surface area units (acre) in the application rate 
			to cm[2] for the DFR value (2.47 x 10[-8] acre/cm[2]).
  
PDR = TTR x SA x FQ x ET x SE x CF1	    
            BW
            		           
PDR	=	Potential dose rate (mg/day);
TTR	=	Turf transferable residue (ug/cm[2] turf);
SA	=	Surface area of the hands (20 cm[2]/event);
FQ	=	Frequency of hand-to-mouth activity (20 events/hr for short-term) ;
ET	=	Exposure time (hr/day);
CF1		=	Weight unit conversion factor to convert ug units in the TTR value to mg for the daily
			exposure (0.001 mg/ug for turf);
SE	=	Saliva Extraction Factor (50%); and,
BW	=	Body Weight (15 kg).

Hand-to-Mouth Exposure and Risk Estimate

Short-term hand-to-mouth (HTM) exposure resulted in an MOE greater than the level of concern (MOEs >= 100) and therefore poses no risk of concern.  Table 5 provides a summary of the short-term HTM exposure estimate.

Table 5.  Amicarbazone Children's Short-term Non-Dietary Ingestion (Hand-to-Mouth) Exposure and Risk Estimate.
Product
TTR 1 (ug/cm[2])
SA (cm[2]/event)
FQ
SE
ET (hr/day)
CF1
BW (kg)
HTM Dose [2]
(mg/kg/day)
HTM MOE [3]
Amicarbazone DF Herbicide (DINAMIC 
70 WDG HERBICIDE)
70% ai
(EPA Reg. No. 66330-46)
0.2576
                                      20
                                      20
                                      0.5
                                       2
                                     0.001
                                      15
                                    0.00687
                                      910
   1. Turf Transferable Residues = (TTR) = 
   AR (0.46 lb ai/A) x F (0.05) x (1-D)[0] x CF2 (4.54E[8] ug/lb) x CF3 (2.47E[-8] acre /cm[2]) = 0.2576 ug/cm[2].
   2. HTM Dose = [TTRt x SA x FQ x ET x SE x CF1]/BW.
   3. HTM MOE = NOAEL (6.28 mg/kg/day)/HTM Dose (mg/kg/day).
   
   
4.0.4 Non-Dietary Ingestion (Object to Mouth Ingestion of Treated Turf) Exposure

This scenario estimates exposure to children (3-6 yrs) resulting from incidental ingestion of pesticide and/or residential turf grass that has been treated with pesticides.  It assumes that pesticide from a treated object or turf is ingested by children who play on treated areas.  

Assumptions:

   * On the day of application it is assumed that 20% of the application rate is available to be ingested.
   * Oral postapplication exposure was estimated using the standard assumption for the initial fraction of residues available and assuming a 10% daily dissipation rate. 
   * Assumed ingestion rate for grass for children (3 years old) is 25 cm[2]/day.
   * Children are assumed to weigh 15 kg.

Equations:

GRt = AR x F x (1-D)[t] x CF2 x CF3

GRt	=	grass residue on day t (ug/cm[2]);
AR	=	application rate (lb ai/A);
F	=	fraction of ai available on the grass (unitless) (0.2);
D	=	fraction of residue that dissipates daily (unitless) (0.1);
t	=	postapplication day on which exposure is being assessed;
CF2		=	weight unit conversion factor to convert the lbs ai in the application rate to ug for grass 
			residue value (4.54 x 10[8] ug/lb); and,
CF3	=	area unit conversion factor to convert surface area units (A) in the application rate to cm[2] 
		for grass residue value (2.47 x 10[-8] A/cm[2]).

PDD = GR t x IgR x CF1

PDD	=	potential daily dose (mg/kg/day);
GRt	=	grass residue (ug/cm[2]);
IgR	=	ingestion rate of grass (cm[2]/day); and,
CF1	=	weight unit conversion factor to convert the ug of residues on the grass to mg to 	provide 
		units of mg/day (1.0 x 10[-3] mg/ug).

Object-To-Mouth Exposure and Risk Estimate

The object-to-mouth (OTM) scenario resulted in an MOE greater than the level of concern (MOEs >= 100) and therefore poses no risk of concern.  Table 6 provides a summary of the OTM exposure and risk estimate.

Table 6.  Amicarbazone Children's Non-Dietary Ingestion (Object - to-Mouth) Exposure and Risk Estimate.
                                    Product
GR 1 (ug/cm[2])
CF1 (mg/ug)
IgR  (cm[2]/day) 
BW (kg)
OTM Dose 2 (mg/kg/day)
OTM MOE [3]
Amicarbazone DF Herbicide (DINAMIC 70 WDG HERBICIDE)
70% ai
(EPA Reg. No. 66330-46)
1.03
0.001
25
15
0.0017
3,700
  1. GR (grass residue) = Application Rate x F x (1-D)[0] x CF2 x CF3. 
  2. OTM Dose = [GR 0 x IgR x CF1]/BW.
  3. OTM MOE = NOAEL (6.28 mg/kg/day)/OTM Dose (mg/kg/day).

0.3.2 Non-Dietary Ingestion Incidental Ingestion of Soil 

This scenario assumes children who play on treated areas ingest pesticide residues in soil as a result of normal mouthing activities.  

Assumptions: 

   * On the day of application, it is assumed that 100% of the application rate is located within the soil's uppermost 1 cm.
   * Postapplication must be assessed on the same day the pesticide is applied.
   * Assumed soil ingestion rate for children is 100 mg/day.
   * Children are assumed to weigh 15 kg.

Equations:

      SR0 = AR x F x (1-D)[t] x CF2 x CF3 x CF4

SR0	=	soil residue on day 0 (ug/g);
AR	=	application rate (lb ai/A);
F	=	fraction of ai available in uppermost cm of soil (1 cm);
D	=	fraction of residue that dissipates daily (unitless);
t	=	postapplication day on which exposure is being assessed (day 0);
CF2		=	weight unit conversion factor to convert the lbs ai in the application rate for soil residue                                   			 value (4.54 x 10[8] ug/lb);
CF3		=	area unit conversion factor to convert surface area units (A) in the application rate to cm[2]    
			for soil residue value (2.47 x 10[-8] A/cm[2]); and,
CF4		=	volume to weight unit conversion factor to convert the volume units (cm[3]) to weight units 
			for the SR value (0.67 cm[3]/g soil).

      PDD = SR0 x IgR x CF1

PDD	=	potential daily dose on day 0;
SR0	=	soil residue on day 0 (ug/g);
IgR	=	ingestion rate of soil (mg/day); and,
CF1	=	weight unit conversion factor to convert the ug of residues on the soil to mg to provide 
		units of mg/day (1.0 x 10[-][6] g/ug).

Soil Ingestion Exposure and Risk Estimate

The soil-ingestion scenario resulted in a MOE much greater than the level of concern (MOEs >= 100) and therefore poses no risk of concern.  This assessment should be considered conservative in that it assumed no dissipation of soil residues would occur over the exposure period.  Table 7 provides a summary of the soil ingestion exposure and risk estimate.

Table 7.  Amicarbazone Children's Soil Ingestion Exposure and Risk Estimate.
                                    Product
SR 1 (ug/g)
CF1
(g/ug)
IgR  (mg/day) 
BW (kg)
Dose 2 (mg/kg/day)
MOE [3]
Amicarbazone DF Herbicide (DINAMIC 70 WDG HERBICIDE)
70% ai
(EPA Reg. No. 66330-46)
3.45
0.000001
100
15
0.000023
270,000
   1. SR0 (soil residue) = Application Rate (lb ai/A) x F(1) x (1-D)[0] x 0.67 x (4.54x10[8] ug/lb)x (2.47 x 10-8 A/cm[2]).
   2. Soil Ingestion Dose (mg/kg/day) = SR0 (ug/g) x IgR (mg/day) x CF1 (g/ug)/BW (kg).
   3. Soil Ingestion MOE = NOAEL (6.28 mg/kg/day)/Soil Ingestion Dose (mg/kg/day).

4.3      Summary of Residential Risk Estimates

HED combines risk values resulting from separate exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population.  In evaluating combined residential uses of amicarbazone, HED reviewed all residential sources of exposure which consisted of: 1) adult inhalation handler (lawns only) exposure, and 2) child postapplication oral exposure.  

Since a dermal endpoint was not selected for amicarbazone, the only relevant route of exposure for adults is through the inhalation route, and therefore, a combined residential exposure assessment is not applicable.  

The children's oral exposure estimate for the purpose of conducting an aggregate risk assessment is based on postapplication hand-to-mouth exposures only.  To include exposure from object-to-mouth and soil ingestion in addition to hand-to-mouth could result in a very conservative estimate of exposure since the assumptions for each of the individual oral exposure calculations are high end.

The hand-to-mouth residential postapplication scenario also represents the worst case of oral exposure (i.e., to include exposure from object-to-mouth and soil ingestion in addition to hand-to-mouth could result in a very conservative estimation of exposure as it would overestimate the potential of oral exposure).  Table 8 identifies the residential scenarios and MOEs for adults and children for use in performing an aggregate exposure assessment as part of the amicarbazone human health risk assessment.  There are no risks of concern.

Table 8.  Amicarbazone Summary of Residential Exposure and Risk Estimates. 
Product
Use Site
Handler InhalationMOE [1]
Postapplication Dermal MOE 
Hand-to-Mouth MOE [2]
Combined MOE [3]
                                    Adult 
Amicarbazone DF Herbicide (DINAMIC 
70 WDG HERBICIDE
(EPA Reg. No. 66330-46)
                                 Lawns (turf) 
                                       
                                     3,600
                                       
                                      NA
                                       
                                      NA
                                       
                                       
                                      NA
                                     Child
Amicarbazone DF Herbicide (DINAMIC 
70 WDG HERBICIDE)
(EPA Reg. No. 66330-46)
                                 Lawns (turf)
                                       
                                      NA
                                       
                                      NA
                                       
                                      910
                                       
                                       
                                      NA
   1. See Table 4: Residential Handler Exposure and Risk (Low Pressure Handwand).
   2. See Table 5. Hand-To-Mouth Exposure and Risk.
   3. Child MOE = NOAEL (6.28 mg/kg/day)/HTM Dose (0.00687 mg/kg/day).

4.4	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for amicarbazone.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.

It is noted that the 0.46 lb ai/acre application rate for turf was modeled to estimate postapplication residential exposure of children.  As this rate is the same as the maximum agricultural single application rates (0.46 lb ai/A), this scenario is protective of any exposure of farm children via spray drift from agricultural applications of amicarbazone.
5.0		Occupational Exposure

Amicarbazone DF Herbicide (Alternate Brand Name: DINAMIC 70 WDG Herbicide), is a dry flowable (water-dispersible granular) formulation for the control of weeds in turfgrass, including golf courses (i.e., fairways, roughs, tees and approaches), seed production, sod production, and residential and commercial sites (i.e., homes, schools, playgrounds, parks, recreational areas, sports fields and common areas) as well as in tree sites (i.e., tree nurseries and Christmas tree farms).  This product will be applied as a spray after mixing with water or a liquid fertilizer.  Based on information provided by the registrant, this product is intended to be applied only by professional applicators (MRID No. 48237522).  Therefore, the potential for occupational handler and postapplication exposure does exist.

5.1	Occupational Handlers

Based upon the proposed use pattern, HED expects the most highly exposed occupational pesticide handler scenarios to be:

   1) mixing/loading dry flowable for ground applications;
   2) applying sprays via open cab groundboom equipment; 
   3) mixing/loading/applying liquids with manually pressurized (low-pressure) handwand; and,
   4) mixing/loading/applying liquids with a backpack sprayer. 
   
Handler exposure is expected to be short- or intermediate-term in duration based on information provided on proposed labels.  Long-term exposures are not expected; therefore, a long-term assessment was not conducted.  

Unit Exposures

It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, and the Outdoor Residential Exposure Task Force (ORETF) database.  Some of these data are proprietary (e.g., AHETF data, MRID No. 44339801), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures", are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html.

For pesticide handlers, it is HED standard practice to present estimates of dermal exposure for "baseline", that is, for workers wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes plus socks and no protective gloves, as well as for "baseline" and the use of protective gloves or other Personal Protective Equipment (PPE) might be necessary to achieve a MOE greater than the LOC.  The proposed product label involved in this assessment directs applicators and other handlers to wear long sleeved shirt and long pants, shoes plus socks, and chemical-resistant gloves. 

Body Weight:

The standard body weight for the general population (70 kg) was used for all exposure scenarios covered in this risk assessment.
  
Dermal Absorption:

Although a dermal absorption rate of 5% was calculated for amicarbazone, HED has concluded that a dermal risk assessment is not needed.

Exposure Frequency:

No data on the number of exposure days per year was provided.  For this risk assessment, it was assumed that handlers would be exposed for less than 6 months per year (i.e. short-/intermediate- term durations).  

Equations:

Daily handler exposures are estimated for each applicable handler task with the application rate, the area treated in a day, and the applicable dermal and/or inhalation unit exposure using the following formula:

Daily Exposure (mg ai/day) = 
Unit Exposure (mg ai/lb ai handled) x Application Rate (lbs ai/Acre) x Daily Area Treated (area/day) 
Where:  

      Daily Exposure		=	Amount (mg or ug ai/day) inhaled that is available for inhalation absorption or amount absorbed that is available for dermal absorption;
      Unit Exposure 		=	Unit exposure value (mg or ug ai/lb ai) derived from OPHED;
      Application Rate		=	Normalized application rate based on a logical unit treatment, such as acres, square feet, or gallons.  Maximum values are generally used (lb ai/A, lb ai/sq ft, lb ai/gal); 
	Daily Area Treated 	=	Normalized application area based on a logical unit treatment such as acres (A/day), square feet  (sq ft/day), gallons per day (gal/day); and, 
	
The daily dose is calculated by normalizing the daily exposure by body weight and adjusting, if necessary, with an appropriate dermal and/or inhalation absorption factor using the following formula:

Average Daily Dose (mg/kg/day) = 
[Daily Exposure (mg ai/day) x Absorption Factor] / Body Weight (kg))

Where:

      Average Daily Dose 		= 	Absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/kg body weight/day);
      Daily Exposure 			=	Amount (mg ai/day) inhaled/absorbed that is available for inhalation/dermal absorption;
      Absorption Factor 		= 	A measure of the amount of chemical that crosses a biological boundary such as the lungs/skin; and
      Body Weight 			= 	Body weight determined to represent the population of interest in a risk assessment (70 kg for amicarbazone).

Risks for each applicable handler scenario are calculated using a MOE, which is a ratio of the NOAEL or LOAEL to the daily dose.  In the case of amicarbazone, a NOAEL was used in the calculation.  All MOE values were calculated using the formula below:
                                       
MOE= NOAEL (mg/kg/day) / Daily Dose (mg/kg/day)

Occupational Handler Exposure and Risk Estimates

Table 9 presents the estimated short- and intermediate-term inhalation risks for workers.  All occupational handler scenarios resulted in MOEs greater than the level of concern at the baseline PPE level of protection (i.e. single layer clothing and no respirator).  The MOEs shown in the table are all significantly higher than HED's level of concern of an MOE of 100, with the lowest MOE of 1,300 identified for handlers conducting mixing/loading activities for application to sod farms.  

Based on communication with the registrant, the proposed label will prohibit the use of a mechanically pressurized handgun for application to Christmas trees.  
Table 9.  Occupational Handler Exposures and Risks Estimates for Amicarbazone.
Exposure Scenario and Product
Crops
Application Rate[a]

Area Treated or Amount Treated
Inhalation Unit Exposure [b]
(mg/lb)
Inhalation Dose [c]
(mg/kg/day)
Inhalation MOE [d]
                                 Mixer/Loader
Ground  -  
Dry Flowable
Golf courses
                                       
                                     0.46
                                    lb ai/A

                                     40 A
                                       
                              0.00896 (Baseline)
                                    (AHETF)
                                    0.00235
                                     2,700

Sod farms (turf), Christmas trees
                                       
                                     80 A
                                       
                                    0.00471
                                     1,300
                                  Applicator
Open Cab Groundboom
Golf courses 
                                       
                                     0.46
                                    lb ai/A

                                     40 A
                                       
                              0.00034 (Baseline)
                                    (AHETF)
                                   0.0000894
                                    70,000

Sod farms (turf), Christmas trees
                                       
                                     80 A
                                       
                                   0.000178
                                    35,000
                            Mixer/Loader/Applicator

Backpack Sprayer 
Christmas trees
(Ground-Directed)
                                0.023 lb ai/gal
                                       
                                    5 gals
                              0.00258 (Baseline)
                                (MRID 44339801)
                                   0.0000042
                                   1,500,000

Turf, golf course, sod farms, parks, recreation and athletic fields 
                                       
                                       
                                       
                                       
                                       
Manually-pressurized Handwand
Turf, Christmas trees
                                0.023 lb ai/gal
                                       
                                       
                                    5 gals
                                0.03 (Baseline)
                                    (PHED)
                                   0.000049
                                    130,000
Mechanically-pressurized Handgun Sprayer (WDG)

Turf, golf courses
(Broadcast)
                                     0.46
                                    lb ai/A
                                       
                                       
                                      5 A
                                       
                               0.042 (Baseline) 
                                    (ORETF)
                                    0.00138
                                     4,500
a.  Application Rate = (70% ai) (1 lbsolid/16 oz) (10.5 oz/A) = 0.46 lb ai/A (1 A/20gal) = 0.023 lb ai/gal.
b.  Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 26, 2011).
c.  Inhalation Dose (mg/kg/day) = Inhalation Unit Exposure (mg/lb ai) * Application Rate * Acres Treated or Amount Handled / Body Weight (70 kg).
d.  Inhalation MOE = NOAEL (6.28 mg/kg/day) / Inhalation Dose (mg/kg/day).

5.2	Occupational/Commercial Postapplication Exposure 

5.2.1	Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for amicarbazone at this time primarily because it has a low vapor pressure (2.3 x 10[-][8] mm Hg), it is applied at a maximum single application rate of 0.46 lb ai/A and it is not projected to be applied via typically high inhalation exposure application equipment (e.g., airblast and aerial equipment).  However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearby to pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for amicarbazone.

Although a quantitative occupational postapplication inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than postapplication exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of occupational postapplication inhalation exposure scenarios.

5.2.2	Postapplication Dermal Exposure

 Postapplication exposure assessments were not performed because no dermal endpoints were selected.
 
Restricted Entry Interval
The restricted entry interval (REI) listed on proposed labels is based on the acute toxicity of the technical material.  Amicarbazone exhibits low acute toxicity and is classified as Toxicity Category III for eye irritation and Category IV for acute dermal and dermal irritation.  It is not a dermal sensitizer.  Acute toxicity Category III and IV chemicals require a 12-hour REI.  Therefore, the 12-hour REI which appears on the proposed labels is considered appropriate.