Document ID: EPA-HQ-OPP-2012-0420-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-12-27T05:00Z

\* MERGEFORMAT
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                      OFFICE OF CHEMICAL SAFETY AND
                                                     POLLUTION PREVENTION

MEMORANDUM

DATE: 	08/27/2013

SUBJECT:	Indoxacarb:  Residential Exposure and Aggregate Human-Health Risk Assessment for Proposed Amendment for Indoor Uses of Arilon (EPA reg. No 100-1501) Label. 

PC Code:  067710
DP Barcode:  D413735
Decision No.:   481544
Registration No.: EPA Reg. No. 100-1501
Petition No.: 
Regulatory Action: Label Amendment/Section 3
Risk Assessment Type Single Chemical Aggregate
Case No.:  NA
TXR No.:  NA
CAS No.: 173584-44-6
MRID Nos.:  NA
40 CFR: §180.564
	        									
FROM:	Ana Rivera-Lupiáñez, Chemist 
			Risk Assessment Branch V
			Health Effects Division (7509P)

	THROUGH: 	Danette Drew, Chemist 
			Kelly Lowe, Environmental Scientist
			Michael Metzger, Branch Chief
		Risk Assessment Branch V
		Health Effects Division (7509P)

TO:		Jennifer Urbanski/John Hebert, Risk Manager
	Registration Division (7505P)
		
	 

1.0    Executive Summary

Indoxacarb, (S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl] amino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate, a reduced risk pesticide, is an oxadiazine class insecticide active ingredient (ai).  It is formulated as granular, impregnated materials, water dispersible granules, emulsifiable, flowable, soluble concentrates, and solution-ready-to-use. Indoxacarb formulations can be used by homeowners and by commercial applicators in agricultural and non-agricultural use sites.

THE LAST HUMAN-Health Risk Assessment for indoxacarb (5/2/13, D402099, D. Drew, et al, Indoxacarb. Human Health Risk Assessment for the Proposed New Use on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13-07F and Low Growing Berry Subgroup (except strawberry) 13-07H; (PP#2E8029)) identified post-application risk estimates of concern for children (hand-to-mouth oral exposure) as a result of spot-directed treatment scenarios to indoor surfaces. The Health Effects Division (HED) recommended amending the EPA Reg. No. 100-1501 label to withdraw indoor spot treatments, and restrict indoor residential uses to only crack and crevice treatments limiting applications to areas not accessible to young children. The registrant had been notified of this and responded by submitting an amended label which, rather than restrict the use to crack and crevice only, reduced the maximum spray volume allowed to be applied for indoor spot treatments. The Registration Division (RD) requested that HED determine if this labeling language is acceptable. The residential exposure and risk estimates were also revised, as was the aggregate (residential plus dietary) assessment, for the amended indoor use. 
	
Proposed Use Profile
Indoxacarb products are frequently formulated as a mixture of the insecticidally active S-enantiomer and the insecticidally inactive R-enantiomer.  The percentage of active ingredient and application rates listed on the product labels only reflect the S-enantiomer and not the R-enantiomer.  Adjustments are made in this assessment to add in the percent of R-enantiomer in product mixtures so that the total amount of indoxacarb (both S- and R- enantiomers) applied is accounted for as both are residues of toxicological concern.  

Arilon Insecticide 20% ai (EPA Reg. No. 100-1501, a water-soluble packaging (WSP) formulation of indoxacarb (75:25 ratio of S- and R-enantiomers), is registered for insect control on households and domestic dwellings. The product registrant, Syngenta Crop Protection LLC, has submitted a proposed label amendment to the indoor surface use directions for crack and crevice and spot directed spray applications. 

The original indoor application (i.e., crack and crevice and spot directed spray treatment) allowed for a maximum application rate of 0.66 oz product (dry) per gallon of water (i.e., 0.011 lb ai total isomer /gal) with a maximum application volume of 4 gallons diluted product per 1000 sq ft (equivalent to a maximum application rate of 0.00004 lb ai total isomer/ft[2]). The amended label proposes to limit the maximum volume of product used for indoor applications to 1 gallon diluted product per 1000 sq ft, equivalent to a maximum application rate of 0.00001 lb ai total isomer/ft[2].

Hazard Profile  

The toxicology database for indoxacarb is complete and is sufficient for characterizing hazard.  The indoxacarb endpoints that most frequently defined the lowest-observed-adverse-effect-level (LOAEL) in laboratory animals were non-specific, and included decreases in body weight, weight gain, food consumption and food efficiency.  Indoxacarb also affected the hematopoietic system in animals by decreasing the red blood cell count, hemoglobin and hematocrit.  

The FQPA safety factor (SF) for indoxacarb is reduced to 1X based on the following:  1) the hazard and exposure databases are complete; 2) there are no concerns for pre- and/or postnatal toxicity; 3) there are no residual uncertainties with regard to pre- and/or post-natal toxicity; and 4) the acute neurotoxicity (ACN), subchronic neurotoxicity (SCN) and developmental neurotoxicity (DNT) studies are available and all endpoints used in this risk assessment are protective of any neurotoxic effects.

See the 5/2013 risk assessment (D402099) for the complete details regarding the hazard characterization and selection of  toxicity endpoints and points of departure for indoxacarb.

Residential Exposure/Risk
The residential exposure and risk estimates were revised for the amended indoor use label since they will impact the aggregate (residential plus dietary exposures) assessment for indoxacarb. Dermal exposures resulting from residential uses are not quantitatively assessed as a dermal toxicity endpoint is not identified for indoxacarb. Only inhalation (adult and children) and incidental oral (children) exposures are assessed. The handler and post-application exposures for this residential use are expected to be short-term in duration. 

Residential handler (adults) risk estimates result in inhalation MOEs that do not exceed HED's level of concern (i.e., MOEs >= 100) from the Arilon indoor application exposure scenarios. All adult and children post-application risk estimates from the Arilon indoor surface directed sprays scenarios (crack and crevice and spot treatments) do not exceed HED's level of concern (MOEs are  >= 100) at the proposed reduced maximum volume rate of 1 gallon diluted product per 1000 sq ft. 

Aggregate Risk
The short- term aggregate (residential plus dietary food and water) risk estimates for adults and children are below HED's level of concern when considering the post-application exposure to indoor spray treated surfaces assuming a reduced volume application rate of 1 gallon diluted product per 1000 sq. ft.  

2.0	Risk Assessment Conclusions and Recommendations

2.1	Summary of Risk Estimates

The residential handler scenarios assessed resulted in inhalation MOEs that do not exceed HED's level of concern (i.e., MOEs >= 100 for short-term exposure durations). All adult and children inhalation and incidental oral post-application short-term risk estimates from indoor surface directed sprays scenarios (crack and crevice and spot treatments) resulted in MOEs that do not exceed HED's level of concern (i.e., MOEs >= 100) at the proposed reduced maximum volume rate of 1 gallon diluted product per 1000 sq ft. The short- term aggregate (residential plus dietary food and water) risk estimates for adults and children are below HED's level of concern when considering residential exposures from indoor surface directed sprays (spot treatments) assuming a reduced volume application rate of 1 gallon diluted product per 1000 sq. ft.  

2.2	Label Recommendations from Residential Assessment

HED recommends amending the "Application Directions" section of the Arilon label (EPA Reg. No. 100-1501) to list the maximum spray volume allowed (i.e., 1 gallon diluted product per 1000 sq ft) for all indoor application scenarios. 

3.0	Residential Exposure and Risk Estimates

Both residential handler and post-application exposures have been previously assessed for the indoor uses of indoxacarb (05/01/2013, D464583, A. Rivera-Lupianez).  The residential exposures for the proposed amendment to the Arilon indoor use label are reassessed below. 

Dermal exposures resulting from residential uses are not quantitatively assessed as a dermal toxicity endpoint is not identified for indoxacarb. Only inhalation and incidental oral exposures are assessed for the indoor residential uses of indoxacarb. The handler and post-application exposures for this residential use are expected to be short-term in duration. The risk estimates from residential exposures will impact the human health aggregate risk assessment for indoxacarb.
3.1	Residential Handler Exposure/Risk Estimates

HED uses the term "handlers" to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task.  Residential handlers are addressed somewhat differently by HED as homeowners are assumed to complete all elements of an application without use of any protective equipment. 

The quantitative exposure/risk assessment developed for residential handlers for the indoxacarb indoor use is based on the following scenario:  

   (1) Mixing/loading/applying water-soluble packaging formulation for indoor spray applications with manually-pressurized hand wand (crack and crevice and spot directed treatments) for insect control on households/domestic dwellings.

Residential Handler Exposure Data and Assumptions
A series of assumptions and exposure factors served as the basis for completing the residential post-application risk assessment for indoxacarb. Each assumption and factor is detailed in the previous occupational and residential assessment (D464583).

Application Rate: 
0.011 lb ai total isomer/gal for indoor spray applications of water-soluble packaging formulation. 

Summary of Residential Handler Non-Cancer Exposure and Risk Estimates

The residential handler scenarios assessed resulted in inhalation MOEs that do not exceed HED's level of concern (i.e., MOEs >= 100 for short-term exposure durations). Table 3.1 presents a summary of the residential handler scenario assessed. 

Table 3.1.  Residential Handler Short -Term Exposure and Risk Estimates for Indoxacarb Indoor Surface Treatments of Arilon 20% (KN128/KN127:75:25 Isomeric Mixture). 
                               Exposure Scenario
                               Level of Concern
                           Inhalation Unit Exposure 
                                  (mg/lb ai)
                          Maximum Application Rate[a]
                    Area Treated or Amount Handled Daily[b]
                                  Inhalation
                                       
                                       
                                       
                                       
                                       
                              Dose (mg/kg/day)[c]
                                    MOE[d]
                        Mixer/Loader/Applicator (M/L/A)
     Crack and Crevice and Spot-Directed Treatments (Indoor Environments)
              Arilon Insecticide 20% ai  - EPA Reg. No. 100-1501 
Manually Pressurized Hand Wand (water dispersible packets)
                                      100
                                      1.1
                                0.011 lb ai/gal
                                       
                             (0.00001 lb ai/ft[2])
                                    0.5 gal
                                   0.000076
                                    80,000
a..	Based on registered label (EPA Reg. No.100-1501). Application rates = maximum application rates from label (EPA Reg. No.: 100-1501). The application rates have been adjusted by a 4/3 factor to account for 4 parts of total (S- and R-) indoxacarb for every 3 parts of S- indoxacarb.
b..Based on HED's 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).
c.	Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A/day or gallons/day) / Body Weight (80 kg).
d.	Inhalation MOE = Inhalation NOAEL (6 mg/kg/day) / Inhalation Dose (mg/kg/day).
3.2	Residential Post-application Exposure/Risk Estimates from Indoor Surfaces Directed Spray Scenarios (Crack and Crevice and Spot Treatments)

Post-application exposure can result from pesticide residue transfer to the skin of individuals who contact previously treated indoor surfaces (e.g., carpets, floors, furniture, and other surfaces) during standard activities and/or who inhale pesticide vapors that emit from treated surfaces after application.  Such exposure is assumed to occur for adults and small children.  An assessment has been conducted for inhalation (adults and children 1 to < 2 years), and incidental oral (children 1 to < 2 years) exposures from the proposed amended indoor use of indoxacarb. These lifestages are not the only lifestages that could be potentially exposed for these post-application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages.

Residential Post-application Exposure Data and Assumptions
A series of assumptions and exposure factors served as the basis for completing the residential post-application risk assessment for indoxacarb. Each assumption and factor is detailed in the previous occupational and residential assessment (D464583).

Application Rate: 
0.011 lb ai total isomer/gal and maximum spray volume allowed of 1 gallon diluted product per 1000 sq ft equivalent to 0.00001 lb ai total isomer /ft[2].

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates
A summary of the adult and children short-term exposure and risk estimates from the proposed indoor surfaces directed spray scenarios is shown in Table 3.2.  All adult and children inhalation risk estimates do not exceed HED's level of concern (MOEs >= 100). All children oral non-dietary ingestion risk estimates for indoor treatments do not exceed HED's level of concern (MOEs >= 100). Combined inhalation and oral non-dietary ingestion risk estimates for children are not of concern to the Agency at the proposed reduced maximum volume rate of 1 gallon diluted product per 1000 sq ft. 

Table 3.2.  Residential Post-application ST (Non-Cancer) Exposure and Risk Estimates for Indoxacarb Indoor Surface Treatments of Arilon 20% (KN128/KN127:75:25 Isomeric Mixture).
                                   Lifestage
                      Post-application Exposure Scenario
                                  Application
                                   Rate [a,]
                                 (lb ai/ft[2])
                             Dose [b], (mg/kg/day)
                                   MOEs [c]
                                Combined Routes
                    (X indicates included in Combined MOE)
                               Combined MOEs [d]
                                       
                               Route of Exposure
                                   Use Site
                                       
                                       
                                       
                                       
                                       
Crack and Crevice and Spot Directed Treatments (Indoor Surface Directed Sprays Scenario)
               Arilon Insecticide 20% ai- EPA Reg. No. 100-1501
                                     Adult
                                  Inhalation
                            Surface directed sprays
                                       
                      0.00001 lb ai  total isomer /ft[2]
                               (0.011 lb ai/gal)
                                       
                                 2.5x 10[-][8]
                                  2.4 x 10[8]
                                       
                                      NA
                           Child 1 < 2 years old
                                     Oral
           Hand-to-Mouth from carpets (crack and crevice treatment)
                                       
                                    0.0032
                                      630
                                       
                                      130
                                       
                                       
             Hand-to-Mouth from carpets (spot directed Treatment)
                                       
                                    0.0158
                                      130
                                       X

                                       
                                       
          Object-to- Mouth from carpets (crack and crevice treatment)
                                       
                                    0.0004
                                     4,800
                                       

                                       
                                       
            Object-to- Mouth from carpets (spot directed Treatment)
                                       
                                    0.0021
                                      950
                                       

                                       
                                  Inhalation
                            Surface directed sprays
                                       
                                 1.1x 10[-][7]
                                  5.7x 10[7]
                                       X

Note: Assumes both spot treatment and crack and crevice directions are amended to reduce the maximum volume of product used to 1 gallon diluted product per 1000 sq. ft.

a. Based on maximum application rates from proposed amended label (EPA Reg. No.: 100-1501). The application rate
   have been adjusted by a 4/3 factor to account for 4 parts of total (S- and R-) indoxacarb for every 3 parts of S
   indoxacarb.

b. Crack and Crevice and Spot Directed Treatment Scenarios Dose Equations	
    Hand-to-Mouth Dose (mg/kg/day) = [(Fraction of ai on Hands (0.15) x Dermal Exposure (0.14)) / (2 x Surface Area
    of 1 hand (150 cm[2]) ) x Fraction of Hand Mouthed  (0.13) x Exposure Time per Day (carpet, 4; hard  surfaces, 2 
    hours hrs/day) x # of Replenishment Intervals per Hour (4 int/hr) x (1-((1-Saliva Extraction Factor (0.5)) ^ (Number 
    of Hand-to-Mouth Events per Hour (20 events/hr)  /  ( # of Replenishment Intervals per Hour (4)))]  / Body 
    Weight (child, 11 kg)]

    Object-to-Mouth Dose (mg/kg/day) = [(Deposited Residue (1.0 μg/cm[2]) x Fraction of Residue Transferred to an  Object(carpet, 0.06; hard  surface, 0.08)) x Unit Conversion Factor (0.001 mg/ug) x Object Surface Area Mouthed  (10 cm[2]/event) x Exposure Time (carpet, 4; hard surface, 2 hrs/day) x # Replenishment Intervals per Hour (4 int/hr) x (1-((1- Saliva Extraction Factor (0.50)) ^ (# Object-to-Mouth Events per Hour (14 events/hr) / # Replenishment Intervals per Hour (4/ hr))) / Body Weight (child, 11 kg)]

   Inhalation Daily Dose (mg/kg/day) = [(Inhalation Rate (0.64, adult; 0.33 child m[3]/hr) x Mass of Active Ingredient Applied (298 mg ai)) / (Air Exchanges per Hour (0.45/hr) x Volume of Room (33 m[3])) / [1  -  ((Air Exchanges per Hour (0.45/hr) x e ^ (-First Order Decay Rate (2.1 x 10[-5]) x Exposure Time (hr)))  -  (First Order Decay Rate (2.1 x 10[-5]) x e ^ (-Air Exchanges per Hour (0.45/hr) x Exposure Time (hr))) / (Air Exchanges per Hour (0.45/hr)  -  First Order Decay Rate (2.1 x 10[-5]))] / Body Weight (child, 11 kg)]

c. MOEs: Inhalation MOE = Inhalation NOAEL (6 mg/kg/day) / Inhalation Dose (mg/kg/day). 
   Oral MOE = NOAEL (2 mg/kg/day) / Oral Dose (mg/kg/day)
d. Combined MOE = 1 / [(1/incidental oral MOE) + (1/ Inhalation MOE)], where applicable.
3.3	Short-Term Aggregate Assessment

The short- term aggregate risk for indoxacarb includes background contribution from dietary (food and drinking water) exposure plus the short- and/or intermediate-term post-application exposure to spray-treated indoor areas. The scenarios used in the aggregate assessment for indoxacarb are detailed below:
   * The short -term residential exposure for use in the adult aggregate assessment reflects residential handler inhalation from indoor treatments with surface directed sprays (spot treatments). 
   * The short -term residential exposure for use in the child (1<2 years) aggregate assessment reflects combined post-application inhalation and incidental oral (hand-to-mouth) exposures from indoor treatments with surface directed sprays (spot treatments).  

The short- term aggregate (residential plus dietary) risk estimates for adults and children are below HED's level of concern when considering residential exposures from indoor surface directed sprays (spot treatments) assuming a reduced spray volume application rate of 1 gallon diluted product per 1000 sq. ft (Table 3.3).

Table 3.3.   Short-Term Aggregate Risk Calculations
Residential (Indoor Spray) plus Dietary (Food and Water) Exposures 
Population
Short- Term Scenario

LOC for Aggregate Risk[a]
Dietary
MOE[b] 
MOE Oral Residential Exposure[c] 
MOE Inhalation Residential Exposure[d]
Aggregate MOE (food, water, and residential)[e]
Adult  
100
1,800
NA
80,000
1,800
Child (1<2 yrs)
100
840
130
5.7 x 10[7]
110
[a] LOC=100 (10x inter- and 10x intra- species uncertainty factors)
[b] MOE dietary = [(short- or intermediate-term oral NOAEL)/(chronic dietary exposure)].  Oral NOAEL= 2.0 mg/kg/day.  Chronic dietary exposure value from D402099, 05/02/2013; Table 5.4.5.  
[c] MOE oral = [(short- or intermediate-term oral NOAEL)/(hand-to-mouth residential exposure)].  Oral NOAEL= 2 mg/kg/day.  
[d] MOE inhalation = [(short- or intermediate-term inhalation NOAEL)/ (high end inhalation residential exposure)]. Inhalation NOAEL= 6.0 mg/kg/day.  Adult residential handler exposure value from Table 3.1 and child residential exposure value from Table 3.2.
[e]MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE inhalation)]

4.0	References

Rivera-Lupiáñez A., D464583, 05/01/2013. Indoxacarb: Revised Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on Bean (dry), Bean (snap), Bean (forage), and Small Fruit Vine Climbing Subgroup 13-07F and Low-Growing Berry Subgroup 13-07H.

Drew D. et al; D402099, 05/02/2013. Indoxacarb: Human Health Risk Assessment for the Proposed New Use on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13-07F and Low Growing Berry Subgroup (except strawberry) 13-07H.