
                    UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

                            WASHINGTON, D.C.  20460
                                       

                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
	                                                                                                POLLUTION PREVENTION
                                                                               
MEMORANDUM

Date:		XX-APR-2010

SUBJECT:	Novaluron:  Human-Health Risk Assessment for Proposed Section 3 Uses on Sweet Corn and in Food- or Feed-Handling Establishments.  

PC Code:  124002
DP Barcodes:  D378387, D377471
Decision Nos.:  432483, 430432
Registration Nos.:  66222-35, 66222-ERT
Petition Nos.:  0E7723, 0F7708
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical Aggregate
Case No.:  7615
TXR No.:  NA
CAS No.:  116714-46-6
MRID No.:  NA 
40 CFR:  §180.598

FROM:	Lata Venkateshwara, Environmental Scientist
      Julie L. Van Alstine, MPH, Environmental Health Scientist
      Anwar Dunbar, Ph.D., Pharmacologist
		Risk Assessment Branch 1 (RAB1)
		Health Effects Division (HED; 7509P)

THROUGH:  Dana M. Vogel, Branch Chief 
	George F. Kramer, Ph.D., Branch Senior Chemist 
	RAB1/HED (7509P)

TO:		Barbara Madden/Laura Nollen (RM 05)
		Registration Division (RD; 7505P)
		
		And

		John Hebert (RM 07)/ Jennifer Gaines
		RD (7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered and proposed uses of novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy] phenyl]amino]carbonyl]-2,6-difluorobenzamide).  A summary of the findings and an assessment of human risk resulting from the registered and proposed uses for novaluron are provided in this document.  The risk assessment and occupational/residential exposure assessment were provided by Lata Venkateshwara (RAB1), the residue chemistry data review and dietary risk assessment were provided by Julie Van Alstine (RAB1), the hazard characterization by Anwar Dunbar (RAB1), and the drinking water assessment by Iwona Maher of the Environmental Fate and Effects Division (EFED).

The most recent human-health risk assessment was conducted in conjunction with a request for the use of novaluron on grain sorghum (Memo, J. Van Alstine, et al., 23-FEB-2010; D364307).  A detailed hazard characterization for novaluron is presented in a previous HED risk assessment (Memo, M. Clock-Rust, et al., 25-MAR-2004; D295824).  This document contains only those aspects of the risk assessment which are affected by the proposed Section 3 requests for use of novaluron on sweet corn and in food- or feed-handling establishments.  

                               Table of Contents

1.0	EXECUTIVE SUMMARY	4
2.0	INGREDIENT PROFILE	13
2.1	Summary of Proposed Uses	13
2.2	Structure and Nomenclature 	15
2.3	Physical and Chemical Properties	15
3.0	HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS	16
3.1	FQPA Considerations	17
3.2	Endocrine Disruption	20
4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION	21
4.1	Food Residue Profile	21
4.2	Drinking Water Residue Profile	26
4.3	Dietary Exposure and Risk	27
4.4	Anticipated Residue and %CT Information	28
5.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION	29
5.1	Residential Handler Exposure and Risk	29
5.2	Residential Post application Exposure and Risk	32
5.3	Combined Residential Risk Estimates	38
5.4      Bystander Post-application Inhalation Exposure	38
5.5	Spray Drift	39
6.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	39
6.1	Short-Term Aggregate Risk	40
6.2	Intermediate-Term Aggregate Risk	42
6.3	Chronic Aggregate Risk	42
7.0	CUMULATIVE RISK	43
8.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	43
8.1.1	Occupational Pesticide Handler Exposure and Risk for Sweet Corn	43
8.1.2	Occupational Pesticide Handler Exposure and Risk for Crack and Crevice	46
8.2	Occupational Post-Application Worker Exposure and Risk	49
9.0	DATA NEEDS AND LABEL RECOMMENDATIONS	53
9.1	Toxicology	53
9.2	Residue Chemistry	53
9.3	Occupational and Residential Exposure	55
Appendix A:  TOXICOLOGY ASSESSMENT	56
A.1.	Acute Toxicity Profile	56
A.2	Toxicity Profiles	56

1.0	EXECUTIVE SUMMARY

Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), as amended, the Interregional Research Project No. 4 (IR-4) has submitted a petition (PP#0E7723) to register the end-use product Rimon[(R)] 0.83 Emulsifiable Concentrate (EC) Insecticide (EPA Reg. No. 66222-35) for use on sweet corn.  To support the submission for permanent tolerances for residues of novaluron in/on sweet corn stover, forage, and kernel plus cob with husks removed (K+CWHR), IR-4 has also proposed tolerance increases for residues of novaluron in/on milk and milk fat.  Concurrently, Makhteshim-Agan of North America (MANA) has submitted a petition (PP#0F7708) to register the end-use product Rimon[(R)] Supra 10EC Insecticide (EPA Est. No. 66222-ERT) for indoor and outdoor control of roaches and crickets in food- and feed-handling establishments.  Both products are EC formulations which contain 9.3% novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy] phenyl]amino]carbonyl]-2,6-difluorobenzamide) by weight [equivalent to 0.83 pound (lb) ai/gallon (gal)].  

Novaluron, a benzoylphenyl urea compound, is a pesticide chemical belonging to the class of insecticides called insect-growth regulators (IGRs).  Tolerances for residues of novaluron are established under 40 CFR §180.598 in/on a wide variety of crops at levels ranging from 0.05 to 40 ppm.  Tolerances for residues of novaluron are also established in/on the following livestock commodities:  eggs, milk, milk fat, the meat, fat, kidney, liver, and meat byproducts (except kidney and liver) of cattle, goat, horse, and sheep, and the meat, fat, kidney, liver, and meat byproducts of poultry and hog.  A time-limited tolerance, with an expiration date of 31-DEC-2011, is established in association with a Section 18 Emergency Exemption for strawberries at 0.50 ppm.  

All existing uses for novaluron are agricultural or commercial in nature.  The proposed food- and feed-handling establishment use of novaluron includes uses in residential and commercial buildings and structures, and their immediate surroundings, and on modes of transportation.  This is the first proposed residential use of novaluron.  

Hazard Characterization

Novaluron has low acute toxicity via the oral (Toxicity Category IV), dermal (Toxicity Category III), and inhalation routes (Toxicity Category IV).  No ocular (Toxicity Category IV) or dermal irritation (Toxicity Category IV) was noted.  Novaluron is not a dermal sensitizer.  In subchronic and chronic toxicity studies, novaluron primarily produced hematotoxic effects (toxicity to blood) such as methemoglobinemia, decreased hemoglobin, decreased hematocrit, and decreased red blood corpuscles (RBCs or erythrocytes) that were associated with compensatory erythropoiesis.  No maternal and/or developmental toxicity was observed in animals tested up to the limit dose in either the rat or rabbit developmental toxicity studies.  In the two-generation reproductive toxicity study, increased spleen weights were observed in parents and offspring at the same dose, and reproductive toxicity was observed in males only at a higher dose.  Neurotoxic effects, including clinical signs, changes in functional-observation battery (FOB) parameters, and neuropathology were observed following a single dose at the limit dose only (2000 mg/kg/day) in the acute neurotoxicity study in rats.  However, no signs of neurotoxicity or neuropathology were observed following repeated dosing in the subchronic neurotoxicity study in rats at similar doses, no evidence of neuropathology was observed in subchronic and chronic toxicity studies in rats, mice, or dogs, and novaluron is not considered acutely toxic (LD50>5000 mg/kg).  Therefore, RAB1 toxicologists reaffirmed the HED Hazard Identification Assessment Review Committee (HIARC) conclusion that there is not a concern for neurotoxicity resulting from exposure to novaluron.  There was no evidence of either carcinogenic or genotoxic potential with novaluron.    

Dose Response and Endpoint Selection

The RAB1 toxicologists reevaluated the novaluron database, including the previous conclusion that the Food Quality Protection Act (FQPA) Safety Factor (SF) for increased susceptibility of infants and children can be reduced to 1X.  RAB1 toxicologists have determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF were reduced to 1X.  The decision was based on a lack of increased susceptibility in developmental toxicity studies at levels up to the limit dose in the rat or rabbit or in the two-generation reproduction study in rats.  The risk assessment team concluded that the FQPA SF for increased susceptibility of infants and children can be reduced to 1X based on toxicological considerations (above), the conservative residue assumptions used in the dietary risk assessments, the completeness of the residue chemistry database, and conservative drinking water assessment.  RAB1 toxicologists also reaffirmed the endpoints previously selected by the HIARC (16-DEC-2003; TXR# 0052361).  There is no concern for neurotoxicity resulting from exposure to novaluron and the overall weight of evidence suggests that novaluron does not directly target the immune system.  An immunotoxicity study is required as part of the revised 40 CFR Part 158 toxicology data requirements for novaluron; however, HED does not believe that conducting a functional immunotoxicity study will result in a lower NOAEL than the regulatory dose being used for risk assessment, and an additional UF for database uncertainty (UFDB) is not needed to account for the lack of the required immunotoxicity study.

An oral acute reference dose (aRfD) for the general population, including infants and children, was not established since an endpoint of concern attributable to a single dose was not identified.  The chronic reference dose (cRfD) of 0.011 mg/kg/day was determined on the basis of the chronic toxicity/carcinogenicity study in the rat.  An uncertainty factor (UF) of 100 (10-fold for interspecies extrapolation and 10-fold for intraspecies variability) was applied to the no-observed-adverse-effect-level (NOAEL) of 1.1 mg/kg/day to derive the cRfD.  The lowest-observed-adverse-effect-level (LOAEL) of 30.6 mg/kg/day was based on evidence of RBC damage and turnover resulting in a regenerative anemia.  The FQPA SF of 1X is applicable for chronic dietary risk assessment.  Therefore, the chronic population-adjusted dose (cPAD) is 0.011 mg/kg/day.

Based on the toxicological database, a short-term dermal endpoint was not selected; therefore, only intermediate-term dermal exposure was assessed.  Short- and intermediate-term inhalation toxicological endpoints have been selected and are the same; therefore, the estimates of risk for short-term duration inhalation exposures are protective of those for intermediate-term inhalation duration exposures.  A 10% dermal-absorption factor was based on an acceptable dermal-absorption study in rats in which the maximum total absorbed dose (expressed as percent of administered dose) ranged from approximately 0.5% to 10% of the applied dose.  The level of concern (LOC) for occupational and residential dermal and inhalation exposures are for margins of exposure (MOEs) <100.  

In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (JUL-1999), novaluron is classified as "not likely to be carcinogenic to humans" based on the lack of evidence for carcinogenicity in mice and rats.

Endpoints applicable to risk assessments performed for novaluron in this document are summarized below.

Exposure Scenario
Dose
Endpoint
Study/Effect
Chronic dietary
NOAEL = 1.1 mg/kg/day
cRfD and cPAD = 0.011 mg/kg/day
Combined chronic toxicity/carcinogenicity feeding study-rat-erythrocyte damage and turnover resulting in a regenerative anemia at the LOAEL of 30.6 mg/kg/day. 
Intermediate-term dermal
(10% absorption rate)
NOAEL = 4.38 mg/kg/day
LOC for MOEs <100 (occupational/residential)
90-day feeding study-rat-clinical chemistry and histopathology at the LOAEL of 8.64 mg/kg/day.
Short-term inhalation



Intermediate-term inhalation




Dietary Exposure Estimate

An acute dietary assessment was not conducted for novaluron because an endpoint of concern attributable to a single dose was not identified.  A cancer dietary assessment was not conducted because novaluron was classified as "not likely to be carcinogenic to humans." 

A partially refined chronic dietary (food and drinking water) exposure and risk assessment was conducted for the proposed new uses on sweet corn and in food- and feed-handling establishments, all established uses, and drinking water.  EFED provided the estimated drinking water concentrations (EDWCs) which were incorporated into the analysis.  A percent crop treated for new use (PCTn) memorandum for sweet corn was provided by the Biological and Economic Analysis Division (BEAD).  Additionally, data from a previously provided Screening Level Usage Analysis (SLUA) memorandum for existing uses and a PCTn memorandum for grain sorghum were used.  The chronic analysis incorporated average percent crop treated (%CT) data for apples, cabbage, cotton, pears, and potatoes, and average PCTn data for sweet corn and grain sorghum.  100% CT was assumed for the remaining food commodities.  Anticipated residues (ARs) for meat, milk, hog, and poultry commodities were calculated using average field trial residues, average PCTn for sweet corn and grain sorghum, average %CT for apple and cotton, and assumed 100% CT for sugarcane and cowpea seed.  The chronic analysis also incorporated average field trial residues, average greenhouse trial residues for tomatoes, empirical processing factors for apple juice (translated to pear and stone fruit juice), cottonseed oil, dried plums, and tomato paste and purée, and Dietary Exposure Evaluation Model (DEEM[(TM)], ver. 7.81) default processing factors for the remaining processed commodities.  In accordance with HED Standard Operating Procedure (SOP) 2000.1, average field trial residues were translated from representative commodities in the crop group to other commodities in that crop group as needed.   

For this action, the chronic dietary (food and drinking water) exposure to novaluron is below HED's LOC for the general U.S. population and all population subgroups.  The chronic dietary exposure results in a risk estimate that is 21% of the cPAD for the general U.S. population and 72% of the cPAD for children 1-2 years old, the most highly exposed population subgroup.  

Residential Exposure/Risk

Novaluron is proposed for indoor and outdoor uses for the control of roaches and crickets (crack and crevice and spot treatments).  Applications in residential areas, such as homes and apartment buildings, are allowed per label instructions.  As stated earlier, this is the first proposed residential use of novaluron.  Residential handler dermal and inhalation exposures were assessed for application via low-pressure handwands and trigger-pump sprayers.  All residential handler risks do not exceed HED's level of concern (i.e., MOEs >=100).   

Residential post-application inhalation exposures were assessed for adults and children following indoor low-pressure handwand and trigger pump sprayer applications and no risks of concern were identified.  

Residential post-application dermal exposures were also assessed.  Since there is no short-term dermal endpoint, these exposures are representative of intermediate-term exposures and are considered conservative since it has been assumed that adults and children are exposed to day-0 residues for the length of the exposure duration (i.e., no dissipation or removal of residues has been assumed).  At the maximum application rate (3.1 oz/gal and 0.1 gal per 1000 ft[2]), all dermal MOEs for adults and children are greater than the target MOE of 100 and do not exceed HED's level of concern.
	
Residential post-application incidental oral exposures were assessed for children (3 to <6 years old).  At the maximum application rate (3.1 oz/gal and 0.1 gal per 1000 ft[2]), short- and intermediate-term incidental oral MOEs are greater than the target MOE of 100 and do not exceed HED's level of concern.    

A combined residential assessment was included for the indoor crack and crevice/spot use.  The combined scenarios consisted of adult dermal and inhalation post-application exposures as well as children (3 to <6 years old) dermal, inhalation and oral (hand-to-mouth) post-application exposures.  All of the combined MOEs for adults and children (3 to <6 year olds) are greater than the target MOE of 100 and do not exceed HED's level of concern

Aggregate Exposure Scenarios and Risk Conclusions

For the proposed uses, human-health aggregate risk assessments have been conducted for short-term aggregate exposure (food + drinking water + residential), intermediate-term aggregate exposure (food+ drinking water + residential), and chronic aggregate exposure (food + drinking water) exposure scenarios.  An acute aggregate assessment was not conducted for novaluron because an endpoint of concern attributable to a single dose was not identified.  A cancer aggregate risk assessment was not performed because novaluron was classified as "not likely to be carcinogenic to humans."  All potential exposure pathways were assessed in the aggregate risk assessment as a conservative, health-protective measure.  All aggregate risk estimates do not exceed HED's level of concern for the scenarios listed above.  

Occupational Exposure Estimates

Occupational handler and post-application exposure from the proposed uses of novaluron are anticipated.  Based on label information, exposure is expected to occur for short- and intermediate-term exposure durations.  No chemical-specific handler exposure data were submitted in support of this Section 3 registration.  It is the policy of HED to use data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in the PHED Surrogate Exposure Guide (AUG-1998) to assess handler exposures for regulatory actions when chemical-specific monitoring data are not available [HED Science Advisory Council for Exposure (ExpoSAC) Draft SOP #7, dated 28-JAN-1999].  

HED has determined that risks do not exceed HED's level of concern (i.e., MOEs >=100), provided workers wear chemical-resistant gloves as recommended on the label.  No short-term point of departure (POD) was selected for the dermal route of exposure; therefore, the risks presented for handlers are representative of intermediate-term exposures and would be considered protective of short-term exposures.

The MOEs for occupational post-application exposure are all greater than the target MOE of 100 on day 0 (12 hours after application) for all crops and activities and do not exceed HED's level of concern.  Post-application dermal risks were calculated based on an intermediate-term POD and are considered highly conservative for the included activities.

Since the post-application assessment is not a concern on Day 0 (12 hours following application), the restricted-entry interval (REI) is based on the acute toxicity of novaluron technical material.  The proposed label for Rimon[(R)] has a 12-hour REI.  The technical material has a Toxicity Category III for acute dermal and a Toxicity Category IV for acute oral and inhalation and primary eye and skin irritation.  It is not a dermal sensitizer.  Per the Worker Protection Standard (WPS), a 12-hour REI is required for chemicals classified under Toxicity Categories III and IV and is adequate for the proposed use patterns.  

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent possible, were considered in this human-health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the Continuing Surveys of Food Intakes by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

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 to determine their dermal and inhalation exposure.  Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED and the Outdoor Residential Exposure Task Force (ORETF) database.  EPA has reviewed all the studies in these multi-pesticide generic exposure databases, and on the basis of available evidence has found them to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted.  There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied.

Recommendation for Tolerances and Registration

Pending submission of revised Sections B and F and new analytical standards, there are no residue chemistry, toxicology, or occupational and residential exposure issues that would preclude granting a conditional registration for the use of novaluron on sweet corn and in food- and feed-handling establishments where food or feed products are held, processed, or prepared.  Registration should be made conditional upon submission of an immunotoxicity study as specified in the new 40 CFR Part 158 data requirements and a 90-day inhalation toxicity study.

The proposed uses and the submitted data support the permanent tolerances for residues of the insecticide novaluron, including its metabolites and degradates, in or on the commodities listed below.  Compliance with the tolerance levels specified below is to be determined by measuring only novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide) in or on the following raw agricultural commodities (RACs):

         Corn, Sweet, Stover	50 ppm
         Corn, Sweet, Forage	16 ppm
         Corn, Sweet, Kernel Plus Cob With Husks Removed	0.05 ppm
         Food/feed commodities (other than those covered by a higher tolerance as a result of use on growing crops) in food/feed handling establishments	0.01 ppm
Data Needs and Label Recommendations

The residue chemistry, toxicology, and occupational and residential databases will support unconditional registration upon submission of data/information which adequately addresses the following issues:  

Toxicology
	
   * A 90-day inhalation toxicity study is requested for further characterization of inhalation risk.  Due to the potential for repeated inhalation exposure anticipated from the proposed residential use pattern, there is concern for toxicity by the inhalation route.  An inhalation study would provide a dose and endpoint via the route of exposure of concern (i.e. route specific study) and thus would avoid using an oral study and route-to-route extrapolation.  
   * An immunotoxicity study is required as specified in the new 40 CFR Part 158 data requirements.
   
Residue Chemistry
860.1200 Directions for Use
A revised Section B for PP#0E7723 should be submitted which:

            *       prohibits the use of novaluron on turnips harvested for the root and prohibits the feeding of turnip tops to livestock as previously requested (Memo, J. Van Alstine, 09-SEP-2009; D357060).  This affects the current petition because it could result in increased livestock dietary burdens.

A revised Section B for PP#0F7708 should be submitted which:

   * specifies an application rate of 0.1 gallons per 1000 ft[2] for indoor spot, crack and crevice, space spray, and general surface applications; 
   * states that all food processing surfaces (including equipment) and utensils should be covered during treatment or thoroughly washed prior to use; 
   * states the livestock feed items should be removed or covered prior to application; and
   * removes all references to fogger and fog applications in the label, and specifies that applications should be made with mechanical cold mist/ultra-low volume (ULV) equipment. 

860.1550 Proposed Tolerances
A revised Section F for PP#0E7723 should be submitted which:
   * cites the appropriate CAS name for novaluron:
         "Tolerances are established for residues of the insecticide novaluron, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide) in or on the following raw agricultural commodities:"; and

   * reflects the recommended tolerances and commodity definitions presented in Table 4.1.1.  

Additionally, a revised Section F for PP#0F7708 should be submitted which:

   * reflects the commodity definition presented in Table 4.1.1.  

860.1650 Submittal of Analytical Reference Standards
The available analytical reference standards for novaluron have expired.  MANA is required to submit an updated Certificate of Analysis (COA) or a new analytical standard to the EPA National Pesticide Standards Repository at the following address:   

      USEPA
      	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP
      	701 Mapes Road
      	Fort George G. Meade, MD  20755-5350

Please note that the extended zip code is required for delivery.

Note to RD:  Based on the Chemistry Science Advisory Council (ChemSAC) guidance that meat byproduct tolerances should be set at the highest residue level seen in any livestock commodity (minutes from 12-JAN-2011), several meat byproduct tolerances in 40 CFR § 180.598(a) should be updated so that they are based on the highest expected residue.  Additionally, two commodity descriptions should be updated.  The tolerances and commodity descriptions should be updated as follows:

                         Current Commodity Description
                         Updated Commodity Description
                            Current Tolerance (ppm)
                          Updated Tolerance (ppm)[1]
Cattle, meat byproducts, except kidney and liver
                                       -
                                     0.60
                                      11
Goat, meat byproducts except kidney and liver
                                       -
                                     0.60
                                      11
Horse, meat byproducts, except kidney and liver
                                       -
                                     0.60
                                      11
Sheep, meat byproducts, except kidney and liver
                                       -
                                     0.60
                                      11
Hog, meat byproducts
Hog, meat byproducts, except kidney and liver[2]
                                     0.10
                                      1.5
Poultry, meat byproducts
Poultry, meat byproducts, except kidney and liver[3]
                                     0.80
                                      7.0
1 Based on the based on the highest expected secondary tissue residue [peritoneal fat in cattle (translated to goat, horse, and sheep); peritoneal fat in hog; abdominal fat in poultry]. 
2 Separate tolerances have been established for hog, kidney (0.10 ppm) and hog, liver (0.10 ppm).  
[3] Separate tolerances have been established for poultry, kidney (0.80 ppm) and poultry, liver (0.80 ppm).  

Occupational and Residential Exposure
A revised label (Section B) for PP#0E7723 should be submitted which:
   * specifies that the retreatment of sweet corn with novaluron is prohibited (i.e., only 1 application is allowed at a rate of 0.078 lb ai/A) in California and other arid areas which receive less than 20 inches of precipitation per year. 
A revised label (Section B) should also be submitted for PP#0F7708 which:
   * specifies an application rate of 0.1 gallons per 1000 ft[2] for indoor spot, crack and crevice, space spray, and general surface applications; and
   * requires the addition of chemical-resistant gloves.  
   
2.0	INGREDIENT PROFILE

2.1	Summary of Proposed Uses

IR-4 and MANA have submitted draft labels for Rimon[(R)] 0.83EC Insecticide (EPA Reg. No. 66222-35) and Rimon[(R)] Supra 10EC Insecticide (EPA Reg. No. 66222-ERT) to include the proposed new uses (see Table 2.1) on sweet corn and in food- and feed-handling establishments, including residential sites.  The current label for Rimon[(R)] Supra 10EC did not include an application rate for spot, crack and crevice, surface spray, and general surface applications; HED's application rate calculations are included in the chemistry and ORE memos.  

Under petition PP#0F7708, novaluron is proposed for indoor and outdoor uses for the control of roaches and crickets (spot and crack and crevice treatments).  The proposed label also recommends fogger applications; however, based on correspondence with the Registrant, this application is not made with an actual fogger, but rather with mechanical cold mist/ ULV equipment that deliver a very light mist that targets the treatment spots (such as, but not limited to, wooden pallet structures, under sink/counter voids, under equipment, enclosed machinery housings, etc.).  This application method is not considered to be a space or aerosol spray treatment, where a fogger or vaporizer is used.  

The label directions recommend applying a dilute solution of 2.3 to 3.1 ounces of product per gallon of water (0.01 to 0.02 lb ai/gal).  For outdoor perimeter treatments, the label recommends applications at a spray rate of 1 gal/1000 ft[2].  An indoor spray rate per area was not provided on the proposed label.  Based on the submitted food handling residue study (MRID 48034903), an application rate of 0.1 gal/1000 ft[2] was calculated for the proposed indoor use.  HED assumed this spray rate for this assessment.  

It is anticipated that occupational and residential handlers will potentially be exposed through the crack and crevice use of novaluron.  In addition, residents (adults and children) may potentially be exposed after treatments in residential areas.  


Table 2.1.  Summary of Proposed Use Pattern for Novaluron on Sweet Corn and in Food- or Feed-Handling Establishments.
Applic. Equip.
Formulation
[EPA Reg. No.]
Applic. Rate
(lb ai/A)
Max. No. Applic. per Season
Max. Seasonal Applic. Rate
(lb ai/A)
PHI
(days)
Use Directions and Limitations
                            Sweet Corn  (PP#0E7723)
Aerial/ Ground-boom
                                0.83 lb/gal EC
                                  [66222-35]
                                  0.058-0.078
                                      5-6
                                     0.39
                                       1
Apply in sufficient volume to ensure full coverage of foliage and developing ears.  Use higher rates and higher spray volumes when larvae are large or foliage canopy is tall or dense.  The use of surfactants/adjuvants (including non-ionic surfactants) is prohibited.  Repeat applications as needed to protect new growth, but not less than 7 days apart.  
Residential and Commercial Buildings and Structures and Their Immediate Surroundings and on Modes of Transport[a]  (PP#0F7708)
Low-pressure handwand, trigger sprayer, ULV sprayer c  
                                0.83 lb/gal EC
                                  [66222-ERT]
                             0.1 gal/1000 ft[2][b]
                                Not  indicated
                3.1 ounces per gallon of water = 0.02 lb ai/gal
                                       
                             Spray rate per area:
                             0.1 gal/1000 ft[2] =
                            0.002 lb ai/1000 ft[2]
                                       
                                      NA
Prepare diluted spray solution by adding 2.3 to 3.1 ounces per gallon of water.  

Prior to application, remove or cover all food items in the area to be treated.  In the home, all food-processing surfaces and utensils should be covered during treatment or thoroughly washed before use.

Do not replace food containers or foodstuffs until spray has dried.

A retreatment interval (RTI) is not specified.  The label states the product is effective for 180 days (26 weeks or 6 months).  
[a] The permitted areas of use include non-food/non feed areas of stores; warehouses, transportation equipment, manufacturing sites, industrial buildings, houses, apartment buildings, office buildings, laboratories, schools, daycare centers, nursing homes, hospitals, hotels and on vessels, railcars, aircraft, buses, trucks, and trailers.
[b] The current label for Rimon[(R)] Supra 10EC did not include an application rate for spot, crack and crevice, surface spray, and general surface applications; please refer to for the chemistry and ORE memos for HED's application rate calculations.
c  Correspondence from MANA indicated that they do not intend to have a fogger use, but rather that applications should be made as a mechanical cold mist/ULV mist which targets the treatment spots.  There are no unit exposures for this scenario but the available low-pressure handwand and trigger sprayer unit exposure data are protective of mechanical cold mist/ULV mist applications.

Conclusions:  The proposed labels are adequate to allow evaluation of the residue data relative to the proposed new uses on sweet corn and in food- and feed-handling establishments; however, a revised Section B for PP#0E7723 should be submitted which:

   * specifies that the retreatment of sweet corn with novaluron is prohibited (i.e., only 1 application is allowed at a rate of 0.078 lb ai/A per growing season) in California and other arid areas, which receive less than 20 inches of precipitation per year; and
   * prohibits the use of novaluron on turnips harvested for the root and prohibits the feeding of turnip tops to livestock as previously requested (Memo, J. Van Alstine, 09-SEP-2009; D357060).  This affects the current petition because it could result in increased livestock dietary burdens.

Additionally, a revised Section B is requested for PP#0F7708 which:  

   * requires the addition of chemical-resistant gloves;  
   * specifies an application rate of 0.1 gallons per 1000 ft[2] for indoor spot, crack and crevice, space spray, and general surface applications; 
   * states that all food processing surfaces (including equipment) and utensils should be covered during treatment or thoroughly washed prior to use; 
   * states the livestock feed items should be removed or covered prior to application; and
   * removes all fogger and fog references on the label, and specifies that applications should be made with mechanical cold mist/ULV equipment. 

2.2	Structure and Nomenclature 
	
Table 2.2.  Novaluron Nomenclature.
Chemical structure
                                       
Common name
Novaluron
IUPAC name
1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)phenyl]-3-[2,6-difluorobenzoyl]urea
CAS name
N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide
CAS registry number
116714-46-6
End-use products (EPs)
Rimon[(R)] 0.83EC Insecticide (0.83 lb/gal EC; EPA Reg. No. 66222-35); Rimon[(R)] Supra 10EC Insecticide (0.83 lb/gal EC; EPA Est. No. 66222-ERT)

2.3	Physical and Chemical Properties

Table 2.3.  Physicochemical Properties of Technical Grade Novaluron.
Parameter
Value
Reference
Melting range
176.5 - 178.0C
DP# 315780, 3-NOV-2005, S. Levy
pH
6.5

Density
1.56 g/cm[3] at 22C

Water solubility
3 μg/L at 20C

Solvent solubility (at 25C)
0.00839 g/L in n-heptane
1.88 g/L in xylene
14.5 g/L in methanol
198 g/L in acetone
113 g/L in ethyl acetate
0.98 g/L in n-octanol

Vapor pressure (mm Hg)
1.2 x 10[-7]

Dissociation constant, pKa
Not determined due to low water solubility.

Octanol/water partition coefficient, Log(KOW)
4.3 at 25C

UV/visible absorption spectrum
Molar absorption coefficients of at 3 maximum absorbances:
15,400 L/mol  cm at 253 nm (neutral)
9,780 L/mol  cm at 253 nm (acidic)
20,500 L/mol  cm at 263 nm (basic)


3.0	HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS

A detailed hazard characterization for novaluron is presented in a previous HED risk assessment (Memo, M. Clock-Rust, et al., 25-MAR-2004; D295824).  Novaluron has low acute toxicity via the oral (Toxicity Category IV), dermal (Toxicity Category III), and inhalation routes (Toxicity Category IV).  No ocular (Toxicity Category IV) or dermal irritation (Toxicity Category IV) was noted.  Novaluron is not a dermal sensitizer.  In subchronic and chronic toxicity studies, novaluron primarily produced red blood cells effects , such as methemoglobinemia, decreased hemoglobin, decreased hematocrit, and decreased RBCs (or erythrocytes) that were associated with compensatory erythropoiesis. Unlike white blood cells (leukocytes) which are cells of the immune system, red blood cells function to deliver oxygen to body tissues and are not involved in eliciting an immune response. Increased spleen weights and/or hemosiderosis in the spleen were considered to be due to enhanced removal of damaged erythrocytes and not to an immunotoxic effect.

There was no maternal or developmental toxicity seen in the rat and rabbit developmental toxicity studies up to the limit doses.  In the two-generation reproductive toxicity study in rats, both parental and offspring toxicity (increased spleen weights) were observed at the same dose. Reproductive toxicity (decreases in epididymal sperm counts and increased age at preputial separation in the F1 generation) was observed at a higher dose than the hematotoxicity.  Clinical signs of neurotoxicity and neuropathology were seen in the rat acute neurotoxicity study at the limit dose.  However, no signs of neurotoxicity or neuropathology were observed in the subchronic neurotoxicity study in rats at similar doses or in any other subchronic or chronic toxicity study in rats, mice or dogs.  In addition, there were no clinical signs of toxicity observed in the acute oral toxicity study with novaluron (LD50 >5,000 milligrams/kilogram (mg/kg)).  Therefore, there is no concern for neurotoxicity resulting from exposure to novaluron.   No toxicity was observed at the limit dose in the dermal study and there were no developmental toxicity concerns at the limit-dose; therefore, quantification of short-term dermal risk is not necessary.   Aditionally, in a rat dermal penetration study the maximum total absorbed dose (expressed as per cent of administered dose and determined as the sum of radioactivity in excreta, cage wash, untreated skin, fat, blood, and residual carcass) ranged from about 0.5% to 10% of that administered, indicating low dermal absorption.  There was no evidence of carcinogenic potential in either the rat or mouse carcinogenicity studies and no evidence of mutagenic activity in the submitted mutagenicity studies, including a bacterial (Salmonella, E. coli) reverse mutation assay, an in vitro mammalian chromosomal aberration assay, an in vivo mouse bone-marrow micronucleus assay and a bacterial DNA damage/repair assay.  Based on the results of these studies, EPA has classified novaluron as "not likely to be carcinogenic to humans."  

3.1	FQPA Considerations

The RAB1 risk assessment team concluded that the FQPA SF can be reduced to 1X based on the following:

   * There is no evidence of increased susceptibility in the rat or rabbit developmental toxicity studies up to the limit dose or in the two-generation reproduction study in rats.
   * There are no concerns or residual uncertainties for pre- and/or postnatal toxicity.
   * Acute and subchronic neurotoxicity screening batteries were performed with novaluron in rats.  Novaluron is not considered neurotoxic, since effects observed in the acute neurotoxicity study were observed at the limit dose only and were not reproduced at similar, repeated doses in the subchronic neurotoxicity study.  In addition, no evidence of neuropathology was observed in subchronic and chronic toxicity studies in rats, mice, or dogs, and novaluron is not considered acutely toxic (LD50>5000 mg/kg).
   * A developmental-neurotoxicity (DNT) study is not required.
   * Histopathological examination of the organs of the immune system (i.e., thymus, spleen, lymph nodes) showed an increase in spleen weight and increased incidence and severity of hemosiderosis in the spleen in the chronic studies in rats and mice and in the reproduction study in rats.  These findings were associated with the primary hematotoxicity of novaluron, which caused secondary accumulation of damaged erythrocytes in the spleen following removal from the blood.  Therefore, these are not considered immunotoxic effects.  The overall weight of evidence suggests that novaluron does not directly target the immune system.  An immunotoxicity study is required as part of the revised 40 CFR Part 158 toxicology data requirements for novaluron; however, HED does not believe that conducting a functional immunotoxicity study will result in a lower NOAEL than the regulatory dose being used for risk assessment, and an additional UF for database uncertainty (UFDB) is not needed to account for the lack of the required immunotoxicity study.
   * The protective residue assumptions were used in the dietary exposure risk assessment such as  assuming average residues based on field trial data [maximum application rate; minimum pre-harvest interval (PHI); and samples were frozen immediately after harvest].  Additionally, the current chronic analysis could be further refined through the use of monitoring data and preparation/cooking factors.  
   * The completeness of the residue chemistry database and conservative drinking water assessment.
   * The residential exposure assessment was conducted using high-end estimates of use and potential exposure providing a conservative, health protective estimate of risk.

The doses and toxicological endpoints selected for human health risk assessment are summarized in Table 3.1.

Table 3.1.  Summary of Toxicological Dose and Endpoints for Novaluron.
                                   Exposure
                                   Scenario
                       Dose Used in Risk Assessment, UF
                      FQPA SF and LOC for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary 
(all populations)

Not applicable
None
An endpoint of concern attributable to a single dose was not identified.  An acute RfD was not established.
Chronic Dietary
(all populations)
NOAEL = 1.1 mg/kg/day
UF = 100

FQPA SF = 1X
cRfD = cPAD = 0.011 mg/kg/day
Combined chronic toxicity/carcinogenicity feeding in rat.
LOAEL = 30.6 mg/kg/day based on erythrocyte damage and turnover resulting in a regenerative anemia.
Short-Term 
Incidental Oral 
(1-30 days)


NOAEL = 4.38 mg/kg/day
Residential LOC for MOE <100
90-day feeding study in rat.
LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased hemoglobin, hematocrit, and RBC counts) and histopathology (increased hematopoiesis and hemosiderosis in spleen and liver).
Intermediate-Term 
Incidental Oral 
(1-6 months)


NOAEL = 4.38 mg/kg/day
Residential LOC for MOE <100
90-day feeding study in rat.
LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased hemoglobin, hematocrit, and RBC counts) and histopathology (increased hematopoiesis and hemosiderosis in spleen and liver).
Short-Term Dermal (1-30 days)
Not applicable
None
No toxicity was observed at the limit dose in the dermal study and there were no developmental toxicity concerns at the limit-dose; therefore, quantification of short-term dermal risk is not necessary.
Intermediate-Term
Dermal 
(1-6 months)
Oral NOAEL = 4.38 mg/kg/day
(dermal-absorption rate = 10%)
Residential/ Occupational LOC for MOE <100 
90-day feeding study in rat.
LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased hemoglobin, hematocrit, and RBC counts) and histopathology (increased hematopoiesis and hemosiderosis in spleen and liver).
Long-Term Dermal 
(>6 months)


Oral NOAEL = 1.1 mg/kg/day
(dermal-absorption rate = 10%)
Residential/ Occupational LOC for MOE <100 
Combined chronic toxicity/carcinogenicity feeding in rat. LOAEL = 30.6 mg/kg/day based on erythrocyte damage and turnover resulting in a regenerative anemia.
Short-Term Inhalation 
(1-30 days)
Oral NOAEL = 4.38 mg/kg/day
(inhalation-absorption rate = 100%)
Residential/ Occupational LOC for MOE <100 
90-day feeding study in rat.
LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased hemoglobin, hematocrit, and RBC counts) and histopathology (increased hematopoiesis and hemosiderosis in spleen and liver).
Intermediate-Term Inhalation 
(1-6 months)

Oral NOAEL = 4.38 mg/kg/day
(inhalation-absorption rate = 100%)
Residential/ Occupational LOC for MOE <100
90-day feeding study in rat.
LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased hemoglobin, hematocrit, and RBC counts) and histopathology (increased hematopoiesis and hemosiderosis in spleen and liver).
Long-Term Inhalation 
(>6 months)

Oral NOAEL = 1.1 mg/kg/day
(inhalation-absorption rate = 100%)
Residential/ Occupational LOC for MOE <100 
Combined chronic toxicity/carcinogenicity feeding in rat.
LOAEL = 30.6 mg/kg/day based on erythrocyte damage and turnover resulting in a regenerative anemia.
Cancer
Not likely to be carcinogenic to humans.
UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no-observed-adverse-effect-level, LOAEL = lowest-observed-adverse-effect-level, PAD = population-adjusted dose (a = acute, c = chronic), RfD = reference dose, MOE = margin of exposure, LOC = level of concern.

A 90-day inhalation toxicity study in the rat is requested for further characterization of inhalation risk.  Due to the potential for repeated inhalation exposure anticipated from the proposed residential use pattern, there is concern for toxicity by the inhalation route.  An inhalation study would provide a dose and endpoint via the route of exposure of concern (i.e. route specific study) and thus would avoid using an oral study and route-to-route extrapolation.

3.2	Endocrine Disruption

As required under Federal Food, Drug, and Cosmetic Act (FFDCA) section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  The EDSP employs a two-tiered approach to making the statutorily required determinations.  Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data.  Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.  This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios.  This list should not be construed as a list of known or likely endocrine disruptors.

Novaluron is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP.  Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals.  Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website:  http://www.epa.gov/endo/.

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

The residue chemistry data submitted in support of the proposed uses are summarized in the pending HED memorandum by J. L. Van Alstine (D378631).  The chronic dietary exposure assessment is summarized in the pending HED memorandum by J. L. Van Alstine (D383133).

4.1	Food Residue Profile

Nature of the Residue - Plants:  HED previously concluded that the nature of the residue in plants is adequately understood based on acceptable metabolism studies conducted on apples, cabbage, cotton, and potatoes using [difluorophenyl-U-[14]C]novaluron and [chlorophenyl-U-[14]C]novaluron as the test substances (Memo, G. Kramer, 22-MAR-2004; D285474).  These studies indicate that novaluron is not extensively metabolized in these crops.  The parent compound, novaluron, was either the only residue component identified or was the predominant residue component in all analyzed plant matrices.  The reviewed studies also indicate that novaluron, when foliarly applied during the vegetative growth stage, is not readily translocated to mature apple fruit, potato tubers, or cottonseed (Memo, G. Kramer, 22-MAR-2004; D285474).  Based on these studies, the Metabolism Assessment and Review Committee (MARC) determined that the residue of concern in crops for purposes of tolerance enforcement and risk assessment is novaluron only (Memo, G. Kramer et al., 03-FEB-2004; D297646).    

Nature of the Residue - Livestock:  HED also previously concluded that the nature of the residue in livestock is adequately understood based on the submitted goat and hen metabolism studies (Memo, G. Kramer, 22-MAR-2004; D285474).  The HED MARC determined that the residue of concern in livestock for purposes of tolerance enforcement and risk assessment is novaluron only (Memo, G. Kramer et al., 03-FEB-2004; D297646).

Residue Analytical Enforcement Method - Plant:  MANA previously submitted a gas chromatography/electron-capture detection (GC/ECD) residue analytical method for the analysis of novaluron residues in/on pome fruit, cabbage, and potato commodities; HED concluded that the method was adequate for gathering data on novaluron.  A second method, high-performance liquid chromatography/ultraviolet (HPLC/UV), was submitted for the analysis of novaluron residues only in/on cotton commodities.  Both methods were adequately validated by the petitioner and by an independent laboratory.  Acceptable radiovalidation data for the GC/ECD method have been submitted and reviewed in a previous HED memorandum (Memo, S. Levy, 23-AUG-2006; D325183) and both methods were forwarded to the EPA Analytical Chemistry Branch (ACB)/Biological and Economics Analysis Division (BEAD) for petition method validation (PMV; Memo, G. Kramer, 05-DEC-2003; D296264).

ACB concluded that based upon review of the submitted method validation data, without laboratory validation, that the GC/ECD and HPLC/UV methods appear suitable for food tolerance enforcement in plants (apples, cabbage, and potatoes) and cotton.  ACB recommended that the analytical methods do not need to be laboratory validated by EPA (Memo, S. Levy, 15-SEPT-2004; D306998).  Both methods have been forwarded to the Food and Drug Administration (FDA) for inclusion in the Pesticide Analytical Manual, Volume II (PAM II) as a Letter Method (S. Levy, 15-SEPT-2004; D307595).  An interference study was requested and a specific single-analyte confirmatory method was submitted and considered acceptable (Memo, J. Langsdale, 21-OCT-2008; D355574).

For sweet corn, the enforcement method, with minor modifications, was used for data collection and the method was adequately validated in conjunction with the sweet corn field trials.  The appropriate enforcement method for food- and feed-handling establishments is Method 243C-106 (MRID 48034901), which was used for data collection for the food-handling establishment field trial and was adequately validated.  

Multiresidue Methods:  Novaluron was tested through the FDA MRM Test guidelines in PAM I, Appendix II (JAN-1994).  The results indicate that novaluron is not adequately recovered by any of the MRMs.  This study was forwarded to FDA for further evaluation and updating of PAM Vol. I, Appendix I (Memo, S. Levy, 19-OCT-2005; D322359).

Magnitude of the Residue - Livestock:  The potential for secondary transfer of novaluron residues of concern in meat, milk, and eggs exists because there are livestock feedstuffs associated with the proposed/registered novaluron uses.  Livestock dietary burdens of novaluron were calculated, which incorporate the proposed/registered uses of novaluron.  The calculations reflected the most recent guidance from HED (OPPTS 860.1000 Supplement, Table 1 Feedstuffs, 30-JUN-2008) concerning revisions of feedstuff percentages and constructing reasonably balanced dietary burdens (RBDBs).  

The currently established livestock tolerances are based on the following RBDBs for novaluron:  16.9 ppm for beef cattle and 11.9 ppm for dairy cattle (Memo G. Kramer, 22-MAR-2004; D285474), and 2.4 ppm for poultry and 2.5 ppm for swine (Memo, J. Van Alstine, 23-FEB-2010; D374420).  Based on the proposed/registered uses, the revised RBDBs for novaluron are 9.6 ppm for beef cattle, 18.3 ppm for dairy cattle, 2.4 for poultry, and 2.5 for swine.  No changes are necessary for the tolerances for secondary residues in/on cattle, goat, horse, sheep, poultry, and swine commodities.  Although IR-4 requested increasing tolerances for residues of novaluron in milk from 1.0 to 1.5 ppm and milk, fat from 20 to 35 ppm, increased tolerances are not required for these commodities at this time.  IR-4 is requested to submit a revised Section F which removes the proposed changes to milk and milk fat tolerances.  Additionally, based on ChemSAC guidance that meat byproduct tolerances should be set at the highest residue level seen in any livestock commodity (minutes from 12-JAN-2011), several meat byproduct tolerances in 40 CFR § 180.598(a) should be updated so that they are based on the highest expected residue.  Additionally, two commodity descriptions should be updated.  The tolerances and commodity descriptions should be updated as outlined in Table 4.1.2.

Magnitude of the Residue  -  Sweet Corn:  The number and locations of field trials are in accordance with OPPTS Guideline 860.1500 for sweet corn.  The field trial data reflect the proposed use rate and PHI for sweet corn.  The field trial data for sweet corn stover and forage were entered into the Agency's tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data Standard Operating Procedure (SOP) to determine appropriate tolerance levels; see Appendix II.  All residues in/on K+CWHR were less than the lowest level of method validation (LLMV; 0.05 ppm); therefore, the recommended tolerance for sweet corn K+CWHR is 0.05 ppm.  The available data support tolerances of 50 ppm, 16 ppm, and 0.05 ppm for residues of novaluron in/on sweet corn sweet corn stover, forage, and K+CWHR, respectively.

Magnitude of the Residue  -  Food-Handling Establishments:  The food-handling study is adequate and reflects the use of novaluron as a space spray treatment to a simulated commercial food establishment at a rate of 38.75 mg ai/m[2] (3X application rate), with a product application rate of 0.1 gal/1000 ft[2] [refer to the chemistry summary memo (J. Van Alstine; D378631) for calculations].  An exaggerated rate was used to generate worst-case residues.  The residues for all covered food matrices samples treated at a 3X application rate were below the limit of quantitation (LOQ; <0.010 ppm) except for one sample of bread (0.0142 ppm) collected 4 hours post-application.  HED does not expect residues to be higher than 0.01 ppm in covered food and feed items following treatment at a 1X application rate because 29 out of 30 measured residues were below the LOQ, even when treated at a 3X rate, and the food-handling establishment label states that food items should be removed or covered prior to treatment and that packaged food items should be stored in such a way that direct contact with foodstuff is not anticipated.  The available data support the proposed tolerance of 0.01 ppm for residues in/on food/feed commodities (other than those covered by a higher tolerance as a result of use on growing crops) in food- and feed-handling establishments.

Processed Food and Feed:  HED does not require residue data for any processed commodities associated with sweet corn.  Therefore, data requirements for processed food and feed are not relevant to sweet corn commodities.  Additionally, since the food and feed handling establishment label states that food items should be removed or covered prior to treatment and that packaged food items should be stored in such a way that direct contact with foodstuff is not anticipated, data requirements for processed food and feed are not relevant to this use pattern.  

Submittal of Analytical Reference Standards:  The available analytical reference standards for novaluron expired on 22-NOV-2010 (personal communication with Theresa Cole, 22-NOV-2010).  MANA is required to submit an updated COA or a new analytical standard to the EPA National Pesticide Standards Repository at the following address:   

         USEPA
         	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP
         	701 Mapes Road
         	Fort George G. Meade, MD  20755-5350
            
            Please note that the extended zip code is required for delivery.

Confined/Field Accumulation in Rotational Crops:  The sweet corn commodities associated with the current petitions may be rotated.  Based on the results of the submitted confined rotational crop study, the appropriate plantback interval (PBI) for all non-labeled crops is 30 days.  The current and proposed labels include a restriction that only registered crops may be rotated to a treated field within 30 days of the final application, which is appropriate for this petition.  Future uses that have significantly higher application rates will require confined rotational crop studies at higher rates using chlorophenyl-labeled novaluron.  The HED MARC has determined that for tolerance assessment and risk assessment, parent only is the residue of concern in rotational crops (Memo, G. Kramer et al., 03-FEB-2004; D297646).
   
Tolerance Summary:  Permanent tolerances for novaluron have been established for a variety of commodities under 40 CFR §180.598.  The HED MARC determined that the residue of concern in plants (primary and rotational crops) and livestock for purposes of tolerance enforcement and risk assessment is novaluron only (Memo, G. Kramer et al., 03-FEB-2004; D297646).  Revised Section Fs are requested for PP#0E7723 and PP#0F7708 which reflect the HED-recommended tolerances and commodity definitions presented in Table 4.1.1.  Additional, the revised Section F for PP#0E7723 should be submitted which cites the appropriate CAS name for novaluron:

         "Tolerances are established for residues of the insecticide novaluron, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide) in or on the following raw agricultural commodities:"

No Codex, Canadian, or Mexican maximum residue limits (MRLs) have been established for novaluron in/on sweet corn stover, forage, and K+CWHR.  Canada is currently in the process of reviewing the use of novaluron on sweet corn stover, forage, and K+CWHR.  The EPA and the Pest Management Regulatory Agency (PMRA) tolerance recommendations have been harmonized at 0.05 ppm for sweet corn K+CWHR.  The PMRA is also proposing an increase in its MRL for milk to 1.0 ppm from 0.5 ppm, and as a result, the EPA and PMRA milk tolerances/MRLs are now harmonized.  The PMRA does not recommend MRLs for livestock feed commodities; therefore it is not possible to harmonize tolerances/MRLs for sweet corn stover and sweet corn forage.  The PMRA has not received a petition for the use of novaluron in food and feed handling establishments; therefore, it is not possible to harmonize for the residues resulting from this proposed use.    

The Agency's Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized for determining appropriate tolerance levels.

Table 4.1.1.  Tolerance Summary for Novaluron.
Commodity
                           Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
Comments; 
Correct Commodity Definition
Corn, Sweet, Stover
                                      50
                                      50
Corn, sweet, stover
Corn, Sweet, Forage
                                      20
                                      16
Corn, sweet, forage
Corn, Sweet, Kernel Plus Cob With Husks Removed	
                                     0.05
                                     0.05
Corn, sweet, kernel plus cob with husks removed
Milk
                                      1.5
                                      1.0
An increase in the tolerance for residues of novaluron in milk is not needed at this time.
Milk, fat
                                      35
                                      20
An increase in the tolerance for residues of novaluron in milk fat is not needed at this time.
All food/feed items other than those covered by a higher tolerance as a result of use on growing crops
                                     0.01
                                     0.01
Food/feed commodities (other than those covered by a higher tolerance as a result of use on growing crops) in food/feed handling establishments

Note to RD:  Based on ChemSAC guidance that meat byproduct tolerances should be set at the highest residue level seen in any livestock commodity (minutes from 12-JAN-2011), several meat byproduct tolerances in 40 CFR § 180.598(a) should be updated so that they are based on the highest expected residue.  Additionally, two commodity descriptions should be updated.  The tolerances and commodity descriptions should be updated as outlined in Table 4.1.2.

Table 4.1.2.  HED-Proposed Updates to 40 CFR § 180.598 (a) Based on 12-JAN-2011 ChemSAC Guidance.  
                         Current Commodity Definition
                         Updated Commodity Description
                            Current Tolerance (ppm)
                          Updated Tolerance (ppm)[1]
Cattle, meat byproducts, except kidney and liver
                                       -
                                     0.60
                                      11
Goat, meat byproducts except kidney and liver
                                       -
                                     0.60
                                      11
Horse, meat byproducts, except kidney and liver
                                       -
                                     0.60
                                      11
Sheep, meat byproducts, except kidney and liver
                                       -
                                     0.60
                                      11
Hog, meat byproducts
Hog, meat byproducts, except kidney and liver[2]
                                     0.10
                                      1.5
Poultry, meat byproducts
Poultry, meat byproducts, except kidney and liver[3]
                                     0.80
                                      7.0
1 Based on the based on the highest expected secondary tissue residue [peritoneal fat in cattle (translated to goat, horse, and sheep); peritoneal fat in hog; abdominal fat in poultry]. 
2 Separate tolerances have been established for hog, kidney (0.10 ppm) and hog, liver (0.10 ppm).  
[3] Separate tolerances have been established for poultry, kidney (0.80 ppm) and poultry, liver (0.80 ppm).  


4.2	Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED (R. Miller, 29-SEP-2010; D378389).  Since the application rates for the proposed new uses are significantly lower than the use rates for pome fruits and stone fruits, the EDWCs provided in the previous drinking water assessments dated 10-MAR-2009 (D357061) and 11-FEB-2004 (D285477) are applicable for the proposed uses.  EDWCs were not generated for the food- and feed-handling establishment uses because the use pattern is not expected to result in contamination of drinking water.  The HED MARC concluded that parent and the chlorophenyl urea and chloroaniline degradates are residues of potential concern to be included in the drinking water assessment.  Monitoring data are not available for novaluron or its chlorophenyl urea and chloroaniline degradates in surface water or ground water.  Concentrations in surface water and ground water were estimated using standard EFED drinking water models.

Tier II Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) modeling was performed to estimate drinking water concentrations for surface water for the parent novaluron.  The scenarios were selected to provide high-end drinking water concentrations for each crop and represent the geographic locations where the specific crops are grown in large quantities.  The most-conservative estimates were obtained for aerial applications to apples grown in PA at the maximum annual application rate of 0.972 lb ai/acre, applied three times at approximately 0.32 lb ai/acre, with an interval between applications of ten days.  For surface water, the 1-in-10-year annual mean EDWC for the parent novaluron is 0.76 ppb.  

A Tier I drinking water analysis was performed for the chlorophenyl urea and chloroaniline degradates using the FQPA Index Reservoir Screening Tool (FIRST) model to obtain surface water estimates.  For surface water, the annual average EDWC for chlorophenyl urea is 0.89 ppb and the annual average EDWC for chloroaniline is 2.6 ppb.  The chlorophenyl urea estimate is based upon the maximum application rate in peaches [approximately 0.32 lb ai/A applied 3 times per season every 7 days (0.972lb ai/year)] and the chloroaniline estimate is based upon the maximum application rate in apples [approximately 0.32 lb ai/A applied 3 times per season every 10 days (0.972 lb ai/year)].

For ground water, the Screening Concentration in Ground Water (SCI-GROW) model was used to predict a ground water concentration for novaluron at the annual application rate of 0.972 lb ai/acre (i.e., three applications of approximately 0.32 lb ai/acre).  The estimate for the parent novaluron is 0.0056 ppb in drinking water from shallow ground water sources.  For the chlorophenyl urea degradate, the predicted ground water concentration is 0.0045 ppb, and for the chloroaniline degradate, the concentration is 0.0090 ppb.  These concentrations were estimated with the same assumptions used for surface water modeling, and may be considered as both the peak and annual average upper-bound exposures.

These EDWC values are meant to represent upper-bound estimates of the concentrations that might be found in surface water and ground water based upon existing and proposed uses.  Of the three EDWC values, chronic estimates for the terminal chloroaniline metabolite are the highest (100% conversion from parent to aniline was assumed).  This is consistent with the expected degradation pattern for novaluron.  Therefore, the EDWC value for the chloroaniline degradate (2.6 ppb) was used to assess chronic aggregate risk.

Table 4.2.  EDWCs Resulting from the Application of Novaluron.
                         Drinking Water Source (Model)
                               Use(Modeled Rate)
                               Application Type
                           1-in-10-Year Acute (ppb)
                          1-in-10-Year Chronic (ppb)
                             30-Year Average (ppb)
                                   Novaluron
Surface Water (PRZM/EXAMS)
PA Apples
(0.972 lbs ai/A/year)
aerial application
                                    4.59[1]
                                     0.76
                                     0.62

GA Peach
(0.972 lbs ai/A/year)
aerial application
                                    4.72[1]
                                     0.51
                                     0.43
Groundwater
(SCIGROW)
Apples/Peaches
(0.972 lbs ai/A/year)
aerial application
                                    0.0056
                                    0.0056
                                   <=0.0056
                               Chlorophenyl Urea
Surface water
(FIRST)
Apples
(0.972 lbs ai/A/year)
Aerial Application
                                     4.55
                                     0.86
                                    <=0.86

Peaches
(0.972 lbs ai/A/year)
Aerial Application
                                     4.74
                                     0.89
                                    <=0.89
Groundwater
(SCIGROW)
Apples/Peaches
(0.972 lbs ai/A/year)
Aerial Application
                                    0.0045
                                    0.0045
                                   <=0.0045
                                 Chloroaniline
Surface water
(FIRST)
Apples/Peaches
(0.972 lbs ai/A/year)
Aerial Application
                                    11.4[2]
                                     2.60
                                    <=2.60
Groundwater
(SCIGROW)
Apples/Peaches
(0.972 lbs ai/A/year)
Aerial Application
                                     0.009
                                     0.009
                                   <=0.009
1 These values exceed the measured water solubility of novaluron; i.e., 3 ug/L.
[2] This value exceeds the estimated water solubility of chloroaniline; i.e., 10.6 ug/L.

4.3	Dietary Exposure and Risk

An acute dietary assessment was not conducted for novaluron because an endpoint of concern attributable to a single dose was not identified.  A cancer dietary assessment was not conducted because novaluron was classified as "not likely to be carcinogenic to humans."  A partially refined chronic dietary exposure and risk assessment was conducted to support Section 3 requests for use of novaluron on sweet corn and in food- and feed-handling establishments using the DEEM-FCID, Version 2.03, which uses food consumption data from USDA's CSFII from 1994-1996 and 1998.  

The partially refined chronic dietary exposure and risk assessment was conducted for the proposed new uses on sweet corn and in food- and feed-handling establishments, all established uses, and drinking water to support Section 3 requests for use of novaluron on sweet corn and in food- and feed-handling establishments.  A PCTn memorandum for sweet corn was provided by BEAD.  Additionally, data from a previously provided SLUA memorandum for existing uses and a PCTn memorandum for grain sorghum were used.  The chronic analysis incorporated average %CT data for apples, cabbage, cotton, pears, and potatoes, and PCTn data for grain sorghum and sweet corn.  100% CT was assumed for the remaining food commodities.  

ARs for meat, milk, hog, and poultry commodities were calculated using average field trial residues, PCTn data for grain sorghum and sweet corn, average %CT data for apple and cotton, and assumed 100% CT for sugarcane and cowpea seed.  The chronic analysis also incorporated average field trial residues, average greenhouse trial residues for tomatoes, empirical processing factors for apple juice (translated to pear and stone fruit juice), cottonseed oil, dried plums, and tomato paste and purée, and DEEM (ver. 7.81) default processing factors for the remaining processed commodities.  In accordance with HED SOP 2000.1, average field trial residues were translated from representative commodities in the crop group to other commodities in that crop group as needed.

The chronic dietary (food and drinking water) exposure to novaluron is below HED's LOC for the general U.S. population and all population subgroups.  The chronic dietary exposure results in a risk estimate that is 21% of the cPAD for the general U.S. population and 72% of the cPAD for children 1-2 years old, the most highly exposed population subgroup.  

 Table 4.3.  Summary of Chronic Dietary Exposure (Food and Drinking Water) and Risk for Novaluron[1][,2].
                              Population Subgroup
                                 Acute Dietary
                                Chronic Dietary
                                     Cancer
                                        
                          Dietary Exposure (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                      N/A
                                      N/A
                                   0.002298
                                      21
                                      N/A
                                      N/A
 All Infants (<1 year old)
                                        
                                        
                                   0.002922
                                      27
                                        
                                        
 Children 1-2 years old
                                        
                                        
                                   0.007955
                                      72
                                        
                                        
 Children 3-5 years old
                                        
                                        
                                   0.005989
                                      54
                                        
                                        
 Children 6-12 years old
                                        
                                        
                                   0.003676
                                      33
                                        
                                        
 Youth 13-19 years old
                                        
                                        
                                   0.002098
                                      19
                                        
                                        
 Adults 20-49 years old
                                        
                                        
                                   0.001632
                                      15
                                        
                                        
 Adults 50+ years old
                                        
                                        
                                   0.001576
                                      14
                                        
                                        
 Females 13-49 years old
                                        
                                        
                                   0.001570
                                      14
                                        
                                        
1 The chronic RfD (cRfd= cPAD = 0.011 mg/kg/day).
2 The highest dietary exposure is bolded.  

4.4	Anticipated Residue and %CT Information

A SLUA memorandum entitled, "Usage Report Package in Support of Registration for the Insecticide Novaluron (124002), BEAN DP# 371221" (A. Grube, 17-NOV-2009) and PCTn memorandums entitled, "Percent Crop Treated for New Use (PCTn): Novaluron (124002) Use on Sorghum, DP# 371615" (C. Doucoure, et al., 29-DEC-2009) and "Percent Crop Treated for Novaluron on Proposed New Uses for Sweet Corn (PC# 124002, DP# 384687)" (J. Alsadek et al., 18-FEB-2011) were provided by BEAD.  The SLUA memo included %CT data for apples, cabbage, cotton, pears, and potatoes.  The market leader approach was used by BEAD to determine the PCTn for sorghum and sweet corn.  New SLUA and grain sorghum PCTn memorandums were not required because the memos were completed within approximately one year of this analysis.  

The chronic dietary analysis incorporated average %CT data for apples (15%), cabbage (10%), cotton (2.5%), pears (10%), and potatoes (2.5%), and average PCTn data for grain sorghum (5%) and sweet corn (59%).  100% CT was assumed for the remaining food commodities.  Livestock dietary burdens of novaluron were calculated based on the proposed/registered uses, average field trial residues, average PCTn data for grain sorghum (5%) and sweet corn (59%), average %CT data for apple (15%) and cotton (2.5%), and an assumption of 100% CT for sugarcane and cowpea seed.  These livestock dietary burdens were used, along with average transfer coefficients, to calculate anticipated secondary residues for meat, milk, hog, and poultry commodities which were incorporated into the chronic dietary assessment.  

5.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

Novaluron is proposed for indoor (crack and crevice and spot treatments) and outdoor (perimeter) uses for the control of roaches and crickets.  Novaluron is proposed for use in residential and commercial buildings and structures and their immediate surroundings and on modes of transportation.  The permitted areas of use include non-food/non feed areas of stores, warehouses, transportation equipment, manufacturing sites, industrial buildings, houses, apartment buildings, office buildings, laboratories, schools, daycare centers, nursing homes, hospitals, hotels and on vessels, railcars, aircraft, buses, trucks and trailers.  There is a potential for exposure in residential settings during the application process for homeowners who use products containing novaluron.  There is also a potential for exposure from entering novaluron-treated areas that could lead to exposures to adults and children.  Risk assessments have been completed for both residential handler and post-application scenarios. Only the indoor use has been assessed as this is believed to cover the outdoor perimeter treatment.  The outdoor perimeter treatment is to areas that adults and children would not spend much time, such as around window frames and doors.  Dermal, inhalation and incidental oral exposure is expected to be higher from the indoor crack and crevice and spot treatments.   

A residential exposure assessment for novaluron was prepared in a pending HED memorandum (L. Venkateshwara; D378634).  See Table 2.1 for a summary of the proposed use patterns.  

5.1	Residential Handler Exposure and Risk

Based upon the proposed use pattern, HED expects the following residential pesticide handler scenarios:

   * Mixing/loading/applying  emulsifiable concentrate formulations with low-pressure handwand (PHED), and
   * Applying ready to use formulations via trigger-pump sprayer (ORETF).

Assessing exposures and risks resulting from residential uses is very similar to assessing occupational exposures and risks, except that a tiered approach for personal protection using increasing levels of personal protective equipment PPE is not used in residential handler risk assessments.  Homeowner handler assessments are based on the assumption that individuals are wearing shorts, short-sleeved shirts, socks, and shoes.

No chemical-specific data were available with which to assess potential exposure to residential pesticide handlers.  The estimates of exposure to pesticide handlers are based upon surrogate study data available in the PHED (v. 1.1, 1998) and ORETF.  MANA is a member of ORETF.

For the purposes of assessing a crack and crevice exposure scenario, HED used the mixing/loading/applying wettable powders with a low-pressure handwand scenario as a surrogate to assess handler exposure to the emulsifiable concentrate formulation.  Usually, HED would use surrogate data for liquid formulations as surrogate for EC formulation.  However, the unit exposure values provided for the wettable powder formulation are based on actual exposures measured during crack and crevice applications; whereas, the unit exposure values for the liquid formulation are based on applications to chicken houses and greenhouses.  Therefore, although the proposed product is formulated as an emulsifiable concentrate, HED believes that the use of unit exposure values resulting from crack and crevice applications provides a more accurate representation of handler exposure.

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

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

Where:  

      Daily Exposure		=	Amount (mg ai/day) deposited on the surface of the skin that is available for dermal absorption or amount inhaled that is available for inhalation absorption;
      Unit Exposure 		=	Unit exposure value (mg ai/lb ai) derived from August 1998 PHED or ORETF data;
      Application Rate		=	Normalized application rate based on a logical unit treatment, such as acres; and
      Daily Area Treated 	=	Normalized application area based on a logical unit treatment such as acres (A/day). 

The daily dermal or inhalation dose is calculated by normalizing the daily exposure by body weight and adjusting, if necessary, with an appropriate dermal or inhalation absorption factor using the following formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x (Absorption Factor (%/100)) / Body Weight (kg)

Where:

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

Non-cancer dermal and inhalation risks for each applicable handler scenario are calculated using an MOE, which is a ratio of the NOAEL to the daily dose.  All MOE values were calculated using the formula below:

      MOE = NOAEL or LOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day).

Dermal and inhalation risks were combined in this assessment, since the toxicological effects for these exposure routes were similar.  

Dermal and inhalation risks were combined using the following formula:

                Total MOE = NOAEL / (Dermal + Inhalation Dose).


Table 5.1 provides estimates of short-term exposure and risk for residential handlers.  Since there is no short-term dermal endpoint, these exposures are representative of intermediate-term dermal exposures and are considered conservative since intermediate-term exposures are not likely because of the intermittent nature of applications by homeowners.  Although a PoD from an oral study was used to assess residential handler inhalation risks for novaluron, HED does not believe this assessment is under-protective of adult handlers.  The inhalation MOEs calculated for residential handlers were all > 1 million, thus providing an ample margin of safety to account for any uncertainties in route-to-route extrapolation. The MOE calculated exceeds the LOC of 100 and, therefore, is not of concern.

Table 5.1.  Residential Handler Exposure and Risk for Novaluron.
                      Application Rate (lb ai/gallon)[a]
                          Amount Handled (gallons)[b]
                                 Unit Exposure
                                  (mg/lb ai)c
                             Dose (mg/kg/day)[e,f]
                                   MOE[g,h]
                                       
                                       
                              Baseline Dermal[d]
                            Baseline Inhalation[d]
                                Baseline Dermal
                              Baseline Inhalation
                Combined Baseline Dermal +  Baseline Inhalation
                                Baseline Dermal
                              Baseline Inhalation
                     Baseline Dermal + Baseline Inhalation
  Mixing/Loading/Applying Wettable Powders with Low-pressure Handwand (PHED)
                                     0.02 
                                      0.5
                                      100
                                     0.03
                                    0.0014
                                   0.0000043
                                    0.0014
                                     3,100
                                   1,000,000
                                     3,100
     Applying Ready to Use  Formulations Via Trigger Pump Sprayer (ORETF)
                                     0.02 
                                     0.125
                                      54
                                     0.019
                                    0.00019
                                       
                                    6.8E-07
                                       
                                       
                                    0.0002
                                       
                                       
                                    23,000
                                       
                                       
                                   6,500,000
                                       
                                    23,000
a.	Application rate based on proposed use on label for novaluron  product RIMON[(R)] EC Insecticide (Reg. No. 66222-ERT).  Maximum 	rate = 3.1 oz/gal (0.02 lb ai/gal).
b. 	ExpoSAC Policy #12.  Assumed 16-oz bottle for trigger pump sprayer (16 oz * 128 oz/gal = 0.125 gallon).
c. 	Unit Exposures for low-pressure handwand scenario based on PHED Version 1.1.  For purposes of assessing a crack and crevice 		exposure scenario, HED used the mixing/loading/applying wettable powders with a low-pressure handwand scenario as a surrogate to 	assess handler exposure to the liquid formulation.  See text above table for full explanation.  Unit exposures for trigger-pump sprayer 	scenario based on ORETF (OMA006; MRID 444598-01).  
d. 	Baseline Dermal:  Short-sleeve shirt, shorts, and no gloves.  Baseline Inhalation: no respirator.
e. 	Dermal Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) * application rate (lb ai/gallon) * amount handled (gallons) * dermal absorption factor (10%) / body weight (70 kg).
f. 	Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/gallon) * amount handled (gallons) * inhalation absorption (100%) / body weight (70 kg).  
g. 	MOE = NOAEL (short- and intermediate-term = 4.38 mg/kg/day) / daily dose (mg/kg/day).  LOC = 100.
h. 	Baseline Dermal + Baseline Inhalation MOE = NOAEL (mg/kg/day) / (Baseline Dermal dose + Baseline Inhalation dose).

5.2	Residential Post-application Exposure and Risk

HED believes that short and intermediate residential post-application exposures are likely from the proposed use.  Intermediate-term exposures have been estimated using Day-0 residue values along with an intermediate-term POD (applicable for exposures up to 6 months), which is considered a conservative assumption for longer-term exposures since residue values would be expected to dissipate over time.  For the proposed indoor use, HED anticipates that dermal (adults and children), inhalation (adults and children), and incidental oral (children only) exposures are possible.  

Post-application Inhalation
Post-application inhalation exposure can result from the proposed indoor use.  The saturation concentration in air for novaluron was calculated and used as a screening level air concentration for the inhalation post-application exposure assessment.  The following equation was used to estimate the saturation concentration for novaluron:

                 Csat = (VP * CF1 * MW * CF2 * CF3) / (R * T)

Where:
      Csat	=	Saturation concentration (mg/m[3]),
      VP	=	Vapor pressure (mmHg),
      MW	=	Molecular weight (g/mol),
      R	=	Gas constant = 0.0821 L-atm/mol-K,
      T	=	Temperature of the air (296 K),
      CF1	=	Conversion factor (atm/760 mm Hg),
      CF2	=	Conversion factor (10[3] mg/g), and
      CF3	=	Conversion factor (10[3] L/m[3]).

The vapor pressure of novaluron is 1.2 x 10[-7] mm Hg at 20[o]C and the molecular weight is 492.7 g/mol.  The saturation concentration was then used to calculate post-application inhalation exposure using the following assumptions:

      * inhalation rate = 0.55 m[3]/hr for adults and 0.36 m[3]/hr for toddlers based on ExpoSAC Policy #12, and
      * exposure time = 16 hours based on mean time spent in a residence from the U.S EPA Exposure Factors Handbook (1997).

Post-application inhalation dose is calculated as follows:

                    Dose (mg/kg/day) = Csat * IR * ET / BW 

Where:
      Csat	=	Saturation concentration (mg/m[3]),
      IR	=	Inhalation rate (m[3]/hr),
      ET	=	Exposure time (hr/day), and
      BW	=	Body weight (kg).
      
All post-application inhalation scenarios resulted in MOEs greater than 100 and do not exceed HED's level of concern.  Table 5.2.1 summarizes the post-application inhalation exposure and risk from the indoor uses of novaluron.  Although a PoD from an oral study was used to assess residential post-application inhalation risks for novaluron, HED does not believe this assessment is under-protective.  The post-application inhalation MOEs calculated were all > 3,000, thus providing an ample margin of safety to account for any uncertainties in route-to-route extrapolation. Further, calculating postapplication inhalation exposure and risk using the saturation concentration should be considered a very conservative approach.  The saturation concentration represents what would occur if a large amount of chemical were spilled in a non-ventilated room and allowed to evaporate until equilibrium is reached.

Table 5.2.1.  Post-application Inhalation Exposure for Children and Adults. 
                                  Population
                               Csat (mg/m[3])[a]
                                 IR (m[3]/hr)
                                    ET (hr)
                        Inhalation Dose (mg/kg/day)[b]
                               Inhalation MOE[c]
                                       
                                       
                                       
                                       
                                       
                                  Short- and 
                               Intermediate-term
                                     Adult
                                    0.0032
                                     0.55
                                      16
                                    0.0004
                                    11,000
                                   Children 
                            (3 to <6 years old)
                                       
                                     0.36
                                      16
                                    0.0012
                                     3,600
a.	Csat = [Vapor pressure (1.2 X 10[-7] mmHg) * Conversion factor (atm/760 mm Hg) * Molecular Weight (492.7 g/mol) * Conversion factor (10[3] mg/g) * Conversion factor (10[3] L/m[3])] / [R (Gas constant = 0.0821 L-atm/mol-K)* Temperature (296 K)].
b.	Inhalation Dose (mg/kg/day) = Csat * Inhalation Rate (m[3]/hr) * Exposure Time (hr) / Body Weight (kg).
c.	Inhalation MOE = NOAEL (Short- and intermediate-term = 4.38 mg/kg/day) / Dose (mg/kg/day).

Post-application Dermal
Post-application dermal 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.  Such exposure is assumed to occur for adults and children.  An assessment has been conducted for dermal exposures from the proposed indoor use (crack and crevice/spot).  Since there is no short-term dermal endpoint, these exposures are representative of intermediate-term exposures.

Crack and Crevice/Spot Use

The following data, assumptions, and equations were used to assess dermal post-application exposure from the proposed indoor crack and crevice/spot use:

   * Deposited residue: 
         o Maximum application rate:  3.1 ounces per gallon (0.02 lb ai/gal),  
         o Based on information from a Registrant submitted food handling residue study (MRID 48034903), assumed a spray rate of 0.1 gallon per 1000 sq feet,
         o Dermal post-application exposure assessed using the following deposited residue value:
               # 0.02 lb ai/gal and 0.1 gal/1000 ft[2] = 0.002 lb ai/1000 ft[2] = 1.18 ug/cm[2],
   * Fraction of ai available for transfer:  0.05 for carpet and 0.1 for hard surfaces,
   * Transfer coefficient:  16,700 cm[2]/hr for adults and 6,000 cm[2]/hr for children,
   * Exposure time:  8 hours/day for carpet and 4 hours/day for hard surfaces, and
   * Individuals contact previously treated carpets or hard surfaces on the same day a pesticide is applied.  

Dermal exposure for adults and children contacting treated indoor surface residue was calculated with the following equation:
                                       
                                ISR = DepR * F 
Where:

ISR	=	Indoor surface transferable residue (ug/cm[2]),
DepR	=	Deposited residue (ug/cm[2]), and
F	=	Fraction of ai available for transfer from carpet or hard surface (unitless).

                     D = (ISR * CF1 * TC * ET * DAF) / BW
Where:	

D	=	Dermal dose (mg/day),
ISR	=	Indoor surface transferable residue (ug/cm[2]),
CF1	=	Conversion factor (0.001 mg/ug),
TC	=	Transfer coefficient (cm[2]/hr), 
ET	=	Exposure time (hr/day), 
DAF	=	Dermal absorption factor, and
BW	=	Body weight (kg).

Dermal MOEs were calculated as follows:		

           Dermal MOE = NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).

Table 5.2.2 summarizes the dermal post-application exposure and risk from the crack and crevice/spot use at the maximum application rate allowed on the proposed label.  At the maximum application rate (3.1 oz/gal and 0.1 gallon/1000 ft[2]), all dermal MOEs for adults and children are greater than the target MOE of 100 and do not exceed HED's level of concern.  

Table 5.2.2.  Post-application Dermal Exposure for Children (3 to <6 year olds) and Adults for Novaluron Crack and Crevice/Spot Use. 
                                 Surface Type
                                  Population
                   Application rate per 1000 square feet[a]
                         Surface Residue[b] (ug/cm[2])
                             Fraction transferred
                        Transfer Coefficient (cm[2]/hr)
                            Exposure time (hr/day)
                          Dermal Dose[c] (mg/kg/day)
                                 Dermal MOE[d]
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                      I-T
3.1 oz/gal = 0.02 lb ai/gal and 0.1 gal/1000 ft[2] = 0.002 lb ai/1000 ft[2]
                                    Carpet
                                     Adult
                                   0.002[a]
                                     1.18
                                     0.05
                                    16,700
                                       8
                                     0.011
                                      390
                                       
                                   Children 
                             (3 to<6 year olds)
                                       
                                       
                                       
                                     6,000
                                       
                                     0.019
                                      230
                                 Hard Surfaces
                                     Adult
                                       
                                       
                                     0.10
                                    16,700
                                       4
                                     0.011
                                      390
                                       
                                   Children 
                             (3 to<6 year olds)
                                       
                                       
                                       
                                     6,000
                                       
                                     0.019
                                      230
a.	Maximum application rate is 3.1 oz/gal.  The maximum spray rate per area assumed to be 0.1 gallon per 1000 sq ft based on a Registrant submitted food handling study (MRID 48034903).
b.	Surface residue = conversion of the application rate from lb ai per sq ft to ug/cm[2]  using two conversion factors (4.5 x 10[8] ug/lb and 	1.08 x 10[-3] ft[2]/cm[2]).
c.	Dose (mg/kg/day) = Surface residue (ug/cm[2]) * Fraction transferred * Transfer coefficient (cm[2]/hr) * Exposure time (hr/day) * Conversion factor (0.001 mg/ug) * Dermal Absorption Factor (10%) / Body Weight (70 kg for adults and 15 kg for children).
d.	MOE = NOAEL (mg/kg/day) / Dose (mg/kg/day), where intermediate-term (I-T) dermal NOAEL = 4.38 mg/kg/day.  

Post-application Incidental Oral
Post-application incidental oral exposure resulting from hand-to-mouth activity can occur as a result of the indoor crack and crevice/spot use.  The hand-to-mouth exposure scenario was assessed using the HED Draft SOP's for Residential Exposure Assessments (2000), and the Revisions to the SOP's for Residential Exposure Assessment (ExpoSAC Policy #12).  This scenario assumes pesticide residues are transferred to the skin of children during post-application contact with treated indoor areas and are subsequently ingested as a result of hand-to-mouth transfer.  The following assumptions, factors, equations and calculations were used to estimate hand-to-mouth transfer exposure:

   * Deposited residue: 
         o Maximum application rate: 3.1 ounces per gallon (0.02 lb ai/gal),  
         o Based on information from a registrant-submitted food handling residue study (MRID 48034903), assumed a spray rate of 0.1 gallon per 1000 sq feet,
         o Dermal post-application exposure assessed using the following deposited residue value: 
               # 0.02 lb ai/gal and 0.1 gal/1000 ft[2] = 0.002 lb ai/1000 ft[2] = 1.18 ug/cm[2],
   * Fraction of ai available for transfer:  0.05 for carpet and 0.1 for hard surfaces,
   * The median surface area of both hands for children:  20 cm[2],
   * The mean rate of hand-to-mouth activity:  20 times/hour for short-term exposure scenarios and 9.5 events per hour for intermediate-term exposure scenarios,
   * Duration of exposure for children:  4 hours per day,
   * The saliva extraction factor:  50%, and
   * Toddlers are assumed to weigh 15 kg.

Incidental hand-to-mouth exposure for children contacting treated surfaces was calculated with the following equation:

                                   ISR = DepR x F 
Where:

ISR	=	Indoor surface transferable residue (ug/cm[2]),
DepR	= 	Deposited residue (ug/cm[2]), and
F	=	Fraction of ai available for transfer from carpet or hard surface (unitless).

                      D = (ISR x SA x FQ x ET x SE x CF1) / BW

Where:

D	=	Dermal dose (mg/kg/day),
ISR	=	Indoor surface transferable residue (ug/cm[2]),
SA	=	Surface area of the hands (cm[2]/event),
FQ	=	Frequency of hand-to-mouth activity (events/hr), 
ET	=	Exposure time (hr/day),
CF1	=	Conversion factor (0.001 mg/ug),
SE	=	Saliva extraction factor, and
BW	=	Body weight (15 kg).
                  
Incidental oral MOEs were calculated as follows:

  Incidental oral MOE = NOAEL (mg/kg/day) / Incidental Oral Dose (mg/kg/day).

Table 5.2.3 summarizes the MOEs for hand-to-mouth transfer of pesticide residues from the indoor crack and crevice/spot use at the maximum application rate allowed on the proposed label.  At the maximum application rate (3.1 oz/gal and 0.1 gallon/1000 ft[2]), short- and intermediate-term incidental oral MOEs are greater than the target MOE of 100 and do not exceed HED's level of concern.  


Table 5.2.3.  Post-application Incidental Oral (Hand-to-Mouth) Exposure for Children (3 to <6 year olds) for Novaluron Crack and Crevice/Spot Use.
                                Type of Surface
                    Application Rate (lb ai/1000 sq ft)[a]
                           Fraction ai dislodgeable
                       Surface area of the hand (cm[2])
                        Exposure Frequency (events/hr)
                           Saliva Extraction Factor
                            Exposure Time (hrs/day)
                          Surface Residue (ug/cm[2])
                    Average Daily Oral Dose (mg/kg/day)[b]
                            Incidental Oral MOE[c]
                                       
                                       
                                       
                                       
                                  Short-term
                               Intermediate-term
                                       
                                       
                                       
                                  Short-term
                               Intermediate-term
                                  Short-term
                               Intermediate-term
3.1 oz/gal = 0.02 lb ai/gal and 0.1 gallon/1000 ft[2] = 0.002 lb ai/1000 ft[2]
                                    Carpet
                                     0.002
                                     0.05
                                      20
                                      20
                                      9.5
                                      50%
                                       8
                                     1.18
                                     0.006
                                     0.003
                                      690
                                     1,500
                                 Hard surfaces
                                     0.002
                                     0.10
                                      20
                                      20
                                      9.5
                                      50%
                                       4
                                     1.18
                                     0.006
                                     0.003
                                      690
                                     1,500
a.	Maximum application rate is 3.1 oz/gal.  The maximum spray rate per area assumed to be 0.1 gallon per 1000 sq ft based on a Registrant submitted food handling study (MRID 48034903).
b.	Dose (mg/kg/day) = Surface residue (ug/cm[2]) * Fraction transferred * Surface area of hands (cm[2]/event) * Exposure frequency (events/hr) * Exposure time (hr/day) x Saliva extraction 	factor x Conversion factor (0.001 mg/ug) / Body Weight (15 kg for children).
c.	MOE = NOAEL (mg/kg/day) / Dose (mg/kg/day), where short- and intermediate-term (S-T and I-T) incidental oral NOAEL = 4.38 mg/kg/day.  


5.3	Combined Residential Risk Estimates

HED combines risk values resulting from separate residential exposure scenarios when it is likely they can occur simultaneously based on the use-pattern and the behavior associated with the exposed population.  Furthermore, since similar endpoints were selected for dermal, inhalation and oral exposures, risks from the three exposure routes may be combined.  Therefore, all non-dietary sources of post-application exposure were combined to obtain an estimate of potential combined exposure which could be used for the aggregate assessment.

A combined residential assessment has been included here based on the indoor crack and crevice/spot use.  These scenarios consisted of adult dermal and inhalation handler and post-application exposures, as well as children (3 to <6 years old) dermal, inhalation and oral (hand-to-mouth) post-application exposures.  All of the combined MOEs for adult and children (3 to <6 year olds) are greater than the target MOE of 100 and do not exceed HED's level of concern.  Table 5.3.1 provides a summary of the combined residential post-application indoor crack and crevice exposures and risks for adult and children and handler indoor crack and crevice exposures and risks for adults. 

Table 5.3.1.  Combined Residential Exposure and Risk Estimates from the Indoor Crack and Crevice/Spot Use.
                                  Short-term
                               Intermediate-term
                                  Population
                               Combined Dose[1]
                                Combined MOE[2]
                                  Population
                               Combined Dose[1]
                                Combined MOE[2]
                        Residential Handler Exposure[3]
Adults 
(inhalation only)
                                   0.0000043
                                   1,000,000
Adults 
(dermal + inhalation)
                                    0.0014
                                     3,100
                     Residential Post-Application Exposure
Adults 
(inhalation only)
                                    0.0004
                                    11,000
Adults 
(dermal + inhalation)
                                    0.0114
                                      380
Children 
(inhalation + HTM)
                                    0.0072
                                      580
Children 
(dermal + inhalation + incidental oral)
                                     0.023
                                      190
[1] Combined Dose = see Table 5.1 for handler exposures and Tables 5.2.1 through 5.2.3 for post-application exposures.
[2] Combined MOE = NOAEL (mg/kg/day) / Combined Dose (mg/kg/day); where S-T and I-T NOAEL = 4.38 mg/kg/day.
3 The values for the wettable powder exposure scenario were used because the wettable powder baseline doses were larger than the ready to use formulation baseline doses for both baseline inhalation and baseline combined (dermal + inhalation).  


5.4      Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander post-application inhalation exposure assessment was not performed for novaluron at this time.  However, volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby to pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA 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 post-application 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 post-application inhalation exposure assessment for novaluron.

5.5	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 additionally employed for novaluron.  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.  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[(R)] 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 and risks associated with aerial as well as other application types where appropriate.

6.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources:  food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  In the case of novaluron, aggregate risk assessments were performed for short-term aggregate exposure (food + drinking water + residential), intermediate-term aggregate exposure (food + drinking water + residential), and chronic aggregate exposure (food + drinking water).  Residential long-term exposure was not assessed because there are no chronic residential exposure scenarios for the registered and proposed uses, and was therefore not incorporated into the chronic aggregate exposure assessment.  An acute aggregate assessment was not conducted for novaluron because an endpoint of concern attributable to a single dose was not identified.  Additionally, a cancer aggregate assessment was not conducted because novaluron was classified as "not likely to be carcinogenic to humans."  All potential exposure pathways were assessed in the aggregate risk assessment. 


6.1	Short-Term Aggregate Risk

The short-term aggregate risk assessment estimates risks likely to result from 1- to 30-day exposures to novaluron residues from food, drinking water, and residential pesticide uses.  Short-term estimates of residential exposure are combined with background food and drinking water exposures.

Short-term aggregate risk assessments are necessary for both adults and children as there is potential for both short-term dermal and inhalation handler exposure and short-term post-application exposure from the residential uses of novaluron.  For the short-term aggregate risk assessment, potential residential post-application exposures were combined with food and drinking water exposures.  A short-term dermal endpoint has not been selected for novaluron; therefore the short-term adult and child aggregate risk estimates do not include dermal exposures.   Specifically, for young children, the short-term aggregate assessment combines dietary exposure with potential inhalation and incidental oral exposure (from hand-to-mouth contact with treated surfaces) resulting from the crack and crevice uses.  The short-term aggregate assessment for adults combines dietary exposures with exposure from potential post-application inhalation exposures resulting from indoor crack and crevice uses.  See Table 5.3.1 for more information on combined exposures.  

This is the first proposed residential use of novaluron; therefore, the short-term crack and crevice post-application exposure estimates were aggregated with the chronic dietary (food) to provide a worst-case estimate of short-term aggregate risk for the U.S. population and children 1-2 years old (the child population subgroup with the highest estimated chronic dietary food exposure).  As the short-term aggregate MOEs are greater than 100, risks do not exceed HED's level of concern.


Table 6.1.  Short-Term Aggregate Risk Calculations for Novaluron Using Post-Application Exposure Estimates.
                                  Population
                                   Subgroups
                            Short-Term Scenario[1]
                                       
                                     NOAEL
                                  (mg/kg/day)
                                    LOC[2]
                                Max Exposure[3]
                                  (mg/kg/day)
                           Average Dietary Exposure
                                  (mg/kg/day)
                            Residential Exposure[4]
                                  (mg/kg/day)
                                 Aggregate MOE
                         (dietary and residential)[5]
U.S. Population
                                     4.38
                                      100
                                     0.04
                                   0.002298
                                    0.0004
                                     1600
Children 1-2 years old
                                     4.38
                                      100
                                     0.04
                                   0.007955
                                    0.0072
                                      290
[1] A short-term dermal endpoint has not been selected for novaluron; therefore dermal exposure was not included in the short-term aggregate assessment.  Additionally post-application inhalation exposure estimates were used for adults as opposed to handler inhalation exposure estimates because the post-application inhalation dose was higher than the handler inhalation dose and resulted in a more conservative estimate of aggregate risk.  
[2] The LOC (target MOE) includes 10X for interspecies extrapolation and 10X for intraspecies variation.
[3] Maximum Exposure (mg/kg/day) = NOAEL/Target MOE.
[4] Residential Exposure = [Oral exposure + Inhalation Exposure].  
[5] Aggregate MOE = [NOAEL / (Avg. Dietary Exposure + Residential Exposure)].
	

6.2	Intermediate-Term Aggregate Risk 

The intermediate-term aggregate risk assessment estimates risks likely to result from 1 to 6 month exposures to novaluron residues from food, drinking water, and residential pesticide uses.  Intermediate-term estimates of residential exposure are combined with background food and drinking water exposures.

Intermediate-term aggregate risk assessments are necessary for both adults and children as there is potential for both intermediate-term dermal and inhalation handler exposure and intermediate-term post-application exposure from the residential uses of novaluron.  For the intermediate-term aggregate risk assessment, potential residential post-application exposures were combined with food and drinking water exposures.  Specifically, for young children, the intermediate-term aggregate assessment combines dietary exposure with potential dermal, inhalation, and incidental oral exposure (from hand-to-mouth contact with treated surfaces) resulting from the crack and crevice uses.  The intermediate-term aggregate assessment for adults combines dietary exposures with exposure from potential post-application dermal and inhalation exposures resulting from indoor crack and crevice uses.  See Table 5.3.1 for more information on combined exposures.

This is the first proposed residential use of novaluron; therefore, the intermediate-term crack and crevice exposure estimates were aggregated with the chronic dietary (food) exposures to provide a worst-case estimate of intermediate-term aggregate risk for the U.S. population and children 1-2 years old (the child population subgroup with the highest estimated chronic dietary food exposure).  As the intermediate-term aggregate MOEs are greater than 100, risks do not exceed HED's level of concern.

Table 6.2.  Intermediate-Term Aggregate Risk Calculations for Novaluron Using Post-Application Exposure Estimates.
                                  Population
                                   Subgroups
                         Intermediate-Term Scenario[1]
                                       
                                     NOAEL
                                  (mg/kg/day)
                                    LOC[2]
                                Max Exposure[3]
                                  (mg/kg/day)
                           Average Dietary Exposure
                                  (mg/kg/day)
                            Residential Exposure[4]
                                  (mg/kg/day)
                                 Aggregate MOE
                         (dietary and residential)[5]
U.S. Population
                                     4.38
                                      100
                                     0.04
                                   0.002298
                                    0.0114
                                      320
Children 1-2 years old
                                     4.38
                                      100
                                     0.04
                                   0.007955
                                     0.023
                                      140
  [1] Combined post-application exposure estimates were used as opposed to combined handler exposure estimates because the combined post-application dose was higher than the combined handler dose and resulted in a more conservative estimate of aggregate risk.  
  [2]The LOC (target MOE) includes 10X for interspecies extrapolation and 10X for intraspecies variation.
  [3] Maximum Exposure (mg/kg/day) = NOAEL/Target MOE.
  [4] Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure].  
  [5] Aggregate MOE = [NOAEL / (Avg. Dietary Exposure + Residential Exposure)].

6.3	Chronic Aggregate Risk 

The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of novaluron (food and drinking water) and residential uses.  Residential long-term exposure was not assessed because there are no chronic residential exposure scenarios for the registered and proposed uses of novaluron, and was therefore not incorporated into the chronic aggregate exposure assessment.  As a result, the chronic aggregate risk assessment considered exposure from food and drinking water only.  The chronic dietary exposure estimates are below HED's LOC (<100% cPAD) for the general U.S. population (21% of the cPAD) and all population subgroups (see Table 4.3).  The most highly exposed population subgroup is children 1-2 years old, at 72% of the cPAD.  Therefore, the chronic aggregate risk associated with the proposed uses of novaluron does not exceed HED's LOC for the general U.S. population or any population subgroups.

7.0	CUMULATIVE RISK	

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to novaluron and any other substances and novaluron does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that novaluron has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

8.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

An occupational exposure assessment for the proposed use of novaluron on sweet corn was prepared in a pending HED memorandum (L. Venkateshwara; D378630).  An occupational and residential exposure assessment for a proposed crack and crevice use was also prepared in a pending HED memorandum (L. Venkateshwara; D378634).  See Table 2.1 for a summary of the proposed use patterns.  

8.1.	Occupational Pesticide Handler Exposure and Risk 

8.1.1 	Sweet Corn Use

Occupational handler and post-application exposures from the proposed use of novaluron on sweet corn are anticipated.  Based on label information, exposure is expected to occur for short- and intermediate-term exposure durations (e.g., maximum of 6 applications, 7 days apart).

Occupational handler's exposure and risk were estimated for the following scenarios: 
	
Mixer/Loader:
  1. Mixing/loading liquids for aerial application;
  2. Mixing/loading liquids for groundboom application;
Applicator:
  3. Applying sprays via aerial applications;
  4. Applying sprays via groundboom applications; and
Flagger:

  5. Flagging to support aerial applications.
No chemical-specific data were available with which to assess potential exposure to pesticide handlers.  The estimates of exposure to pesticide handlers are based upon surrogate study data available in the PHED (August, 1998).  For occupational  pesticide handlers, HED presents estimates of dermal exposure for "baseline" (i.e., 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 PPE, as might be necessary.  The novaluron product labels direct applicators and other handlers to wear a long-sleeved shirt, long pants, protective eyewear, chemical-resistant gloves, and shoes plus socks. 

Handler exposure is expected to be short- and intermediate-term based on information provided on the proposed label for sweet corn (e.g., maximum of 6 applications, 7 days apart).  There is no short-term dermal POD; therefore, only intermediate-term dermal exposure has been assessed and is anticipated to be protective of short-term dermal exposure.  Short- and intermediate-term inhalation exposures have been assessed.  The short- and intermediate-term inhalation toxicological points of departure are the same; therefore, the estimates of risk for short-term duration inhalation exposures are protective of those for intermediate-term inhalation duration exposures.  The average adult body weight of 70 kg was used for estimating inhalation and dermal dose.  Long-term exposures are not expected; therefore, a long-term assessment was not conducted. Exposures, doses and MOEs were calculated using the equations presented in the residential section (Section 5.1).

                                        
Table 8.1.1 presents the estimated risks for workers based on the intermediate-term dermal and short- and intermediate-term inhalation exposures at baseline and with PPE.  HED has determined that risks do not exceed HED's level of concern (i.e., MOEs >=100), provided workers wear chemical-resistant gloves as recommended on the label.  No short-term POD was selected for dermal exposure; therefore, the risks presented for handlers are representative of intermediate-term exposures and would be considered protective of short-term exposures.  It should be noted that only engineering control data are available to assess dermal and inhalation risks to handlers operating aircraft (enclosed cockpit).  The risks do not exceed HED's level of concern for pilots using enclosed cockpits.


Table 8.1.1.  Occupational Handler Dermal and Inhalation Exposures and Risks from the Use on Sweet Corn.
                                  Dermal and
                           Inhalation Unit Exposures
                                  (mg/lb ai)
                               Application rate
                                 (lb ai/A)[1]
                           Area Treated Daily (A)[2]
               Short- and Intermediate-term Doses (mg/kg/day)[3]
                                 Total Dose[4]
                       Short- and Intermediate-term MOE
Total MOEs 5
                  (1) Mixer/Loader  -  Groundboom Application
                                    Dermal
                                Baseline: 2.9 
                                       
                         Single layer w/gloves:  0.023
                                       
                                  Inhalation
                              Baseline:  0.0012 
                                     0.078
                                      80
                                    Dermal
                              Baseline[6]: 0.026
                                       
                      Single layer w/gloves[8]:  0.00021
                         Baseline Dermal + Inhalation
                                     0.026
                                       
                      Single layer w/gloves + Inhalation
                                    0.00032
                                    Dermal
                                 Baseline[6]: 
                                      170
                       Single layer w/gloves[8]: 21,000
                         Baseline Dermal + Inhalation
                                      170
                                       
                  Single layer w/gloves + Baseline Inhalation
                                    14,000
                                       
                                       
                                       
                                  Inhalation 
                             Baseline[7]:  0.00011
                                       
                        Inhalation Baseline[7]:  41,000
                                       
                    (2) Mixer/Loader  -  Aerial Application
                                    Dermal
                                 Baseline: 2.9
                                       
                         Single layer w/gloves:  0.023
                                       
                                  Inhalation
                              Baseline:  0.0012 
                                     0.078
                                      350
                                    Dermal
                                Baseline:  0.11
                                       
                            Single layer w/gloves:
                                    0.00090
                          Baseline Dermal + Inhalation
                                     0.11
                                       
                      Single layer w/gloves + Inhalation
                                    0.0014
                                    Dermal
                                 Baseline:  39
                                       
                            Single layer w/gloves:
                                    13,000
                         Baseline Dermal + Inhalation
                                      39
                                       
                  Single layer w/gloves + Baseline Inhalation
                                     3,200
                                       
                                       
                                       
                                  Inhalation
                               Baseline: 0.00047
                                       
                                  Inhalation
                                Baseline: 9,400
                                       
                   (3) Applicator  -  Groundboom Application
                                    Dermal
                               Baseline:  0.014
                                       
                                  Inhalation
                              Baseline:  0.00074
                                     0.078
                                      80
                                    Dermal
                              Baseline:  0.00012
                         Baseline Dermal + Inhalation
                                    0.0002
                                    Dermal
                               Baseline: 35,000
                         Baseline Dermal + Inhalation
                                    23,000
                                       
                                       
                                       
                                  Inhalation
                              Baseline:  0.000066
                                       
                                  Inhalation
                               Baseline: 66,000
                                       
                     (4) Applicator  -  Aerial Application
                                    Dermal
                         Engineering Control:  0.0050
                                       
                                  Inhalation
                        Engineering Control:  0.000068 
                                     0.078
                                      350
                                    Dermal
                             Engineering control:
                                    0.0002
                         Combined Engineering Control
                                    0.00023
                                    Dermal
                             Engineering control:
                                    22,000
                         Combined Engineering Control
                                    20,000
                                       
                                       
                                       
                                  Inhalation
                        Engineering control:  0.000027
                                       
                                  Inhalation
                         Engineering control:  170,000
                                       
                      (5) Flagger  -  Aerial Application
                                    Dermal
                                Baseline: 0.011
                                       
                                  Inhalation
                              Baseline: 0.00035 
                                     0.078
                                      350
                                    Dermal
                               Baseline: 0.00043
                                       
                         Baseline Dermal + Inhalation
                                    0.0006 
                                    Dermal
                               Baseline: 10,000
                         Baseline Dermal + Inhalation
                                     7,700
                                       
                                       
                                       
                                  Inhalation
                              Baseline:  0.00014 
                                       
                                  Inhalation
                               Baseline:  32,000
                                       
1 Application rate is the maximum recommended rate provided on the novaluron product label.
2 Area treated per day values are HED estimates based on ExpoSAC Policy #9 "Standard Values for Daily Acres Treated in Agriculture," industry sources, and HED estimates.
3 Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x % Absorption (10% dermal and 100% inhalation assumed) / Body weight.  The body weight is 70 kg for the inhalation and dermal dose. 
4 Total Dose = Dermal + Inhalation Dose.
5 Short-/Intermediate-term MOE = Intermediate-term dermal or Short/Intermediate-term inhalation NOAEL (4.38 mg/kg/day) / Dermal or Inhalation dose (mg/kg/day)
6 Total MOE = NOAEL (4.38 mg/kg/day)/Total Dose.
7 Baseline Dermal:  long-sleeved shirt, long pants, no gloves.
8 Baseline Inhalation:  no respirator.
9 Single layer with gloves:  single layer baseline attire plus chemical-resistant gloves.


8.1.2	Crack and Crevice/Spot Use

There is also a potential for occupational handler exposure from the proposed use for indoor and outdoor control of roaches and crickets.  Occupational handler's exposure and risk were estimated for the following scenarios: 

   * Mixing/loading/applying emulsifiable concentrate formulations with low-pressure handwand (PHED), and
   * Applying ready to use formulations via trigger-pump sprayer (ORETF).

Chemical-specific data were not submitted to the Agency in support of this Section 3 application.  It is HED policy to use data from PHED Version 1.1 and/or the ORETF to assess handler exposures when chemical-specific data are not submitted.  

As with the residential assessment for purposes of assessing a crack and crevice exposure scenario for commercial applicators, HED used the mixing/loading/applying wettable powders with a low-pressure handwand scenario as a surrogate to assess handler exposure to the emulsifiable concentrate formulation.  Usually, HED would use surrogate data for liquid formulation as surrogate for EC formulation.  However, The unit exposure values provided for the wettable powder formulation are based on actual exposures measured during crack and crevice applications; whereas, the unit exposure values for the liquid formulation are based on applications to chicken houses and greenhouses.  Therefore, although the RIMON[(R)] SUPRA 10EC Insecticide is formulated as an EC, HED believes that the use of unit exposure values resulting from crack and crevice applications provides a more accurate representation of handler exposure.  

There is no short-term dermal POD; therefore, only intermediate-term dermal exposure has been assessed and should be considered protective of short-term dermal exposure.  Short- and intermediate-term inhalation exposures have been assessed.  In addition, the short- and intermediate-term inhalation toxicological points of departure are the same; therefore, the estimates of risk for short-term duration inhalation exposures are protective of those for intermediate-term inhalation duration exposures.  The average adult body weight of 70 kg was used for estimating inhalation and dermal dose.  A 10% dermal-absorption factor was used to estimate dermal exposure for all durations.  Long-term exposures are not expected; therefore, a long-term assessment was not conducted.  Exposures, doses and MOEs were calculated using the equations presented in the residential section (Section 5.1).	

				
Table 8.1.2 presents a summary of the short- and intermediate-term occupational handler exposures and risks.  The results of the occupational handler exposure and risk assessment indicate that MOEs do not exceed HEDs LOC (i.e., MOEs >=100) with either baseline attire (i.e., single layer of clothing, no respirator) or with the addition of gloves.  There is no unit exposure data for the mixing/loading/applying wettable powders scenario with baseline attire and no gloves; therefore, this scenario was only assessed assuming handlers were wearing gloves.   The proposed label for novaluron does not currently recommend any personal protective equipment for handlers.  HED recommends RD require the addition of chemical-resistant gloves to the label. 

Table 8.1.2.  Short- and Intermediate-Term Occupational Handler Exposure and Risk for Novaluron. 
                              Application Rate[a]
                           Amount applied Daily[b] 
                         Unit Exposures (mg/lb ai)[c]
                             Dose (mg/kg/day)[f,g]
                    Short- and Intermediate-term MOEs[h,i]
                                       
                                       
                              Baseline Dermal[d] 
                            Baseline Inhalation[d]
                               PPE-G Dermal[e] 
                                Baseline Dermal
                              Baseline  Inhalation
                                 PPE-G Dermal
                                Baseline Dermal
                             Baseline Inhalation 
                                 PPE-G Dermal
                                   Total MOE
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                     Baseline Dermal + Baseline Inhalation
                      PPE-G Dermal + Baseline Inhalation
   Mixing/Loading/Applying Wettable Powders with Low-Pressure Handwand (PHED)
                                0.02 lb ai/gal
                                  40 gallons
                                    No Data
                                      1.1
                                      8.6
                                      N/A
                                     0.013
                                    0.0098
                                      N/A
                                      350
                                      450
                                      N/A
                                      200
      Applying Ready-to-Use Formulations via Trigger-Pump Sprayer (ORETF)
                                0.02 lb ai/gal
                                   2 gallons
                                      42
                                     0.019
                                      1.8
                                    0.0024
                                   0.000011
                                    0.0001
                                     1,800
                                    400,000
                                    43,000
                                     1,800
                                    39,000
	a.	Application rate based on proposed use on label for novaluron product RIMON[(R)] EC Insecticide (Reg. No. 66222-ERT).  Maximum rate = 3.1 oz/gal (0.02 lb ai/gal).
	b. 	ExpoSAC Policy # 9.1.
	c. 	Unit Exposures for low-pressure handwand scenario based on PHED Version 1.1.  For purposes of assessing a crack and crevice exposure scenario for commercial applicators, 
              HED used the mixing/loading/applying wettable powders with a low-pressure handwand scenario as a surrogate to assess handler exposure to the liquid formulation.  See text above table for full explanation.  Unit exposures for trigger-pump sprayer scenario based on ORETF (OMA006; MRID 444598-01).  
	d. 	Baseline Dermal:  Long-sleeve shirt, long pants, and no gloves (none is specified on the label); Baseline Inhalation: no respirator.  Unit exposure data for the 				mixing/loading/applying wettable powders with low pressure handwand scenario at baseline with no gloves is not available; therefore, this scenario was only assessed with the use 			of gloves.

	e. 	PPE-G Dermal: Baseline plus chemical-resistant gloves.
	f. 	Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/gallon) * amount handled (gallons) * dermal absorption factor (10%) / body weight (70 kg).
	g. 	Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/gallon) * amount handled (gallons) * inhalation absorption (100%) / body weight (70 kg).  
	h. 	MOE = NOAEL (short- and intermediate-term = 4.38 mg/kg/day) / daily dose (mg/kg/day).  LOC = 100.
	i. 	Total MOEs = NOAEL (mg/kg/day) / (Dermal dose + Inhalation dose).
      


8.2	Occupational Post-Application Worker Exposure and Risk

8.2.1 	Occupational Post-Application Worker Exposure and Risk for Sweet Corn

The proposed use is for a post emergent application; therefore, a dermal post-application exposure assessment was conducted.  The registrant submitted two studies:

      Willard, T. (2002) Foliar Dislodgeable Residue Dissipation of Novaluron in Cotton: Final Study Report: Lab Project Number: AA010705: R-13884:989W. Unpublished study prepared by American Agricultural Services, Inc. 214 p. {OPPTS 875.2100}

Willard, T. (2002) Foliar Dislodgeable Residue Dissipation of Novaluron in Apple: Lab Project Number: AA01076: R-13883: AA010706.CA. Unpublished study prepared by American Agricultural Services, Inc. 204 p. {OPPTS 875.2100}

HED decided not to use the apple study due to some study limitations and differences in the use pattern (different application rate and application equipment used) and differences in plant/leaf morphology (apple versus corn).  

HED did use chemical-specific data provided in the cotton study.  This study was designed to determine the dissipation of dislodgeable foliar residues (DFR) of novaluron applied to cotton foliage at two test sites located in Porterville, California and Washington, Louisiana.  Three applications of Rimon(R) 10EC, an EC formulation containing novaluron (0.83 lb ai/gal) were made to cotton foliage at a target rate of 0.091 lb ai/A/application.  The re-treatment interval was 7 days.  Applications were made as a foliar broadcast spray at a spray volume of approximately 21 to 28 gallons of spray solution per acre (GPA) using groundboom equipment.  There were no surfactants/adjuvants included in the spray mixtures. 

At the California site, the highest average DFR value occurred immediately after the third application (0.673 μg/cm2).  The residues declined to an average of 0.361 μg/cm2 by Day 21 after the third application, and then increased to an average of 0.483 μg/cm2 by Day 35 after the third application.  At the Louisiana site, the highest average DFR value occurred immediately after the third application (0.142 μg/cm2).  The residues then declined to below the LOQ by Day 28 after the third application.  The registrant generated dissipation curves using a linear first order kinetic model of the natural log transformed data.  The analysis was conducted using the individual DFR values collected immediately after the third application through the last day of sampling.  The registrant's calculated half-lives for novaluron in cotton foliage were 59 days for the California site and 8 days for the Louisiana site.  This difference in dissipation is due to the difference in climate, with Louisiana being a more humid climate (more rainfall), and California being a more arid climate (less rainfall).  In California and other arid areas which receive less than 20 inches of precipitation per year, the residues are not expected to dissipate, and therefore only 1 application of novaluron should be required.  The registrant should submit a revised label which specifies that the retreatment of sweet corn with novaluron is prohibited (i.e., only 1 application is allowed at a rate of 0.078 lb ai/A) in California and other arid areas which receive less than 20 inches of precipitation per year.  See Memo, L. Venkateshwara, 29-MAR-2011; D387931 for the analysis of the data from the CA site, and see memo, L. Venkateshwara, 29-MAR-2011; D387932 for the analysis of the data from the LA site.

 Post-application exposures have been assessed using the submitted dislodgeable foliar residue data as well as dermal transfer coefficients from HED's ExpoSAC Policy Number 3.1 "Agricultural Transfer Coefficients" (August, 2000).  Table 8.2.1 summarizes the scenarios assessed.  In addition, the following assumptions were used in the calculations: 
 
      * Application Rate	           		 = 	0.078 lb ai/A  
      * Exposure Duration		 =	8 hours per day
      * Body Weight			 =	70 kg for adult male		
      * Dermal Absorption		 = 	10%
      * Dislodgeable foliar residue (DFR) =	chemical-specific data from MRID # 456384-16.

 Table 8.2.1.  Anticipated Post-application Activities and Dermal Transfer Coefficients.
                                 Proposed Crop
                           Policy Crop Group Category
                        Transfer Coefficients (cm[2]/hr)
                                   Activities
                                   Sweet Corn
                              Field/row crop tall
                                      100
                                  Hand weeding
                                        
                                        
                                      1000
                            Irrigation and scouting
                                        
                                        
                                     17000
                          Detasseling and hand harvest

Equations/Calculations:

Daily dermal exposures were calculated on each post-application day after application using the following equation:
                                       
Daily Dermal Doset  =  [DFRt (ug/cm[2]) x 0.001 mg/ug x TC (cm[2]/hr) x DA x ET (hrs)]  /  BW (kg)

Where:
		DFRt 	=	dislodgeable foliage residue on day "t" (ug/cm[2]);
		TC	=	transfer coefficient (cm[2]/hr);
		DA	=	dermal absorption factor (100%);
		ET	=	exposure time (8 hr/day); and
		BW	=	body weight (70 kg).

Once daily exposures are calculated, the calculation of daily absorbed dose and the resulting MOEs use the same algorithms that are described above for the handler exposures.  These calculations are completed for each day or appropriate block of time after application.

Table 8.2.2 presents a summary of occupational post-application risks associated with use of novaluron at the Louisiana site and Table 8.2.3 presents the summary of the occupational post-application risks associated with use of novaluron at the California site. 


Table 8.2.2.  Post-application Risks for Novaluron Using Data from the Louisiana Site.
                                     Crop
                               Application  Rate
                                   (lb ai/A)
                             Transfer Coefficient
                                  (cm[2]/hr)
                                    DFR[1]
                                   (ug/cm[2])
                             Days After Treatment
                                 Daily Dose[2]
                                  (mg/kg/day)
                                    MOE[3]
                                   Sweet Corn
                                     0.078
                                      100
                                     0.118
                               12 hours (0 days)
                                   0.000137
                                    32,000
                                       

                                     1,000
                                       
                                       
                                    0.00137
                                     3,200
                                       

                                     17000
                                       
                                       
                                     0.023
                                      190
  The information in the table is based on proprietary and non-proprietary data.
  [1] DFR calculated from MRID #456384-16 Louisiana site.
  [2] Daily Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug x Dermal Absorption (10%) x 8 hrs/day] / Body Weight (70 kg).
  [3] NOAEL/Daily Dose (Intermediate-term NOAEL = 4.38 mg/kg/day).

Table 8.2.3.  Post-application Risks for Novaluron Using Data from the California Site.
                                     Crop
                               Application  Rate
                                   (lb ai/A)
                             Transfer Coefficient
                                  (cm[2]/hr)
                                    DFR[1]
                                   (ug/cm[2])
                             Days After Treatment
                                 Daily Dose[2]
                                  (mg/kg/day)
                                    MOE[3]
                                   Sweet Corn
                                     0.078
                                      100
                                     0.58
                               12 hours (0 days)
                                    0.00066
                                     6,600
                                       

                                     1,000
                                       
                                       
                                    0.0066
                                      660
                                       

                                     17000
                                       
                                       
                                     0.113
                                      39
  The information in the table is based on proprietary and non-proprietary data.
  [1] DFR calculated from MRID #456384-16 California site.
  [2] Daily Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug x Dermal Absorption (10%) x 8 hrs/day] / Body Weight (70 kg).
  [3] NOAEL/Daily Dose (Intermediate-term NOAEL = 4.38 mg/kg/day).

Based on the differences in DFR data from the Louisiana site (a more humid climate) and the California site (a dry climate), HED is recommending two different retreatment intervals, one for humid climates and one for arid climates.  For humid climates a retreatment interval of 7 days is acceptable; however, for arid climates where DFR data show that there is no dissipation, only 1 application should be allowed at a rate of 0.078 lb ai/A.  Table 8.2.4 shows the calculations for the MOE at the California site after one application.  The MOE at the highest TC is 175, which is greater than 100.  

Table 8.2.4.  Post-application Risks for Novaluron at California Site after 1 Application.
                                     Crop
                               Application  Rate
                                   (lb ai/A)
                             Transfer Coefficient
                                  (cm[2]/hr)
                                DFR (ug/cm[2])
                             Days After Treatment
                                 Daily Dose[1]
                                  (mg/kg/day)
                                    MOE[2]
                                   Sweet Corn
                                     0.078
                                      100
                                     0.13
                               12 hours (0 days)
                                    0.00015
                                    29,000
                                       

                                     1,000
                                       
                                       
                                    0.0015
                                     2,900
                                       

                                     17000
                                       
                                       
                                     0.025
                                      175
The information in the table is based on proprietary and non-proprietary data.
[1]  Daily Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug x Dermal Absorption (10%) x 8 hrs/day] / Body Weight (70 kg)
[2]  NOAEL/Daily Dose (Intermediate-term NOAEL = 4.38 mg/kg/day)

Inhalation

Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for novaluron at this time.  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA 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 as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application 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 occupational post-application inhalation exposure assessment for novaluron.

Restricted Reentry Interval 
	
Novaluron is classified as acute Toxicity Category III for acute dermal toxicity.  It is classified as Toxicity Category IV for primary eye irritation and primary skin irritation.  Therefore, the interim WPS REI of 12 hours is adequate to protect agricultural workers from post-application exposures to novaluron.

8.2.2 	Crack and Crevice/Spot Use

Based on the proposed use sites associated with the indoor crack and crevice/spot use, HED believes the presence of commercial workers in treated areas is minimal after application.  Therefore, an occupational quantitative post-application assessment for this product was not conducted. 

9.0	DATA NEEDS AND LABEL RECOMMENDATIONS

9.1	Toxicology
   * A 90-day inhalation toxicity study is requested for further characterization of inhalation risk.  Due to the potential for repeated inhalation exposure anticipated from the proposed residential use pattern, there is concern for toxicity by the inhalation route.  An inhalation study would provide a dose and endpoint via the route of exposure of concern (i.e. route specific study) and thus would avoid using an oral study and route-to-route extrapolation.  An immunotoxicity study is required as specified in the new 40 CFR Part 158 data requirements.
   * An immunotoxicity study is required as specified in the new 40 CFR Part 158 data requirements.
   
9.2	Residue Chemistry
   * 860.1200 Directions for Use
         o A revised Section B for PP#0E7723 should be submitted which:
               # prohibits the use of novaluron on turnips harvested for the root and prohibits the feeding of turnip tops to livestock as previously requested (Memo, J. Van Alstine, 09-SEP-2009; D357060).  This affects the current petition because it could result in increased livestock dietary burdens.

         o A revised Section B for PP#0F7708 should be submitted which:
               # specifies an application rate of 0.1 gallons per 1000 ft[2] for indoor spot, crack and crevice, space spray, and general surface applications; 
               # states that all food processing surfaces (including equipment) and utensils should be covered during treatment or thoroughly washed prior to use; 
               # states the livestock feed items should be removed or covered prior to application; and
               # removes all references to fogger and fog applications in the label and specifies that applications should be made with mechanical cold mist/ULV equipment. 

   * 860.1550 Proposed Tolerances
         o A revised Section F for PP#0E7723 should be submitted which:
               # cites the appropriate CAS name for novaluron:
               "Tolerances are established for residues of the insecticide novaluron, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide) in or on the following raw agricultural commodities:"; and

               # reflects the recommended tolerances and commodity definitions presented in Table 14.  

         o Additionally, a revised Section F for PP#0F7708 should be submitted which:
               # reflects the commodity definition presented in Table 14.  
   * 860.1650 Submittal of Analytical Reference Standards
         o The available analytical reference standards for novaluron have expired.  MANA is required to submit an updated COA or a new analytical standard to the EPA National Pesticide Standards Repository at the following address:   
      
               USEPA
               National Pesticide Standards Repository/Analytical Chemistry Branch/OPP
               701 Mapes Road
               Fort George G. Meade, MD  20755-5350
   
               Please note that the extended zip code is required for delivery.

Note to RD:  Based on ChemSAC guidance that meat byproduct tolerances should be set at the highest residue level seen in any livestock commodity (minutes from 12-JAN-2011), several meat byproduct tolerances in 40 CFR § 180.598 (a) should be updated so that they are based on the highest expected residue.  Additionally, two commodity descriptions should be updated.  The tolerances and commodity descriptions should be updated as follows:


                         Current Commodity Description
                         Updated Commodity Description
                            Current Tolerance (ppm)
                          Updated Tolerance (ppm)[1]
Cattle, meat byproducts, except kidney and liver
                                       -
                                     0.60
                                      11
Goat, meat byproducts except kidney and liver
                                       -
                                     0.60
                                      11
Horse, meat byproducts, except kidney and liver
                                       -
                                     0.60
                                      11
Sheep, meat byproducts, except kidney and liver
                                       -
                                     0.60
                                      11
Hog, meat byproducts
Hog, meat byproducts, except kidney and liver[2]
                                     0.10
                                      1.5
Poultry, meat byproducts
Poultry, meat byproducts, except kidney and liver[3]
                                     0.80
                                      7.0
1 Based on the based on the highest expected secondary tissue residue [peritoneal fat in cattle (translated to goat, horse, and sheep); peritoneal fat in hog; abdominal fat in poultry]. 
2 Separate tolerances have been established for hog, kidney (0.10 ppm) and hog, liver (0.10 ppm).  
[3] Separate tolerances have been established for poultry, kidney (0.80 ppm) and poultry, liver (0.80 ppm).  

9.3	Occupational and Residential Exposure

   * A revised label (Section B) for PP#0E7723 should be submitted:
               o             which specifies that the retreatment of sweet corn with novaluron is prohibited (i.e., only 1 application is allowed at a rate of 0.078 lb ai/A) in California and other arid areas which receive less than 20 inches of precipitation per year. 
   * A revised label (Section B) should also be submitted for PP#0F7708 which:
               o            specifies an application rate of 0.1 gallons per 1000 ft[2] for indoor spot, crack and crevice, space spray, and general surface applications; and
               o             requires the addition of chemical-resistant gloves.  

Attachments:

Appendix A:  TOXICOLOGY ASSESSMENT
A.1	Acute Toxicity Profile.
A.2	Toxicity Profiles.



cc: L. Venkateshwara, J. Van Alstine, 
RDI: RAB1 Branch (03/09/11); G. Kramer (3/7/11); D. Vogel (03/09/11)
L.Venkateshwara:S10956:Potomac Yard 1:703-308-2722:7509P:RAB1
Appendix A:  TOXICOLOGY ASSESSMENT

A.1.	Acute Toxicity Profile

Table A.1.  Acute Toxicity of Novaluron.
Guideline No.
Study Type
MRID #(s)
Results
Toxicity Category
870.1100
(81-1)
Acute Oral (rat)
44961001
LD50 > 5000 mg/kg
IV
870.1200
(81-2)
Acute Dermal (rat)
 45003201
LD50 > 2000 mg/kg
III
870.1300
(81-3)
Acute Inhalation (rat)
45003202
LC50 > 5.15 mg/L
IV
870.2400
(81-4)
Primary Eye Irritation (rabbit)
45003203 
Not an eye irritant
IV
870.2500
(81-5 )
Primary Skin Irritation (rabbit)
45003204
Not a dermal irritant
IV
87.2600
(81-6)
Dermal Sensitization (guinea pig)
45084001 
Not a dermal sensitizer
N/A

A.2	Toxicity Profiles

Table A.2.  Toxicity Profile of Novaluron.
Guideline No/ 
Study type

MRID No.(year)/Doses/Classification

Results
870.3100
90-Day oral toxicity rodents
45651504/45651503 (1993/1990);
Acceptable/guideline

Study I: 0, 50, 100, 200, or 400 ppm (equivalent to 0, 3.52, 6.93, 13.03, and
27.77 mg/kg bw/day, respectively in males and 0, 4.38, 8.64, 17.54, and 34.39 mg/kg bw/day, respectively in females)

Study II: 0, 10, 320, or 10,000
ppm (equivalent to 0, 0.7, 22.2, and 713 mg/kg bw/day, respectively in males and 0, 0.8, 24.3, and 754 mg/kg bw/day, respectively in females)
NOAEL = 320 ppm (22.2 mg/kg/day) in males and 50 ppm (4.38 mg/kg/day) in females.

LOAEL = 400 ppm (27.77 mg/kg/day) in males based on increased occurrence of extramedullary hematopoiesis and hemosiderosis in spleen; and 100 ppm (8.64 mg/kg/day) in females based on reduction in hemoglobin, hematocrit, and RBC count; increased occurrence of extramedullary hematopoiesis in the spleen and hemosiderosis in the spleen and liver.
870.3200
28-day Dermal Toxicity - rat
45288501 (1998);
0, 75, 400, 1000 mg/kg/day 

Acceptable/Guideline
Systemic NOAEL = 1000 mg/kg/day; LOAEL = not established.

Dermal NOAEL = 1000 mg/kg/day; LOAEL = not established.
870.3700 Prenatal Developmental in rodents-Rat
45082602 (1997); 

0, 250, 500, 1000 mg/kg/day

Acceptable/Guideline
Maternal NOAEL = 1000 mg/kg/day; LOAEL = not established. 
Developmental NOAEL = 1000 mg/kg/day; LOAEL = not established.
870.3700 Prenatal Developmental in nonrodents-Rabbit
45638316, 45638318, 45638317
(1997,1998);

0, 100, 300, 1000 mg/kg/day 

Acceptable/Guideline
Maternal NOAEL = 1000 mg/kg/day; LOAEL = not established.
Developmental NOAEL = 1000 mg/kg/day; LOAEL = not established.

870.3800 Reproduction  and fertility- rat
45651505 (Main Study, 1999), 45638319 (Preliminary Study, 1998); 

0, 1000, 4000, or 12,000 ppm ;
M:  0, 74.2, 297.5, or 894.9 mg/kg/day 
F:  0, 84.0, 336.7, or 1009.8 mg/kg/day

Acceptable/Guideline
Parental NOAEL = Not established; LOAEL (M/F) = 74.2/84.0 mg/kg/day based on increased absolute and relative spleen weights.

Offspring NOAEL = Not established; LOAEL (M/F) = 74.2/84.0 mg/kg/day based on increased absolute and relative spleen weights.

Reproductive NOAEL (M/F) = 74.2/1009.8 mg/kg/day; LOAEL (M) = 297.5 mg/kg/day based on decreased epididymal sperm counts and increased age of preputial separation in the F1 generation; Reproductive LOAEL for females was not established.
870.4100
Chronic toxicity - dog
45638320 (1999);

0, 10, 100, 1000 mg/kg/day 

Acceptable/Guideline
NOAEL = 10 mg/kg/day.
LOAEL = 100 mg/kg/day based on hematologic changes associated with histopathological changes in liver and spleen.
870.4300 Chronic/ Carcinogenicity-rat
45651506 (1995);

0, 25, 700, or 20,000 ppm test material;
M:  0, 1.1, 30.6, and 884.2 mg/kg/day 
F:  0, 1.4, 39.5, and 1113.5 mg/kg/day

Acceptable/Guideline
NOAEL (M/F) = 1.1/1.4 mg/kg/day.
LOAEL (M/F) = 30.6/39.5 mg/kg/day based on erythrocyte damage and turnover resulting in a regenerative mild anemia.


870.4300 Chronic/ Carcinogenicity-mouse
45651507/45877901 (2000/2003);

0, 30, 450, or 7000 ppm test material;
M:  0, 3.6, 53.4, or 800.0 mg/kg/day 
F:  0, 4.3, 63.3, or 913.4 mg/kg/day

Acceptable/Guideline
NOAEL (M/F) = 3.6/4.3 mg/kg/day.
LOAEL (M/F) = 53.4/63.3 mg/kg/day based on increased erythrocyte turnover due to hemoglobin oxidation and resulting in a mild anemia.
870.5100
Salmonella typhimurium and  Escherichia coli Reverse Mutation Assay
44961013 (1997);

0, 312.5, 625, 1250, 2500, or 5000 μg/plate in the presence and absence of metabolic activation (+-S9)

Acceptable/Guideline
Novaluron, tested up to the limit of solubility (2500 μg/plate) and the limit dose (5000 μg/plate), was not cytotoxic with or without S9 activation in four S. typhimurium strains and one strain of E. coli, and did not induce a genotoxic response in any strain.
870.5100
Salmonella typhimurium- bacterial reverse gene mutation assay
45030003 (1986);

0, 10, 33, 100, 333, 1000, or 3333 μg/plate in the presence and absence of mammalian metabolic activation (+-S9)

Acceptable/Guideline
Novaluron, tested up to the limit of solubility (3333 μg/plate), was not cytotoxic with or without S9 activation in five S. typhimurium strains, and did not induce a genotoxic response in any strain.
870.5300
Gene Mutation
45638321(1989);

0, 50, 100, 125, 150, 175, or 200 μg/mL with and without metabolic activation (S9-mix) in two independent assays.

Acceptable/Guideline 
There was no evidence of biologically significant induction of mutant colonies over background.
870.5375
In vitro mammalian chromosome aberration test
44961015 (1992);

40, 200, and 1000 μg/mL, with and without metabolic activation (+-S9)

Acceptable/Guideline
Novaluron produced no evidence of clastogenic activity in primary human lymphocytes, in the presence or absence of S9 activation.
870.5395
Mammalian erythrocyte micronucleus test in mice
45638322(1989);

0, 1250, 2500, or 5000 mg/kg body weight

Acceptable/Guideline
There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or harvest time.
870.5500
Mutagenicity - Rec assay with Bacillus subtilis
44961014 (1998);

50, 150, 500, 1,500, or 5,000 μg/plate, with and without mammalian metabolic activation (+-S9)

Acceptable/Guideline
Novaluron was equivocal for bacterial DNA damage in the absence of S9 activation, and negative for bacterial DNA damage in the presence of S9 activation.
870.5550
Unscheduled DNA Synthesis in HeLa S3 Human Epitheliod cells
45030002 (1988);

0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, or 256 μg/mL (+-S9)

Acceptable/Guideline
Novaluron was considered not to show any evidence of causing DNA damage to HeLa S3 epithelioid cells in this unscheduled DNA synthesis test for mutagenic potential.
870.6200
Acute Neurotoxicity screening battery- rat
45082601 (1999);

0, 200, 650, 2000 mg novaluron/kg

Acceptable/Guideline
NOAEL = 650 mg/kg/day; LOAEL = 2000 mg/kg/day based on clinical signs (piloerection, irregular breathing), FOB parameters (increased head swaying, abnormal gait) and neuropathology (sciatic and tibial nerve degeneration).
870.6200
Subchronic Neurotoxicity screening battery- rat
46086204 (2002);

0, 17.5/20.5, 174/207, 1752/2000 mg/kg/day
(M/F)

Acceptable/Guideline
NOAEL (M/F) = 1752/2000 mg/kg/day; LOAEL = not established.
870.7485
Metabolism-rat
45638401 (2000), 45638323 (1998);

single dose of 2 mg/kg or 1000 mg/kg, or 14 multiple 2 mg/kg/day doses of unlabeled novaluron (Lot no. 970211/4, 99.3% chemical purity) followed by a single dose of radiolabeled novaluron.

Acceptable/Guideline
Novaluron exhibited marginal absorption (16-18%), relatively rapid and complete excretion within 48 hours primarily via the feces and to a lesser extent via urine in rat.  Biliary contribution for fecal excretion appears to be insignificant.  Absorption appeared to be approaching saturation at high doses.  Peak plasma concentration occurred at 2-5 hours.  Urinary metabolite profiles revealed 15 components and 8 components following administration of [chlorophenyl-[14]C]novaluron or [difluorophenyl-[14]C]novaluron, respectively.  The most prevalent urinary metabolite was 2,6-difluorobenzoic acid represented the majority of the urinary radioactivity.  Other components individually represented no more than 5.9% of the dose and most represented considerably less than 1%.  Parent compound was the most prevalent contributor in the feces.  The fecal metabolite profile revealed two metabolites; 3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)aniline, and 1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)phenyl]urea.  Quantitatively, these were minor components accounting for <2% of the dose.  In the repeated-dose group, some tissues such as fat contained measurable radioactivity at 168 hours post dose but did not appear to suggest significant potential for bioaccumulation or sequestration at the doses tested.
870.7600
Rat Dermal Penetration
45638415 (2000);

1.0, 0.067, 0.0048, or 0.0003 mg/cm[2] 

Acceptable/Guideline 
Recovery of administered radioactivity was an acceptable 90.19-105.26%.  The maximum total absorbed dose (expressed as per cent of administered dose and determined as the sum of radioactivity in excreta, cage wash, untreated skin, fat, blood, and residual carcass) ranged from about 0.5% to 10% of that administered.


