Novaluron Human - Health Risk Assessment DP#: 364307

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Page 1 of 30 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 OFFICE OF PREVENTION, PESTICIDES , AND TOXIC SUBSTANCES MEMORANDUM Date: 23 - FEB - 2010 SUBJECT: Novaluron : Human - Health Risk Assessment for Proposed Section 3 Use on

Grain Sorghum . PC Code: 124002 DP Barcode: D364307 Decision No.: 407899 Registration No. : 66222 - 35 Petition No.: 9F7547 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Aggregate Case No.: NA T XR No.: NA CAS No.: 116714 - 46 - 6 MRID No .: NA 40 CFR: §180.598 FROM: Julie L. Van Alstine , MPH, Environmental Health Scientist

Lata Venkateshwara, Environmental Scientist Robert Mitkus, Ph . D . , DABT, Toxicologist 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: John Hebert (RM 07)/ Jennifer Gaines

Registration Division (RD; 7505P) The HED of the Office of Pesticide Programs (OPP) is charge d 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, residue chemistry data review, and dietary risk assessment were provided b y Julie Van Alstine (RAB1), the hazard characterization by Robert M itkus (RAB1), the occupational/residential exposure assessment by L ata Venkateshwara (RAB1), and the drinking water assessm ent by Iwona Maher of the Environmental Fate and Effects Division (EFED). The most recent human - health risk assessment was conducted in conjunc tion with a request for the use of novaluron on fruiting vegetables group 8, cucurbit vegetable group 9, low growing berry subgroup 13 - 07G, miscellaneous fruiting vegetables, snap bean, dry bean seed, and SwissNovaluron Human - Health Risk Assessment DP#: 364307

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Page 2 of 30 chard (Memo, J. Van Alstine, et al. , 04 - DEC - 2009 ; D363988 ). A detailed hazard characterization for novaluron is presented in a previous HED risk assessment ( Memo, S. Lev y, et al ., 03 -NOV - 2005; D313322 ). The following information from the 25 - FEB - 2008 risk assessment for the use of novaluron on tomato and sugarcane (Memo, G. Kramer, 25 - FEB - 2008; D347661) can be applied directly to this action:

 Phy sical/Chemical Properties Characterization (Section 2.0; pg. 8 - 9); and  Cumulative Risk (Section 6.0 pg 18 - 19). This document contains only those aspects of the risk assessment which are affected by the proposed Section 3 requests for use of nov a luron on grain sorghum.Novaluron Human - Health Risk Assessment DP#: 364307

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Page 3 of 30 Table of Contents 1.0 EXECUTIVE SUMMARY ................................ ................................ ............................... 4 2.0 PROPOSED USE PATTERN ................................ ................................ ........................... 9 3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS ............................. 10 3.1 FQ PA C onsiderations ................................ ................................ ................................ . 11 3.2 Endocrine Disruption ................................ ................................ ................................ . 13 4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION ................................ ........... 13 4.1 Food Residue Profile ................................ ................................ ................................ ... 13 4.2 Drinking Water Residue Profile ................................ ................................ ................ 17 4.3 Dietary Exposure and Risk ................................ ................................ ........................ 18 4.4 Anticipated Residue and %CT Information ................................ ............................ 19 5.0 RESIDENTIAL (NON - OCCUPATIONAL) EXPOSU RE/RISK CHARACTERIZATION ................................ ................................ ................................ 19 5.1 Spray Drift ................................ ................................ ................................ ................... 19 6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION ........ 20 7.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY ................................ ................... 20 7.1 Occupational Pesticide Handler Exposure and Risk ................................ ............... 20 7.2 Occupational Post - Applica tion Worker Exposure and Risk ................................ .. 23 8.0 DATA NEEDS AND LABEL RECOMMENDATIONS ................................ .............. 25 8.1 Toxicology ................................ ................................ ................................ .................... 25 8.2 Residue Chemistry ................................ ................................ ................................ ...... 25 Appendix A: TOXICOLOGY ASSESSMENT ................................ ................................ ........ 27 A.1. Acute Toxicity Profile ................................ ................................ ................................ . 27 A.2 Toxicity Profiles ................................ ................................ ................................ .......... 27Novaluron Human - Health Risk Assessment DP#: 364307

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Page 4 of 30 1.0 EXECUTIVE SUMMARY Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), as amended, Makhteshim - Agan of North America (MANA) has submitted a petition (PP# 9F7547 ) to register the end - use product Rim o n ® 0.83 Emulsifiable Concentrate ( EC ) In secti ci de (EPA Reg. No. 66222 - 35), a 0.83 pound (lb) active ingredient (ai)/gallon (gal) EC formulation of novaluron (

N - [[[3 - chloro - 4 - [1,1,2 - trifluoro - 2 - (trifluoromethoxy)ethox y] phenyl]amino]carbonyl] - 2,6 - difluorobenzamide) on grain sorghum . To support the submission for permanent tolerances for residues of novaluron in/on grain sorghum grain, forage, stover, and aspirate d grain fractions (AGF) , MANA proposes tolerance increases for residues of novaluron in/on the following livestock commodities: hog and poultry meat, liver, kidney , and fat; and eggs. End - use products containing novaluron as the ai are formulated as an E C, a suspension concentrate (SC), or a water - dispersible granular (WDG). Novaluron, a benzoylphenyl urea compound, is a pesticide chemical belonging to the class of insecticides called insect - growth regulators (IGR s ) . Tolerances for residues of novaluron are established in/on cotton, Brassica head and stem vegetables (subgroup 5A), pome fruit (group 11), tuberous and corm vegetables (subgroup 1C), tomatoes, sugarcane, bushberry subgroup 13 - 07B, Brassica , leafy

greens (subgroup 5B), turnip greens, and ston e fruit (crop group 12) at levels ranging from 0.05 to 30 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 by products (except kidney

and liver) of cattle, goat, horse, and sheep , and the meat, fat, and meat by products 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. Tolerances are pending for fruiting vegetables group 8, cucurbit vegetable s group 9, low growing berry subgroup 13 - 07G (except lowbush blueberry), miscellaneous fruiting vegetable s, snap bean, dry bean seed, and Swiss chard (Memo, J. Van Alstin e et al. , 04 - DEC - 2009; D 363988) . All uses for novaluron, either proposed or existing, are agricultural or commercial in nature. No residential uses are proposed, nor are an y registered or proposed uses expected to result in residential exposure. 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 primaril y produced hematotoxic effects (toxicity to blood) such as methemoglobinemia, decreased hemoglobin, decreased hematocrit, and decreased red blood corpusc les ( RBCs or erythrocy tes) 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 - generat ion reproductive toxicity

study , increased spleen weights were observed in parents and offspring at the same dose, and reproductive toxicity was observed in males onl y at a higher dose. Neurotoxic effects, including clinical signs, changes in functional - o bservation 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 studyNovaluron Human - Health Risk Assessment DP#: 364307

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Page 5 of 30 in rats at similar doses , n o evidence of neuropathology was observed in subchronic and chronic to xicity studies in rats, mice, or dogs , and novaluron is not considered acutely toxic (LD 50 >5000 mg/kg) . Th erefore, 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 genotox ic potential with novaluron. Dose Response and Endpoint Selection The RAB1 toxicologists reevaluated the novaluron database and reaffirmed the previous conclusion of the HIARC (16 - DEC - 2003, TXR# 0052361) that the Food Quality Protection Act (FQPA) Sa fet y Factor (SF) for increased susceptibility of infants and children can be 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 - ge neration 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). An oral acute ref

erence 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 ba sis 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 tox icological 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 o n 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 dermal and inhalati on 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 carcinoge nicity in mice and rats. Endpoints applicable to risk assessments performed for novaluron in this document are summarized below.Novaluron Human - Health Risk Assessment DP#: 364307

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Page 6 of 30 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) 9 0 - 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 end point of concern attributable to a single dose was not identified. A cancer dietary assessment was not conducted because novaluron was classified as “not likel y to be carcinogenic to humans.” A chronic dietary

(food and drinking water) exposure and risk assessment was conducted for the proposed new use on grain sorghum , all established uses , and drinking water. A partiall y refined assessment was conducted. EFED provided the e stimated drinking water concentrations (EDWCs) which were incorporated into th e anal ysis. A Screening Level Usage Analysis (SLUA) memorandum for existing uses and a percent crop treated for new use (PCTn) memorandum for sorghum were provided b y the Biological and Economic Analysis Division (BEAD). The chronic analy sis incorporated average percent crop treated ( %CT ) data for apples, cabbage, cotton, pears, and potatoes and PCTn data for grain sorghum. 100% CT was assumed for the remaining food commodities. Anticipated residues (ARs) for meat, milk, hog, and poultry commodities wer e calculated using PCTn for grain sorghum, average %CT for apple and cotton, and assumed 100% CT for sugarcane. The chronic anal ys is also incorporated average field trial residues for some commodities ; average greenhouse trial residue s for tomatoes; empirical processing factors for apple juice (translated to pear and stone fruit juice ) 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 wat er) 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 11% of the cPAD for the general U.S. population and 32% of the cPAD for children 1 - 2 ye ars old, the most highly exposed population subgroup. Residential Exposure/Risk There are no residential uses proposed or currently registered for novaluron. Therefore, a residential risk assessment is not required. Aggregate Exposure Scenarios an d Risk Conclusions In cluding all existing and proposed uses, an aggregate human - health risk assessment was conducted for chronic aggregate exposure (food + water) onl y . Because there are no uses of novaluron that could result in residential exposures, th is aggregate risk assessment takes into consideration dietary

food + water exposure only . The chronic aggregate exposure and risk estimate s are not of concern .Novaluron Human - Health Risk Assessment DP#: 364307

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Page 7 of 30 Occupational Exposure Estimates Occu pational 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 registratio n. 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 - 19 98) 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 are not of concern (i.e., MOEs ≥ 100), provided workers wear chemical - resistant gloves as recommended on the label . No short - term point of departure 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 are not of concern . Post application dermal risks were calculated based on an intermediate - term point of departure and are considered highl y conservative for the included activities . Since the post - application assessment is not a concern on Day 0 (12 hours followi ng application) , the restricted - entry interval (REI) is based on the acute toxicity of novaluron technical material. The proposed label for Rimon ® has a 12 - hour REI. The technical material has a Toxicity

Category III for acute dermal and a Toxicity Category IV for acut e 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 th e proposed u se 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 Addres s Environmental Justice in Minority Populations and L ow - 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 tha t 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 Survey s of Food Intakes by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the c ountry . 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 onNovaluron Human - Health Risk Assessment DP#: 364307

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Page 8 of 30 home use of pesticide pro ducts 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 by standers 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 the PHED and the Agricultural Reentry Task Force (ARTF) studies in which adult human subjects were intentionall y exposed to a pesticide or other chemical. These studies have been reviewed and have been determined to be ethical. Recommendation for To lerances and Registration Pending submission of revised Sections B and F (see requirements under Dir ections for Use and Proposed Tolerances) , there are no residue chemistry issues that would preclude granting a conditional registration for the use of nova luron on grain sorghum . 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 - (trifluoromethox y)ethox y]phenyl]amino]carbonyl] - 2,6 - difluorobenzamide ) in or on the following raw agricultural commodities ( RACs ) : Grain, aspirated fractions 25 ppm Poultry, fat 7.0 ppm Sorghum, grain, grain 3.0 ppm Egg 1.5 ppm Sorghum, grain, forage 6.0 ppm Hog, meat 0.07 ppm Sorghum, grain, stover 40 ppm Hog, liver 0.10 ppm Poultry, meat 0.40 ppm Hog, kidney 0.10 ppm Poultry, liver 0. 80 ppm Hog, meat byproducts 0.10 ppm Poultry, kidney 0.80 ppm Hog, fat 1.5 ppm Poultry, meat byproducts 0.80 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  The HED HIARC requested a 28 - day inhalation toxicity

study as a condition of registration. However, based on the low volatility an d low inhalation toxicity (Toxicity Category IV) of novaluron and inhalation MOEs >1000 for the proposed uses in this risk assessment, novaluron qualifies for a waiver of the 28 - day inhalation toxicity

study for the proposed uses [HED SOP 2002.01: Guidanc e: Waiver Criteria for Multiple Exposure Inhalation Toxicity Studies , 15 - AUG - 2002]. The requirement for the 28 - day inhalation toxicity study is waived for this action only. If in the future, requests for new uses or formulations are submitted that may re sult in a significant change in either the toxicity

profile or exposure scenarios, HED will reconsider this data requirement.Novaluron Human - Health Risk Assessment DP#: 364307

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Page 9 of 30  An immunotoxicity

study is required as specified in the new 40 CFR Part 158 data requirements . Residue Chemistry 860.1200 Direct ions for Use A revised Section B for petition number 9F7547 should be submitted which:

 Specifies that the use of adjuvants /surfactants on grain sorghum is prohibited;  Specifies that the label is for “grain sorghum” as opposed to “sorghum;”  Specifies separate preharvest interval (PHIs) for grain sorghum forage (7 day s) , grain (14 day s) , and stover (14 days) ; and  States that the use of novaluron on crops grown for food in greenhouses , except tomatoes, is prohibited. 860.1380 Storage Stability Data Storag e stability

data on grain sorghum forage, grain, AGF, and stover for up to 275, 253, 237, and 245 day s, respectively , are required. 860.1550 Proposed Tolerances  A revised Section F for petition number 9F7547 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 determi ned b y measuring only novaluron (

N - [[[3 - chloro - 4 - [1,1,2 - trifluoro - 2 - (trifluoromethox y)ethox y]phenyl]amino]carbonyl] - 2,6 - difluorobenzamide ) in or on the following raw agricultural commodities:”

 A r evised Section F is requested which reflect s the recommende d tolerances and commodity

definitions presented in Table 4.1 . Occupational and Residential Exposure  None. 2.0 PROPOSED USE PATTERN MANA submitted a draft label for Rim o n ® 0.83EC In secti ci de ( EPA Reg. No. 66222 - 35) to include the proposed new use ( see Table 2.0) on grain sorghum.Novaluron Human - Health Risk Assessment DP#: 364307

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Page 10 of 30 Table 2.0 . Summ ary of Proposed Use Pattern for Novaluron on Grain Sorghum . Application Equipment Form

ulation [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 Grain Sorghum Aerial/ Groundboom 0.83 lb/gal

EC [66222 - 35] 0.058 -

0.078 3 0.23 14 A 7 to 14 day retreatment interval (RTI) is specified to protect new

grow th. For the mo st effective control, fields should be scouted twice weekly. REI = 12 hours. Conclusions : The proposed label is adequate to allow evaluation of the residue data relative to the proposed new use on grain sorghum; however, a revised Section B is requested which:

 specifies that the use of adjuvants / surfactants on grain sorghum is prohibited;  specifies that the label is for “grain sorghum” as opposed to “sorghum;”  specifies separate PHIs for grain sorghum forage (7 day s), grain (14 day s), and stover (14 day s); and  s tates that the use of novaluron on crops grown for food in greenhouses , except tomatoes, is prohibited. 3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS A detailed hazard characterization for novaluron is presented in a previous HED risk assessment ( Memo, S. Lev y, et al ., 03 -NOV - 2005; D3 13322 ). Novaluron has low acute toxicity via the oral (Toxicity Category IV), dermal (Toxicity

Category I II) , 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 RBCs (or ery throcy tes) 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 . Inthe two - generation reproductive toxicity study , increased spleen weights were observed in parents and offspring at the same dose, and reproductive toxicity (decreases in epididy

mal sperm counts and increased age at preputial separation in the F 1 generation) was observed in males only at a higher dose. Neurotoxic effects, including clinical signs (piloerection, fast/irregular breathing), FOB parameters (head swaying, abnormal gait), and neuropathology (sciatic and tibial nerve degeneration) were observed following a single dose at the limit dose only (2 000 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 ( 1752 mg/kg/day in males and 2000 mg/kg/day in females ). In addition, novaluron is not considered acutel y toxic (LD 50 >5000 mg/kg). Therefore, RAB1 toxicologists reaffirmed the HED HIARC conclusion that there is not a concern for neurotoxicity resulting from exposure to novaluron. There was no e vidence of carcinogenic potential in either the rat or mouse carcinogenicity studies, and there was no evidence of mutagenic potential in several genotoxicity studies, including the bacterial (Salmonella, E. coli ) reverse - mutation assay , the in vitro mamma lian chromosomal aberrationNovaluron Human - Health Risk Assessment DP#: 364307

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Page 11 of 30 assay , the in vivo mouse bone - marrow micronucleus assay , and the bacterial DNA damage/repair assay . 3.1 FQ PA Considerations The RAB1 risk assessment team concluded that the FQPA SF can be reduced to 1X based on the followi ng:  There is no evidence of increase d susceptibility in the rat or rabbit developmental toxicity studies up to the limit dose or in the two - generation reproduction study in rats .  T here are no concerns or residual uncertainties for pre - and/or postnatal to xicity .  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 observ ed at the limit dose only and were not reprodu ced at similar , repeated doses in the subchronic neurotoxicity study . In addition, n o evidence of neuropathology

was observed in subchronic and chronic to xicity studies in rats, mice, or dogs , and novaluron is not considered acutel y toxic (LD 50 >5000 mg/kg ) .  A developmental - neurotoxicity (DNT) study is not required.  Histopathological examination of the organs of the immune sy stem (i.e., thy mus, spleen, ly mph 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 erythrocy tes in the spleen following remo val from the blood. Therefore, these are not considered immunotoxic effects . The overall weight of evidence suggests that novaluron does not directl y target the immune system. An immunotoxicity study is required as part of the revised 40 CFR Part 158 to xicology data requirements for novaluron; however, HED does not believe that conducting a functional immunotoxicity study will result in a lower NOAE L than the regulatory dose being used for risk assessment, and an additional UF for database uncertainty (U F DB ) is not needed to account for the lack of the required immunotoxicity

study .  T he conservative residue assumptions used in the dietary exposure risk assessment .  T he completeness of the residue chemistry database and conservative drinking water assessment. The doses and toxicological endpoints selected for human health risk assessment are summarized in Table 3.1. Table 3.1. Summ ary 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 Ac ute 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 Com bined chronic toxicity/carcinogenicity feeding in rat LOAEL = 30.6 mg/kg/day based on erythrocyte damage and turnover resulting in a regenerative anemia.Novaluron Human - Health Risk Assessment DP#: 364307

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Page 12 of 30 Table 3.1. Summ ary 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 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 wa s 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 LO AE L = 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 - abso rption rate = 10 %) Residential/

Occupational LOC for MOE < 100 Com bined 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 histopatholo gy (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 ab sorption rate = 100%) Residential/

Occupational LOC for MOE < 100 Com bined 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 carcino genic to humans.Novaluron Human - Health Risk Assessment DP#: 364307

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Page 13 of 30 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 . 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 (includin g pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two - tiered approac h to making the statutoril y required determinations. Tier 1 consists of a battery of 11 screening assay s to identify

the potential of a chemical substance to interact with the estrogen, androgen, or thy roid (E, A, or T) hormonal sy stems. Chemicals that g o through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal s ys tems will proceed to the next stage of the EDSP where EPA will determine which, if an y, of the Tier 2 tests are necessary based on the available data. T ier 2 testing is designed to identify any adverse endocrine related effects caused b y 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 pathway s such as food and water, residential a ctivity , 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 unde r the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingl y, 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 th e proposed uses are summarized in the pending HED memorandum by J. L. Van Alstine ( D 374420 ). The chronic dietary exposure assessment is summarized i n the pending HED memorandum by J. L . Van Alstine ( D 374419 ). 4.1 Food Residue Profile Nature of the Resid

ue - Plants: HED previously concluded that the nature of the residue in plants is adequatel y understood based on acceptable metabolism studies conducted on apples, cabbage, cotton, and potatoes using [difluorophenyl - U 14 C]novaluron and [chlorophen yl - U 14 C ]novaluron as the test substances (Memo, G. Kramer, 22 - MAR - 2004; D 285474) . These studies indicate that novaluron is not extensively metabolized in these crops. The parent compound, novaluron, was either the onl y residue component identified or was the predominant residue component in all anal yz ed plant matrices. The reviewed studies also indicate thatNovaluron Human - Health Risk Assessment DP#: 364307

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Page 14 of 30 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 e t al. , 03 - FEB - 2004; D297646). Nature of the Residue - Livestock: HED also previously concluded that the nature of the residue in livestock is adequatel y understood based on the submitted goat and hen metabolism studies (Memo, G. Kramer, 22 - MAR - 2004; D2 85474). 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 prev iousl y submitted a gas chromatograph y/ electron - capture detection (GC/ECD) residue anal yt ical method for the anal ys is of novaluron residues in/on pome fruit, cabbage, and potato commodities; HED concluded that the method was adequate for gathering data on n ovaluron. A second method, high - performance liquid chromatograph y/ultraviolet (HPL C/UV) , was submitted for the anal ysis of novaluron residues onl y in/on cotton commodities. Both method s w ere adequatel y validated by the petitioner and b y an independent la boratory . Acceptable radiovalidation data for the GC/ECD method have been submitted and reviewed in a previous HED memorandum ( Memo, S. L ev y, 23 - AUG - 2006 ; D325183 ) and both methods were forwarded to the EPA Analy tical Chemistry Branch (ACB)/Biological and Economics Anal ys is 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 HPL C/UV metho ds appear suitable for food tolerance enforcement in plants (apples, cabbage, potatoes) and cotton. ACB recommended that the anal yt ical methods do not need to be laboratory validated by

EPA ( Memo, S. L ev y, 15 - SEP T - 2004 ; D306998). Both methods have been f orwarded to the Food and Drug Administration (FDA) for inclusion in the Pesticide Anal yt ical Manual, Volume II (PAM II) as a Letter Method ( S. Lev y, 15 - SEP T - 2004; D307595). An interference study was requested and a specific single - anal yt e confirmatory method was submitted and considered acceptable (Memo, J. Langsdale, 21 - OCT - 200 8; D 355574) . 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 b y an y of the MRMs. This study was forwarded to FDA for further evaluation and updating of PAM Vol. I , Appendix I (Memo, S. L ev y, 19 - OCT - 2005; D 3 22359) . Magnitude of the Residue - Plants: MANA has submitted field trial data to support the proposed use of novaluron on grain sorghum. Twelve grain sorghum field trials were conducted in the U.S. during the 2007 growing season in North American Free Trade Agreement (NAFTA) Growing Zones 2 (NC; 1 trial), 4 (AR; 1 trial), 5 (I L, KS, and NE; 4 trials), 6 (OK and TX; 1 trial each), 7 (NE, 1 trial), and 8 (KS, OK, and TX; 1 trial each). Each trial site consisted of one untreated plot and one treated plot. The treated plots received three broadcast spray

applications of a 0.83 lb /gal EC formulation of novaluron (EPA Reg. No. 66222 - 35) at 0.076 - 0.081 lb ai/A per application, with 7 - to 15 - day RTIs, for a total rate of 0.232 - 0.239 lb ai/A; forage samples were harvested after onl y two applications, for a total rate ofNovaluron Human - Health Risk Assessment DP#: 364307

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Page 15 of 30 0.156 - 0.160 lb ai/A. Applications were made using ground equipment in approximately 20 - 34 GPA spray

volumes, without an adjuvant. Samples of grain sorghum forage, grain, and stover were taken at normal harvest times, 6 to 7 day s after the second application for forage and 13 to 14 day s after the last application for grain and stover. To evaluate residue decline, additional treated samples were also collected at one trial 1, 3, 10, and 14 day s after the second application (forage) and 10, 14, 17, and 21 day s after the l ast application (grain and stover). R esidues of novaluron ranged from 0.620 to 4.82 ppm in/on 24 samples of treated sorghum forage harvested 6 - 7 days following foliar treatments with the 0.83 lb/gal EC formulation at a total rate of 0.156 - 0.160 lb ai/A. Novaluron residues ranged from 0.586 to 1.96 ppm in/on 22 samples of treated sorghum grain, and from 3.62 to 26.0 ppm in/on 22 samples of treated sorghum stover (adjusted to 88% dry matter) harvested 13 - 14 day s f ollowing foliar treatments at a total rate o f 0.232 - 0.239 lb ai/A. In the residue decline trial, average residues of novaluron generall y decreased in/on forage, from 4.0 ppm at the 1 - day

PHI to 2.0 ppm at the 14 - day PHI , and stover, from 6.7 ppm at the 7 - day PHIto 3.8 ppm at the 21 - day PHI ; averag e residues in/on grain were approximately the same at all sampling intervals. Conclusions: The submitted field trial data for grain sorghum commodities are classified as scientifically

acceptable and will support the establishment of residue tolerances f or novaluron in/on grain sorghum forage (6.0 ppm), grain (3.0 ppm) , and stover (40 ppm), pending submission of freezer storage stability data for residues of novaluron in/on grain sorghum forage, grain, and stover for up to 275, 253 , and 245 day s, respecti vely . Although this is a deficiency , HED recommends a conditional registration for the use of novaluron on grain sorghum. This decision is based on previousl y submitted storage stability data for various commodities which demonstrates the stability of no valuron in/on food commodities for up to 15.3 months, which exceeds the longest storage time (9.0 months for grain sorghum forage) of the grain sorghum commodities in the field trials. The residue chemistry database will support an unconditional registrat ion upon submission of adequate storage stability data along with revised Sections B and F. Processed Food and Feed: A processing study on grain sorghum AGF and flour was submitted which indicate d that residues of novaluron concentrate in AGF (13X ) but do not concentrate in f lour (processing factor of 0.66X ). Sorghum flour is not considered to be a human food item in the U.S. A t olerance value of 25 ppm [i.e., 1.84 ppm (highest - average field trial ( HAFT) ) x 13 = 24 ppm ] was calculated for AGF . For gr ain sorghum AGF, the processed food data are classified as scientificall y acceptable and will support the establishment of residue tolerances for novaluron in/on AGF (25 ppm) pending submission of freezer storage stability data for grain sorghum grain and AGF . Confined/Field Accumulation in Rotational Crops: Based on the results of the submitted confined rotational crop study , the appropriate plantback interval ( PBI ) for all non - labeled crops is 30 day s. The current and proposed labels include a restrict ion that only registered crops may be rotated to a treated field within 30 day s of the final application , which is appropriate for this petition . Future uses that have significantl y 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).Novaluron Human - Health Risk Assessment DP#: 364307

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Page 16 of 30 Magnitude of t

he 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. L ivestock 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 - 20 08) concerning revisions of feedstuff percentages and constructing r easonabl y balanced dietary burdens (RBDBs ) . The currently

established livestock tolerances are based on the following RBDBs for novaluron : 5.9 ppm for beef cattle, 2.3 ppm for dairy cattle, 0.12 for poultry , and 0.09 for swine (Memo G. Kr amer, 07 - FEB - 2008; D 340137) . Based on the proposed/registered uses, the revised RBDBs for novaluron are 9.6 ppm for beef cattle, 12.4 ppm for dairy cattle, 2.4 for poultry , and 2.5 for swine. This increase in the RBDBs necessitates an increase in the tol erances for secondary residues in/on poultry

and hog commodities; however , no changes are necessary for the tolerances for secondary

residues in/on cattle, goat, horse, and sheep. The revised tolerances for residues of novaluron in hog and poultry are as follows: 0.07 ppm in hog meat; 0.10 ppm in hog liver, kidney , and meat by products; 1.5 ppm in hog fat; 1.5 ppm in eggs; 0.40 ppm in poultry meat; 0.80 ppm in poultry liver, kidney , and meat by products; and 7.0 ppm in poultry fat. The petitioner is reques ted to submit a revised Section F reflecting these tolerances. 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). A revised Section F for petition number 9F7547 should be submitted which cites the app ropriate 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 d etermined b y measuring only novaluron (

N - [[[3 - chloro - 4 - [1,1,2 - trifluoro - 2 - (trifluoromethox y)ethox y]phenyl]amino]carbonyl] - 2,6 - difluorobenzamide ) in or on the following raw agricultural commodities:” A revised Section F is requested which reflects the HED - recommended tolerances and commodity

definitions presented in Table 4.1 . No Codex, Canadian , or Mexican MRL s have been established for novaluron in/ on grain sorghum . The Agency ’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized for determining appropriate tolerance levels.Novaluron Human - Health Risk Assessment DP#: 364307

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Page 17 of 30 Table 4.1 . Tolerance Summary for Novaluron. Commodity Proposed Tolerance (ppm) HED - Recommended

Tolerance (ppm) Comments;

Correct Commodity Definition Grain sorghum, grain 3 3 .0 Sorghum, grain , grain Grain sorghum, aspirated grain fractions 25 25 Grain, aspirated fractions Grain sorghum, forage 6 6 .0 Sorghum, grain, forage Grain sorghum, stover 40 40 Sorghum, grain, stover Poultry, fat 7.0 7.0 Poultry, muscle 0.4 0.4 0 Poultry, meat Poultry, liver 0.8 0.8 0 Poultry, kidney 0.8 0.8 0

-- -- 0.8 0 Poultry, meat byproducts Hog, fat 1.5 1.5 Hog, muscle 0.07 0.07 Hog, meat Hog, liver 0.15 0.10 Hog, kidney 0.15 0.10

-- -- 0.10 Hog, meat byproducts Eggs 1.5 1.5 Egg 4.2 Drinking Water R esidue Profile The drinking water residues used in the dietary risk assessment were provided by EFED (Memo, I. Maher, 16 - JUL - 0 9; D363989 ). Since the application rates for the proposed new uses are significantl y lower than the use rates for pome fruits an d 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. The HED MARC concluded that parent and the chlorophen ylurea and chloroaniline degrad ates are residues of potential concern to be included in the drinking water assessment. Monitoring data are not available for novaluron or its chlorophen ylurea and chloroaniline degradates, in surface water or ground water. Concentrations in surface wat er and ground water were estimated using standard EFED drinking water models . Tier II Pesticide Root Zone Model/Exposure Analy sis Modeling Sy stem (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 aeri al applications to apples grown in PA at the maximum annual application rate of 0.9 6 lb ai /acre, applied three times at 0.32 lb ai /acre, with an interval between applications of ten day s. For surface water, the 1 - in - 10 - year annual mean EDWC for the parent novaluron is 0.76 ppb. A Tier I drinking water analy sis was performed for the chlorophen ylurea and chloroaniline degradates. The FQPA Index Reservoir Screening Tool (FIRST) model was used to obtain surface water estimates. For surface water, the annual average EDWC for chlorophen ylurea is 0.89 ppb and the annual average EDWC for chloroaniline is 2.6 ppb. The chlorophenylurea estimate is based upon the maximum application rate in peaches [0.32 lb ai/A applied 3 times perNovaluron Human - Health Risk Assessment DP#: 364307

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Page 18 of 30 season every

7 day s (0.96 lb ai/year)] and the chloroaniline estimate is based upon the maximum application rate in apples [0.32 lb ai/A applied 3 times per season every 10 day s (0.96 lb ai/year)]. For ground water, the Screening Concentration in Ground Water (SCI - GROW) model was u sed to predict a ground water concentration for novaluron at the annual application rate of 0.96 lb ai /acre ( i.e . , three applications of 0.32 lb ai /acre). The estimate for the parent novaluron is 0.0056 ppb in drinking water from shallow ground water sour ces. 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 m odeling, 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. 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 likel y to be carcinogenic to humans.” A chronic dietary

exposure and risk assessment was conducted using the DEEM - FCID  , Version 2.03, which uses food consumption data from USDA’s CSFII from 1994 - 1996 and 1998. The anal ys is was performed to support the request for use of novaluron on grain sorghum . The chronic anal ys is incorporated average %CT data for apples, cabbage, cotton, pears, and potatoes and P CTn data for grain sorghum. 100% CT was assumed for the remaining food commodities. ARs for meat, milk, hog, and poultry commodities which were calculated using PCTn for grain sorghum, average %CT for apple and cotton, and 100% CT for sugarcane were inco rporated into the analy sis . The chronic analy sis also incorporated average field trial residues for some commodities (pome fruit, sugarcane, bushberries, Brassica leafy greens, stone fruit, bell pepper, non - bell pepper, cucumber, summer squash, cantaloupe , strawberry , succulent snap bean, dry bean seed, and Swiss chard); average greenhouse trial residue s for tomatoes; empirical processing factors for apple juice (translated to pear and stone fruit juice) and tomato paste and purée; and DEEM  (ver. 7.81) de fault processing factors for the remaining processed commodities. Inaccordance 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 11% of the cPAD for the general U.S. populatio n and 32% of the cPAD for children 1 - 2 years old, the most highly exposed population subgroup.Novaluron Human - Health Risk Assessment DP#: 364307

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Page 19 of 30 Table 4.3 . Summ ary of Chronic Dietary Exposure (Food and Drinking Water) and Risk for Novaluron 1,2 . Population Subgroup Ac ute Dietary Chronic Dietary Cance r 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 0.001206 11 N/A N/A All Infants (<1 year old) 0.001955 18 Children 1 - 2 years old 0.003537 32 Children 3 - 5 years old 0.002771 25 Children 6 - 12 years old 0.001700 16 Youth 13 - 19 years old 0.001021 9 Adults 20 - 49 years old 0.000884 8 Adults 50+ years old 0.001027 9 Females 13 - 49 years old 0.000874 8 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 and PCTn memorandum were provided by BEAD (A. Grube, 17 -NOV 2009, D371221; C. Doucoure et al. , 29 - DEC - 2009, D371615). The SLUA memo included %CT data for apples, cabbage, cotton, pears, and potatoes. The market leader approach was used b y BEAD to determine the PCTn for sorghum. The chronic dietary

analy sis incorporated average %CT data for apples (15%), cabbage (10%), cotton ( 2.5%), pears (10%), and potatoes (2.5%) and PCTn data for grain sorghum (5%). 100% CT was assumed for the remaining food commodities. L i vestock dietary burdens of novaluron were calculated based on the proposed/registered uses, tolerance - level residues , and PCTn data for grain sorghum (5%), average %CT data for apple (15%) and cotton (2.5%), and 100% CT for sugarcane. The se 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) EXPOSU RE/RISK CHARACTERIZATION All uses for novaluron, either proposed or existing, are agricultural or commercial in na ture. No residential uses are proposed, nor are an y of the uses expected to result in residential exposure. Therefore, a residential exposure assessment was not performed for this action. 5 .1 Spray Drift Spray drift is alway s a potential source of exp osure to residents nearb y 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 Agen cy

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 b y the Spray Drift Task Force, a membership of U.S.Novaluron Human - Health Risk Assessment DP#: 364307

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Page 20 of 30 pesticide registrants, and is developing a policy on how to appro priatel y apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied by air, orchard airblast , and ground h ydraulic 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 cluding all existing and proposed uses, a human - health aggregate risk assessment has been conducted for the following exposure scenario: chronic aggregate exposure (food + water onl y). An acute aggregate assessment was not conducted for novaluron because an endpoint of concern attributable to a single dose was not identif ied. A cancer aggregate assessment was not conducted because novaluron was classified as “not likely to be carcinogenic to humans.” Because there are no uses of novaluron that could result in residential exposures, this aggregate risk assessment takes into consideration dietary food + water exposure only ; therefore, the chronic aggregate estimates would be the same as the chronic dietary exposure results shown in Table 4.3 . The chronic aggregate exposure and risk estimate is below HED’s LOC . 7 .0 OCCUP ATIONAL EXPOSURE/RISK PATHWAY An occupational exposure assessment for novaluron was prepared in a pending HED memorandum (L. Venkateshwara ; D374418 ). See Table 2. 0 for a summary of the proposed use patterns. 7 .1 Occupational Pesticide Handler Exposure and Risk There is potential for occupational handler exposure from the proposed use on grain sorghum . Handler’s exposure and risk were estimated for the following scenarios: Mixer/L oader: (1) Mixing/loading liquids for aerial application; (2) Mixing/ loading liquids for groundboom application; Applicator: (3) Applying spray s via aerial applications; (4) Applying spray s via groundboom applications; and Flagger: (5) Flagging to support aerial applications . No chemical - specific data were available w ith 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 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 personal - protective equipment (PPE), as might be necessary . The novaluron product labels direct applicators and other handlers to wear aNovaluron Human - Health Risk Assessment DP#: 364307

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Page 21 of 30 long - sleeved shirt, long pants, protective eyewear, chemical - resistant gloves, and shoes plus socks. Handler exposure is expected to be short - an d intermediate - term based on information provided on the proposed labels. There is no short - term dermal point of departure; therefore, onl y 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. T he short - and intermediate - term inhalation toxicological points of departure are the same; therefore, the estimates of risk for short - term duration inhalation exposures are protec tive of those for intermediate - term inhalation duration exposures. The average adult body weight of 70 kg was used for estimating inhalation and dermal dose. L ong - term exposures are not expected ; therefore, a long - term assessment was not conducted. Dail y 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 data; Application Rate = Normalized application rate based on a logical unit treatment, such as acres; and Daily Area Treated = Normalized ap plication 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 fa ctor 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 chemic al that crosses a biological boundary such as the skin or lungs (% of the total available absorbed); and Body Weight = Body w eight 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 o f the NOAEL to the daily dose. All MOE values were calculated using the formula below:Novaluron Human - Health Risk Assessment DP#: 364307

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Page 22 of 30 MOE = NOAEL or LOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day) Dermal and inhalati on 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 7 .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 are not of concern (i.e., MOEs ≥ 100), provided workers wear chemical resistant gloves as recommended on the label . No short - term point of departure was selected for dermal exposure ; therefore, the risks presented for handlers are representative of intermediate - term exposures and would be considered protectiv e of short - term exposures. It should be noted that only engineering control data are available to assess dermal and inhalation risks to handlers operatin g aircraft (enclosed cockpit). The risks are not of concern for pilots using enclosed cockpits. Tab le 7.1. Occupational Handler Dermal and Inhalation Exposures and Risks. 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 Intermediat e 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 Si ngle 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) Mi xer/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 0.001 4 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 ApplicationNovaluron Human - Health Risk Assessment DP#: 364307

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Page 23 of 30 Tab le 7.1. Occupational Handler Dermal and Inhalation Exposures and Risks. 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 Intermediat e term MOE Total MOEs 5

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 A pplication Dermal Engineering Control: 0.0050 Inhalation Engineering Control: 0.000068 0.078 350 Dermal Engineering control: 0.0002 Com

bined Engineering Control 0.00023 Dermal

Engineering control: 22,000 Com

bined Engineering Control 20,000 Inhalatio n 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: 1 0,000 Baseline

Dermal + Inhalation 7,700 Inhalation Baseline: 0.00014 Inhalation Baseline: 32,000 1 Application rates are the maximum recommended rates provided on the novaluron product label . 2 Area treated per day values are HED estimates base d on ExpoSAC Policy #9 “Standard Values for Daily Acres Treated in Agriculture,” industry sources, and HED estimates. 3 Dose (mg/kg/day) = Uni t exposure (mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x % Absorption (10% dermal and 100% inhal ation assumed) / Body weight. The body weight is 70 kg for the inhalation and dermal dose. 4 Total Dose = Dermal + Inhalation Dose . 5 Total MOE = NOAEL (4.38 mg/kg/day)/Total Dose . 6 Baseline Dermal: long - sleeve d shirt, long pants, no gloves . 7 Baseline Inhalation: no respirator. 8 Single layer with gloves: s ingle layer baseline attire plus chemical - resistant gloves. 7 .2 Occupational Post - Application Worker Exposure and Risk HED assumes that inhalation exposures are minimal following outdoor applications of an active ingr edient with low vapor pressure. Since novaluron is applied only in outdoor settings and has a low vapor pressure ( 1.2 x 10 - 7 mm Hg at 22o C ), a quantitative post - application inhalation exposure and risk assessment was not conducted . The proposed use is for a postemergent application ; therefore, a dermal post application exposure assessment was conducted. Since no post - application data were submitted in support of this registration action, dermal exposures during post - application act ivities were estimated using dermal transfer coefficients from the ExpoSAC Policy Number 3.1: Agricultural Transfer Coefficients, August 2000, summarized in Table 7 .2 .1 below and the following assumptions:

 Application Rate = 0.078 lb ai/A ;Novaluron Human - Health Risk Assessment DP#: 364307

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Page 24 of 30  Exposure Duration = 8 hours per day ;  Body Weight = 70 kg for adult male ;  Derm al Absorption = 10% ; and  Fraction of ai retained on foliage is assum ed to be 20% (0.2) on day zero [ = % d islodgeable - foliar residue (DFR) after initial treatment ] for agricultural crops . T his fraction is assumed to further dissipate at the rate of 10% (0.1) per day on following day s. These are default values established by HED’s ExpoSAC . Table 7.2.1. Anticipated Post - application Activities and Derm al Transfer Coefficients. Proposed Crop s Policy Crop

Group Category Transfer Coefficients (cm2 /hr) Activities Grain Sorghum Field/row crop

tall 100 Scouting and hand weeding

1000 Irrigation and scouting The following equations were used to calculate risks for workers performing post - appli cation activities: DFR t (μg/cm2 ) = AR (lb ai/acre) x F x (1 - D) t x 4.54E8 μg/lb x 2.47E - 8 acre/cm2 Where: DFR

t = dislodgeable foliage residue on day “ t” (μg/cm2 ) ; AR = application rate (lb ai/acre) ; F = fraction of ai retained on foliage (unitless) ; D = fraction of residue that dissipates daily (unitless) ; and Daily dermal dose t (mg/kg - day) = [DFRt (μg/cm2 ) x 1E - 3 mg/μg x Tc (cm 2 /hr) x DA x ET (hrs)] / BW (kg) . Where: t = number of days after application day (days) ; DFR t = dislodgeable foliage res idue on day “ t” (μg/cm2 ) ; Tc = transfer coefficient (cm 2 /hr) ; DA = dermal absorption factor (unitless) ; ET = exposure time (hr/day) ; BW = body weight (kg) ; and MOE = NOAEL (mg/kg/day) / Daily Dermal Dose (mg/kg/day). The post - application exposures a ssociated with the proposed new use are summarized in Table 7 . 2.2 . The resulting MOEs are greater than 100 on day 0 (12 hours after application) for all crops and activities. Post - application dermal risks were calculated based on an intermediate term end point and are considered highly conservative for the included activities. Table 7. 2 . 2. Post - application Risks for Novaluron. Crop Application Rate

(lb ai/A) Transfer Coefficient (cm 2 /hr) DFR

(ug/cm2 ) Day s After

Treatment Daily Dose 1

(mg/kg/ay) MOE 2 Gr ain Sorghum 0.078 100 0.18 12 hours (0 days) 0.0002 21,900 1,000 0.002 2,200 The information in the table is based on proprietary and non -proprietary data. 1 Daily Dose = [DFR (ug/cm2 ) x T C (cm2 /hr) x 0.001 mg/μg x Dermal Absorption (10%) x 8 hrs/day] ÷ Body Weight (70 kg) . 2 NOAEL/Daily Dose (Intermediate - term NOAEL = 4.38 mg/kg/day) .Novaluron Human - Health Risk Assessment DP#: 364307

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Page 25 of 30 Since the post - application assessment is not a concern on Day 0 (12 hours followi ng application), the REI is based on the acute toxicity of novaluron technical materi al. The proposed label for Rimon ® 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 th e WPS, a 12 - hour REIis required for chemicals classified under Toxicity Category III and IV. 8 .0 DATA NEEDS AND LABEL RECOMMENDATIONS 8 .1 Toxicology  The HED HIARC requested a 28 - day inhalation toxicity

study as a condition of registration. However, b ased on the low volatility and low inhalation toxicity (Category IV ) of novaluron and inhalation MOEs >1000 for the proposed uses in this risk assessment, novaluron qualifies for a waiver of the 28 - day inhalation toxicity

study for the proposed uses [HED S OP 2002.01: Guidance: Waiver Criteria for Multiple - Exposure Inhalation Toxicity

Studies, 15 - AUG - 2002]. The requirement for the 28 - day inhalation toxicity study is waived for this action only . If in the future, requests for new uses or formulations are su

bmitted that may

result in a significant change in either the toxicity profile or exposure scenarios, HED will reconsider this data requirement.

 An immunotoxicity

study is required as specified in the new 40 CFR Part 158 data requirements . 8 .2 Residue Ch emistry  860.1200 Directions for Use

A revised Section B for petition number 9F7547 should be submitted which:  Specifies that the use of adjuvants /surfactants on grain sorghum is prohibited;  Specifies that the label is for “grain sorghum” as opposed to “s orghum;”  S pecifies separate PHIs for grain sorghum forage (7 day s), grain (14 day s), and stover (14 days); and  States that the use of novaluron on crops grown for food in greenhouses , except tomatoes, is prohibited.

 860.1380 Storage Stability Data

Stor age stability

data on grain sorghum forage, grain, AGF, and stover for up to 275, 253, 237, and 245 day s, respectively , are required.

 860.1550 Proposed Tolerances

 A revised Section F for petition number 9F7547 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 deter mined by measuring only novaluron ( N - [[[3 - chloro - 4 - [1,1,2 - trifluoro 2 - (trifluoromethox y) ethox y] phen yl ]amino]carbonyl] - 2,6 - difluorobenzamide ) in or on the following raw agricultural commodities:”Novaluron Human - Health Risk Assessment DP#: 364307

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Page 26 of 30  A r evised Section F is requested which reflect s the recommen ded tolerances and commodity definitions presented in Table 4.1. 8 .3 Occupational and Residential Exposure  None. Attachments: Appendix A: TOXI COLOGY ASSESSMENT A.1 Acute Toxicity

Profile . A.2 Toxicity

Profiles .

cc: J . Van Alstine, L. Venkateshwara, R. Mitkus RDI: RAB1 Branch ( 02/ 1 7 /10 ); G. Kramer ( 0 2 / 5 /10 ); D. Vogel ( 02 /23 /10 ) J. Van Alstine: S - 10954: Potomac Yard 1 (PY1): (703)603 - 8866: 7509P: RAB1Novaluron Human - Health Risk Assessment DP#: 364307

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Page 27 of 30 Appendix A: TOXICOLOGY ASSESSMENT A.1 . Acute Toxicity Profile Tab le A.1. Acute Toxicity of Novaluron . Guideline No. Study Type MRID #(s) Results Toxicity Category 870.1100 (81 - 1) Ac ute Oral (rat) 44961001 LD 50 > 5000 mg/kg IV 870.1200 (81 - 2) Ac ute Dermal (rat) 45003201 LD 50 > 2000 mg/kg III 870.1300 (81 - 3) Ac ute I nhalation (rat) 45003202 LC 50 > 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 /C lassification Results 870.3100 90 - Day oral toxicity rodents 45651504/45651503 (1993/1990) ;

A cceptable/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 b w/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 an d 50 ppm (4.38 mg/kg/day) in females . LOAEL = 400 ppm

(27.77 mg/kg/day) in m ales 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 Sy stemic NOAEL = 1000 mg/kg/day; LOAEL = not established . Dermal NOAEL = 1000 mg/kg/day; LOAEL = n ot 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 .Novaluron Human - Health Risk Assessment DP#: 364307

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Page 28 of 30 Table A.2 . Toxicity Profile of Novaluron . Guideline No/ Study type MRID No.(year)/Doses /C lassification Results 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. Re productive 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 F 1 generation ; Reproductive LOAEL for females was not established. 870.4100 Chronic tox icity - 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 4 5651506 (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 e rythrocyte damage and turnover resulting in a regenerative mild anemia . 870.4300 Chronic/ Carcinogenicity

- mo use 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/Guid eline 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 44961 013 (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), wa s 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 in duce 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 .Novaluron Human - Health Risk Assessment DP#: 364307

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Page 29 of 30 Table A.2 . Toxicity Profile of Novaluron . Guideline No/ Study type MRID No.(year)/Doses /C lassification Results 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 o f 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 statist ically 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 S 9 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 d amage to HeLa S3 epithelioid cells in this unscheduled DNA synthesis test for mutagenic potential . 870.6200 Ac ute 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 mul tiple 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 wi thin 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 conce ntration 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 repres ented the majority of the urinary radioactivity. Other components individually represented no more than 5.9% of the dose and mo st represented considerably le ss than 1%. Parent compound was the most prevalentNovaluron Human - Health Risk Assessment DP#: 364307

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Page 30 of 30 Table A.2 . Toxicity Profile of Novaluron . Guideline No/ Study type MRID No.(year)/Doses /C lassification Results contributor in the feces. The fecal metabolit e 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/cm2 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 radioact ivity in excreta, cage wash, untreated skin, fat, blood, and residual carcass) ranged from about 0.5% to 10% of that administered.