Novaluron Human - Health Risk Assessment DP#: 363988

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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: 04 - DEC - 2009 SUBJECT: Novaluron : Human - Health Risk Assessment for Proposed Section 3 Uses on

Vegetable, Fr

uiting, Group 8; Vegetable, Cucurbit, Group 9; Berry, Low growing, Subgroup 13 - 07G ; Miscellaneous Fruiting Vegetables; Bean, Snap; Bean, Dry , Seed; and Swiss Chard . PC Code: 124002 DP Barcode: D 363988 Decision No.: 407555 Registration No. : 66222 - 35 Petition No.: 9E7546 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 Hea lth 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 Che mist RAB1/HED (7509P) TO: Barbara Madden/Laura Nollen (RM 05)

Registration Division (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 re quested 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 Mitkus (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).Novaluron Human - Health Risk Assessment DP#: 363988

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Page 2 of 30 The most recent human - health risk assessment was conducted in conjunc tion with a request for the use of novaluron on bushberry subgroup 13 - 07B; Brassic a , leafy greens, subgroup 5B; turnip, greens; and fruit, stone, group 12 (Memo, J. Van Alstine, et al. , 09 - SEP - 2009; D 357078). A detailed hazard characterization for novaluron is presented in a previous HED risk assessment ( Memo, S. Lev y, et al ., 03 -NOV - 2 005; 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 fruiting vegetables group 8, cucurbit vegetab le group 9, low - growing berry subgroup 13 - 07G, miscellaneous fruiting vegetables, snap bean, dry bean seed, and Swiss chard .Novaluron Human - Health Risk Assessment DP#: 363988

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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 ............................. 11 3.1 FQ PA Con siderations ................................ ................................ ................................ .. 11 3.2 Endocrine Disruption ................................ ................................ ................................ .. 13 4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION ................................ ........... 14 4.1 Food Residue Profile ................................ ................................ ................................ .... 14 4.2 Drinking Water Residue Profile ................................ ................................ ................. 16 4.3 Dietary Exposure and Risk ................................ ................................ ......................... 17 5.0 Residential (Non - Occupational) Exposure/Risk Characterization ............................. 18 5.1 Spray Drift ................................ ................................ ................................ .................... 18 6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION ........ 19 7.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY ................................ ................... 19 7.1 Oc cupational Pesticide Handler Exposure and Risk ................................ ................ 19 7.2 Occupational Post - Application Worker Exposure and Risk ................................ ... 22 8.0 DATA NEEDS AND LABEL RECOMMENDATIONS ................................ .............. 25 8.1 Toxicology ................................ ................................ ................................ ..................... 25 8.2 Residue Chemistry ................................ ................................ ................................ ....... 25 8.3 Occupational and Residential Exposure ................................ ................................ .... 26 A.1. Acute Toxicity Profile ................................ ................................ ................................ .. 27 A.2 Toxicity Profiles ................................ ................................ ................................ ........... 27Novaluron Human - Health Risk Assessment DP#: 363988

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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, the Interregional Research Project No. 4 (IR - 4) has submitted a petition (PP# 9E7546 ) 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 - difluorobenz amide) on vegetables, fruiting, group 8; vegetable, cucurbit, group 9; berry, low - growing, subgroup 13 - 07G ; miscellaneous fruiting vegetables; bean, snap; bean, dry , seed; and Swiss chard . The basic producer of novaluron is Makhteshim Agan of North Americ a (MANA). End - use products containing novaluron as the ai are formulated as EC, suspension concentrate (SC), or water - dispersible granular (WDG). Novaluron, a benzoylphenyl urea compound, is a pesticide chemical belonging to the class of insecticides cal led insect - growth regulators (IGR s ) . IGRs slowly kill insects over a period of a few day s by

disrupting the normal growth and development of immature insects. Novaluron acts as an insecticide mainly

by ingestion, but has some contact activity . It is cur rentl y registered for uses on pome fruits, Brassica head and stem vegetables, tuberous and corm vegetables, cotton, tomatoes, and sugarcane. Registrations on bushberry subgroup 13 - 07B, Brassica , leafy greens (subgroup 5B), turnip greens, and stone fruit ( crop group 12) are pending . 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 Cha racterization 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. Nov aluron is not a dermal sensitizer. In subchronic and chronic toxicity

studies, novaluron primaril y produced hematotoxic effects such as methemoglobinemia, decreased hemoglobin, decreased hematocrit, and decreased red blood corpuscles ( RBCs or erythrocy tes ) that were associated with compensatory ery thropoiesis. 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 subc hronic neurotoxicity study in rats at similar doses. 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 and reaffirmed the previous conclusion of the HIARC (16 - DEC - 2003, TXR# 0052361) that the Food Quality Protection ActNovaluron Human - Health Risk Assessment DP#: 363988

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Page 5 of 30 (FQPA) Safet 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 the rat and/or rabbit developmental toxicity studies at levels up to the limit dose. Also, no increased qualitative and/or quantitative evidence of increased susceptibility was found following pre/post - natal exposure in a two - generation reproduction study in rats. The risk assessment team conclud ed 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 reference dose (aRfD) for the general population, including infants and c hildren, 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 carcinogenicity

study in the rat. An uncertainty f actor (UF) of 100 (10 - fold for interspecies extrapolation and 10 - fold for intraspecies variabilit y) 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 m g/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 to xicological database, a short - term dermal endpoint was not selected; therefore, only intermediate - term dermal exposure was assessed. Short - and intermediate - term inhalation exposures have been assessed. In addition, the short - and intermediate - term inha lation toxicological endpoints 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 acceptab le 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 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 mic e 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 toxic ity/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) 90 - day feed ing study - rat - clinical chemistry and histopathology at the LOAEL of 8.64 mg/kg/day. Short - term inhalation Intermediate - term inhalationNovaluron Human - Health Risk Assessment DP#: 363988

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Page 6 of 30 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 likel y to be carcinogenic to humans.” The current chronic dietary

anal ys is assumed 100% crop treated for all commodities and was refined through the use of empirical processing factors, some average field trial residues , average greenhouse trial residues for tomatoes, and anticipated residues ( ARs ) for meat, hog, and milk commodities . Empirical processing factor s for apple juice were translated to pear and other pome fruit juice and all stone fruit juice. In accordance with HED Standard Operating Procedure (SOP) 2000.1, average field trial residues were translated from representative commodities in the crop grou p to other commodities in that crop group as needed. Estimated drinking water concentrations (EDWCs), provided by

EFED, were included in this assessment as well. For this action, the chronic dietary

(food and drinking water) exposure to novaluron is belo w HED’s LOC for the general U.S. population and all population subgroups. The chronic dietary exposure results in a risk estimate that is 25% of the cPAD for the general U.S. population and 84% of the cPAD for children 1 - 2 years old, the most highly expos ed population subgroup. Aggregate Exposure Scenarios and 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, this aggregate risk assessment takes into consideration dietary

food + water exposure only . The chronic aggregate exposure and risk estimate s are not of concern . Occupational Exposure Estimates It is anticipated that there will be occupational handler and post - application exposure for the proposed uses of novaluron. No chemical - specific handler exposure data were submitted in support of this Section 3 registration. It is the policy of HED to us e data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in PHED Surrogate Exposure Guide ( AUG - 19 98) to assess handler exposures for regulatory actions when chemical - specific monitoring data are not available [ HED Science Adviso ry 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 s elected 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 a 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. S ince 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 novaluronNovaluron Human - Health Risk Assessment DP#: 363988

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Page 7 of 30 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 acute oral and inhalation and primary

eye and skin irritation. It is not a dermal sensitizer. Per the Worker Pr otection Standard (WPS), a 12 - hour REI is required f or chemicals classified under Toxicity Category III and IV and is adequate for th e proposed use patterns . Environmental Justice Considerations Potential areas of environmental justice concerns, to the extent possible, were considered in this human - heal th risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations, ” ( http://www.hss.energy .gov/nuclearsafet y/ 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 estim ates 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 consump tion 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 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 by standers and farm workers as well as lifest yle and traditional dietary patterns amon g 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. Th ese studies have been reviewed and have been determined to be ethical. Recommendation for Tolerances 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 , toxicology , or occupational exposure issues that would preclude granting a conditional registration for the use of novaluron on the requested crops. The proposed uses and the submitted data support the following permanent tolerances for resi dues 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 b y measuring only novaluron ( N - [[[3 - chloro - 4 - [1,1,2 - trifluor o - 2 - (trifluoromethox y)ethox y]phenyl]amino]carbonyl] - 2,6 - difluorobenzamide ) in or on the following raw agricultural commodities (RACs) :Novaluron Human - Health Risk Assessment DP#: 363988

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Page 8 of 30 Vegetable, cucurbit, group 9 0.15 ppm Okra 1.0 ppm Vegetable, fruiting, group 8 1.0 ppm Roselle 1.0 ppm Cocona 1. 0 ppm Sunberry 1.0 ppm Eggplant, African 1.0 ppm Tomato, bush 1.0 ppm Eggplant, pea 1.0 ppm Tomato, currant 1.0 ppm Eggplant, scarlet 1.0 ppm Tomato, tree 1.0 ppm Goji berry 1.0 ppm Berry, low - growing, subgroup 13 - 07G 0.45 ppm Huckleberry, g arden 1.0 ppm Bean, snap, succulent 0.60 ppm Martynia 1.0 ppm Bean, dry, seed 0.30 ppm Naranjilla 1.0 ppm Swiss chard 12 ppm Data Needs and Label Recommendations Toxicology  The HED HIARC requested a 28 - day inhalation toxicity

study as a conditio n of registration. However, based on the low volatility and 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 toxi city

study for the proposed uses [HED SOP 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, requ ests for new uses or formulations are submitted 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 . Residue Chemistry 860.1200 Directions for Use A revised Section B for petition number 9E7546 should be submitted which:

 Specifies that the use of adjuvants /surfactants (including non - ionic surfactants) on fruiting vegetable group 8, cucurbit vegetable group 9 , strawberry , and low - growing berry subgroup 13 - 07G is prohibited;  Corrects “lowbush berry” to “lowbush blueberry” in the low - growing berry subgrou p 13 - 07G section of the label ; and  States that the use of novaluron on crops gr own for food in greenhouses , except tomatoes, is prohibited. 860.1550 Proposed Tolerances  The proposed tolerance expression for petition number 9E7546 is written in terms of “tolerances for combined residues of the insecticide novaluron, 1 - [3 - chloro - 4(1 ,1,2 - trifluoro - 2 - trifluoro - methoxyethox y) phen yl ] - 3 - (2,6 - difluorobenzoyl)urea . ” A revised Section F for petition number 9E7546 should be submitted to remove the word combined and cite 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 b y measuring onlyNovaluron Human - Health Risk Assessment DP#: 363988

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Page 9 of 30 novaluron (

N - [[[3 - chloro - 4 - [1,1,2 - tri fluoro - 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 recommended tolerances and commodity

definitions presented in Table 4 .1 . Notes to RD: The currently established tomato tolerance and the time - limited tolerance for strawberry

should be removed from 40 CFR §180.598. Additionally , the pending tolerance for bushberry subgroup 13 - 07B (7.0 ppm) should be amended to “bushberry subgroup 13 - 07B, except lowbush blueberry .” Occupational and Residential Exposure  None. 2.0 PROPOSED USE PATTERN IR - 4 has submitted a draft label, dated 16 - MAR - 2009, for Rim o n ® 0.83 EC Insecti ci de ( EPA Reg. No. 66222 - 35) to include the proposed ne w use s (see Table 2.0 ) on fruiting vegetable group 8, cucurbit vegetable group 9, low - growing berry subgroup 13 - 07G, cocona, African eggplant, pea eggplant, scarlet eggplant, goji berry , garden huckleberry , mart ynia, naranjilla, okra, roselle, sunberry , bu sh tomato, currant tomato, tree tomato, snap bean , dry bean seed, and Swiss chard . Table 2.0 . Summ ary of Proposed Use Pattern for Novaluron. Application Equipment Form

ulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seaso nal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations Fruiting Vegetables (field) [tomatoes (including bush, currant, and tree tomatoes ) , peppers, eggplants (including African, pea, and scarlet eggplants), tomatillo, groun dcherry, pepino, o kra, cocona, g oji berry, garden huckleberry, martynia, naranjilla, roselle, and sunberry] Groundboom/ Aerial 0.83 lb/gal

EC [66222 - 35] 0.058 -

0.078 3 - 4 1 ,2,3 0.23 1 Repeat applications as needed to protect new foliage growth, blooms, and fruit, but not less than 7 days apart. 1 - day PHI; 12 - hour REI. Low - Growing Berry Subgroup 13G [cranberry, lingonberry, muntries, partridgeberry, bearberry, bilberry , low bush berry, and cloudberry] Groundboom/ Aerial 0.83 lb/gal

EC [66222 - 35] 0.078 3 3 0.23 1 Repeat applicati ons as needed to protect new foliage growth, blooms, and fruit, but not less than 7 days apart. 1 - day PHI ; 12 - hour REI . Strawberry Groundboom/ Aerial 0.83 lb/gal

EC [66222 - 35] 0.058 -

0.078 3 - 4 0.23 1 Repeat applications as needed to protect new foliage gr owth, blooms, and fruit, but not less than 14 days apart. 1 - day PHI; 12 - hour REI. Swiss ChardNovaluron Human - Health Risk Assessment DP#: 363988

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

ulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seaso nal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Groundboom/ Aerial 0.83 lb/gal

EC [66222 - 35] 0.058 -

0.078 3 - 4 3 0.23 1 Repeat applications as needed to protect new foliage growth, blooms, and fruit, but not les s than 7 days apart. Do not use surfactants of any kind with Rimon ® 0.83EC on this crop. 1 - day PHI; 12 - hour REI. Beans (Snap, Dry)

Groundboom/ Aerial 0.83 lb/gal

EC [66222 - 35] 0.039 -

0.078 3 - 6 2,3 0.23 1 Repeat applications as needed to protect new foliag e growth, blooms, and fruit, but not less than 7 days apart. Do not use surfactants of any kind with Rimon ® 0.83EC on this crop. 1 - day PHI; 12 - hour REI. Cucurbit Vegetables [balsam apple, balsam pear, chayote (fruit), cantaloupe, cucumber, Chinese cucum ber, gherkin (West Indian), edible gourd, melon, citron melon, muskmelon, bittermelon, pumpkin, squash, summer squash, winter squash, watermelon, and Chinese waxgourd]

Groundboom/ Aerial 0.83 lb/gal

EC [66222 - 35] 0.058 -

0.078 3 - 4 2,3 0.23 1 Repeat applicatio ns as needed to protect new foliage growth, blooms, and fruit, but not less than 14 days apart. Use of a non ionic surfactant to enhance coverage and penetration may improve performance. 1 - day PHI; 12 - hour REI. 1 For the Colorado potato beetle, no more than t wo applications should be made to a single generation and it should not be applied to successive generations. 2 No more than two applications against whiteflies or thrips per season should be used. 3 For most effective control, fields should be s couted . Conclusions : The proposed label is adequate to allow evaluation of the residue data relative to the proposed new uses on fruiting vegetable group 8, cucurbit vegetable group 9, low - growing berry crop subgroup 13 - 07G, cocona, African eggplant, pea eggplant, scarlet eggplant, goji berry , garden huckleberry , mart ynia, naranjilla, okra, roselle, sunberry, bush tomato, currant tomato, tree tomato, snap beans, dry beans, and Swiss chard. A revised Section B is requested which :  Specifies that the us e of adjuvants /surfactants (including non - ionic surfactants) on fruiting vegetable group 8, cucurbit vegetable group 9 , strawberry , and low - growing berry subgroup 13 - 07G is prohibited;  Corrects “lowbush berry” to “lowbush blueberry” in the low - growing berry subgrou p 13 - 07G section of the label ; and  States that the use of novaluron on crops grown for food in greenhouses , except tomatoes, is prohibited.Novaluron Human - Health Risk Assessment DP#: 363988

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Page 11 of 30 3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS A detailed hazard characterization for novaluron is pres ented in HED’s previous risk assessment ( Memo, S. Lev y, et al ., 03 -NOV - 2005; D313322 ). 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 such as methemoglobinemia, decreased hemoglobin, decre ased hematocrit, and decreased RBCs (or ery throcy tes) that were associated with compensatory ery

thropoiesis. No maternal and/or developmental toxicity was observed in animals tested up to the limit dose in either the rat or rabbit developmental toxicity s tudies . 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 (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 doses up to 1752 mg/kg/day in males and 2000 mg/kg/day

in females. Therefore, RAB1 toxicologists reaffirmed the HED HIARC conclusion that there is not a concern for neurotoxicity resulting from exposure to novaluron. There was no evidence of carcinoge nic 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 mammalian chromosomal abe rration 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 following:

 There is no evi dence 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 toxicity .  Acute and su

bchronic neurotoxicity

screening batteries were performed with novaluron in rats. Novaluron is not considered neurotoxic since the effects observed in the acute neurotoxicity

study were observ ed at a very

high dose with little to no relevance to expected human exposures (i.e., the limit dose ) and were not reproduced at similar 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.  A development al - 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 th e chronic studies in rats and mice and the reproduction study in rats. These findings were associated with the hematotoxicity of novaluron , which caused removal from the blood and accumulation of abnormalNovaluron Human - Health Risk Assessment DP#: 363988

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Page 12 of 30 erythrocy tes in the spleen , and are not considered immunotoxic effects . The overall weight of evidence suggests that novaluron does not directly target the immune sy stem. An immunotoxicity

study is required as part of the revised 40 CFR Part 158 toxicology data requirements for novaluron; however, HED d oes 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 (UF 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. Short - Term Incidental Oral (1 - 30 days) NOAEL = 4.38

mg/kg/day Residential LOC for

MO E = 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 Ora l (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 hemosid erosis 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 LOAEL = 8.64 mg/kg/day based on clinical chemistry (decrea sed hemoglobin, hematocrit , and RBC counts) and histopathology (increased hematopoiesis and hemosiderosis in spleen and liver). Long - Term Oral NOAEL = 1.1 Residential/ Com bined chronicNovaluron Human - Health Risk Assessment DP#: 363988

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Page 13 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 Dermal (>6 months) mg/kg/day

(dermal - absorption rate = 10 %) Occupational LOC for

MOE = 100 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 h emoglobin, 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 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 carcinogenic to humans. UF = uncertainty factor, FQPA SF = FQP A 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, NA = Not Applicable . 3.2 Endocrine Disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there were scientific bases for including, as part of the program, androgen and thy roid hormone s ys tems, in addition to the estrogen hormone sy stem. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. When the appropriate screening and/or testing protocols being considered under the Agency ’s Endocrine Disrupter Screening Program (EDSP) have been developed and vetted, novaluron may

be subjected to additional screening and/or testing to better characteri ze effects related to endocrine disruption.Novaluron Human - Health Risk Assessment DP#: 363988

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Page 14 of 30 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 ( D364237 ). The chronic dietary exposure assessment is summarized i n the pending HED memorandum b y J. L . Van Alstine ( D364235 ). 4.1 Food Residue Profile Nature of the Residue - Plants: HED previously concluded that the nature of the residue in plants is adequatel y understood based o n 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 novaluro n 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 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 adequatel y understood based on the submitted goat and poultry metabolism studies (Memo, G. Kramer, 22 - MAR - 2004; D285474). The HED MARC determined that the residue of concern in livestock for purposes of tolerance enforcem ent and risk assessment is novaluron only

(Memo, G. Kramer et al. , 03 - FEB - 2004; D297646). Residue Analytical Enforcement Method - Plant: MANA previousl 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 novaluron. 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 laboratory. Acceptable radiovalidation data for the GC/ECD method have been submitted and reviewed in a previ ous 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). ACB concluded that based upon review of the submitted method validation data, without laboratory

validation, that the GC/ECD and HPL C/UV methods 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 forwarded 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. Le vy , 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) .Novaluron Human - Health Risk Assessment DP#: 363988

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Page 15 of 30 Magnitude of the Residue - Plants: The submitted field trial data for bell and non - bell pepper, cucumber, cantaloupe, summer squash, strawberry, snap bean, dry bean seed, and Swiss chard are adequate and will support the establishment of residue tolerances for novaluron in/on fruiting vegetables group 8 (1.0 p pm) , cucurbit vegetable group 9 (0.15 ppm) , low - growing berry subgroup 13 - 07G (0.45 ppm) , cocona (1.0 ppm) , African eggplant (1.0 ppm) , pea eggplant (1.0 ppm) , scarlet eggplant (1.0 ppm) , goji berry (1.0 ppm) , garden huckleberry (1.0 ppm) , mart ynia (1.0 pp m) , naranjilla (1.0 ppm) , okra (1.0 ppm) , roselle (1.0 ppm) , sunberry (1.0 ppm) , bush tomato (1.0 ppm) , currant tomato (1.0 ppm) , tree tomato (1.0 ppm) , snap bean (0.60 ppm) , dry bean seed (0.30 ppm) , and Swiss chard (12 ppm) . Processed Food and Feed: HED does not require residue data for an y processed commodities associated with the proposed crops . Therefore, data requirements for processed fo od and feed are not relevant to these commodities . Confined/Field Accumulation in Rotational Crops: The co mmodities associated with the current petitions may

be rotated. The available confined rotational crop study is adequate. The HED MARC has determined that for tolerance assessment and risk assessment, parent onl y is the residue of concern (Memo, G. Krame r et al. , 03 - FEB - 2004; D297646) . Based on the results of a previously

submitted confined rotational crop study ( Memo, G. Kramer, 22 - MAR - 2004; D 285474 ) , the appropriate plantback interval ( PBI ) for all non - labeled crops is 30 day s. The current and propose d 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 . Tolerance Summary: Permanent tolerances for novaluron have been established f or a variet y of commodities under 40 CFR §180.598. HED has determined that the residue of concern in plants for tolerance enforcement is novaluron only . The proposed tolerance expression for petition number 9E7546 is written in terms of “tolerances for c ombined residues of the insecticide novaluron, 1 - [3 - chloro - 4(1,1,2 - trifluoro - 2 - trifluoro - methoxyethox y)phen yl ] - 3 - (2,6 - difluorobenzoyl)urea . ” A revised Section F should be submitted to remove the word combined and cite the appropriate CAS name for novaluro n:

“ 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 b y measuring onl y no valuron ( 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:” A summary

of the recommended tolerances for the current petition are listed in Table 4 .1 . A r evised Section F is requested which reflect s the recommended tolerances and commodity definitions presented in Table 4.1 . HED notes that cocona, African eggplant, pea eggplant, scarlet eggplant, goji berry , garden huckleberry , marty nia, naranjilla , okra, roselle, sunberry , bush tomato, currant tomato, and tree tomato residue data have not been submitted and concludes that the fruiting vegetable crop group 8 tolerance (1.0 ppm) may be translated to the proposed commodities (see Reviewer's Guide and Summary of HED ChemSAC Approvals for Amending Commodity

Definitions (40 CFR 180.1(h)) and Crop Group/Subgroups (40 CFR 180.41)). No Codex, Canadian , or Mexican MRL s have been established for novaluron in/ on the proposed commodities . Canada is currentl y in the process of reviewing the use of novaluron on strawberries, snap beans, and bell and non - bell peppers. EPA and PMRA toleranceNovaluron Human - Health Risk Assessment DP#: 363988

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Page 16 of 30 recommendations have been harmonized at 0.45 ppm for low - growing berry subgroup 13 - 07G and 0.60 for edible - podded snap beans. The PMRA has not received petitions for the use of novaluron on fruiting vegetable group 8 and will be setting tolerances for bell and non - bell peppers at 0.80 ppm and 0.90 ppm, respectivel y (personal communication with Melissa W atchorn of PMRA, 30 -NO V - 2009). The Agency ’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized for determining appropriate tolerance levels. Notes to RD: The currently established tomato tolerance and the time - limited tolerance for strawberry

sh ould be removed from 40 CFR §180.598. Additionally , the pending tolerance for bushberry subgroup 13 - 07B (7.0 ppm) should be amended to “bushberry subgroup 13 - 07B, except lowbush blueberry .” Table 4.1 . Tolerance Summary for Novaluron. Commodity Propose d Tolerance (ppm) HED Recommended

Tolerance (ppm) Comments;

Correct Commodity Definition Vegetable, fruiting, group 8 1.1 1.0 Vegetable, cucurbit, group 9 0.25 0.15 Berry , low

growing, subgroup 13 - 07G 0.50 0.45 Berry , low - growing, subgroup 13 - 0 7G Cocona 1.1 1.0 Eggplant, African 1.1 1.0 Eggplant, pea 1.1 1.0 Eggplant, scarlet 1.1 1.0 Goji berry 1.1 1.0 Huckleberry, garden 1.1 1.0 Martynia 1.1 1.0 Naranjilla 1.1 1.0 Okra 1.1 1.0 Roselle 1.1 1.0 Sun berry 1.1 1.0 Tomato, bush 1.1 1.0 Tomato, currant 1.1 1.0 Tomato, tree 1.1 1.0 Bean, snap, succulent 0.60 0.60 Bean, dry 0.20 0.30 Bean, dry, seed Swiss chard 12 12 4.2 Drinking Water Residue 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 and stone fruits, the EDWCs provided in th e 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 degradates are residues of potential concern t o be included in the drinking water assessment. Monitoring data are not available for novaluron or itsNovaluron Human - Health Risk Assessment DP#: 363988

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Page 17 of 30 chlorophen ylurea 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 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 selecte d 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 0.9 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 chlorophenylurea i s 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 per 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 used to predict a ground water concentrat ion 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 sources. For the chlorophenyl urea degradat e, 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 th e 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, c hronic 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 degra date (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 assessm ent 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 1 994 - 1996 and 1998. The anal ys is was performed to support the request for use of novaluron fruiting vegetable group 8; cucurbit vegetable group 9; lo w - growing berry subgroup 13 - 07G ; miscellaneous fruiting vegetables; snap bean; dry bean seed; and Swiss chard .Novaluron Human - Health Risk Assessment DP#: 363988

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Page 18 of 30 The chronic dietary

(food and drinking water) exposure and risk assessment was conducted for the proposed uses on fruiting vegetables group 8, cucurbit vegetable group 9, low - growing berry subgroup 13 - 07G, miscellaneous fruiting vegetables, snap bean, dry bean seed, and Swiss chard; all established uses; and drinking water. A partially refined assessment was conducted. EDWCs were provided b y EFED. The chronic anal ys is assumed 100% crop treated for all commodities; incorporated average field trial re sidues 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 tri al residue s for tomatoes; empirical processing factors for apple juice (translated to pear and stone fruit) and tomato paste and purée ; and DEEM  (ver. 7.81) default processing factors for the remaining processed commodities. Furthermore, ARs were used fo r meat, hog, and milk commodities. 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 25% of the chronic population - adjusted dose (cPAD) for the general U.S. population and 84% of the cPAD for children 1 - 2 years old, the most highl y exposed population subgroup. Table 4.3 . Summ ary of Chronic Dietary Exposure (Food and Drinking Water) and Risk for Novaluron 1 . Population Subgroup Ac ute 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 0.002749 25 N/A N/A All Infants (<1 year old) 0.004732 43 Children 1 - 2 years old 0.009204 84 Children 3 - 5 years old 0.007142 65 Children 6 - 12 years old 0.004307 39 Youth 13 - 19 years old 0.002365 22 Adults 20 - 49 years old 0.001944 18 Adults 50+ years old 0.001965 1 8 Females 13 - 49 years old 0.001856 17 1 The chronic RfD (cRfd= cPAD = 0.011 mg/kg/day). 5.0 Residential (Non - Occupational) Exposure/Risk Characterization All uses for novaluron, either proposed or existing, are agricultural or commercial in natur e. 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 exposure 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 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 itsNovaluron Human - Health Risk Assessment DP#: 363988

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Page 19 of 30 evaluation of the new database submitted b y the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropri atel 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 pr actices 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 as sessment 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 identified . 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 OCCUPAT IONAL EXPOSURE/RISK PATHWAY An occupational exposure assessment for novaluron was prepared in an HED memorandum dated 05 - NOV - 20 09 (L. Venkateshwara ; D 364236 ). 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 uses on agricultural crops. Handler’s exposure and risk were estimated for the following scenarios: Mixer/L oader: (1) Mixing/loading liquids for aerial applicati on; (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 we re 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 pesticide handlers, HED presents estimates of dermal exposure for “baseline” (i.e., workers wearing a single lay er of work clothing consisting of a long - sleeved shirt, long pants, shoes plus socks, and no protective gloves), as well as forNovaluron Human - Health Risk Assessment DP#: 363988

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Page 20 of 30 “baseline” and the use of protective gloves or other personal - protec tive equipment (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 t o be short - and intermediate - term based on information provided on proposed labels (e.g., depending on the crop, 3 - 6 applications per season are allowed ranging from 7 - 14 day s apart) . There is no short - term dermal point of departure; therefore, onl y inter mediate - 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. 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. L ong - term exposures are not expected, therefore, a long - term assessment was not conducted. Daily dermal or inhalation handler exposures are estimated for each applicable handler task with the application rate, the area treated i n 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 application area based on a logical unit treatment such as acres (A/day). The daily dermal or inhalation dose is calculated by normal izing 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 W eight (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 absorpt ion 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 w eight determined to represent the population of interest in a risk assessment (kg).Novaluron Human - Health Risk Assessment DP#: 363988

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Page 21 of 30 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:

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 7 .1 presents the estimated risks for workers based on the intermediate - term dermal and short - and intermediate - term inhalati on 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 woul d 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 operatin g aircraft (enclosed cockpit). The risks are not of concern for pilots using enclosed cockpits. Table 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 Dos e 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 Ba seline 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: 9,400Novaluron Human - Health Risk Assessment DP#: 363988

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Page 22 of 30 Table 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 Dos e 4 Short - and Intermediate term MOE Total MOEs 5 (3) Applicator – Groundboom Appl ication 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 Com

bined Engineering Control 0.00023 Dermal

Engineering control: 22,000 Com

bined 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 rates are the maximum recommended rates provided on the novaluron product labels. 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) = Uni t 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 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 Celsius ), a quantitative post - application inhalation exposure and ris k 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 expos ures during post - application activities were estimated using dermal transfer coefficients from the ExpoSAC Policy Number 3.1: Agricultural Transfer Coefficients, August 2000, summarized in Table 7 .2 below and the following assumptions:Novaluron Human - Health Risk Assessment DP#: 363988

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Page 23 of 30  Application Rate = 0.078 lb ai/A ;  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 treatme nt ] for agricultural crops . This 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. Anticipated Post - application Activities and Derm al Transfer C oefficients. Proposed Crops Policy Crop

Group Category Transfer

Coefficients (cm2 /hr) Activities Fruiting Vegetables Fruiting

Vegetables 500 Scouting (minimum foliage), hand weeding, thinning

700 Scouting (full foliage), irrigation 1000 Hand harves t, pruning, staking, tying

Swiss Chard Vegetable, leafy 500 Hand weeding, irrigation (minimum foliage), scouting (minimum foliage), thinning (minimum foliage) 1,500 Irrigation (full foliage), scouting (full foliage) 2500 Hand harvesting, hand prunin g, thinning (full foliage) Beans (snap and dry) Field/row crop

low/medium 100 Scouting (minimum foliage), irrigation (minimum foliage), hand weeding 1500 Scouting (full foliage), irrigation (full foliage) 2500 Hand harvesting Cucurbit Vegetables Ve getable,

cucurbit 500 Irrigation, scouting, thinning, hand weeding (minimum foliage)

1500 Irrigation, scouting, hand weeding (full foliage) 2500 Hand harvest, thinning (full foliage), hand pruning Low growing Berries Berry, low 400 Scouting, hand we eding, irrigation, hand pruning, thinning 1500 Hand harvest, hand pruning Strawberry Berry, low 400 Irrigation, mulching, scouting, hand pruning and hand weeding 1500 Hand harvesting, pinching, hand pruning, training The following equations were used to calculate risks for workers performing post - application 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) ;Novaluron Human - Health Risk Assessment DP#: 363988

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Page 24 of 30 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 af ter application day (days) ; DFR t = dislodgeable foliage residue 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) / D aily Dermal Dose (mg/kg/day). The post - application exposures associated with the proposed new use are summarized in Table 7 .3 . The resulting MOEs are greater than 100 on day 0 (12 hours after application) for all crops and activities. Post - application d ermal risks were calculated based on an intermediate - term endpoint and are considered highl y conservative for the included activities. Table 7.3. Post - application Risks for Novaluron. Crop Application

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

(u g/cm2 ) Day s After

Treatment Daily Dose 1

(mg/kg/ay) MOE 2 Fruiting Vegetables 0.078 500 0.18 12 hours (0 days) 0.001 4,400 700 0.0014 3,100 1,000 0.002 2,200 Swiss Chard 0.078 500 0.18 12 hours (0 days) 0.001 4,400 1,500 0.003 1,500 2,500 0.005 880 Beans (snap and dry) 0.078 100 0.18 12 hours (0 days) 0.0002 22,000 1,500 0.003 1,500 2,500 0.005 880 Cucurbit Vegetables 0.078 500 0.18 12 hours (0 days) 0.001 4,400 1,500 0.003 1,500 2,500 0.18 12 hours (0 days) 0.005 880 Lo w - growing Berries 0.078 400 0.18 12 hours (0 days) 0.0008 5,500 1,500 0.003 1,500 Straw berry 0.078 400 0.18 12 hours (0 0.0008 5,500Novaluron Human - Health Risk Assessment DP#: 363988

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Page 25 of 30 Table 7.3. Post - application Risks for Novaluron. Crop Application

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

(u g/cm2 ) Day s After

Treatment Daily Dose 1

(mg/kg/ay) MOE 2 1,500 days) 0.003 1,500 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) . 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 techn ical 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 acute oral and inhalation and primary eye and skin irritation. It is not a dermal sensitiz er. Per the 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, based 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 SOP 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 formulat ions are submitted 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 Chemistry  860.1200 Directions for Use

A revised Section B for petition number 9E7546 should be submitted which:

 Specifies that the use of adjuvants /surfactants (including non - ionic surfactants) on fruiting vegetable group 8, cucurbit vegetable group 9 , strawberry , and low - growing berry subgroup 13 - 07G is prohibited;  Corrects “lowbush berry” to “lowbush blueberry” in the low - growing berry subgrou p 13 - 07G section of the label ; and  States that the use of novaluron on crops grown for food in greenhous es , except tomatoes, is prohibited.

 860.1550 Proposed Tolerances

 The proposed tolerance expression for petition number 9E7546 is written in terms of “tolerances for combined residues of the insecticide novaluron, 1 - [3 - chloro - 4(1,1,2 - trifluoro - 2 - trifluoro - methoxyethox y)phen yl ] - 3 - (2,6 - difluorobenzoyl)urea . ” A revised Section F for petition number 9E7546 should be submitted to remove the word combined and cite the appropriate CAS name for novaluron:Novaluron Human - Health Risk Assessment DP#: 363988

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Page 26 of 30 “ Tolerances are established for residues of the insectici de 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 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 recommended tolerances and commodity

definitions presented in Table 4.1 . Notes to RD: The c urrently established tomato tolerance and the time - limited tolerance for strawberry

should be removed from 40 CFR §180.598. Additionally , the pending tolerance for bushberry subgroup 13 - 07B (7.0 ppm) should be amended to “bushberry subgroup 13 - 07B, except lowbush blueberry .” 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 (11/18/09); G. Kramer ( 04 / 12 /09); D. Vogel ( 04 / 12 /09 ) J. Van Alstine: S - 10954: Potomac Yard 1 (PY1): (703)603 - 8866: 7509P: RAB1Novaluron Human - Health Risk Assessment DP#: 363988

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Page 27 of 30 Appendix A: TOXICOLOGY ASSESSMENT A.1 . Acute Toxicity Profile Table A.1. Acute Toxicity of Novaluron . Guideline No. Study Type MRID #(s) Re sults 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 Inhalation (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) ;

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 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 males based on increased occurrence of extramedullary hematopoiesis and hemos iderosis 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 T oxicity - 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= not established . 870.3700 Prenatal Developmental in rodents - Rat 45082602 (1997 );

0, 250, 500, 1000 mg/kg/day Acceptable/Guideline Maternal NOAEL: > 1000; LOAEL: not established . Developmental NOAEL: > 1000; 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; LOAEL: not established. Developmental NOAEL: > 1000; LOAEL: not established .Novaluron Human - Health Risk Assessment DP#: 363988

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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 sple en 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 = 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 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 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/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, 250 0, 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 induce a genotoxic respons e 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 o f mutant colonies over background .

870.5375 44961015 (1992) ; Novaluron produced no evidence of clastogenicNovaluron Human - Health Risk Assessment DP#: 363988

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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 In vitro mammalian chromosome aberration test 40, 200, and 1000 μg/mL, with and

without metabolic activation (±S9) Acceptable/Guideline activity i n 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 incre ase 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 . 8 70.5550 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 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 b ased 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, 174, 1752 mg/kg/day 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 nova luron (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 conce ntration occurred at 2 - 5 hours. Urinary metabolite profiles rev ealed 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 radioac tivity. 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 prevalent contributor in the feces. The fecal metabolite profile revealed two metabolites; 3 - chl oro - 4 - (1,1,2 - trifluoro - 2 - trifluoromethoxyethoxy)aniline,Novaluron Human - Health Risk Assessment DP#: 363988

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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 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 radioactivity in excreta, cage wash, untreated skin, fat, blood, and residual carcass) ranged from about 0.5% to 10% of that administered.