Page 1 of 41 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION** 

**MEMORANDUM Date:**  18 - JUN - 2015 **SUBJECT: Novaluron:**  Human Health Risk Assessment for the Petition for the

Establishment of Permanent Tolerances for Residues of Novaluron in/on Avocado; Carrot; Succulent Bean; Vegetable, Fruiting, Crop Group 8 - 10; Fruit, Pome, Crop Group 11 - 10; Cherry Subgroup 12 - 12A; Peach Subgroup 12 - 12B; and Plum Subgroup 12 - 12C; and Revisions to the Label to Include Uses on Greenhouse - Grown Cucumber . **PC Code:** 124002 **DP Barcode:** D426068 **Decision No.:** 487502 **Registration No. :**  66222 - 35 **Petition No.:** 4E8241 **Regulatory Action:** Section 3 **Risk Assessment Type:** Single Chemical/Aggregate **Case No.:** 7615 **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

Anwar Y. Dunbar, Ph.D., Pharmacologist Lata Venkateshwara, Environmental Scientist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED; 7509P) **THROUGH:** Charles W. Smith III , Branch Chief

George F. Kramer, Ph.D., Branch Senior Chemist RAB1/HED (7509P) **TO:** Barbara Madden (RM 05)/Laura Nollen/Sidney Jackson 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 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 w as provided b y Julie Van Alstine (RAB1), the occupational and residential exposure assessments were provided by L ata Venkateshwara (RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), the drinking water assessment wasNovaluron Human - Health Risk Assessment DP No. 426068

Page 2 of 41 provided b y He Zhong of the Environmental Fate and Effects Division (EFED ), and the dietary assessment was provided by Richard Duncan of the Department of Pesticide Regulation at the California Environmental Protection Agency . The most recent human h ealth risk assessment was conducted in conjunction with a request for the use of novaluron to c ontrol pests on f urniture, in animal quarters, carpets, kennels, livestock and poultry

h ouses, f ood and n on - f

ood w arehouses, in f

ood - h andling e stablishments, around perimeters, and l awns (Memo, J. Van Alstine, et al. , 05 - FEB - 2014; D409210 ).Novaluron Human - Health Risk Assessment DP No. 426068

Page 3 of 41 **Table of Contents** 1.0 Executive Summary ................................ ................................ ................................ ............. 5 2.0 HED Recommendations ................................ ................................ ................................ ....... 7 2.1 Data Deficiencies ................................ ................................ ................................ ............. 7 2.2 Tolerance Considerations ................................ ................................ ................................ . 7 2.2.1 Enforcement Anal ytical Method ................................ ................................ .................. 7 2.2.2 Recommended Tolerances ................................ ................................ ............................ 8 2.2.3 Revisions to Petitioned - For Tolerances ................................ ................................ ........ 9 2.2.4 International Harmonization ................................ ................................ ......................... 9 2.3 Label Recommendations ................................ ................................ ................................ 10 3.0 Introduction ................................ ................................ ................................ ........................ 10 3.1 Chemical Identity ................................ ................................ ................................ ........... 10 3.2 Phys ical/Chemical Characteristics ................................ ................................ ................. 10 3.3 Pesticide Use Pattern ................................ ................................ ................................ ...... 11 3.4 Anticipated Exposure Pathways ................................ ................................ ..................... 12 3.5 Consideration of Environmental Justice ................................ ................................ ........ 12 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................ 13 4.1 Toxicology

Studies Available for Analy sis ................................ ................................ ... 13 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ................................ .... 13 4.3 Toxicological Effects ................................ ................................ ................................ ..... 13 4.4 Safety

Factor for Infants and Children (FQPA Safety Factor) ................................ ....... 14 4.4.1 Completeness of the Toxicology Database ................................ ................................ 14 4.4.2 Evidence of Neurotoxicity ................................ ................................ .......................... 14 4.4.3 Evidence of Sensitivity /Susceptibility in the Developing or Young Animal ............. 14 4.4.4 Residual Uncertainty in the Exposure Database ................................ ......................... 15 4.5 Toxicity

Endpoint and Point of Departure Selections ................................ .................... 15 4.5.1 Dose - Response Assessment ................................ ................................ ....................... 15 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........... 16 4.5.3 Cancer Classification and Risk Assessment Recommendation ................................ .. 16 4.5.4 Summary

of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment ................................ ................................ ................................ ................................ 16 5.0 Dietary

Exposure and Risk Assessment ................................ ................................ ............ 18 5.1 Residues of Concern Summary and Rationale ................................ ............................... 18 5.2 Food Residue Profile ................................ ................................ ................................ ...... 19 5.3 Water Residue Profile ................................ ................................ ................................ .... 20 5.4 Dietary

Risk Assessment ................................ ................................ ................................ 21 5.4.1 Description of Residue Data Used in Dietary Assessment ................................ ......... 21 5.4.2 Percent Crop Treated Used in Dietary Assessment ................................ .................... 22 5.4.3 Acute Dietary

Risk Assessment ................................ ................................ ................. 22 5.4.4 Chronic Dietary

Risk Assessment ................................ ................................ .............. 22 5.4.5 Cancer Dietary

Risk Assessment ................................ ................................ ................ 22 5.4.6 Summary

Table ................................ ................................ ................................ ........... 22 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ .... 23 6.1 Residential Handler Exposure and Post - Application Exposure ................................ ..... 23 6.2 Combined Residential Risk Estimates ................................ ................................ ........... 24 6.3 Residential Risk Estimates for Use in Aggregate Assessment ................................ ...... 2 4 6.4 Spray

Drift ................................ ................................ ................................ ...................... 27 6.5 Residential Bystander Post - Application Inhalation Exposure ................................ ....... 27Novaluron Human - Health Risk Assessment DP No. 426068

Page 4 of 41 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ ....... 27 7.1 Short - Term Aggregate Risk ................................ ................................ ........................... 28 7.2 Intermediate - and Long - Term Aggregate Risk ................................ .............................. 28 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ..... 29 9.0 Occupational Exposure/Risk Characterization ................................ ................................ .. 29 9.1 Short - /Intermediate - Term Handler Risk ................................ ................................ ........ 29 9.2 Short - /Intermediate - Term Post - Application Risk ................................ .......................... 33 9.2.1 Inhalation Post - application Risk ................................ ................................ ................. 33 9.2.2 Dermal Post - application Risk ................................ ................................ ..................... 33 10.0 References ................................ ................................ ................................ .......................... 34 Appendix A. Toxicology Profile and Executive Summaries ................................ ....................... 36 A.1 Toxicology

Data Requirements ................................ ................................ ...................... 36 A.2 Toxicity

Profiles ................................ ................................ ................................ ............. 37 Appendix B. Phy sical/Chemical Properties ................................ ................................ ................. 41 Appendix C. Review of Human Research ................................ ................................ ................... 41Novaluron Human - Health Risk Assessment DP No. 426068

Page 5 of 41 **1.0 Executive Summary**  **Background:** Novaluron, a benzoylphenylurea compound, is a pesticide chemical belonging to the class of insecticides called insect - growth regulators (IGRs). Tolerances for residues of novaluron are established under 40 CFR §180.598 in/on a wide variety of crops at levels ranging from 0.01 to 50 ppm. Tolerances for residues of novaluron are also established in/on the following livestock commodities: eggs, milk, milk fat, and the meat, fat, kidney , liver, and meat by products (except kidney

and liver) of cattle, goat , horse, sheep, poultry , and hog. Additionally , novaluron is registered for use in food and feed handling establishments, and a tolerance of 0.01 ppm has been established for residues of novaluron in/on food and feed commodities other than those covered b y a higher tolerance as a result of use on growing crops. The Interregional Research Project No. 4 (IR - 4) has submitted a Section 3 request for the proposed new use s of novaluron on avocado and carrot, to expand the use pattern for succulent beans , to update crop group commodity definition s for f

ruiting v egetable group 8 - 10, p ome f ruit group 11 - 10, c herry s ubgroup 12 - 12A, p each s ubgroup 12 - 12B, and p lum s ubgroup 12 - 12C , and to add greenhouse - grown cucumbers to the label. The end - use product associated with these registration requests is Rimon ® 0.83EC Insecticide (EPA Reg. No. 66222 - 35) which contains 9.3% ai b y weight [equivalent to 0.83 pound (lb) ai/gallon (gal)]. A tolerance may now be established for residues of novaluron in/on bean, succulent based on the newly submitted lima bean field trial data and the previousl y submitted succulent snap bean field trial data. Since the proposed application scenario s for the updated croup group commodity definitions of f

ruiting v egetable group 8 - 10, p ome f ruit group 11 - 10, cherry s ubgroup 12 - 12A, p each s ubgroup 12 - 12B, and p lum s ubgroup 12 - 12C are identical or lower than the rates previously reviewed, no residue data were subm itted for these commodities and none are required. A tolerance has already been established for residues of novaluron in/on cucurbit vegetable group 9 ; however, use of novaluron on greenhouse - grown cucumbers was prohibited. The petitioner has provided fi eld trial data for greenhouse - grown cucumbers to expand the use pattern to include greenhouse grown cucumbers. **Hazard Assessment:** Insubchronic and chronic toxicity studies, novaluron primarily produced hematotoxic effects (toxicity to blood) such as m ethemoglobinemia, decreased hemoglobin, decreased hematocrit, and decreased red blood corpuscles (RBCs or ery throcy tes) that were associated with compensatory ery thropoiesis. No maternal and/or developmental toxicity was observed in animals in either the rat or the 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, n o signs of neurotoxicity

or neuropathology

were observed following repeated dosing in the subchronic neurotoxicity

study in rats at similar doses and there was no evidence of neuropathology observed in subchronic and chronic toxicity studies in rats, mice, or dogs. 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 . Potential signs of immunotoxicity

occurred at twice the limit dose and consisted only of a decreased anti - sheep red blood cell (SRBC) response in female rats. There was no evidence of either carcinogenic orNovaluron Human - Health Risk Assessment DP No. 426068

Page 6 of 41 genotoxic potential and novaluron has been classified as “not likely to be carcinogenic to humans” based on the lack of evidence for carcinogenicity in mice and rats. Consistent with previous risk assessments for novaluron , the novaluron risk assessment team recommends that the 10X Food Quality Protection Act Safety Factor (FQPA SF) be reduced to 1X for all exposure scenarios, as discussed in Section 4.4. **Food Residue Profile:** The nature of the residue in plants and livestock is adequatel y understood. The Organizatio n for Economic Co - operation and Development (OECD) tolerance calculation procedures and the submitted residue data sets were used to calculate the HED recommended tolerance s . There is an adequate residue anal ytical method for the purposes of tolerance enforcement. The submitted field trial residue data are adequate, and provided that the data deficiencies identified in Section 2.1 are addressed, there are no residue chemist ry issues that would preclude establishing permanent tolerances for residues of novaluron in the raw agricultural commodities (RACs) outlined in Table 2.2.2. The U.S., Canadian, and Codex residue definitions are harmonized. HED has considered harmonizati on in the tolerance recommendations that are presented in Table 2.2.2. **Exposure/Risk Assessment Characterization :**  An acute dietary assessment was not conducted for novaluron because an endpoint of concern attributable to a single dose was not identified. A chronic risk assessment was conducted for dietary (food and drinking water) exposure based on the existing and proposed uses. The chronic assessment directly incorporated drinking water estimates provided b y EFED . Assumptions for the chronic dietary assessment included average field trial residues for the majority of commodities, anticipated residues (ARs) for meat, milk, hog, and poultry

commodities, average percent crop treated (PCT) data for apples, blueberries, cabbage, cauliflower, cotton, dry be ans, pears, peppers, potatoes, strawberries, and tomatoes , and percent crop treated for new use (PCTn) data for the recently registered grain sorghum and sweet corn uses. For the remaining food commodities, 100% P CT was assumed. The registered food handl ing use was also incorporated into the dietary assessment. Empirical processing factors for apple juice (translated to pear and stone fruit juice), cottonseed oil, dried plums, and tomato paste and purée, and DEEM (ver. 7.81) default processing factors fo r the remaining processed commodities were also used. All exposure and risk estimates were not of concern. A cancer dietary assessment was not conducted because novaluron is classified as “not likely to be carcinogenic to humans.” The currently registered residential uses ( indoor spot/crack and crevice, outdoor perimeter, pet spot - on, etc. ) are expected to result in dermal and inhalation exposures for adults (handlers and post - application) and post - application dermal, incidental oral , and inhalation exposures for children (1 to <2 ye ars old). The dermal route of exposure was not quantitatively assessed because a dermal endpoint was not selected for any exposure duration. These registered uses were previousl y updated in the February 2014 risk assessment to reflect use of the 2012 Residential Standard Operating Procedures (SOPs) . A ll residential handler (adult) and post application ( adult and children) scenarios resulted in margins of exposure (MOEs) greater than 100 and are not of concern to H ED. For the proposed and registered uses, human health aggregate risk assessments have been conducted for short - and intermediate - /long - term aggregate exposure (food + drinking water + residential) scenarios. An acute aggregate assessment was not conducted for novaluron because an endpoint of concern attributable to a single dose was not identified. A cancer aggregate riskNovaluron Human - Health Risk Assessment DP No. 426068

Page 7 of 41 assessment was not performed because novaluron was classified as “not likely to be carcinogenic to humans.” All potential exposure pathway s were assessed in the aggregate risk assessment as a conservative, health -protective measure. No aggregate risk estimates exceed HED’s level of concern (LOC) for the scenarios listed above. Based on the proposed uses, occupational exposures to novaluron are expected for short - and intermediate - term durations during mixing, l oading, appl ying, and other handling activities . S hort - and intermediate - term inhalation risks do not exceed HED’s LOC (i.e., all MOEs were greater than 100 for short - and intermediate - term exposures) at baseline personal - protective equipment (PPE). A quantitative occupational post - application inhalation exposure assessment was not performed . Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that the handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. The dermal route of exposure was no t quantitatively assessed for handler and post - application exposure because a dermal endpoint was not selected for any exposure duration. This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. Please refer to Appendix C for a discussion of the human study data used in this risk assessment. **2.0 HE**  **D Recommendations** Pending resolution of the de ficiencies outlined in Section 2.1 , there are no other residue chemistry , residential, occupational, or toxicology data deficiencies that would preclude granting a registration for the requested uses of Rimon ® 0. 83EC Insecticide and the establishment of permanent tolerances under 40 CFR §180.598 (a) as outlined in Table 2.2.2. **2.1 Data Deficiencies**  860.1650 Submittal of Analy tical Reference Standards An anal ytical standard for novaluron is currently available in the National Pesticide Standards Repository

(personal communication with Theresa Cole, 29 - JAN - 2015 ); h owever, the standard expire d on 07 - MAR - 2015. A new reference standard should be sent to the Analy tical Chemistry Lab, which is located at Fo rt Meade, to the attention of either Theresa Cole or Thuy Nygen at the following address: USEPA National Pesticide Standards Repository /Anal ytical Chemistry

Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755 - 5350 (Note that the mail will be returned if the extended zip code is not used.) **2. 2**  **Tolerance Considerations 2.2.1**  **Enforcement Analytical Method**Novaluron Human - Health Risk Assessment DP No. 426068

Page 8 of 41 Makhteshim - Agan of North America (MANA) previously submitted under PP#2F6430 a gas chromatography/ electron - capture detection (GC/ECD) residue anal ytical method for the anal ys is of residues of novaluron in/on pome fruit, cabbage, and potato commodities. A second method, high - performance liquid chromatography /ultraviolet (HPL C/UV), was also submitted for the anal ys is of novaluron residues only in/on cotton commodities. Successful independent laboratory

validations (ILVs) of the GC/ECD and HPL C/UV methods have been completed with apples and undelinted cottonseed, respectivel y. Acceptable radiovalidation data have been submitted and reviewed in D325183 for the GC/ECD method. An interference study was requested and a specific single - anal yt e confirmatory metho d was submitted, reviewed, and considered acceptable (Memo, J. Langsdale, 21 - OCT - 2008; D355574). The Anal ytical Chemistry Branch (ACB) of the Biological and Economics Analysis Division (BEAD) 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 and cotton. The ACB recommended that the anal ytical methods do not need to be laboratory validated by

EPA (Memo, S. L evy , 15 - SEP - 2004; D 306998). Both methods have been forwarded to the FDA for inclusion in the Pesticide Analy tical Method Volume II (PAM II) as a Letter Method (Letter, S. L evy to the FDA, 15 - SEP - 2004; D307595). **2.2.2 Recommended Tolerances**  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 in Table 2.2.2 . Compliance with the tolerance levels specified b elow is to be determined by measuring only

novaluron (

N - [[[3 - chloro - 4 - [1,1,2 - trifluoro - 2 - (trifluoromethox y)ethox y]phenyl]amino]c arbonyl ] - 2,6 - difluorobenzamide). A revised Section F is required for PP# 4E8241 which cites the appropriate CAS name for novaluron (

N - [[[3 - chloro - 4 - [1,1,2 - trifluoro - 2 - (trifluoromethoxy)ethox y] phenyl]amino]carbonyl] - 2,6 - difluorobenzamide ) and reflects the recommended tolerances and commodity definitions presented in Table 2.2.2 . **Table 2.2.2**  **. Tolerance Summary for Novaluron.**  Commodity Proposed Tolerance (ppm) HED - Recommended

Tolerance (ppm) Comments;

Correct Commodity Definition Avocado 0.60 0.60 Carrot 0.05 0.05 Bean 0.60 0 .7 0 Harmonize with Codex MRL Bean, succulent1 Vegetable, fruiting, group 8 - 10 2 1.0 1.0 Fruit, pome, group 11 - 10 3 2.0 3 .0 Harmonize with Codex MRL Cherry subgroup 12 - 12A4 8.0 8.0 Peach subgroup 12 - 12B 5 1.9 1.9 Plum subgroup 12 - 12C 5 1.9 1.9 Vegetable, cucurbit, group 9 -- 0.20 Harmonize with Codex MRL Plum, prune, dried -- 3.0 Harmonize with Codex MRL 1 This tolerance will replace the existing tolerance of 0. 60 ppm on bean, succulent, snap . The dry bean tolerance will not be impacted.Novaluron Human - Health Risk Assessment DP No. 426068

Page 9 of 41 2 This tolerance wi ll replace the existing tolerances of 1.0 ppm on v egetable, fruiting, group 8, and also cocona, African eggplant, pea eggplant, scarlet eggplant, goji berry, garden huckleberry, martynia, naranjilla, okra, roselle, sunberry, bush tomato, currant tomato, and tree tomato. 3 This tolerance wi ll replace the existing tolerance of 2.0 ppm on f ruit, pome, group 11. 4 This tolerance wi ll replace the existing tolerance of 8.0 ppm on c herry. 5 These tolerance s will replace the existing tolerance of 1.9 ppm on f ruit, stone, group 12, except cherry. **2.2.3 Revisio**  **ns to Petitioned -**  **For Tolerances** The OECD calculator and available data support a tolerance of 0 . 7 0 ppm for residues of novaluron in/on lima beans. A tolerance is currently established for residues of novaluron in/on b ean, snap, succulent at 0.6 0 ppm and the petitioner has requested a crop group tolerance for “beans.” Based on the available data, a tolerance should be established for residues of novaluron in bean, succulent and HED is recommending for a tolerance value of 0.7 0 ppm in order to har monize with the established Codex tolerance of 0.7 ppm for residues of novaluron in common beans (pods and/or immature seeds). This recommendation will not impact the tolerance established for residues in/on dry beans. No new pome fruit crop field trial data were submitted. The petitioner has requested that the existing tolerance be expanded to fruit, pome, group 11 - 10 . HED recommends that the U.S. tolerance be increased from 2.0 to 3.0 ppm in order to harmonize with Codex. The OECD tolerance calculator and the submitted greenhouse - grown cucumber data support a tolerance of 0.15 ppm for residues of novaluron in greenhouse - grown cucumbers , which is the same as the established tolerance for residues of novaluron in/on v egetable, cucurbit, group 9 . Co dex has established a tolerance for residues of novaluron in fruiting vegetable cucurbits at 0.2 ppm ; therefore, HED is recommending that the U.S. tolerance for v egetable, cucurbit, group 9 be revised to 0.20 ppm in order to harmonize with Codex. The following tolerance s for residues of novaluron in/on stone fruit have been established : cherry at 8.0 ppm ; f

ruit, stone, group 12, except cherry at 1.9 ppm; and p lum, prune, dried at 2.6 ppm [40 CFR §180.598 (a)] . No new plum field trial data were submitted. The petitioner has requested that the existing tolerance s for residues of novaluron in/on stone fruit be expanded to c herry subgroup 12 - 12A, p each subgroup 12 - 12B, and p lum subgroup 12 - 12C . The stone fruit tolerance level s are harmonized with Canada (8.0 ppm for cherry , 1.9 ppm for f ruit, stone, group 12, except cherry , and 2.6 ppm for p lum, prune, dried); however , they are not harmonized with Codex (7 ppm for stone fruit and 3 ppm for prunes). HED recommends for harmonization of the p lum, prune, dri ed tolerance level with Codex (3.0 ppm). **2.2. 4**  **International Harmonization** No Canadian, Codex, or Mexican MRL s have been established for residues of novaluron in/on avocado and carrot. Codex has established the following MRL s for residues of novaluron: 0.7 ppm common bean (pods and/or immature seeds) ; 0.7 ppm on fruiting vegetables other than cucurbits ; 3 ppm in pome fruit; 3 ppm in prunes; 7 ppm in stone fruits; and 0.2 ppm in fruiting vegetables cucurbits . Canada has established the follow ing MRL s for residues of novaluron: 0.6 ppm in edible -podded snap beans ; 0.8 ppm in bell peppers; 0.9 ppm in non - bell peppers; 2 ppm in apples, Asian pears, crabapples, loquats, may haws, pears, and quinces ; 2.6 ppm in plum, prune, dried ; 8 ppm in sweet an d tart cherries; and 1.9 ppm in apricots, fresh prune plums,Novaluron Human - Health Risk Assessment DP No. 426068

Page 10 of 41 nectarines, peaches, plumcots, and plums. HED is recommending to harmonize tolerance/MRL levels with Codex for the following commodities and crop groups: bean, succulent (0.70 ppm) ; v egetable, cucurbit, group 9 (0.20 ppm); f ruit, pome, group 11 - 10 (3.0 ppm); and plum, prune, dried (3.0 ppm). HED does not recommend to lower the tolerance level for residues of novaluron in vegetable, fruiting, group 8 - 10 to harmonize with Codex and Canada since the current U .S. tolerance is based on greenhouse - grown tomato data that support a tolerance value of 1.0 ppm ( Memo, G. Kramer , 07 - FEB - 2008; D340137 ) . **2.3 Label Recommendations**  A revised Section B is requested which:  Updates the pear application - rate information so that the maximum seasonal application rate and maximum numbers of applications are concordant. The proposed label implies that up to two 32 - ounce applications may be made per season, which would result in a maximum seasonal rate of 64 ounces (~0.4 lb ai/A/season) ; however , the label specificall y indicates that the maximum seasonal application rate is 96 ounces (~0.6 lb ai/A/season; equivalent to 3 applications) . The field trial data support a maximum seasonal application rate of 0.97 lb ai/A.  Indicates that the produ ct may be used on “beans, succulent” and “beans, dry” instead of the proposed “beans.” **3.0 Introduction**  **3.1 Chemical Identity**  **Table 3.1. Novaluron N om**  **enclature.**

Chemical structure

Common name Novaluron IUPAC name 1 - [3 - chloro - 4 - (1,1,2 - trifluoro - 2 - trifluoromethoxyethoxy)phenyl] - 3 - [2,6 - difluorobenzoyl]urea CAS name N - [[[3 - chloro - 4 - [1,1,2 - trifluoro - 2 - (trifluoromethoxy)ethoxy]phenyl]amino]carbonyl] - 2,6 - difluorobenzamide CAS registry number 116714 - 46 - 6 End - use product (EP) Rimon ® 0.83EC Insecticide (EPA Reg. No. 66222 - 35) **3.2 Physical/Chemical Characteristics**  Novaluron acts as an insecticide mainly by ingestion, but has some contact activity . It has a low vapor pressure (1.2 x 10 - 7 mm Hg) and appears to be immobile in soils according to the McCall classification (McCall et al. , 1980). A table of the phy sicochemical properties can be found in Appendix B. O N H N H O F

F Cl O O C F 3 F F FNovaluron Human - Health Risk Assessment DP No. 426068

Page 11 of 41 **3.3 Pesticide Use Pattern**  IR - 4 has submitted a draft label for Rimon ® 0.8 3EC Insecticide (EPA Reg. No. 66222 - 35 ) to include the proposed new uses and updated crop groupings. The proposed label requires applicators and other handlers to wear a long - sleeve d shirt, long pants, protective eyewear, chemical - resistant gloves, and sh oes plus socks. There are no proposed application rate changes for cucurbits, fruiting vegetables, pome fruit, and stone fruit. The pear maximum seasonal application rate on the proposed label is lower than the maximum seasonal application rate that was assessed to establish the tolerance for residues of novaluron in pome fruit. A revised Section B is required, as discussed in Section 2.3 . **Table 3.3**  **. Summ**  **ary of Directions for Proposed**  **Use of Novaluron. Applic.**  **Timing, Type, and**  **Equip. †**  **Form ulation** 

**[EPA Reg. No.]**  **Max Applic.** 

**Rate (lb ai/A)**  **Max. No.**

**Applic. per**  **Season Max.** 

**Seasonal Applic. Rate**  **(lb ai/A) 1**  **PHI**

**(days) Use Directions and** 

**Limitations Proposed Uses**  **Avocado** Aerial, Airblast Emulsifiable

Concentrate [66222 - 35] 0.125 3 (at max. single appl. rate) 0.375 1 Use a minimum spray volume of 100 GPA RTI: 14 days **Carrot** Aerial, Ground Emulsifiable

Concentrate [66222 - 35] 0.080 3 (at max. single appl. rate) 0.2 40 3 Use a minimum spray volume of 20 GPA RTI: 7 days **Greenhouse Cucumbers** Ground, or Handheld spray equipment Emulsifiable

Concentrate [66222 - 35] 0.059

– 0.078

Or 0.0008 lb ai/gal 3 (at max.

single appl. rate) 0.234 1 The use of novaluron on crops grown for food in greenhouses, except tomatoes and cucumbers, is prohibited. To mato RTI: 7 days Cucumber RTI: 14 days. **Proposed Crop Group Expansion (Same Application Scenario that is Currently Registered) Bean**  **, Succulent**  **2** Aerial, Ground Emulsifiable

Concentrate [66222 - 35] 0.039 - 0.078 3 (at max. single appl. rate) 0.234 1 RTI: 7 days **Proposed Crop Group Commodity**  **Updates (Sam**  **e Application Scenarios that are Currently Registered) Pears (Group 11**  **- 10 pear;**  **Asian pear)** Aerial, Ground Emulsifiable

Concentrate [66222 - 35] 0.13

– 0.21 2 or 3 (at max. single appl. rate) 0.42 or 0.63 3 14 For use only in Colorado, Michigan, New York, Pennsylvania, Washington and Oregon. Not registered in California RTI: 10 days **Fruit, Pome, Group 11 -**  **10 Except Pears (Apple; azarole; crabapple; loquat; mayhaw; medlar; quince; Chinese quince; Japanese quince; tejocote; cultivars, varieties, and/or hybrids of these )**  Aerial, Ground Emulsifiable

Concentrate [66222 - 35] 0.097

– 0.32 3 (at max. single appl. rate) 0.97 14 Not registered in California. RTI: 10 days **Stone Fruit (capulin; black cherry; Nanking cherry; sweet cherry; tart cherry; cultivars, varieties, and/or hybrids of these;**  **nectarine; peach; cultivars, varieties, and/or hybrids of these: apricot; Japanese apricot; Chinese jujube; plum;**  **Am erican plum; beach plum; Canada plum; cherry plum; Chickasaw plum; Damson plum; Japanese plum; Klamath** 

**plum; prune plum; plumcot; sloe; cultivars, varieties, and/or hybrids of these)** Aerial, Ground Emulsifiable

Concentrate [66222 - 35] 0.129

– 0.32 3 (at max. single appl. rate) 1 0.97 8 Not registered in California. RTI: 7 daysNovaluron Human - Health Risk Assessment DP No. 426068

Page 12 of 41 **Table 3.3**  **. Summ**  **ary of Directions for Proposed**  **Use of Novaluron. Applic.**  **Timing, Type, and**  **Equip. †**  **Form ulation** 

**[EPA Reg. No.]**  **Max Applic.** 

**Rate (lb ai/A)**  **Max. No.**

**Applic. per**  **Season Max.** 

**Seasonal Applic. Rate**  **(lb ai/A) 1**  **PHI**

**(days) Use Directions and** 

**Limitations Vegetable,**  **F ruiting,**  **G roup 8**  **- 10 [tomatoes (including bush, currant, and tree tomatoes), peppers, eggplants**  **(including African, pea, and scarlet eggplants), tomatillo, groundcherry, pepino, okra, cocona, goji berry, garden huckleberry,**  **martynia, naranjilla, roselle, and sunberry]** Ground, or Handheld spray equipment Emulsifiable

Concentrate [66222 - 35] 0.059

– 0.078

Or 0.0008 lb ai/gal 3 (at max.

single appl. rate) 0.233 1 The use of novaluron on crops grown for food in greenhouses, except tomatoes and cucumbers, is prohibited. RTI: 7 days 1 Maximum seasonal rates may not match the maximum application rate times the maximum number of applications due to rounding. 2 Novaluron is already registered for use on succulent snap beans and dry beans. Based on the submitted lima bean data, HED is recommending for a tolerance to be established in beans, succulent. T his will replace the succulent snap bean tolerance, but will not impact dry beans. The use pattern is the same as what was previously registered. 2 It is not clear from the current label whether two applications or three applications may be made per se ason. The label implies that two applications may be made; however the maximum seasonal application rate is for three applications. A revised label is required. **3.4 Anticipated Exposure Pathways**  RD has requested an assessment of human health risk to support the IR - 4 - p roposed new uses of novaluron on avocado and carrot, to expand the use pattern for succulent beans , to update croup group commodity

definitions for f

ruiting v egetable group 8 - 10, p ome f ruit group 11 - 10, cherry s ubgroup 12 - 12A, p each s ubgroup 12 - 12B, and p lum s ubgroup 12 - 12C , and to add greenhouse grown cucumbers to the label . Humans may be exposed to novaluron in food and drinking water, since novaluron may be applied directl y to growing crops and application may result in novaluron reaching surface and ground water sources of drinking water. Adults and children may be exposed to novaluron in residential settings due to the currently registered uses. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application and post - application . This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of novaluron, but also considers the existing registered uses for the dietary and residential exposure assessments. **3.5 Consideration of Environmen**  **tal Justice** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Popul ations and Low - Income Populations,” (http://epa.gov/compliance/ej/resources/policy /exec_order_12898.pdf

) . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA; 2003 - 2008) 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 basedNovaluron Human - Health Risk Assessment DP No. 426068

Page 13 of 41 on age and ethnic group. 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 currentl y 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 tradition al dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **4.1 Toxicology Studies Available for Analysis**  The hazard database for novaluron is complete and adequate for risk assessment of the proposed uses . On March 15, 2012, the Hazard and Science Policy Council (HASPOC) concluded, based on a weight - of

- evidence (WOE) approach, that a subchronic inhalation toxicity study was not required (TXR# 0052351). This approach considered all of the available hazard and exposure information for novaluron. However, this study may be necessary

to support future uses. Additionally , a guideline immunotoxicity study has been submitted and reviewed b y the Agency (MRID 48690105). **4.2 Absorption, Distribution, Metabolism,**  **and Excretion (ADME)** Novaluron exhibited marginal oral absorption (16 - 18%), and absorption appeared to be saturated for the high dose. Peak plasma concentrations occurred at 2 - 5 hours. The most prevalent urinary metabolite was 2, 6 - difluorobenzoic acid . Other components individually represented no more than 5.9% of the dose and most represented considerabl y less than 1%. Quantitatively , fecal metabolites accounted for <2% of the dose. In the repeated - dose group, some tissues such as fat contained mea surable radioactivity at 168 hours post dose, but did not appear to suggest significant potential for bioaccumulation or sequestration at the doses tested. Biliary contribution for fecal excretion appears to be insignificant. Excretion was relatively rap id and was complete within 48 hours primarily via the feces and to a lesser extent via urine in rat. **4.3 Toxicological Effects**  In subchronic and chronic toxicity studies, novaluron’s primary and most sensitive effects were on the hematopoietic s ys tem. These effects do not appear to worsen with time, and included methemoglobinemia, decreased hemoglobin, decreased hematocrit, decreased RBCs (or erythrocy tes), and increased reticulocy te counts that were associated with compensatory erythropoiesis. Increase d spleen weights and/or hemosiderosis in the spleen were considered to be due to enhanced removal of damaged ery throcy tes and not to a direct immunotoxic effect (at doses ≥27 mg/kg/day) . There was no maternal or developmental toxicity seen in the rat an d rabbit developmental toxicity studies up to the limit doses (1000 mg/kg/day) . In the two - generation reproductive toxicity study in rats, both parental and offspring toxicity (increased spleen weights) were observed at the same dose (74.2 mg/kg/day) . Reproductive toxicity (decreases in epididy

mal sperm counts and increased age at preputial separation in the F 1 generation) was observed at aNovaluron Human - Health Risk Assessment DP No. 426068

Page 14 of 41 higher dose than the increased spleen weights and were consistent with the primary effects in the database. Clini cal signs of neurotoxicity (piloerection, irregular breathing), changes in FOB parameters (increased head swaying, abnormal gait), and neuropathology (sciatic and tibial nerve degeneration) were seen in the rat acute neurotoxicity study at the limit dose ( 2000 mg/kg/day) . However, no signs of neurotoxicity or neuropathology

were observed in the subchronic neurotoxicity

study in rats at similar doses or in any other subchronic or chronic toxicity study in rats, mice, or dogs. In the submitted immunotoxicity study , the onl y sign of potential immunotoxicity for novaluron was a decreased anti - SRBC response at twice the limit dose in female rats. Novaluron was categorized as having low acute toxicity via the oral (Toxicity

Categ ory 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 and no adverse effects were observed in th e 28 - day dermal study

in rats up to the limit dose (1000 mg/kg/day) . **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  The RAB1 risk assessment team concluded that the FQPA SF could be reduced to 1X based on the following considerations outlined in more detail in the sections below: 1) the toxicology database for novaluron is complete and adequate for risk assessment of the proposed and registered uses ; 2) novaluron is not considered neurotoxic; 3) there is no evidence of increased susceptibility to offspring ; and 4) the exposure databases are sufficient and are unlikel y to underestimate exposure. **4.4.1 Completeness of th**  **e Toxicology Database** The toxicology

database for novaluron is adequate for quantification of risk for dietary , residential, and occupational uses and FQPA SF evaluation. The following acceptable studies are available for evaluation of neurotoxicity and offspring sensitivity : developmental toxicity studies in rats and rabbits, a two - generation reproduction study in rats, and acute and subchronic neurotoxicity

studies in rats. **4.4.2 Evidence of Neurotoxicity**  Acute and subchronic neurotoxicity screenin g batteries were performed with novaluron in rats. Novaluron is not considered neurotoxic, since effects observed in the acute neurotoxicity study were observed at the limit dose only and were not reproduced at similar, repeated doses in the subchronic neurotoxicity

study . In addition, no evidence of neuropathology was observed in subchronic and chronic toxicity studies in rats, mice, or dogs. **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  There is no evidence of increas ed susceptibility in the rat or rabbit developmental toxicity studies up to the limit dose or in the two - generation reproduction study in rats.Novaluron Human - Health Risk Assessment DP No. 426068

Page 15 of 41 **4.4.4 Residual Uncertainty in the Exposure Database**  There are no residual uncertainties with regard to dietary and residential exposure assessments . The chronic dietary

food exposure assessment utilized average field trial residues , ARs for livestock commodities, average PCT and PCTn data , and empirical and default processing factors. The registered food - handl ing use was also incorporated into the dietary assessment. The dietary drinking water assessment utilized water concentration values generated by the Pesticide Root Zone Model for Ground Water (PRZM - GW). The resulting screening - level estimated drinking w ater concentrations (EDWCs) provide conservative, health - protective, high - end estimates of water concentrations that will not likely be exceeded. Although data were used to refine the dietary

exposure assessments, the assessments are not expected to underestimate dietary (food and water) exposures. The residential handler and post - application exposure assessments are based upon the 2012 Residential SOPs. The residential SOPs are based upon reasonable worst - case assumptions and are not expected to under estimate risk. These assessments of exposure are not likely to underestimate the resulting estimates of risk from exposure to novaluron. **4.5 Toxicity Endpoint and Point of Departure Selections**  **4.5.1 Dose**  **- Response Assessment**  Acute Dietary Endpoint: An acute reference dose (aRfD) for the general U.S. population, including infants and children, was not established since an endpoint of concern attributable to a single dose was not identified. In the acute neurotoxicity study , neurotoxic signs and neuropathology

were seen only

at the l owest - observed adverse - effect level (LOAEL) of 2000 mg/kg (limit dose) . The no - observed adverse - effect level (NOAEL) is 650 mg/kg. These effects are not of concern for acute dietary risk assessment based upon the magnitude o f the dose and also in relation to the most sensitive effects and target organs in novaluron’s hazard database. N o developmental toxicity was seen at the limit dose in either rat or rabbit prenatal developmental toxicity

studies. Chronic Dietary Endpoint : The chronic reference dose (cRfD) of 0.011 mg/kg/day was determined on the basis of the chronic/carcinogenicity study in rats. The LOAEL of 30.6 mg/kg/day

is based on evidence of ery throcy te damage and turnover resulting in a regenerative anemia. This study

provides the most protective point of departure (POD) in the hazard database with a NOAEL of 1.1 mg/kg/day . A total uncertainty factor (UF) of 100X (10X for interspecies extrapolation, 10X for intraspecies variability, and a 1X FQPA SF) was applied to the NOAEL of 1.1 mg/kg/day . Therefore, the chronic population - adjusted dose (cPAD) is 0.011 mg/kg/day . This study

is appropriate for the duration of exposure and is protective of the general U.S. population. Incidental Oral Endpoints f or All Duratio ns: The POD chosen for all incidental oral scenario durations is based on the NOAEL of 4.38 mg/kg/day from the 90 - day

feeding study

in rats. The LOAEL is 8.64 mg/kg/day based upon clinical chemical effects (decreased hemoglobin, hematocrit, and RBC counts) and change s in histopathology (increased hematopoiesis and hemosiderosis in spleen and liver). The LOC is 100 (10X for interspecies extrapolation and 10X for intraspecies variability and an FQPA SF of 1X). This study is protective of the offspringNovaluron Human - Health Risk Assessment DP No. 426068

Page 16 of 41 effects observed in the two - generation reproductive study and is thus protective of infants and children in residential settings. Dermal Endpoint for All Durations: No adverse dermal or s ys temic effects were observed in the 28 - day dermal study

in rats; therefore, a sh ort - term dermal endpoint was not selected. The dermal study

specifically looked for blood effects, the target for novaluron, and there were no treatment related effects up to the limit dose. Although dermal endpoints were previousl y selected for the intermediate - and long - term scenarios, the toxicity profile for novaluron does not show progression of toxicity with increased duration. Furthermore, there is no concern for susceptibility

since no effects were observed in the developmental or reproduction to xicity studies in rats or rabbits. Therefore, there is no concern for any duration of dermal exposure and a quantitative dermal assessment is not required. Inhalation Endpoints for All Durations: Similar to the incidental oral endpoint, the POD chosen f or all inhalation scenario durations is based on the NOAEL of 4.38 mg/kg/day from the 90 - day feeding study in rats. The LOAEL is 8.64 mg/kg/day based upon clinical chemical effects (decreased hemoglobin, hematocrit, and RBC counts) and changes in histopathology (increased hematopoiesis and hemosiderosis in spleen and liver). The LOC for residential and occupational exposures are for MOEs <100 (similar to the intermediate - term dermal endpoint). This study is protective of children and adults in residential settings, as well as workers in occupational settings. **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  Based upon common effects and the use of an oral 90 - day study in rats for the incidental oral and inhalation routes, these exposures can be combined for all residential scenarios for all durations. Since there are no dermal endpoints for novaluron, dermal exposures do not need to be combined with inhalation exposures for residential and occupational assessments. **4.5.3 Can**  **cer Classification and Risk Assessment Recommendation** In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July 1999), novaluron is classified as “not likely to be carcinogenic to humans” based on the lack of evidence for carcinogenicity in mice and rats (TXR# 0052361). **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment Table 4.5.4.1. Summ**  **ary of Toxicological Doses and Endpoints for Novaluron for Use in Dietary and Non**   ** Occupational** **Hum an**  **health Risk Assessments.**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/** 

**FQPA SFs RfD, PAD,** 

**LOC for Risk**  **Assessment Study and Toxicological Effects**  Ac ute Dietary (General Population, including Infants and Children) None None None An endpoint of concern attributable to a single dose was not identified. An acute RfD was not established.Novaluron Human - Health Risk Assessment DP No. 426068

Page 17 of 41 **Table 4.5.4.1. Summ ary of Toxicological Doses and Endpoints for Novaluron for Use in Dietary and Non**  **** **Occupational Hum**  **an health**  **Risk Assessments. Exposure/**  **Scenario Point of** 

**Departure Uncertainty/** 

**FQPA SFs RfD, PAD,** 

**LOC for Risk**  **Assessment Study and Toxicological Effects**  Chronic Dietary (All Populations) NOAEL =

1.1 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Chronic RfD

= 0.011 mg/kg/day cPAD = 0.011 mg/kg/day **Combined chronic**

**toxicity/carcinogenicity feeding in rat** LOAEL = 30.6 mg/kg/day based on erythrocyte damage resulting in a compensatory regenerative anemia. Incidental Oral, All Durations NOAEL =

4.38 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X 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). Dermal, All Durations A short - term de rmal endpoint was not selected since there were no adverse dermal or systemic effects observed in the 28 - day dermal study in rats and no concern for increased offspring susceptibility . Therefore, there is no concern for any duration of dermal exposure and no dermal endpoints are required. Inhalation, All Durations NOAEL =

4.38 mg/kg/day (inhalation absorption rate = 100%) UF A = 10X

UF H =10X FQPA SF = 1X 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). Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans. Point of departure = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no - observed adverse - effect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population - adjusted dose (c = chronic). RfD = reference dose. LOC = level of concern. MOE = margin of exposure. **Table 4.5.4.2. Summ ary of Toxicological Doses and Endpoints for Novaluron for Use in Occupational**  **Hum an health**  **R isk Assessments.**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/** 

**FQPA SF**  **s RfD, PAD,** 

**LOC for Risk**  **Assessment Study and Toxicological Effects**  Dermal, All Durations A short - term dermal endpoint was not selected since there were no adverse dermal or systemic effects observed in the 28 - day dermal study in rats. Therefore, there is no concern for any duration of dermal exposure and no dermal endpoints are required. Inhalation, All Durations NOAEL =

4.38 mg/kg/day (inhalation absorption rate = 100%) UF A = 10X

UF H =10X 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 l iver). Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans. Point of departure = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant humanNovaluron Human - Health Risk Assessment DP No. 426068

Page 18 of 41 exposures. NOAEL = no - observed adverse - effect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Residues of Concern Summary and Rationale**  HED previousl y co ncluded that the nature of the residue in plants is adequately understood based on acceptable metabolism studies conducted on apples, cabbage, cotton, and potatoes using [difluorophenyl - U 14 C]novaluron and [chlorophenyl - U 14 C]novaluron as the test substanc es (Memo, G. Kramer, 22 - MAR - 2004; D285474). These studies indicate that novaluron is not extensively

metabolized in these crops. The parent compound, novaluron, either was 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; D28547 4). 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). Additionally , the HED MARC 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). HED also previousl y 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; D285474). The HED MARC determined that the residue of concern in livestock for purposes of tolerance enforcement and risk assessment is novaluron only (Memo, G. Kramer et al. , 03 - FEB - 2004; D297646). The HED MARC concluded that parent and the chlorophenylurea and chloroaniline degradates are residues of potential concern to be included in the drinking water assessment. Monitoring data are not available for novaluron or its chlorophenyl urea and chloroaniline degradates in surface water or ground water. Concentrations in surface water and ground water were estimated using standard EFED drinking water models. **Table 5.1. Summ ary of**  **Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.**  **1 Matrix**  **Residues I**  **ncluded in Risk**  **Assessment Residues**  **I ncluded**  **in Tolerance Expression**  Plants Primary Crop Novaluron Novaluron

Rotational Crop Novaluron Novaluron Livestock Ruminant Novaluron Novaluron

Poultry Novaluron Novaluron Drinking Water Novaluron and chlorophenyl urea and chloroaniline degradates Not Applicable 1 Memo, G. Kramer et al. , 03 - FEB - 2004; D297646.Novaluron Human - Health Risk Assessment DP No. 426068

Page 19 of 41 **5. 2**  **Food Residue Profile** No new data were submitted to support tolerances for residues of novaluron in/on f ruiting v egetable group 8 - 10, p ome f ruit group 11 - 10, cherry s ubgroup 12 - 12A, p each s ubgroup 12 - 12B, and p lum s ubgroup 12 - 12C . The petitioner has requested that existing tol erances be expanded to their updated croup group commodity definitions . A tolerance has already been established for residues of novaluron in/on cucurbit vegetable group 9 ; however, the use of novaluron on greenhouse - grown cucumbers was excluded in the la bel. The petitioner has provided field trial data for greenhouse - grown cucumbers to expand the use pattern to include greenhouse - grown cucumbers. Field trial data were previousl y submitted and reviewed for succulent snap beans. The current petition includes field trial data for lima bean. There are adequate field trial data available to establish a tolerance for residues of novaluron in/on bean, succulent based on the available lima bean and succulent snap bean field trial data. The submitted field trial residue data for avocado, carrot, cucumber, and lima bean are adequate to support the establishment of the requested tolerances. GC/ECD method s that are similar to the enforcement method were used for data collection and the methods were adequatel y validated in conjunction with the avocado, carrot, greenhouse cucumber, and lima bean field trials. The field trial data re flect the proposed use pattern and an adequate number of trials were conducted in the appropriate geographic regions . Although onl y five independent lima bean field trials were submitted, an additional field trial is not required since HED does not expect that the submission of an additional lima bean field trial would result in a higher recommended tolerance for residues of novaluron in/on succulent beans. The remaining proposed tolerances pertain to updates to the crop group/subgroup commodity definitions. Since the proposed a pplication scenario s are identical or lower than the application scenarios previously reviewed, no residue data were submitted and none are required. Concurrent storage stability data were submitted for avocado, carrot, cucumber, and lima bean. These data demonstrate that residues of novaluron were stable for the durations that the field trial samples were frozen. HED previousl y requested storage stability data on dried plums and on grain sorghum forage, grain, aspirated grain fractions (AGF), and stov er. Acceptable dried plum and sorghum grain and forage storage stability have been submitted; therefore, these deficiencies are now resolved. There are no processed commodities associated with avocado, carrot, cucumber, and lima bean. There are processe d commodities associated with fruiting vegetables, pome fruit, and stone fruit ; however, processing studies were not required for the submission since the petitioner has requested updates to the crop group commodity definitions that are supported with prev iously submitted data, including processing studies. The field trial data for avocado, greenhouse - grown cucumber, and lima bean were entered into the OECD tolerance calculator to determine the appropriate tolerance level. The OECD tolerance calculation procedures were not used for carrot because all of the residues were less than the lowest level of method validation (LLMV; 0.05 ppm). The output from the tolerance calculator and the submitted field trial data support the HED - recommended tolerances outlined in Table 2.2.2. When possible, the recommended tolerances have been harmonized with Codex. Carrot culls are the only

livestock feed item associate d with the current petition. The incorporation of carrot culls into the reasonably balanced dietary

burdens (RBDBs) calculationsNovaluron Human - Health Risk Assessment DP No. 426068

Page 20 of 41 did not result in increased livestock dietary burdens. As a result, revised RBDBs and livestock tolerances were not required. The carrot, cucumber, and bean commodities associated with the current petitions may be rotated. Avocados, pome fruit, and stone fruit are not rotated. Based on the results of the submitted confined rotational crop study, the appropriate PBI for all non - labeled crops is 30 day s. The current and proposed labels include a restriction 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. **5. 3**  **Water Residue Profile** The residues of concern in drinking water for purposes of risk assessment are novaluron, the chlorophenylurea degradate (1 - [3 - chloro - 4 - (1,1,2 - trifluoro - 2 - trifluoromethox yethox y) phenyl]urea), and the chloroaniline degradate (3 - chloro - 4 - (1,1,2 - trifluoro - 2 - trifluoromethoxyethox y) aniline) (Memo, G. Kramer et al. , 03 - FEB - 04; D297646). The drinking water concentrations used in the dietary risk assessment were provided by EFED in the following memorandum: “Drinking Water Assessment in Support of the New Indoor and Outdoor non - food Use of Novaluron for Pest Control” ( H. Zhong , 07 - AUG - 2013; D412441) and were incorporated directly into this dietary assessment under the food categories “water, direct, all s ources” and “water, indirect, all sources.” Surface and ground water EDWCs were calculated using the Pesticide Root Zone Model/Exposure Analysis Modeling S ys tem (PRZM/EXAMS) , the Screening Concentration in Ground Water ( S CI - GROW), and Pesticide Root Zone Model for Ground Water (PRZM - GW) models . A summary of the modeled scenarios can be found in the drinking water memo (H. Zhong , 07 - AUG - 2013; D412441). EFED has indicated that revised drinking water estimates are not required based on the proposed uses ( Memo, H. Zhong, 2 - SEP - 2014; D418740 ). The EDWC values are meant to represent upper- bound estimates of the concentrations that might be found in surface water and groundwater based upon existing and proposed uses. Since the residues of concern in drinking w ater for risk assessment purposes are novaluron, the chlorophenylurea degradate, and the chloroaniline degradate, these EDWCs were calculated using a molecular weight conversion and then combined for each modeled scenario. The degradates are assumed to h ave equal toxicity to the parent. The chronic dietary exposure and risk assessment incorporated the highest total EDWC of 77.8 μg/L(0.0778 ppm) that was simulated using the PRZM - GW model with the proposed poultry operation use and WIcorn scenario (Table 5.2). **Table 5.2. Summ ary of Novaluron EDWCs from** **Ground Water Using PRZ M**  **- GW Modeling for Poultry**  **Operations. 1** 

**Crop/Scenario Highest Daily**  **Value (μg/L) Post Breakthrough** 

**Average (μg/L) Average Sim** **ulation**

**Breakthrough Time (Days)** Novaluron Wisconsin Corn - WI Central Sands Met File (14920.dvf) 2.58E - 18 Incomplete Incomplete C hlorophenyl Urea Degradate Wisconsin Corn - WI Central Sands Met File (14920.dvf) 0.00815 Incomplete Incomplete Chloroaniline Degradate Wisconsin Corn - WI Central Sands 84.2 77.8 15,661Novaluron Human - Health Risk Assessment DP No. 426068

Page 21 of 41 Met File (14920.dvf)

Total of Novaluron and Chlorophenyl Urea and Chloroaniline Degradates Wisconsin Corn - WI Central Sands Met File (14920.dvf) 84.21 77.8 15,661 1 EFED simulated ground water EDWCs using a newer PRZM - GW model for six vulnerable sites in VA, FL, GA, NC, and WI. This table summarizes the highest EDWCs for novaluron and its degradates that resulted from the proposed poultry operation uses combined with the Wisconsin Corn - WI Central Sands site. The WI site provides the highest total EDWC, and was used in the dietary exposure assessment. A value of 0 was used for novaluron and chlorophenyl urea in the total calculation since the post -breakthrough ave rages are incomplete for these EDWCs. **5. 4**  **Dietary Risk Assessment 5.**  **4 .1**  **Description of Residue Data Used in Dietary Assessment** A partially

refined chronic dietary- exposure (food plus water) and risk assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM - FCID) Version 3.16, which uses food consumption data from the USDA’s NHANES/WWEIA from 2003 through 2008 . The assessment was performed for the general U.S. population and all population subgroups. The chronic anal ys is incorporated recentl y updated average PCT and PCTn data. ARs for meat, milk, hog, and poultry commodities were calculated using average field trial residues, PCTn and PCT data, and 100 P CT for some commodities. The chronic anal ys is also incorporated average field trial residues for the majority of commodities, average greenhouse trial residues for tomatoes and cucumbers , and half - LOQ residues for food commodities other than those covered b y a higher tolerance as a res ult of use on growing crops from the registered use in food and feed handling establishments. Additionally , empirical processing factors for apple juice (translated to pear and stone fruit juice), cottonseed oil, dried plums, and tomato paste and purée, a nd DEEM (ver. 7.81) default processing factors for the remaining processed commodities, where provided were incorporated. The chronic dietary

exposure and risk assessment incorporated the highest total EDWC of 77.8 μg/L (0.0778 ppm) that was simulated using the PRZM - GW model with the proposed poultry operation use and WI corn scenario.Novaluron Human - Health Risk Assessment DP No. 426068

Page 22 of 41 **5. 4**  **.2 Percent Crop Treated Used in Dietary Assessment**  A Screening Level Usage Anal ys is (SLUA) memorandum entitled, “Usage Report Package in Support of Novaluron ( 124002), BEAN DP# 421177 ” (C. Doucoure, 30 - JUN - 2014) and a PCTn memorandum entitled, “Update of Percent Crop Treated for New Use (PCTn): Novaluron (124002) Use on Sorghum and Sweet Corn” (C. Doucoure, et al. , 01 - FEB - 2013) were provided by BEAD. The market leader approach was used by BEAD to determine the PCTn values for sorghum and sweet corn. The chronic dietary

analysis incorporated average PCT data for apples (10%), blueberries (<1%), (cabbage (5%), cauliflower (<2.5%), cotton (<2.5%), dry beans (<1 %), pears (15%), peppers (<2.5%), potatoes (<2.5%), strawberries (35%), and tomatoes (<2.5%) and average PCTn data for grain sorghum (2%) and sweet corn (36%). 100 P CT was assumed for the remaining food commodities. Livestock dietary burdens of novaluron were calculated based on the registered uses, and incorporated average field trial residues, PCTn data for grain sorghum (2%) and sweet corn (36%), average PCT data for apple (10%) and cotton (<2.5%), and an assumption of 100 P CT for sugarcane, AGF, and c owpea seed. These livestock dietary burdens were used, along with average transfer coefficients, to calculate anticipated secondary residues for meat, milk, hog, and poultry

commodities, which were incorporated into the chronic dietary assessment. **5. 4**  **. 3**  **Acute Dietary Risk Assessment** An acute dietary

assessment was not conducted for novaluron because an endpoint of concern attributable to a single dose was not identified. **5. 4**  **.4 Chronic Dietary Risk Assessment**  Chronic dietary

risk estimates (food and drinking water) are not of concern for the general population or any

other population subgroup. The assessment was partially refined and the highest exposure and risk estimates were for the population subgroup children 1 - 2 years old, which utilized 73 % of the cPAD for novaluron. The chronic exposure estimate for the gen eral U.S. population utilized 28 % of the cPAD. A summary table of dietary

exposure and risk for novaluron can be found in Section 5. 4 .6. Although further refinement to the anal ys is is n ot required at this time, future assessments could be refined using additional average field trial values, additional PCT data, cooking factors, and/or monitoring data. **5. 4**  **.5 Cancer Dietary Risk Assessment**  A cancer dietary

assessment was not conducted because novaluron is classified as “not likel y to be carcinogenic to humans.” **5. 4**  **.6 Summary Table**  **Table 5. 4**  **.6. Summary of Chronic Dietary Exposure (Food and Drinking Water) and Risk for Novaluron. 1**  **Population Subgroup Acute Dietary**  **Chronic Dietary Cancer**  **Dietary Exposure**  **(m g/kg/day)**  **% aPAD Dietary**  **Exposure (m**  **g/kg/day) % cPAD**  **Dietary Exposure**  **(m g/kg/day)**  **Risk** General U.S. Population N/A N/A 0.003071 2 8 N/A N/A All Infants (<1 year old) 0.006289 5 7Novaluron Human - Health Risk Assessment DP No. 426068

Page 23 of 41 **Table 5. 4**  **.6. Summary of Chronic Dietary Exposure (Food and Drinking Water) and Risk for Novaluron. 1**  **Population Subgroup Acute Dietary**  **Chronic Dietary Cancer**  **Dietary Exposure**  **(m g/kg/day)**  **% aPAD Dietary**  **Exposure (m**  **g/kg/day) % cPAD**  **Dietary Exposure**  **(m g/kg/day)**  **Risk Children 1**  **- 2 years old**  **0.008014 7**  **3** Children 3 - 5 years old 0.005711 5 2 Children 6 - 12 years old 0.003746 3 4 Youth 13 - 19 years old 0.002424 22 Adults 20 - 49 years old 0.002659 2 4 Adults 50 - 99 years old 0.002671 2 4 Females 13 - 49 years old 0.002640 24 1 Population with the greatest exposure is in bold. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  There are no new propose d residential uses for the current action ; however there are currentl y registered use of novaluron for indoor (spot/crack and crevice) and outdoor (perimeter) applications for the control of roaches and crickets, as well as on pets as a spot - on product for the control of fleas and ticks. Novaluron is also registered to control fleas, cockroaches, flies, mosquitoes, gnats, crickets, litter beetles and ants on furniture, animal quarters, carpets, kennels, poultry houses and lawns. The risks are presented here for the recommentadion of scenarios to be in the aggregate assessment. Details of the exposure and risk estimate are provided in a previous occupational and residentail exposure assessments (L . Venkateshwara, 05 - FEB - 2014; D412298 ). **6.1 Residential Handler Exposure**  **and Post** **- Application**  **Exposure** Table 6.1 provides a summary of the residential handler and post - application exposures and risk estimates for the currently registered uses of novaluron. All residential handler and post application scenarios resulted in MOEs greater than 100 and , therefore, are not of concern to HED. **Table 6**  **. 1**  **. Summ ary of Residential Exposure/Risk Estimates**  **for Registered Uses of Novaluron. Use**  **Exposure Scenario Dose**  **(m g/kg/day)**  **MOE Source** 

Indoor crack and crevice / spot treatment Residential

Handler Inhalation Mixing/loading/applying wettable

powders with manually pressurized handwand 0.00014 ST: 3,200

D401261 Applying ready - to - use formulations with trigger -pump

sprayer 0.0000076 ST: 570,000 Post application Inhalation Adults 0.000049 ST: 89,000 Children (1 to <2 years old) 0.00021 ST: 21,000 Post application Incidental Oral 1 Crack

and Crevice Carpet Children (1 to <2 years old) 0.00059 ST: 7,400 Hard surfaces 0.000196 ST: 22,000 Spot Carpet 0.00288 ST: 1,500

Hard surfaces 0.00096 ST: 4,600 Pet Spot - on Post application Incidental Children

(1 to <2 years old) 0.00022 ST/IT/LT: 20,000 D410803Novaluron Human - Health Risk Assessment DP No. 426068

Page 24 of 41 **Table 6**  **. 1**  **. Summ ary of Residential Exposure/Risk Estimates**  **for Registered Uses of Novaluron. Use**  **Exposure Scenario Dose**  **(m g/kg/day)**  **MOE Source**  Oral

Indoor broadcast/spot/crack and crevice treatment Residential

Handler Inhalation Mixing/Loading/Applying Liquids

with Manually- Pressurized Handwand 0.000011 410,000

D4 12298 Post application Inhalation Adults 0.0000038 1 , 100 , 000 Children (1 to <2 years old) 0.000016 270 , 000

Post application Incidental Oral 1 Broadcast Carpet Children (1 to <2 years old) 0.004 5 980 Hard Surfaces 0.001 5 2,900 Spot Carpet 0.0022 2,000

Hard Surfaces 0.000757 5,900 Crack and Crevice Carpet 0.000472 9,300

Hard Surfaces 0.000157 28,000

Liquid Application to Turf Residential

Handler Inhalation Mixing/Loading/Applying Liquids

with Hose End Sprayer 0.0000047 940,000 Mixing/Loading/Applying Liquids with Manually- Pressurized Handwand 0.00000018 24,000,000 Mixing/Loading/Applying Liquids with S prinkler C an 0.0000021 2,000,000 Mixing/Loading/Applying Liquids with B ackpack 0.0000014 3,100,000 Post application Incidental Oral ST Hand - to - Mouth 0.0005 8 , 500

ST Object - to - mouth 0.00002 280 , 000 ST/IT Soil Ingestion 1.2E - 06 3 , 800 , 000 **6.2 Combined**  **Residential Risk Estimates** Table 6 .2 provides a summary of the combined (i.e., dermal, incidental oral, and inhalation) residential exposure and risk estimates for children 1 to <2 years old for the registered indoor use of novaluron . The combined exposure estimates resulted in MOEs greater than 100 and , therefore, are not of concern to HED. **Table 6.2. Residential Combined Exposure and Risk Estim**  **ates for Registered Uses of Novaluron. Combined**  **Exposure Scenario**  **Lifestage Exposure Scenario**  **Route of**  **Exposure Dose**  **Combined Short**  **- term**  **Total Dose 1**  **Combined**

**Short -**  **term Total MOEs**  **2**

Indoor Application Scenario Child Post - application: Indoor Carpet Crack and Crevice Dermal N/A 0.0008 5,500 Inhalation 0.00021 Hand to Mouth 0.00059 Post - application: Indoor Carpet

– Spot Treatment Dermal N/A 0.0031 1,400 Inhalation 0.00021 Hand to Mouth 0.00288 Post - application

–Indoor Carpet

Broadcast Dermal N/A 0.0046 940 Inhalation 0.00016 Hand to Mouth 0.00448 1 Combined Dose = see Table 6.2 for residential exposures. 2 Combined MOE = NOAEL (mg/kg/day) / Combined Dose (mg/kg/day); where the short - term NOAEL = 4.38 mg/kg/day. **6 .3**  **Residential Risk Estimates for Use in Aggregate Assessment**Novaluron Human - Health Risk Assessment DP No. 426068

Page 25 of 41 Table 6.3 reflects the residential risk estimates that are recommended for use in the aggregate assessment for novaluron.  The recommended residential exposure for use in the short - term adult aggregate assessment reflects handler inhalation exposure from crack and crevice applications to both indoor use sites via manually- pressurized handwand (see D401261 ) .  The recommended residential exposure for use in the short - term children 1 to <2 years old aggregate assessment reflects post - application inhalation and hand - to - mo uth exposures from the registered indoor carpet broadcast applications (see D412298) .  The recommended residential exposure for use in the intermediate - and long - term children 1 to <2 ye ars old aggregate assessment reflects post - application hand - to - mouth exposures from the dog spot - on use (see D410803).Novaluron Human - Health Risk Assessment DP No. 426068

Page 26 of 41 **T able**  **6.3 . Recommendations for the Residential Exposures for the**  **Novaluron Aggregate Assessment. 1**  **Lifestage Residential Handler**  **Residential Post -**  **application**

**Dose (mg/kg/day) 2**  **MOE 3**  **Dose (mg/kg/day) 4**  **MOE 5**  **Dermal Inhalation**  **Total Dermal**  **Inhalation Total**  **Dermal Inhalation**  **Oral Total**  **Dermal Inhalation**  **Oral Total**  **Short -**  **Term** Adult NA 0.00014 0.00014 NA 3,200 **3,200** NA 0.000049 N/A 0.000049 NA 89,000 N/A 89,000 Child N/A NA 0.000 16 0.00448 0.00464 NA 270,000 980 **940 Intermediate**  **- and**  **Long -**  **Term** Child N/A N/A N/A 0.00022 0.00022 N/A N/A 20,000 **20,000** 1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed. Total = inhalation only. 3 Residential Handler MOE = the MOEs associated with the highest doses identified. Total = I nhalation MOE only. 4 Residential Post - application Dose = the highest post - application dose for each applicable lifestage of all scenarios assessed. Total = inhalation + incidental oral, where applicable. 5 Residential Post - application MOE = the MOEs associated with the highe st doses identified. Total = 1/(1/I nhalation MOE) + (1/I

ncidental oral MOE), where applicable.Novaluron Human - Health Risk Assessment DP No. 426068

Page 27 of 41 **6.4 Spray Drift**  Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularl y the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) emplo yed for novaluron **.** The A gency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call - Inissued by

EPA), EPA Regional Offices and State L ead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency ’s Spray Drift website for more information). 1 The agency has also developed a policy on how to appropriatel y consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently . The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non - occupational exposure to drift. **6.5 Residential Bystander Post**  **- Applica**  **tion Inhalation Exposure** Volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html). The A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA - HQ - OPP - 2014 - 0219). D uring Registration Review, the A gency will utilize this analysis to determine if data (i.e., flux studies, route - specific inhalation toxicological studies) or further analysis is required for novaluron . **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate pesticide expo sures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk s themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. In the case of novaluron, aggregate risk assessments were performed for short - and intermediate - /long - term a ggregate exposures (food + drinking water + residential). An acute aggregate assessment was not conducted for novaluron because an endpoint of concern attributable to a single dose was not identified. Additionally, a cancer aggregate assessment was not c onducted because novaluron was classified as “not likely to be carcinogenic to humans.” All potential exposure pathways were assessed in the aggregate risk assessment.

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmNovaluron Human - Health Risk Assessment DP No. 426068

Page 28 of 41 **7.1 Short** **- Term Aggregate Risk**  Short - term (1 - to 30 - day) aggregate risk assessments are necessary for both adults and children since there is potential for both short - term handler exposure and short - term post - application exposure from the residential uses of novaluron. For the short - term aggregate risk assessment, potential residential exposures were combined with dietary (food and drinking water) exposures. A dermal endpoint has not been selected for novaluron; therefore, the short - term adult and child aggregate risk estimates do not include dermal exposures. Specifically , the short - ter m aggregate assessment for adults combines dietary exposures with handler inhalation exposures resulting from the registered indoor crack and crevice uses. For young children, the short - term aggregate assessment combines dietary exposure with potential po st - application inhalation and incidental oral exposure (from hand- to mouth contact with treated surfaces) resulting from the registered indoor uses. See Table 6. 3 for more information on the residential risk estimates that are recommended for use in the a ggregate assessment for novaluron. The short - term residential exposure estimates were aggregated with the chronic dietary (food + drinking water) to provide a worst - case estimate of short - term aggregate risk for the U.S. population and children 1 - 2 year s old (the child population subgroup with the highest estimated chronic dietary

food + drinking water exposure). As the short - term aggregate MOEs are greater than 100, risk estimates do not exceed HED’s LOC. **Table 7.1. Short -**  **Term Aggregate Risk**  **Calculations for Novaluron. Population**  **Subgroups Short**  **- Term Scenario**  **1**

**NOAEL (m**  **g/kg/day) LOC**  **2 Max**  **Exposure 3**  **(m g/kg/day)**  **Average**

**Dietary Exposure**  **(m g/kg/day)**  **Residential**

**Exposure 4**  **(m g/kg/day)**  **Aggregate**

**MOE (dietary and**  **residential) 5**  Adult 4.38 100 0.0438 0.002671 0.00014 1 560 Children 1 - 2 years old 4.38 100 0.0438 0.008014 0.00464 350 1 A d ermal endpoint has not been selected for novaluron; therefore , dermal exposure was not included in the short - term aggregate assessment. 2 The LOC (target MOE) includes 10X for interspecies extrapolation and 10X for intraspecies variation. 3 Maximum Exposure (mg/kg/day) = NOAEL/Target MOE. 4 Residential Exposure = Handler Inhalation Exposure for Adults and Post - application Oral Exposure + Post - application Inhalation Exposure for Children. 5 Aggregate MOE = [NOAEL ÷ (Avg. Dietary Exposure + Residential Exposure)]. **7.2 Intermediate**  **- and**  **Long -**  **Term Aggregate Risk** Intermediate - term (1 - to 6 - months) and l ong - term (>6 months) aggregate risk assessments are necessary since there is the potential for intermediate - and long - term post - application exposure from the registered pet spot - on use of n ovaluron. For the intermediate - and long - term aggregate risk assessment, potential residential exposures were combined with dietary (food and drinking water) exposures. A dermal endpoint has not been selected for novaluron, and inhalation exposure is con sidered negligible for the application of spot - on products; therefore, the intermediate - and long - term aggregate risk estimates do not include dermal and inhalation exposures. For young children, the intermediate - and long - term aggregate assessment combin es dietary exposure with potential post - application incidental oral exposure (from hand- to - mouth contact with treated pets) resulting from the dog spot - on use. For adults, since there is no dermal endpoint and inhalation exposure is expected to be negligible, the average dietaryNovaluron Human - Health Risk Assessment DP No. 426068

Page 29 of 41 consumption (food + drinking water) exposure estimate is representative of intermediate - and long - term aggregate risk. See Table 6. 3 for more information on the residential risk estimates that are recommended for use in the aggreg ate assessment for novaluron. The intermediate - and long - term indoor residential exposure estimates were aggregated with the chronic dietary

(food+ drinking water) to provide a worst - case estimate of intermediate - and long - term aggregate risk for adults and children 1 - 2 years old (the child population subgroup with the highest estimated chronic dietary food + drinking water exposure). As the intermediate and long - term aggregate MOEs are greater than 100, risk estimates do not exceed HED’s LOC. **Tab le 7.2.**  **Interm ediate**  **- and**  **Long -**  **Term Aggregate Risk Calculations for Novaluron. Population**  **Subgroups Intermediate/** **Long -**  **Term Scenario s**  **1**

**NOAEL (m**  **g/kg/day) LOC**  **2 Max**  **Exposure 3**  **(m g/kg/day)**  **Average**

**Dietary Exposure**  **(m g/kg/day)**  **Residential**

**Exposure 4**  **(m g/kg/day)**  **Aggregate**

**MOE (dietary and**  **residential) 5**  Adult 4.38 100 0.0438 0.002671 N/A 1 64 0 Children 1 - 2 years old 4.38 100 0.0438 0.008014 0.00022 530 1 A dermal endpoint has not been selected for novaluron, and inhalation exposure is considered negligible for the application o f spot - on products; therefore, the intermediate - and long - term aggregate risk estimates do not include dermal and inhalation exposures. 2 The LOC (target MOE) includes 10X for interspecies extrapolation and 10X for intraspecies variation. 3 Maximum Exposure (mg/kg/day) = NOAEL/Target MOE. 4 For adults, since there is no dermal endpoint and inhalation exposure is expected to be negligible, there is no residential exposure estimate to combine with dietary exposures. For children, Residential Exposure = Incidental Oral Exposure. 5 Aggregate MOE = [NOAEL ÷ (Avg. Dietary Exposure + Residential Exposure)]. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to novaluron and any other substances and novaluron does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that novaluron has a co mmon mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’ s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk**  **Characterization** Occupational exposure assessments of the proposed uses were provided in HED memorandum dated 20 - MAR - 2015 (L. Venkateshwara; D423666 ) . **9.1 Short** **- /Intermediate**  **- Term Handler Risk**  HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target beingNovaluron Human - Health Risk Assessment DP No. 426068

Page 30 of 4 1 treated, and the level of protection used b y a handler can cause exposure levels to differ in a manner specific to each application event. Based on the anticipated use patterns and current labeling, typ es of equipment and techniques that can potentially

be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on mixing, loading , and applying l iquids via aerial, groundboom, and airblast equipment, mixing , loading, and appl ying liquids by backpack sprayer s, manually- pressurized handwand s, and mechanically- pressured handgun s, and flagging to support aerial applications . In addition, the petitioner has requested to expand the use pattern for succulent beans and to update crop groupings for fruiting vegetables (group 8 - 10), pome fruit (group 11 - 10), cherry (subgroup 12 - 12A), peach (subgroup 12 - 12B), and plum (subgroup 12 - 12C). No amendment s to the use patterns (i.e., maximum use rates, RTI s , PHI s , use of adjuvants, etc.) on the subject crops have been proposed , including the proposed expanded use on succulent beans . Since there is no difference between the occupational scenarios and the agronomics/practices already assessed for the revised crop group definitions, the additional crops are already covered by an existing risk assessment within its crop group (D364236, L. Venkateshwara, 11/5/2009). It is the policy

of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical - specific data, include the Pesticide Handlers Exposure Database (PHED 1.1), the Agricultural Handlers Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant - submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 2 , ” which, along with additional informati on on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 3

. Based on HED Science Advisory Council for Exposure (ExpoSAC) SOP No. 9.1, the amount treated in a day

was assumed to be:  80 acres for groundboom applications for typical acreage crops (carrot),  40 acres for airblast applications for orchard crops (avocado),  350 acres for aerial applications for typical acreage crops (carrot) and orchard crops (avocado),  350 acres for flagging to su pport aerial treatment,  40 gals for mixing/loading and appl ying to support backpack and manually- pressurized handwand, and  1000 gals for mixing/loading and applying to support mechanically- pressurized handgun. HED classifies exposures from 1 to 30 days as short - term and exposures and 30 day s to 6 months as intermediate - term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most commercial pest control, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one - 2 Available: http://www.epa.gov/opp00001/science/handler - exposure - table.pdf 3 Available: http://www.epa.gov/pesticides/science/handler - exposure - data.htmlNovaluron Human - Health Risk Assessment DP No. 426068

Page 31 of 41 month time frame; however, commercial applicators may appl y a product over a period of weeks. The Rimon ® 0.83EC Insecticide (EPA Reg. No. 66222 - 35) label requires applicators and other handlers to wear a long - sleeve d shirt, long pants, protective eyewear, chemical - resistant gloves, and shoes plus socks. The Agency

matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically o ver the past two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of the Global Positioning S ys tem (GPS) for swath guidance in agricultural aviation has grown steadil y from the mid - 1990s. O ver the same time period, the use of human flaggers for aerial pesticide applications has decreased steadil y from ~15% in the late 1990s to only

1% in the most recent (2012) NAAA survey . The Agency will continue to monitor all available information source s to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications. HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long - sleeve shirt, long pants, shoes, and socks); per the Agency ’s Worker Protection Standard stipulations for engineering controls, pilots are no t required to wear protective gloves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators. The dermal route of exposure was not quantitatively assessed for handler exposure because a d ermal endpoint was not selected for any exposure duration. Table 9 .1 presents the exposures/risks for short and intermediate - term inhalation exposures at baseline. The inhalation risk estimates are not of concern (i.e., MOEs >100) at all baseline scenari os. There is no respirator on the label.Novaluron Human - Health Risk Assessment DP No. 426068

Page 32 of 41 1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013 **)** ; includes data from PHED/ORETF/AHETF (level of mitigation: Baseline, PPE, Eng. Controls). 2 Based on registered or proposed label (Reg. No . # 66222 - 35). 3 Exposure Science Advisory Council Policy #9.1. 4 Inhalation Dose =I

nhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/gallon) x Amount Handled Daily (gallons/day) /BW ( 80 kg). 5 Inhalation MOE = I

nhalation NOAEL (4.38 mg/kg/day)/ I nhalation Dose (mg/kg/day). **Table 9. 1. Short**  **- and Intermediate**  **- Term** **Occupational Exposure and Risk Estim ates for Novaluron**  . **All E**  **stimates are at B**  **aseline M**  **itigation (i.e., W** **ithout R** **espirator, U**  **nless S**  **pecified).**

**Exposure Scenario Crop or**  **Target Inhalation Unit Exposure (ug/lb**  **ai) 1**  **Ma xim**  **um Application Rate**  **2 Area Treated or** 

**Am ount Handled**  **Daily 3**  **Inhalation Mitigation Level**  **Dose (mg/kg/day) 4**  MOE 5

Mixer/Loader M/L, EC, Groundboom Applications Carrot 0.219 0.079 lb ai/A 80 0.0000173 250,000

M/L, EC, Aerial Applications Avocado 0.219 0.125 lb ai/A 350 0.00012 37,000 Carrot 0.079 lb ai/A 0.0000758 58,000 M/L, EC, Airblast Applications Avocado 0.219 0.125 lb ai/A 40 0.0000138 320,000 Applicator Applicator, Spray, Groundboom Open Cab Carrot 0.34 0.079 lb ai/A 80 0.0000034 160,000 Applicator, Spray, Aerial, Broadcast Avocado 0.068 (Engineering Control) 0.125 lb ai/A 350 0.00000268 1,600,000 Carrot 0.068

(Engineering Control) 0.079 lb ai/A 350 0.00000169 2,600,000 Applicator, Spray, Airblast , Broadcast Avocado 4.71 0.125 lb ai/A 40 0.000295 15,000 Flagger Flagger, Liquids Avocado 0.035 0.125 lb ai/A 350 0.000191 23,000 Carrot 0.079 lb ai/A 350 0.000121 36,000 Mixer/Loader/Applicator Mixer/Loader/Applicator, Backpack Sprayer Greenhouse grown vegetable (tomato and cucumber) 0.140 0.0008 lb ai/gal 40 gallons 0.000056 78,000 Mixer/Loader/Applicator, Manuallypressurized Handwand 0.03 0.0008 lb ai/gal 40 gallons 0.000012 370,000 Mixer/Loader/Applicator, Mechanicallypressurized Handgun Sprayer 0.120 0.0008 lb ai/gal 1000 gallons 0.0012 3,700Novaluron Human - Health Risk Assessment DP No. 426068

Page 33 of 41 **9.2 Short** **- /Intermediate**  **- Term Post** **- Application Risk**  HED uses the term post - application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post - application exposure levels vary over time and depend on such things as the ty pe of activity , the nature of the crop or target that was treated, the ty pe of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatl y reduce the potential for post - application exposure. Also post - application exposures are anticipated based on the proposed new uses of novaluron. **9.2. 1**  **Inhalation Post -**  **application Risk** There are multiple potential sources of post - a pplication inhalation exposure to individuals performing post - application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The A gency

sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipol y/ SAP/meetings/2009/120109meeting.html ). The A gency ha s evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail ;D=EPA - HQ - OPP - 2014 - 0219 ). During Registration Review, the A gency

will utilize this analysis to determine if data (i.e., flux studies, route - specific inhalation toxicological studies) or further anal ys is is required for novaluron . In addition, the Agency is continuing to evaluate the available post - application inhalation exposure data generated by the Agricultural Reentry Task Force (ARTF) . Given these two efforts, the Agency

will continue to identify

the need for and, subsequentl y, the way to incorporate occupational post - application inhalation exposure into the agency's risk assessments. Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the us e of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)]. **9.2. 2**  **Dermal Post -**  **application Risk** Although there is potential for dermal post - application exposure, a quantitative dermal post application risk assessment was not conducted because no dermal hazard was identified.Novaluron Human - Health Risk Assessment DP No. 426068

Page 34 of 41 No valuron is classified as acute Toxicity C ategory I II for acute dermal toxicity . It is classified as Toxicity C ategory IV for primary

eye irritation and primary skin irritation. Therefore, the interim W orker P rotection S tandard (WPS) REIof 12 hours is adequate to protect agricultural workers from post - application exposures to novaluron . **10.0 References**  **Previous Risk Assessments**  Van Alstine, J., et al. , 05 - FEB - 2014, D409210 . Novaluron: Human health Risk Assessment for Proposed Section 3 Uses to Control Fleas, Cockroaches, Crickets, Litter Beetles, Ants, and Fl ying Insect Pests on Furniture, Animal Quarters, Carpets, Kennels, Livestock and Poultry

Houses, Food and Non - Food Warehouses, in Food - Handling Establishments, Around Perimeters, and Lawns.

 Van Alstine, J., et al. , 21 - MAY - 2013, D404422. Novaluron: Human health Risk Assessment for Proposed Section 3 Uses as a Dog Spot - O n and in Cattle and Poultry Operations and Horse Barns.

 Van Alstine, J., et al. , 15 - MAY - 2013, D400705. Novaluron: Human health Risk Assessment for Proposed Section 3 Uses on Peanut and Soy bean.

 Venkateshwara, L. et al. , 15 - SEP - 2011, D377471. Novaluron: Human health Risk Assessment for Proposed Section 3 Uses on Sweet Corn and in Food - or Feed - Handling Establishments . **HASPOC Memo**  Van Alstine, J., 17 - APR - 2012, TXR # 0052351 . Novaluron: Summary of Hazard and Science Policy

Council (HASPOC) Meetin g of March 15, 2012: Recommendations on the requirement of a subchronic inhalation study for novaluron. **Dietary Memo**  R. Duncan, et al. , 20 - APR - 2015 , D 426069 . Novaluron. Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Proposed Uses on Avocado; Carrot; Succulent Bean; Updated Crop Groupings for Vegetable, Fruiting, Crop Group 8 - 10; Fruit, Pome, Crop Group 11 - 10; Cherry Subgroup 12 - 12A; Peach Subgroup 12 - 12B; and Plum Subgroup 12 - 12C; and Revisions to the Label to Include Uses on Greenhouse Grown Cucumber . **Drinking Water Memo s**   Zhong , H., 07 - AUG - 2013, D412441. Drinking Water Assessment in Support of the New Indoor and Outdoor non - food Use o f Novaluron for Pest Control.

 Zhong , H. , 02 - SEP - 2014; D418740 . Drinking Water Assessment in Support of IR - 4 New and Revised Uses of Novaluron (RIMON ® 0.83 EC) on Avocado; Beans, Berries (Low Growing), Bushberries, Carrot; Cotton, Cucurbit Vegetables, Fruiting Vegetables, Head and Stem Brassica, Leafy Brassica Greens, Ornamentals (Container Grown Ornamentals in Greenhouses, Shadehous es, Outdoor Nurseries), Peanuts, Pears , Pome Fruits, Potatoes / Sweet P otatoes, Sorghum, Soy beans , Stonefruits, Sweet Corn, Sugarcane , Swiss Chard , and Turnip Greens .Novaluron Human - Health Risk Assessment DP No. 426068

Page 35 of 41 **Chemistry Memo**  Van Alstine , J. 16 - JUN - 2015; D418739 . Novaluron. Petition for the Establishment of Permanent Tolerances for Residues of Novaluron in/on Avocado; Carrot; Bean, Succulent; Vegetable, Fruiting, Crop Group 8 - 10; Fruit, Pome, Crop Group 11 - 10; Cherry Subgroup 12 - 12A; Peach Subgroup 12 - 12B; and Plum Subgroup 12 - 12C; and Revisions to the L abel to Include Uses on Greenhouse - Grown Cucumber . Summary of Analy tical Chemistry

and Residue Data. **Occupational and Res idential Exposure Memos**   Venkateshwara, L . 20 - MAR - 2015, D423666 . Novaluron. Occupational and Residential Exposure Assessment for a Proposed Use on Avocado, Carrot, Greenhouse Tomatoes and Greenhouse Cucumbers, and the Expansion of Various Crop Groups Inc luding: Beans, Fruiting Vegetable Group 8 - 10, Pome Fruit Group 11 - 10, Cherry Subgroup 12 - 12A, Peach Subgroup 12 - 12B, Plum Subgroup 12 - 12C.

 Venkateshwara, L., 06 -NOV - 2013 , D412298 . Novaluron. Occupational and Residential Exposure Assessment for a Proposed Use to Control Fleas, Cockroaches, Crickets, Litter Beetles, Ants and Fl ying Insect Pests on Furniture, Animal Quarters, Carpets, Kennels, Poultry Houses , and Lawns.

 Venkateshwara, L., 21 - MAY - 2013, D410803. Novaluron: Occupational and Residenti al Exposure and Risk Assessment for Proposed Pet Spot - On Use.

 Venkateshwara, L., 30 - APR - 2013, D401261, Novaluron. Occupational and Residential Exposure Assessment for a Proposed Use on Peanuts and Soy beans and a Reevaluation of Existing Residential Uses with the Updated Residential SOPs.

 Venkateshwara, L., 25 - JAN - 2011, DP 378634, Novaluron Occupational and Residential Exposure/Risk Assessment for a Crack and Crevice Use. cc: J. Van Alstine, A. Dunbar, L. Venkateshwara RDI: RAB1 ( 04 - MAR - 2015 ); G. Kramer ( 03 - MAR- 2015 ) ; B. Smith ( 04 - MAR - 2015 ) J. Van Alstine: S - 10951: Potomac Yard 1 (PY1): (703)603 - 8866: 7509P: RAB1Novaluron Human - Health Risk Assessment DP No. 426068

Page 36 of 41 **Appendix A. Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR 158.340) for novaluron are in Table A.1. Use of the new guideline numbers does not im ply that the ne w (1998) guideline protocols were used. **Table A.1. Toxicology Data Requirements** . **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Acute Eye Irritation ................................ ....................... 870.2500 Acute Dermal Irritation ................................ ................. 870.2600 Skin Sensitization ................................ .......................... Yes Yes Yes Yes Yes Yes Yes

Yes Yes Yes Yes Yes 870.3100 90 - Day

Oral Toxicity in Rodents ................................ .. 870.3150 90 - Day

Oral Toxicity in Nonrodents ............................. 870.3200 21/28 - Day Dermal Toxicity ................................ ........... 870.3250 90 - Day

Dermal Toxicity ................................ ................ 870.3465 90 - Day

Inhalation Toxicity ................................ ........... Yes No Yes No No 1 Yes

-- Yes

--

-- 870.3700a Prenatal Developmental Toxicity (rodent) ..................... 870.3700b Prenatal Developmental Toxicity (nonrodent) ............... 870.3800 Reproduction and Fertility Effects ................................ . Yes Yes Yes Yes

Yes Yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Carcinogenicity (rat) ................................ ...................... 870.4200b Carcinogenicity (mouse) ................................ ................ 870.4300 Combined Chronic Toxicity/Carcinogenicity (mice and rats) ................................ ................................ ............................ No Yes No No Yes --

Yes

--

-- Yes 870.5100 Mutagenicity

—Bacterial Reverse Mutation Test .......... 870.5300 Mutagenicity

—Mammalian Cell Gene Mutation Test .. 870.5375 In vitro Mammalian Chromosomal Aberrations ............ 870.5395 Mammalian Erythrocyte Micronucleus ......................... 870.5550 Unscheduled DNA Synthesis 870.5550 Mutagenicity

–Rec assay with Bacillus subtilis Yes Yes Yes Yes Yes Yes Yes

Yes Yes Yes Yes Yes 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90 - Day

Neurotoxicity Screening Battery (rat) ............... 870.6300 Developmental Neurotoxicity ................................ ........ Yes Yes No Yes

Yes

-- 870.7485 Metabolism and Pharmacokinetics ................................ 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. Yes Yes Yes Yes

Yes Yes 1 The HASPOC concluded that a subchronic inhalation toxicity study is not required at this time (Memo, J. Van Alstine, 17 - APR- 2012; TXR # 0052351).Novaluron Human - Health Risk Assessment DP No. 426068

Page 37 of 41 **A.2 Toxicity Profiles**  **Table A.2.1. 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 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 **Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile. Guideline**  **No. Study Type**  **MRID No. (year)/ Classification/Doses**  **Results** 870.3100 90 - Day

oral toxicity (rat) 45651504/45651503

(1993/1990); Acceptable/guideline Study I: 0, 50, 100, 200, or 400 ppm (equivalent to 0, 3.52, 6.93, 13.03, and 27.77 mg/kg bw/day, respectively in males and 0, 4.38, 8.64, 17.54, and 34.39 mg/kg bw/day, respectively in females) Study II: 0, 10, 320, or 10,000 ppm (equivalent to 0, 0.7, 22.2, and 713 mg/kg bw /day , respectively in males and 0, 0.8, 24.3, and 754 mg/kg bw/day, respectively in females) NOAEL = 320 ppm (22.2 mg/kg/day) in males and 50 ppm (4.38 mg/kg/day) in females. LOAEL = 400 ppm

(27.77 mg/kg/day) in males based on increas ed 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 = not established. 870.3700a Prenatal

developmental in (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. 870.3700b Prenatal

developmental in (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 No. 426068

Page 38 of 41 **Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile. Guideline**  **No. Study Type**  **MRID No. (year)/ Classification/Doses**  **Results** 870.3800 Reproduction and

fertility effects (rat) 45651505 (Main Study,

1999), 45638319 (Preliminary Study, 1998); 0, 1000, 4000, or 12,000 ppm ; M: 0, 74.2, 297.5, or 894.9 mg/kg/day F: 0, 84.0, 336.7, or 1009.8 mg/kg/day **Acceptable/Guideline** Parental NOAEL = not established. LOAEL (M/F) = 74.2/84.0 mg/kg/day based on increased absolute and relative spleen weights. Offspring NOAEL = not established. LOAEL (M/F) = 74.2/84.0 mg/kg/day based on increased absolute and relative spleen weights. Reproductive NOAEL ( M/F) = 74.2/1009.8 mg/kg/day. LOAEL (M) = 297.5 mg/kg/day based on decreased epididymal sperm counts and increased age of preputial separation in the F 1 generation. Reproductive LOAEL for females was not established. 870.4100a 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. 870.4200 Chronic/

Carcinogenicity (rat) 45651506 (1995);

0, 25, 700, or 20,000 ppm test material; M: 0, 1.1, 30.6, and 884.2 mg/kg/day F: 0, 1.4, 39.5, and 1113.5 mg/kg/day **Acceptable/Guideline** NOAEL (M/F) = 1.1/1.4 mg/kg/day. LOAEL (M/F) = 30.6/39.5 mg/kg/day based on erythrocyte damage and turnover resulting in a regenerative mild anemia. **No Evidence of Carcinogenicity** 870.4300 Chronic/

Carcinogenicity (mouse) 45651507/45877901

(2000/2003); 0, 30, 450, or 7000 ppm test material; M: 0, 3.6, 53.4, or 800.0 mg/kg/day F: 0, 4.3, 63.3, or 913.4 mg/kg/day **Acceptable/Guideline** NOAEL (M/F) = 3.6/4.3 mg/kg/day. LOAEL (M/F) = 53.4/63.3 mg/kg/day based on increased erythrocyte turnover due to hemoglobin oxidation and resulting in a mild anemia. **No Evidence of Carcinogenicity** 870.5100 Salmonella

ty phimurium and Escherichia coli Reverse Mutation Assay 44961013 (1997);

0, 312.5, 625, 1250, 2500, or 5000 μg/plate in the presence and absence of metabolic activation (±S9) **Acceptable/Guideline** Novaluron, tested up to the limit of solubility (2500 μg/pl ate) and the limit dose (5000 μg/plate), was not cytotoxic with or without S9 activation in four S. typhimurium strains and one strain of E. coli , and did not induce a genotoxic response in any strain. 870.5100 Salmonella

typhimurium bacterial reverse gene mutation assay 45030003 (1986);

0, 10, 33, 100, 333, 1000, or 3333 μg/plate in the presence and absence of mammalian metabolic activation (±S9) **Acceptable/Guideline** Novaluron, tested up to the limit of solubility (3333 μg/plate), was not cytotoxic with or without S9 activation in five S. typhimurium strains, and did not induce a genotoxic response in any strain. 870.5300 Gene Mutation 45638321(1989); 0, 50, 100, 125, 150, 175, or 200 μg/mL with and without metabolic activation (S9 - mix) in two independent assays. **Acceptable/Guideline** There was no evidence of biologically significant induction of mutant colonies over background.Novaluron Human - Health Risk Assessment DP No. 426068

Page 39 of 41 **Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile. Guideline**  **No. Study Type**  **MRID No. (year)/ Classification/Doses**  **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 of clastogenic activity in primary human lymphocytes, in the presence or absence of S9 activation. 870.5395 Mammalian

erythrocyte micronucleus test in mice 45638322(1989);

0, 1250, 2500, or 5000 mg/kg body weight **Acceptable/Guideline** There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or harvest time. 870.5500 Mutagenicity

–Rec assay with Bacillus subtilis 44961014 (1998);

50, 150, 500, 1,500, or 5,000 μg/plate, with and without mammalian metabolic activation (±S9) **Acceptable/Guideline** Novaluron was equivocal for bacterial DNA damage in the absence of S9 activation, and negative for bacterial DNA damage in the presence of S9 activation. 870.5550 Unscheduled

DNA Synthesis in HeLa S3 Human Epitheliod cells 45030002 (1988);

0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, or 256 μg/mL (±S9) **Acceptable/Guideline** Novaluron was considered not to show any evidence of causing DNA damage to HeLa S3 epithelioid cells in this unscheduled DNA synthesis test for mutagenic potential. 870.6200a Ac ute

neurotoxicity screening battery 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). 870.6200b Subchronic

neurotoxicity screening battery 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.Novaluron Human - Health Risk Assessment DP No. 426068

Page 40 of 41 **Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile. Guideline**  **No. Study Type**  **MRID No. (year)/ Classification/Doses**  **Results** 870.7485 Metabolism and

pharmacokinetics (rat) 45638401 (2000),

45638323 (1998); single dose of 2 mg/kg or 1000 mg/kg, or 14 multiple 2 mg/kg/day doses of unlabeled novaluron (Lot no. 970211/4, 99.3% chemical purity) followed by a single dose of radiolabeled novaluron. **Acceptable/Guideline** Novaluron exhibited marginal absorption (16 - 18%), relatively rapid and complete excretion within 48 hours primarily via the feces and to a lesser extent via urine in rat. Biliary contribution for fecal excretion appears to be insignificant. Absorption appeared to be approaching saturation at high doses. Peak plasma concentration occurred at 2 - 5 hours. Urinary metabolite profiles revealed 15 components and 8 components following administration of [chlorophenyl 14 C]novaluron or [difluorophenyl 14 C]novaluron, respectively. The most prevalent urinary metabolite was 2,6 - difluorobenzoic acid represented the majority of the urinary radioactivity. Other components individually represented no more than 5.9% of the dose and most represented considerably less than 1%. Parent compound was the most prevalent contributor in the feces. The fecal metabolite profile revealed two metabolites; 3 - chloro - 4 - (1,1,2 - trifluoro - 2 - trifluoromethoxyethoxy)aniline and 1 - [3 - chloro - 4 - (1,1,2 - trifluoro - 2 - trifluoromethoxyethoxy)phenyl]urea. Quantitatively, these were minor components accounting for <2% of the dose. In the repeated - dose group, some tissues such as fat contained measurable radioactivity at 168 hours post dose but did not appear to suggest significant potential for bioaccumulation or sequestration at the doses tested. 870.7600 Dermal

penetration (rat) 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 percent 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. 870.7600 Immunotoxicity

(mouse) 48690105 (2011);

0, 100, 1,000 , and 10,000 ppm (0, 21, 200, 2,115 mg/kg/day [F]) **Acceptable/Guideline** Sy stemic NOAEL (F) = 2,155 mg/kg/day. Sy stemic LOAEL was no observed when tested above the limit dose. Immunotoxicity NOAEL (F) = 200 mg/kg/day. Immunotoxicity LOAEL = 2,155 mg/kg/day based on decreased anti - SRBC response.Novaluron Human - Health Risk Assessment DP No. 426068

Page 41 of 41 **Appendix B. Physical/Chemical Properties Table**  **B.1 . Physicochem** **ical Properties of Technical Grade Novaluron. Param**  **eter Value**  **Reference** Melting range 176.5 - 178.0  C

DP# 315780, 3 -NOV - 2005, S. Levy pH 6.5 Density 1.56 g/cm3 at 22  C Water solubility 3 μg/L at 20  C Solvent solubility (at 25  C) 0.00839 g/L in n - heptane 1.88 g/L in xylene 14.5 g/L in methanol 198 g/L in acetone 113 g/L in ethyl acetate 0.98 g/L in n - octanol Vapor pressure (mm Hg) 1.2 x 10 - 7 Dissociation constant, pKa Not determined due to low water solubility. Octanol/water partition coefficient, Log(KOW) 4.3 at 25  C UV/visible absorption spectrum Molar absorption coefficients of at three maximum absorbances: 15,400 L/mol  cm

at 253 nm (neutral) 9,780 L/mol  cm at 253 nm (acidic) 20,500 L/mol  cm

at 263 nm (basic) Henry’s Constant at 25  C 2 x 10 - 5 atm•m 3 /mol Product Chemistry, MRID 44961006 **Appendix C. Review of Human Research** This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their u se, can be found at the Agency website 4

.

4 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html