Document ID: EPA-HQ-OPP-2014-0232-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-07-22T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY 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
TXR 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 was provided by Julie Van Alstine (RAB1), the occupational and residential exposure assessments were provided by Lata Venkateshwara (RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), the drinking water assessment was provided by 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 health risk assessment was conducted in conjunction with a request for the use of novaluron to control pests on furniture, in animal quarters, carpets, kennels, livestock and poultry houses, food and non-food warehouses, in food-handling establishments, around perimeters, and lawns (Memo, J. Van Alstine, et al., 05-FEB-2014; D409210). 

                               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 Analytical 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	Physical/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 Analysis	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	25
6.4	Spray Drift	27
6.5	Residential Bystander Post-Application Inhalation Exposure	27
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.  Physical/Chemical Properties	41
Appendix C.  Review of Human Research	41

1.0	Executive Summary

Background:  Novaluron, a benzoylphenyl urea compound, is a pesticide chemical belonging to the class of insecticides called insect-growth regulators (IGRs).  Tolerances for residues of novaluron are established under 40 CFR §180.598 in/on a wide variety of crops at levels ranging from 0.01 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 byproducts (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 by 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 uses of novaluron on avocado and carrot, to expand the use pattern for succulent beans, to update crop group commodity definitions for fruiting vegetable group 8-10, pome fruit group 11-10, cherry subgroup 12-12A, peach subgroup 12-12B, and plum subgroup 12-12C, and to add greenhouse-grown cucumbers to the label.  The end-use product associated with these registration requests is Rimon[(R)] 0.83EC Insecticide (EPA Reg. No. 66222-35) which contains 9.3% ai by 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 previously submitted succulent snap bean field trial data.  Since the proposed application scenarios for the updated croup group commodity definitions of fruiting vegetable group 8-10, pome fruit group 11-10, cherry subgroup 12-12A, peach subgroup 12-12B, and plum subgroup 12-12C are identical or lower than the rates previously reviewed, no residue data were submitted 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 field trial data for greenhouse-grown cucumbers to expand the use pattern to include greenhouse-grown cucumbers.  

Hazard Assessment:  In subchronic and chronic toxicity studies, novaluron primarily produced hematotoxic effects (toxicity to blood) such as methemoglobinemia, decreased hemoglobin, decreased hematocrit, and decreased red blood corpuscles (RBCs or erythrocytes) that were associated with compensatory erythropoiesis.  No maternal and/or developmental toxicity was observed in animals 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, no 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 III), and inhalation routes (Toxicity Category IV).  No ocular (Toxicity Category IV) or dermal irritation (Toxicity Category IV) was noted.  Novaluron is not a dermal sensitizer.  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 or 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 adequately understood.  The Organization for Economic Co-operation and Development (OECD) tolerance-calculation procedures and the submitted residue data sets were used to calculate the HED-recommended tolerances.  There is an adequate residue analytical 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 chemistry 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 harmonization 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 by 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 beans, 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% PCT was assumed.  The registered food-handling 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 for 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 years 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 previously updated in the February 2014 risk assessment to reflect use of the 2012 Residential Standard Operating Procedures (SOPs).  All 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 HED.  

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 risk assessment was not performed because novaluron was classified as "not likely to be carcinogenic to humans."  All potential exposure pathways were assessed in the aggregate risk assessment as a conservative, health-protective measure.  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, loading, applying, and other handling activities.  Short- 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 not 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	HED Recommendations 

Pending resolution of the deficiencies 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[(R)] 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 Analytical Reference Standards
An analytical standard for novaluron is currently available in the National Pesticide Standards Repository (personal communication with Theresa Cole, 29-JAN-2015); however, the standard expired on 07-MAR-2015.  A new reference standard should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, to the attention of either Theresa Cole or Thuy Nygen at the following address:

	USEPA
	National Pesticide Standards Repository/Analytical 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

Makhteshim-Agan of North America (MANA) previously submitted under PP#2F6430 a gas chromatography/electron-capture detection (GC/ECD) residue analytical method for the analysis of residues of novaluron in/on pome fruit, cabbage, and potato commodities.  A second method, high-performance liquid chromatography/ultraviolet (HPLC/UV), was also submitted for the analysis of novaluron residues only in/on cotton commodities.  Successful independent laboratory validations (ILVs) of the GC/ECD and HPLC/UV methods have been completed with apples and undelinted cottonseed, respectively.  Acceptable radiovalidation data have been submitted and reviewed in D325183 for the GC/ECD method.  An interference study was requested and a specific single-analyte confirmatory method was submitted, reviewed, and considered acceptable (Memo, J. Langsdale, 21-OCT-2008; D355574).

The Analytical 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 HPLC/UV methods appear suitable for food tolerance enforcement in plants and cotton.  The ACB recommended that the analytical methods do not need to be laboratory validated by EPA (Memo, S. Levy, 15-SEP-2004; D306998).  Both methods have been forwarded to the FDA for inclusion in the Pesticide Analytical Method Volume II (PAM II) as a Letter Method (Letter, S. Levy 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 below is to be determined by measuring only novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide).

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)ethoxy]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
                                     0.70
Harmonize with Codex MRL 
Bean, succulent[1]
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 12-12A[4]
                                      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.  
2 This tolerance will replace the existing tolerances of 1.0 ppm on vegetable, 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 will replace the existing tolerance of 2.0 ppm on fruit, pome, group 11. 
[4] This tolerance will replace the existing tolerance of 8.0 ppm on cherry. 
[5] These tolerances will replace the existing tolerance of 1.9 ppm on fruit, stone, group 12, except cherry.

2.2.3	Revisions to Petitioned-For Tolerances

The OECD calculator and available data support a tolerance of 0.70 ppm for residues of novaluron in/on lima beans.  A tolerance is currently established for residues of novaluron in/on bean, snap, succulent at 0.60 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 0.70 ppm in order to harmonize 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 vegetable, cucurbit, group 9.  Codex 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 vegetable, cucurbit, group 9 be revised to 0.20 ppm in order to harmonize with Codex.  

The following tolerances for residues of novaluron in/on stone fruit have been established:  cherry at 8.0 ppm; fruit, stone, group 12, except cherry at 1.9 ppm; and plum, 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 tolerances for residues of novaluron in/on stone fruit be expanded to cherry subgroup 12-12A, peach subgroup 12-12B, and plum subgroup 12-12C.  The stone fruit tolerance levels are harmonized with Canada (8.0 ppm for cherry, 1.9 ppm for fruit, stone, group 12, except cherry, and 2.6 ppm for plum, 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 plum, prune, dried tolerance level with Codex (3.0 ppm).  

2.2.4	International Harmonization

No Canadian, Codex, or Mexican MRLs have been established for residues of novaluron in/on avocado and carrot.  Codex has established the following MRLs 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 following MRLs 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, mayhaws, pears, and quinces; 2.6 ppm in plum, prune, dried; 8 ppm in sweet and tart cherries; and 1.9 ppm in apricots, fresh prune plums, 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); vegetable, cucurbit, group 9 (0.20 ppm); fruit, 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 specifically 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 product 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 Nomenclature.
Chemical structure
                                       
Common name
Novaluron
IUPAC name
1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)phenyl]-3-[2,6-difluorobenzoyl]urea
CAS name
N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide
CAS registry number
116714-46-6
End-use product (EP)
Rimon[(R)] 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 physicochemical properties can be found in Appendix B.  

3.3	Pesticide Use Pattern

IR-4 has submitted a draft label for Rimon[(R)] 0.83EC 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-sleeved shirt, long pants, protective eyewear, chemical-resistant gloves, and shoes 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.  Summary of Directions for Proposed Use of Novaluron.
                     Applic. Timing, Type, and Equip.[†]
                          Formulation [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)
                                     0.240
                                       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. 
Tomato 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 (Same 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; American 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 days
Vegetable, Fruiting, Group 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.  This 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 season.  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-proposed new uses of novaluron on avocado and carrot, to expand the use pattern for succulent beans, to update croup group commodity definitions for fruiting vegetable group 8-10, pome fruit group 11-10, cherry subgroup 12-12A, peach subgroup 12-12B, and plum subgroup 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 directly 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 Environmental 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 Populations 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 analyzed and categorized by subgroups based 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 currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

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 by 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 considerably less than 1%.  Quantitatively, fecal metabolites accounted 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.  Biliary contribution for fecal excretion appears to be insignificant.  Excretion was relatively rapid 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 system.  These effects do not appear to worsen with time, and included methemoglobinemia, decreased hemoglobin, decreased hematocrit, decreased RBCs (or erythrocytes), and increased reticulocyte counts that were associated with compensatory erythropoiesis.  Increased spleen weights and/or hemosiderosis in the spleen were considered to be due to enhanced removal of damaged erythrocytes and not to a direct immunotoxic effect (at doses >=27 mg/kg/day).  

There was no maternal or developmental toxicity seen in the rat and 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 epididymal sperm counts and increased age at preputial separation in the F1 generation) was observed at a higher dose than the increased spleen weights and were consistent with the primary effects in the database.  

Clinical 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 only 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 Category IV), dermal (Toxicity Category III), and inhalation routes (Toxicity Category IV).  No ocular (Toxicity Category IV) or dermal irritation (Toxicity Category IV) was noted.  Novaluron is not a dermal sensitizer and no adverse effects were observed in the 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 unlikely to underestimate exposure.

4.4.1	Completeness of the 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 screening batteries were performed with novaluron in rats.  Novaluron is not considered neurotoxic, since effects observed in the acute neurotoxicity study were observed at the limit dose only and were not reproduced at similar, repeated doses in the subchronic neurotoxicity study.  In addition, no evidence of neuropathology was observed in subchronic and chronic toxicity studies in rats, mice, or dogs. 

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased susceptibility in the rat or rabbit developmental toxicity studies up to the limit dose or in the two-generation reproduction study in rats.  

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-handling 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 water 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 underestimate 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 lowest-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 of the dose and also in relation to the most sensitive effects and target organs in novaluron's hazard database.  No 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 erythrocyte 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 for All Durations:  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 changes 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 offspring 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 systemic effects were observed in the 28-day dermal study in rats; therefore, a short-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 previously 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 toxicity 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 for 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	Cancer 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.  Summary of Toxicological Doses and Endpoints for Novaluron for Use in Dietary and Non-Occupational Human health Risk Assessments.
                              Exposure/ Scenario
                              Point of Departure
                                 Uncertainty/
                                   FQPA SFs
                       RfD, PAD, LOC for Risk Assessment
                        Study and Toxicological Effects
Acute 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.
Chronic Dietary (All Populations)
NOAEL = 1.1 mg/kg/day
UFA = 10X
UFH = 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
UFA = 10X
UFH = 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 dermal 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%)
UFA = 10X
UFH =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.  UFA = extrapolation from animal to human (interspecies).  UFH = 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.  Summary of Toxicological Doses and Endpoints for Novaluron for Use in Occupational Human health Risk Assessments.
                              Exposure/ Scenario
                              Point of Departure
                                 Uncertainty/
                                   FQPA SFs
                       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%)
UFA = 10X
UFH =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 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.  UFA = extrapolation from animal to human (interspecies).  UFH = 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 previously concluded that the nature of the residue in plants is adequately understood based on acceptable metabolism studies conducted on apples, cabbage, cotton, and potatoes using [difluorophenyl-U-[14]C]novaluron and [chlorophenyl-U-[14]C]novaluron as the test substances (Memo, G. Kramer, 22-MAR-2004; D285474).  These studies indicate that novaluron is not extensively metabolized in these crops.  The parent compound, novaluron, either was the only residue component identified or was the predominant residue component in all analyzed plant matrices.  The reviewed studies also indicate that novaluron, when foliarly applied during the vegetative growth stage, is not readily translocated to mature apple fruit, potato tubers, or cottonseed (Memo, G. Kramer, 22-MAR-2004; D285474).  Based on these studies, the Metabolism Assessment and Review Committee (MARC) determined that the residue of concern in crops for purposes of tolerance enforcement and risk assessment is novaluron only (Memo, G. Kramer et al., 03-FEB-2004; D297646).  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 previously concluded that the nature of the residue in livestock is adequately understood based on the submitted goat and hen metabolism studies (Memo, G. Kramer, 22-MAR-2004; D285474).  The HED MARC determined that the residue of concern in livestock for purposes of tolerance enforcement and risk assessment is novaluron only (Memo, G. Kramer et al., 03-FEB-2004; D297646).

The HED MARC concluded that parent and the chlorophenyl urea and chloroaniline degradates are residues of potential concern to be included in the drinking water assessment.  Monitoring data are not available for novaluron or its chlorophenyl urea and chloroaniline degradates in surface water or ground water.  Concentrations in surface water and ground water were estimated using standard EFED drinking water models.

Table 5.1.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.[1]
Matrix
Residues Included in Risk Assessment
Residues Included 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.

5.2	Food Residue Profile

No new data were submitted to support tolerances for residues of novaluron in/on fruiting vegetable group 8-10, pome fruit group 11-10, cherry subgroup 12-12A, peach subgroup 12-12B, and plum subgroup 12-12C.  The petitioner has requested that existing tolerances 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 label.  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 previously 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 methods that are similar to the enforcement method were used for data collection and the methods were adequately validated in conjunction with the avocado, carrot, greenhouse cucumber, and lima bean field trials.  The field trial data reflect the proposed use pattern and an adequate number of trials were conducted in the appropriate geographic regions.  Although only 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 application scenarios 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 previously requested storage stability data on dried plums and on grain sorghum forage, grain, aspirated grain fractions (AGF), and stover.  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 processed 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 previously 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 associated with the current petition.  The incorporation of carrot culls into the reasonably balanced dietary burdens (RBDBs) calculations 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 days.  The current and proposed labels include a restriction that only registered crops may be rotated to a treated field within 30 days of the final application, which is appropriate for this petition.  Future uses that have significantly higher application rates will require confined rotational crop studies at higher rates using chlorophenyl-labeled novaluron.  

5.3	Water Residue Profile

The residues of concern in drinking water for purposes of risk assessment are novaluron, the chlorophenyl urea degradate (1-[3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)phenyl]urea), and the chloroaniline degradate (3-chloro-4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)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 sources" and "water, indirect, all sources."  Surface and ground water EDWCs were calculated using the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS), the Screening Concentration in Ground Water (SCI-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 water for risk assessment purposes are novaluron, the chlorophenyl urea 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 have equal toxicity to the parent.  The chronic dietary exposure and risk assessment incorporated the highest total EDWC of 77.8 ug/L (0.0778 ppm) that was simulated using the PRZM-GW model with the proposed poultry operation use and WI corn scenario (Table 5.2).  

Table 5.2.  Summary of Novaluron EDWCs from Ground Water Using PRZM-GW Modeling for Poultry Operations.[1]
                                 Crop/Scenario
                          Highest Daily Value (ug/L)
                       Post Breakthrough Average (ug/L)
                  Average Simulation Breakthrough Time (Days)
                                   Novaluron
                       Wisconsin Corn - WI Central Sands
                             Met File (14920.dvf)
                                   2.58E-18
                                  Incomplete
                                  Incomplete
                          Chlorophenyl Urea Degradate
                       Wisconsin Corn - WI Central Sands
                             Met File (14920.dvf)
                                    0.00815
                                  Incomplete
                                  Incomplete
                            Chloroaniline Degradate
                       Wisconsin Corn - WI Central Sands
                             Met File (14920.dvf)
                                     84.2
                                     77.8
                                    15,661
     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 averages 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 analysis incorporated recently 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 PCT for some commodities.  The chronic analysis 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 by a higher tolerance as a result 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, and 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 ug/L (0.0778 ppm) that was simulated using the PRZM-GW model with the proposed poultry operation use and WI corn scenario.  

5.4.2	Percent Crop Treated Used in Dietary Assessment

A Screening Level Usage Analysis (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 PCT 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 PCT for sugarcane, AGF, and cowpea seed.  These livestock dietary burdens were used, along with average transfer coefficients, to calculate anticipated secondary residues for meat, milk, hog, and poultry commodities, which were incorporated into the chronic dietary assessment.  

5.4.3	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 general 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 analysis is not 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 likely 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 (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                      N/A
                                      N/A
                                   0.003071
                                      28
                                      N/A
                                      N/A
 All Infants (<1 year old)
                                        
                                        
                                   0.006289
                                      57
                                        
                                        
 Children 1-2 years old
                                        
                                        
                                   0.008014
                                      73
                                        
                                        
 Children 3-5 years old
                                        
                                        
                                   0.005711
                                      52
                                        
                                        
 Children 6-12 years old
                                        
                                        
                                   0.003746
                                      34
                                        
                                        
 Youth 13-19 years old
                                        
                                        
                                   0.002424
                                      22
                                        
                                        
 Adults 20-49 years old
                                        
                                        
                                   0.002659
                                      24
                                        
                                        
 Adults 50-99 years old
                                        
                                        
                                   0.002671
                                      24
                                        
                                        
 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 proposed residential uses for the current action; however there are currently 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.  Summary of Residential Exposure/Risk Estimates for Registered Uses of Novaluron.
                                      Use
                               Exposure Scenario
                               Dose (mg/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 Oral
                                   Children 
                            (1 to <2 years old)
                                    0.00022
                               ST/IT/LT:  20,000
                                    D410803
               Indoor broadcast/spot/crack and crevice treatment
                              Residential Handler
                                  Inhalation
      Mixing/Loading/Applying Liquids with Manually-Pressurized Handwand
                                   0.000011
                                    410,000
                                    D412298
                                       
                          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)
                                    0.0045
                                      980
                                       
                                       
                                       
                                       
                                 Hard Surfaces
                                       
                                    0.0015
                                     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 Sprinkler Can
                                   0.0000021
                                   2,000,000
                                       
                                       
                                       
                 Mixing/Loading/Applying Liquids with Backpack
                                   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 Estimates 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

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-mouth 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 years old aggregate assessment reflects post-application hand-to-mouth exposures from the dog spot-on use (see D410803).

Table 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
                                    0.00016
                                    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 = Inhalation 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 highest doses identified.  Total = 1/(1/Inhalation MOE) + (1/Incidental oral MOE), where applicable.  

6.4	Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications.  This is particularly 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) employed for novaluron.  The Agency 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-In issued by EPA), EPA Regional Offices and State Lead 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).  The agency has also developed a policy on how to appropriately 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-Application Inhalation Exposure 

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency 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 Agency 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).  
During Registration Review, the Agency 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 exposures and risks from three major sources:  food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  In the case of novaluron, aggregate risk assessments were performed for short- and intermediate-/long-term aggregate 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 conducted because novaluron was classified as "not likely to be carcinogenic to humans."  All potential exposure pathways were assessed in the aggregate risk assessment. 

58.1 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-term 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 post-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 aggregate 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 years 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
                                  (mg/kg/day)
                                    LOC[2]
                                Max Exposure[3]
                                  (mg/kg/day)
                           Average Dietary Exposure
                                  (mg/kg/day)
                            Residential Exposure[4]
                                  (mg/kg/day)
                                 Aggregate MOE
                         (dietary and residential)[5]
Adult
                                     4.38
                                      100
                                    0.0438
                                   0.002671
                                    0.00014
                                     1560
Children 1-2 years old
                                     4.38
                                      100
                                    0.0438
                                   0.008014
                                    0.00464
                                      350
[1] A dermal 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 long-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 novaluron.  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 considered 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 combines 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 dietary 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 aggregate 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.  

Table 7.2.  Intermediate- and Long-Term Aggregate Risk Calculations for Novaluron.
                                  Population
                                   Subgroups
                      Intermediate/Long-Term Scenarios[1]
                                       
                                     NOAEL
                                  (mg/kg/day)
                                    LOC[2]
                                Max Exposure[3]
                                  (mg/kg/day)
                           Average Dietary Exposure
                                  (mg/kg/day)
                            Residential Exposure[4]
                                  (mg/kg/day)
                                 Aggregate MOE
                         (dietary and residential)[5]
Adult
                                     4.38
                                      100
                                    0.0438
                                   0.002671
                                      N/A
                                     1640
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 of 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)].

6.0 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 by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that novaluron has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

7.0 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 being treated, and the level of protection used by 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, types 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 liquids via aerial, groundboom, and airblast equipment, mixing, loading, and applying liquids by backpack sprayers, manually-pressurized handwands, and mechanically-pressured handguns, 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 amendments to the use patterns (i.e., maximum use rates, RTIs, PHIs, 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," which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website. 

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 support aerial treatment, 
   * 40 gals for mixing/loading and applying 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 days 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-month time frame; however, commercial applicators may apply a product over a period of weeks.

The Rimon(R) 0.83EC Insecticide (EPA Reg. No. 66222-35) label requires applicators and other handlers to wear a long-sleeved 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 over the past two decades.  According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of the Global Positioning System (GPS) for swath guidance in agricultural aviation has grown steadily from the mid-1990s.  Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily 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 sources 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 not 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 dermal 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 scenarios.  There is no respirator on the label.

Table 9.1.  Short-and Intermediate-Term Occupational Exposure and Risk Estimates for Novaluron.  All Estimates are at Baseline Mitigation (i.e., Without Respirator, Unless Specified).  
                               Exposure Scenario
                                Crop or Target
                    Inhalation Unit Exposure (ug/lb ai)[1]
                          Maximum Application Rate[2]
                    Area Treated or Amount 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, Manually-pressurized Handwand
                                       
                                     0.03
                               0.0008 lb ai/gal
                                  40 gallons
                                   0.000012
                                    370,000
       Mixer/Loader/Applicator, Mechanically-pressurized Handgun Sprayer
                                       
                                     0.120
                               0.0008 lb ai/gal
                                 1000 gallons
                                    0.0012
                                     3,700
[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 =Inhalation Unit Exposure (ug/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 = Inhalation NOAEL (4.38 mg/kg/day)/ Inhalation Dose (mg/kg/day).

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 type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly 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-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency 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).  During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis 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, subsequently, 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 use 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 is classified as acute Toxicity Category III for acute dermal toxicity.  It is classified as Toxicity Category IV for primary eye irritation and primary skin irritation.  Therefore, the interim Worker Protection Standard (WPS) REI of 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 Flying 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-On 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 Soybean.  

   * 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) Meeting of March 15, 2012:  Recommendations on the requirement of a subchronic inhalation study for novaluron.

Dietary Memo
   * R. Duncan, et al., 20-APR-2015, D426069.  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 Memos
   * Zhong, H., 07-AUG-2013, D412441.  Drinking Water Assessment in Support of the New Indoor and Outdoor non-food Use of 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[(R)] 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, Shadehouses, Outdoor Nurseries), Peanuts, Pears, Pome Fruits, Potatoes / Sweet Potatoes, Sorghum, Soybeans, Stonefruits, Sweet Corn, Sugarcane, Swiss Chard, and Turnip Greens.

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 Label to Include Uses on Greenhouse-Grown Cucumber.  Summary of Analytical Chemistry and Residue Data.

Occupational and Residential 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 Including: 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 Flying Insect Pests on Furniture, Animal Quarters, Carpets, Kennels, Poultry Houses, and Lawns.

   * Venkateshwara, L., 21-MAY-2013, D410803.  Novaluron:  Occupational and Residential 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 Soybeans 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: RAB1

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 imply that the new (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).  

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)
                               Acute Oral (rat)
                                   44961001
                              LD50 >5000 mg/kg
                                      IV
870.1200
(81-2)
                              Acute Dermal (rat)
                                   45003201
                              LD50 >2000 mg/kg
                                      III
870.1300
(81-3)
                            Acute Inhalation (rat)
                                   45003202
                              LC50 >5.15 mg/L
                                      IV
870.2400
(81-4)
                        Primary Eye Irritation (rabbit)
                                   45003203
                              Not an eye irritant
                                      IV
870.2500
(81-5 )
                       Primary Skin Irritation (rabbit)
                                   45003204
                             Not a dermal irritant
                                      IV
87.2600
(81-6)
                       Dermal Sensitization (guinea pig)
                                   45084001
                            Not a dermal sensitizer
                                      N/A

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 increased occurrence of extramedullary hematopoiesis and hemosiderosis in spleen; and 100 ppm (8.64 mg/kg/day) in females based on reduction in hemoglobin, hematocrit, and RBC count; increased occurrence of extramedullary hematopoiesis in the spleen and hemosiderosis in the spleen and liver.
870.3200

28-Day dermal toxicity (rat)
45288501 (1998);
0, 75, 400, 1000 mg/kg/day 
Acceptable/Guideline
Systemic NOAEL = 1000 mg/kg/day. 
LOAEL = not established.
Dermal NOAEL = 1000 mg/kg/day.
LOAEL = not established.
870.3700a

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.

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 F1 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 typhimurium and  Escherichia coli Reverse Mutation Assay
44961013 (1997);
0, 312.5, 625, 1250, 2500, or 5000 μg/plate in the presence and absence of metabolic activation (+-S9)
Acceptable/Guideline
Novaluron, tested up to the limit of solubility (2500 μg/plate) and the limit dose (5000 μg/plate), was not cytotoxic with or without S9 activation in four S. typhimurium strains and one strain of E. coli, and did not induce a genotoxic response in any strain.
870.5100
Salmonella typhimurium- bacterial reverse gene mutation assay
45030003 (1986);
0, 10, 33, 100, 333, 1000, or 3333 μg/plate in the presence and absence of mammalian metabolic activation (+-S9)
Acceptable/Guideline
Novaluron, tested up to the limit of solubility (3333 μg/plate), was not cytotoxic with or without S9 activation in five S. typhimurium strains, and did not induce a genotoxic response in any strain.
870.5300
Gene Mutation
45638321(1989);
0, 50, 100, 125, 150, 175, or 200 μg/mL with and without metabolic activation (S9-mix) in two independent assays.
Acceptable/Guideline 
There was no evidence of biologically significant induction of mutant colonies over background.
870.5375

In vitro mammalian chromosome aberration test
44961015 (1992);
40, 200, and 1000 μg/mL, with and without metabolic activation (+-S9)
Acceptable/Guideline
Novaluron produced no evidence of clastogenic activity in primary human lymphocytes, in the presence or absence of S9 activation.
870.5395

Mammalian erythrocyte micronucleus test in mice
45638322(1989);
0, 1250, 2500, or 5000 mg/kg body weight
Acceptable/Guideline
There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or harvest time.
870.5500

Mutagenicity - Rec assay with Bacillus subtilis
44961014 (1998);
50, 150, 500, 1,500, or 5,000 μg/plate, with and without mammalian metabolic activation (+-S9)
Acceptable/Guideline
Novaluron was equivocal for bacterial DNA damage in the absence of S9 activation, and negative for bacterial DNA damage in the presence of S9 activation.
870.5550

Unscheduled DNA Synthesis in HeLa S3 Human Epitheliod cells
45030002 (1988);
0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, or 256 μg/mL (+-S9)
Acceptable/Guideline
Novaluron was considered not to show any evidence of causing DNA damage to HeLa S3 epithelioid cells in this unscheduled DNA synthesis test for mutagenic potential.
870.6200a

Acute 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.
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/cm[2] 
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
Systemic NOAEL (F) = 2,155 mg/kg/day.
Systemic 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.

Appendix B.  Physical/Chemical Properties

Table B.1.  Physicochemical Properties of Technical Grade Novaluron.
Parameter
Value
Reference
Melting range
176.5-178.0C
DP# 315780, 3-NOV-2005, S. Levy
pH
6.5

Density
1.56 g/cm[3] at 22C

Water solubility
3 μg/L at 20C

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

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

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

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

UV/visible absorption spectrum
Molar absorption coefficients of at 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 25C
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 by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.