Novaluron Human-Health Risk Assessment DP#: 363988

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

MEMORANDUM

Date: 04-DEC-2009

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

Vegetable, Fruiting, Group 8; Vegetable, Cucurbit, Group 9; Berry, Lowgrowing, Subgroup 13-07G; Miscellaneous Fruiting Vegetables; Bean, Snap; 

Bean, Dry, Seed; and Swiss Chard. 

PC Code: 124002 DP Barcode: D363988

Decision No.: 407555 Registration No.: 66222-35

Petition No.: 9E7546 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical Aggregate Case No.: NA

TXR No.: NA CAS No.: 116714-46-6

MRID No.: NA 40 CFR: §180.598

FROM: Julie L. Van Alstine, MPH, Environmental Health Scientist

Lata Venkateshwara, Environmental Scientist

Robert Mitkus, Ph.D., DABT, Toxicologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED; 7509P)

THROUGH: Dana M. Vogel, Branch Chief 

George F. Kramer, Ph.D., Branch Senior Chemist 

RAB1/HED (7509P)

TO: Barbara Madden/Laura Nollen (RM 05)

Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from all registered 

and proposed uses of novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy] 

phenyl]amino]carbonyl]-2,6-difluorobenzamide). A summary of the findings and an assessment 

of human risk resulting from the registered and proposed uses for novaluron are provided in this 

document. The risk assessment, residue chemistry data review, and dietary risk assessment were 

provided by Julie Van Alstine (RAB1), the hazard characterization by Robert Mitkus (RAB1), 

the occupational/residential exposure assessment by Lata Venkateshwara (RAB1), and the 

drinking water assessment by Iwona Maher of the Environmental Fate and Effects Division 

(EFED).
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The most recent human-health risk assessment was conducted in conjunction with a request for 

the use of novaluron on bushberry subgroup 13-07B; Brassica, leafy greens, subgroup 5B; 

turnip, greens; and fruit, stone, group 12 (Memo, J. Van Alstine, et al., 09-SEP-2009; D357078). 

A detailed hazard characterization for novaluron is presented in a previous HED risk assessment 

(Memo, S. Levy, et al., 03-NOV-2005; D313322). The following information from the 25-FEB2008 risk assessment for the use of novaluron on tomato and sugarcane (Memo, G. Kramer, 25-

FEB-2008; D347661) can be applied directly to this action:

 Physical/Chemical Properties Characterization (Section 2.0; pg. 8-9); and

 Cumulative Risk (Section 6.0 pg 18-19).

This document contains only those aspects of the risk assessment which are affected by the 

proposed Section 3 requests for use of novaluron on fruiting vegetables group 8, cucurbit 

vegetable group 9, low-growing berry subgroup 13-07G, miscellaneous fruiting vegetables, snap 

bean, dry bean seed, and Swiss chard. 
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Table of Contents

1.0 Executive Summary...........................................................................................................4

2.0 PROPOSED USE PATTERN...........................................................................................9

3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS.............................11

3.1 FQPA Considerations..................................................................................................11

3.2 Endocrine Disruption ..................................................................................................13

4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION ...........................................14

4.1 Food Residue Profile....................................................................................................14

4.2 Drinking Water Residue Profile.................................................................................16

4.3 Dietary Exposure and Risk .........................................................................................17

5.0 Residential (Non-Occupational) Exposure/Risk Characterization .............................18

5.1 Spray Drift....................................................................................................................18

6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION ........19

7.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY...................................................19

7.1 Occupational Pesticide Handler Exposure and Risk................................................19

7.2 Occupational Post-Application Worker Exposure and Risk...................................22

8.0 DATA NEEDS AND LABEL RECOMMENDATIONS..............................................25

8.1 Toxicology.....................................................................................................................25

8.2 Residue Chemistry.......................................................................................................25

8.3 Occupational and Residential Exposure....................................................................26

A.1. Acute Toxicity Profile ..................................................................................................27

A.2 Toxicity Profiles ...........................................................................................................27
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1.0 Executive Summary

Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), as 

amended, the Interregional Research Project No. 4 (IR-4) has submitted a petition (PP# 9E7546)

to register the end-use product Rimon

®

0.83 Emulsifiable Concentrate (EC) Insecticide (EPA 

Reg. No. 66222-35), a 0.83 pound (lb) active ingredient (ai)/gallon (gal) EC formulation of 

novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]

phenyl]amino]carbonyl]-2,6-difluorobenzamide) on vegetables, fruiting, group 8; vegetable, 

cucurbit, group 9; berry, low-growing, subgroup 13-07G; miscellaneous fruiting vegetables; 

bean, snap; bean, dry, seed; and Swiss chard. The basic producer of novaluron is MakhteshimAgan of North America (MANA). End-use products containing novaluron as the ai are 

formulated as EC, suspension concentrate (SC), or water-dispersible granular (WDG).

Novaluron, a benzoylphenyl urea compound, is a pesticide chemical belonging to the class of 

insecticides called insect-growth regulators (IGRs). IGRs slowly kill insects over a period of a 

few days by disrupting the normal growth and development of immature insects. Novaluron acts 

as an insecticide mainly by ingestion, but has some contact activity. It is currently registered for 

uses on pome fruits, Brassica head and stem vegetables, tuberous and corm vegetables, cotton, 

tomatoes, and sugarcane. Registrations on bushberry subgroup 13-07B, Brassica, leafy greens

(subgroup 5B), turnip greens, and stone fruit (crop group 12) are pending. All uses for 

novaluron, either proposed or existing, are agricultural or commercial in nature. No residential 

uses are proposed, nor are any registered or proposed uses expected to result in residential 

exposure. 

Hazard Characterization

Novaluron has low acute toxicity via the oral (Toxicity Category IV), dermal (Toxicity Category

III), and inhalation routes (Toxicity Category IV). No ocular (Toxicity Category IV) or dermal 

irritation (Toxicity Category IV) was noted. Novaluron is not a dermal sensitizer. In subchronic 

and chronic toxicity studies, novaluron primarily produced hematotoxic effects such as 

methemoglobinemia, decreased hemoglobin, decreased hematocrit, and decreased red blood 

corpuscles (RBCs or erythrocytes) that were associated with compensatory erythropoiesis. No 

maternal and/or developmental toxicity was observed in animals tested up to the limit dose in 

either the rat or rabbit developmental toxicity studies. In the two-generation reproductive 

toxicity study, increased spleen weights were observed in parents and offspring at the same dose, 

and reproductive toxicity was observed in males only at a higher dose. Neurotoxic effects, 

including clinical signs, changes in functional-observation battery (FOB) parameters, and 

neuropathology were observed following a single dose at the limit dose only (2000 mg/kg/day) 

in the acute neurotoxicity study in rats. However, no signs of neurotoxicity or neuropathology

were observed following repeated dosing in the subchronic neurotoxicity study in rats at similar 

doses. Therefore, RAB1 toxicologists reaffirmed the HED Hazard Identification Assessment 

Review Committee (HIARC) conclusion that there is not a concern for neurotoxicity resulting 

from exposure to novaluron. There was no evidence of either carcinogenic or genotoxic 

potential with novaluron. 

Dose Response and Endpoint Selection

The RAB1 toxicologists reevaluated the novaluron database and reaffirmed the previous 

conclusion of the HIARC (16-DEC-2003, TXR# 0052361) that the Food Quality Protection Act 
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(FQPA) Safety Factor (SF) for increased susceptibility of infants and children can be reduced to 

1X. The decision was based on a lack of increased susceptibility in the rat and/or rabbit 

developmental toxicity studies at levels up to the limit dose. Also, no increased qualitative 

and/or quantitative evidence of increased susceptibility was found following pre/post-natal 

exposure in a two-generation reproduction study in rats. The risk assessment team concluded

that the FQPA SF for increased susceptibility of infants and children can be reduced to 1X based 

on toxicological considerations (above), the conservative residue assumptions used in the dietary

risk assessments, the completeness of the residue chemistry database, and conservative drinking 

water assessment. RAB1 toxicologists also reaffirmed the endpoints previously selected by the 

HIARC (16-DEC-2003; TXR# 0052361).

An oral acute reference dose (aRfD) for the general population, including infants and children, 

was not established since an endpoint of concern attributable to a single dose was not identified. 

The chronic reference dose (cRfD) of 0.011 mg/kg/day was determined on the basis of the 

chronic carcinogenicity study in the rat. An uncertainty factor (UF) of 100 (10-fold for 

interspecies extrapolation and 10-fold for intraspecies variability) was applied to the noobserved-adverse-effect-level (NOAEL) of 1.1 mg/kg/day to derive the cRfD. The lowestobserved-adverse-effect-level (LOAEL) of 30.6 mg/kg/day was based on evidence of RBC 

damage and turnover resulting in a regenerative anemia. The FQPA SF of 1X is applicable for 

chronic dietary risk assessment. Therefore, the chronic population-adjusted dose (cPAD) is 

0.011 mg/kg/day.

Based on the toxicological database, a short-term dermal endpoint was not selected; therefore, 

only intermediate-term dermal exposure was assessed. Short- and intermediate- term inhalation 

exposures have been assessed. In addition, the short- and intermediate-term inhalation 

toxicological endpoints are the same; therefore, the estimates of risk for short-term duration 

inhalation exposures are protective of those for intermediate-term inhalation duration exposures. 

A 10% dermal-absorption factor was based on an acceptable dermal-absorption study in rats in 

which the maximum total absorbed dose (expressed as percent of administered dose) ranged 

from approximately 0.5% to 10% of the applied dose. The level of concern (LOC) for 

occupational dermal and inhalation exposures are for margins of exposure (MOEs) <100. 

In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (JUL-1999), 

novaluron is classified as “not likely to be carcinogenic to humans” based on the lack of 

evidence for carcinogenicity in mice and rats.

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

summarized below.

Exposure Scenario Dose Endpoint Study/Effect

Chronic dietary NOAEL = 1.1 mg/kg/day cRfD and cPAD = 0.011 

mg/kg/day

Combined chronic toxicity/carcinogenicity 

feeding study-rat-erythrocyte damage and 

turnover resulting in a regenerative 

anemia at the LOAEL of 30.6 mg/kg/day. 

Intermediate-term dermal

(10% absorption rate) NOAEL = 4.38 

mg/kg/day

LOC for MOEs < 100 

(occupational)

90-day feeding study-rat-clinical 

chemistry and histopathology at the 

Short-term inhalation LOAEL of 8.64 mg/kg/day.

Intermediate-term inhalation
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Dietary Exposure Estimate

An acute dietary assessment was not conducted for novaluron because an endpoint of concern 

attributable to a single dose was not identified. A cancer dietary assessment was not conducted 

because novaluron was classified as “not likely to be carcinogenic to humans.” The current 

chronic dietary analysis assumed 100% crop treated for all commodities and was refined through 

the use of empirical processing factors, some average field trial residues, average greenhouse 

trial residues for tomatoes, and anticipated residues (ARs) for meat, hog, and milk commodities. 

Empirical processing factors for apple juice were translated to pear and other pome fruit juice 

and all stone fruit juice. In accordance with HED Standard Operating Procedure (SOP) 2000.1, 

average field trial residues were translated from representative commodities in the crop group to 

other commodities in that crop group as needed. Estimated drinking water concentrations 

(EDWCs), provided by EFED, were included in this assessment as well. For this action, the 

chronic dietary (food and drinking water) exposure to novaluron is below HED’s LOC for the 

general U.S. population and all population subgroups. The chronic dietary exposure results in a 

risk estimate that is 25% of the cPAD for the general U.S. population and 84% of the cPAD for 

children 1-2 years old, the most highly exposed population subgroup. 

Aggregate Exposure Scenarios and Risk Conclusions

Including all existing and proposed uses, an aggregate human-health risk assessment was

conducted for chronic aggregate exposure (food + water) only. Because there are no uses of 

novaluron that could result in residential exposures, this aggregate risk assessment takes into 

consideration dietary food + water exposure only. The chronic aggregate exposure and risk 

estimates are not of concern. 

Occupational Exposure Estimates

It is anticipated that there will be occupational handler and post-application exposure for the 

proposed uses of novaluron. No chemical-specific handler exposure data were submitted in 

support of this Section 3 registration. It is the policy of HED to use data from the Pesticide 

Handlers Exposure Database (PHED) Version 1.1 as presented in PHED Surrogate Exposure 

Guide (AUG-1998) to assess handler exposures for regulatory actions when chemical-specific 

monitoring data are not available [HED Science Advisory Council for Exposure (ExpoSAC) 

Draft SOP #7, dated 28-JAN-1999]. 

HED has determined that risks are not of concern (i.e., MOEs ≥ 100), provided workers wear 

chemical resistant gloves as recommended on the label. No short-term point of departure was 

selected for the dermal route of exposure; therefore, the risks presented for handlers are 

representative of intermediate-term exposures and would be considered protective of short-term 

exposures.

The MOEs for occupational post-application exposure are all greater than a MOE of 100 on day

0 (12 hours after application) for all crops and activities and are not of concern. Post-application 

dermal risks were calculated based on an intermediate-term point of departure and are considered 

highly conservative.

Since the post-application assessment is not a concern on Day 0 (12 hours following 

application), the restricted-entry interval (REI) is based on the acute toxicity of novaluron 
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technical material. The proposed label for RIMON®has a 12-hour REI. The technical material 

has a Toxicity Category III for acute dermal and a Toxicity Category IV for acute oral and 

inhalation and primary eye and skin irritation. It is not a dermal sensitizer. Per the Worker 

Protection Standard (WPS), a 12-hour REI is required for chemicals classified under Toxicity

Category III and IV and is adequate for the proposed use patterns. 

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human-health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,”

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the U.S. Department of Agriculture (USDA) under the Continuing Surveys of Food Intakes 

by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from the PHED and the Agricultural Reentry Task 

Force (ARTF) studies in which adult human subjects were intentionally exposed to a pesticide or 

other chemical. These studies have been reviewed and have been determined to be ethical.

Recommendation for Tolerances and Registration

Pending submission of revised Sections B and F (see requirements under Directions for Use and 

Proposed Tolerances), there are no residue chemistry, toxicology, or occupational exposure

issues that would preclude granting a conditional registration for the use of novaluron on the 

requested crops. 

The proposed uses and the submitted data support the following permanent tolerances for 

residues of the insecticide novaluron, including its metabolites and degradates, in or on the 

commodities in the table below. Compliance with the tolerance levels specified below is to be 

determined by measuring only novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-

(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide) in or on the 

following raw agricultural commodities (RACs):
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Vegetable, cucurbit, group 9 0.15 ppm Okra 1.0 ppm

Vegetable, fruiting, group 8 1.0 ppm Roselle 1.0 ppm

Cocona 1.0 ppm Sunberry 1.0 ppm

Eggplant, African 1.0 ppm Tomato, bush 1.0 ppm

Eggplant, pea 1.0 ppm Tomato, currant 1.0 ppm

Eggplant, scarlet 1.0 ppm Tomato, tree 1.0 ppm

Goji berry 1.0 ppm Berry, low-growing, subgroup 13-07G 0.45 ppm

Huckleberry, garden 1.0 ppm Bean, snap, succulent 0.60 ppm

Martynia 1.0 ppm Bean, dry, seed 0.30 ppm

Naranjilla 1.0 ppm Swiss chard 12 ppm

Data Needs and Label Recommendations

Toxicology

 The HED HIARC requested a 28-day inhalation toxicity study as a condition of 

registration. However, based on the low volatility and low inhalation toxicity (Toxicity

Category IV) of novaluron and inhalation MOEs >1000 for the proposed uses in this risk 

assessment, novaluron qualifies for a waiver of the 28-day inhalation toxicity study for 

the proposed uses [HED SOP 2002.01: Guidance: Waiver Criteria for MultipleExposure Inhalation Toxicity Studies, 15-AUG-2002]. The requirement for the 28-day 

inhalation toxicity study is waived for this action only. If in the future, requests for 

new uses or formulations are submitted that may result in a significant change in either 

the toxicity profile or exposure scenarios, HED will reconsider this data requirement.

 An immunotoxicity study is required as specified in the new 40 CFR Part 158 data 

requirements.

Residue Chemistry

860.1200 Directions for Use

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

 Specifies that the use of adjuvants/surfactants (including non-ionic surfactants) on 

fruiting vegetable group 8, cucurbit vegetable group 9, strawberry, and low-growing 

berry subgroup 13-07G is prohibited;

 Corrects “lowbush berry” to “lowbush blueberry” in the low-growing berry subgroup 13-

07G section of the label; and

 States that the use of novaluron on crops grown for food in greenhouses, except tomatoes,

is prohibited. 

860.1550 Proposed Tolerances

 The proposed tolerance expression for petition number 9E7546 is written in terms of 

“tolerances for combined residues of the insecticide novaluron, 1-[3-chloro-4(1,1,2-

trifluoro-2-trifluoro-methoxyethoxy)phenyl]-3-(2,6-difluorobenzoyl)urea.” A revised 

Section F for petition number 9E7546 should be submitted to remove the word combined

and cite the appropriate CAS name for novaluron:

“Tolerances are established for residues of the insecticide novaluron, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only 
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novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-

(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide) in or on 

the following raw agricultural commodities:”

 A revised Section F is requested which reflects the recommended tolerances and 

commodity definitions presented in Table 4.1. 

Notes to RD: The currently established tomato tolerance and the time-limited tolerance for 

strawberry should be removed from 40 CFR §180.598. Additionally, the pending tolerance for 

bushberry subgroup 13-07B (7.0 ppm) should be amended to “bushberry subgroup 13-07B, 

except lowbush blueberry.”

Occupational and Residential Exposure

 None. 

2.0 PROPOSED USE PATTERN

IR-4 has submitted a draft label, dated 16-MAR-2009, for Rimon

®

0.83 EC Insecticide (EPA 

Reg. No. 66222-35) to include the proposed new uses (see Table 2.0) on fruiting vegetable group 

8, cucurbit vegetable group 9, low-growing berry subgroup 13-07G, cocona, African eggplant, 

pea eggplant, scarlet eggplant, goji berry, garden huckleberry, martynia, naranjilla, okra, roselle, 

sunberry, bush tomato, currant tomato, tree tomato, snap bean, dry bean seed, and Swiss chard.

Table 2.0. Summary of Proposed Use Pattern for Novaluron.

Application 

Equipment

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Fruiting Vegetables (field) [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]

Groundboom/

Aerial

0.83 lb/gal 

EC

[66222-35]

0.058-

0.078 3-4

1,2,3 0.23 1

Repeat applications as 

needed to protect new

foliage growth, blooms, and 

fruit, but not less than 7 

days apart. 1-day PHI; 12-

hour REI.

Low-Growing Berry Subgroup 13G [cranberry, lingonberry, muntries, partridgeberry, bearberry, bilberry, 

lowbush berry, and cloudberry]

Groundboom/

Aerial

0.83 lb/gal 

EC

[66222-35]

0.078 3

3

0.23 1

Repeat applications as 

needed to protect new

foliage growth, blooms, and 

fruit, but not less than 7 

days apart. 1-day PHI; 12-

hour REI.

Strawberry

Groundboom/

Aerial

0.83 lb/gal 

EC

[66222-35]

0.058-

0.078 3-4 0.23 1

Repeat applications as 

needed to protect new

foliage growth, blooms, and 

fruit, but not less than 14 

days apart. 1-day PHI; 12-

hour REI.

Swiss Chard
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Table 2.0. Summary of Proposed Use Pattern for Novaluron.

Application 

Equipment

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Groundboom/

Aerial

0.83 lb/gal 

EC

[66222-35]

0.058-

0.078 3-4

3

0.23 1

Repeat applications as 

needed to protect new

foliage growth, blooms, and 

fruit, but not less than 7 

days apart. Do not use 

surfactants of any kind with 

Rimon® 0.83EC on this 

crop. 1-day PHI; 12-hour 

REI.

Beans (Snap, Dry)

Groundboom/

Aerial

0.83 lb/gal 

EC

[66222-35]

0.039-

0.078 3-6

2,3 0.23 1

Repeat applications as 

needed to protect new

foliage growth, blooms, and 

fruit, but not less than 7 

days apart. Do not use 

surfactants of any kind with 

Rimon® 0.83EC on this 

crop. 1-day PHI; 12-hour 

REI.

Cucurbit Vegetables [balsam apple, balsam pear, chayote (fruit), cantaloupe, cucumber, Chinese cucumber, 

gherkin (West Indian), edible gourd, melon, citron melon, muskmelon, bittermelon, pumpkin, squash, summer 

squash, winter squash, watermelon, and Chinese waxgourd]

Groundboom/

Aerial

0.83 lb/gal 

EC

[66222-35]

0.058-

0.078 3-4

2,3 0.23 1

Repeat applications as 

needed to protect new

foliage growth, blooms, and 

fruit, but not less than 14 

days apart. Use of a nonionic surfactant to enhance 

coverage and penetration 

may improve performance. 

1-day PHI; 12-hour REI.

1 For the Colorado potato beetle, no more than two applications should be made to a single generation and it should 

not be applied to successive generations. 

2 No more than two applications against whiteflies or thrips per season should be used. 

3

For most effective control, fields should be scouted.

Conclusions: The proposed label is adequate to allow evaluation of the residue data relative to 

the proposed new uses on fruiting vegetable group 8, cucurbit vegetable group 9, low-growing 

berry crop subgroup 13-07G, cocona, African eggplant, pea eggplant, scarlet eggplant, goji 

berry, garden huckleberry, martynia, naranjilla, okra, roselle, sunberry, bush tomato, currant 

tomato, tree tomato, snap beans, dry beans, and Swiss chard. A revised Section B is requested 

which: 

 Specifies that the use of adjuvants/surfactants (including non-ionic surfactants) on 

fruiting vegetable group 8, cucurbit vegetable group 9, strawberry, and low-growing 

berry subgroup 13-07G is prohibited;

 Corrects “lowbush berry” to “lowbush blueberry” in the low-growing berry subgroup 13-

07G section of the label; and

 States that the use of novaluron on crops grown for food in greenhouses, except tomatoes,

is prohibited. 
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3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS

A detailed hazard characterization for novaluron is presented in HED’s previous risk assessment 

(Memo, S. Levy, et al., 03-NOV-2005; D313322). Novaluron has low acute toxicity via the oral 

(Toxicity Category IV), dermal (Toxicity Category III), and inhalation routes (Toxicity Category

IV). No ocular (Toxicity Category IV) or dermal irritation (Toxicity Category IV) was noted. 

Novaluron is not a dermal sensitizer. In subchronic and chronic toxicity studies, novaluron 

primarily produced hematotoxic effects such as methemoglobinemia, decreased hemoglobin, 

decreased hematocrit, and decreased RBCs (or erythrocytes) that were associated with 

compensatory erythropoiesis.

No maternal and/or developmental toxicity was observed in animals tested up to the limit dose in 

either the rat or rabbit developmental toxicity studies. In the two-generation reproductive 

toxicity study, increased spleen weights were observed in parents and offspring at the same dose, 

and reproductive toxicity (decreases in epididymal sperm counts and increased age at preputial 

separation in the F1 generation) was observed in males only at a higher dose. Neurotoxic effects, 

including clinical signs (piloerection, fast/irregular breathing), FOB parameters (head swaying, 

abnormal gait), and neuropathology (sciatic and tibial nerve degeneration) were observed 

following a single dose at the limit dose only (2000 mg/kg/day) in the acute neurotoxicity study

in rats. However, no signs of neurotoxicity or neuropathology were observed following repeated 

dosing in the subchronic neurotoxicity study in rats at doses up to 1752 mg/kg/day in males and 

2000 mg/kg/day in females. Therefore, RAB1 toxicologists reaffirmed the HED HIARC 

conclusion that there is not a concern for neurotoxicity resulting from exposure to novaluron. 

There was no evidence of carcinogenic potential in either the rat or mouse carcinogenicity

studies, and there was no evidence of mutagenic potential in several genotoxicity studies, 

including the bacterial (Salmonella, E. coli) reverse mutation assay, the in vitro mammalian 

chromosomal aberration assay, the in vivo mouse bone-marrow micronucleus assay, and the 

bacterial DNA damage/repair assay. 

3.1 FQPA Considerations

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

following:

 There is no evidence of increased susceptibility in the rat or rabbit developmental toxicity

studies up to the limit dose or in the two-generation reproduction study in rats.

 There are no concerns or residual uncertainties for pre- and/or postnatal toxicity.

 Acute and subchronic neurotoxicity screening batteries were performed with novaluron in 

rats. Novaluron is not considered neurotoxic since the effects observed in the acute 

neurotoxicity study were observed at a very high dose with little to no relevance to 

expected human exposures (i.e., the limit dose) and were not reproduced at similar doses 

in the subchronic neurotoxicity study. In addition, no evidence of neuropathology was 

observed in subchronic and chronic toxicity studies in rats, mice, or dogs.

 A developmental-neurotoxicity (DNT) study is not required.

 Histopathological examination of the organs of the immune system (i.e., thymus, spleen, 

lymph nodes) showed an increase in spleen weight and increased incidence and severity 

of hemosiderosis in the spleen in the chronic studies in rats and mice and the 

reproduction study in rats. These findings were associated with the hematotoxicity of 

novaluron, which caused removal from the blood and accumulation of abnormal 
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erythrocytes in the spleen, and are not considered immunotoxic effects. The overall 

weight of evidence suggests that novaluron does not directly target the immune system. 

An immunotoxicity study is required as part of the revised 40 CFR Part 158 toxicology

data requirements for novaluron; however, HED does not believe that conducting a 

functional immunotoxicity study will result in a lower NOAEL than the regulatory dose 

being used for risk assessment, and an additional UF for database uncertainty (UFDB) is 

not needed to account for the lack of the required immunotoxicity study.

 The conservative residue assumptions used in the dietary exposure risk assessment.

 The completeness of the residue chemistry database and conservative drinking water 

assessment.

The doses and toxicological endpoints selected for human health risk assessment are summarized 

in Table 3.1.

Table 3.1. Summary of Toxicological Dose and Endpoints for Novaluron.

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

FQPA SF and LOC 

for Risk Assessment Study and Toxicological Effects

Acute Dietary

(all populations)

Not applicable None An endpoint of concern attributable to 

a single dose was not identified. An 

acute RfD was not established.

Chronic Dietary

(all populations)

NOAEL = 1.1 

mg/kg/day

UF = 100

FQPA SF = 1X

cRfD = cPAD = 0.011 

mg/kg/day

Combined chronic 

toxicity/carcinogenicity feeding in rat

LOAEL = 30.6 mg/kg/day based on 

erythrocyte damage and turnover 

resulting in a regenerative anemia.

Short-Term

Incidental Oral 

(1-30 days)

NOAEL = 4.38

mg/kg/day

Residential LOC for 

MOE = 100

90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on 

clinical chemistry (decreased 

hemoglobin, hematocrit, and RBC 

counts) and histopathology (increased 

hematopoiesis and hemosiderosis in 

spleen and liver).

Intermediate-Term

Incidental Oral 

(1-6 months)

NOAEL = 4.38

mg/kg/day

Residential LOC for 

MOE = 100

90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on 

clinical chemistry (decreased 

hemoglobin, hematocrit, and RBC 

counts) and histopathology (increased 

hematopoiesis and hemosiderosis in 

spleen and liver).

Short-Term

Dermal (1-30 

days)

Not applicable None No toxicity was observed at the limit 

dose in the dermal study and there 

were no developmental toxicity 

concerns at the limit-dose; therefore, 

quantification of short-term dermal risk 

is not necessary.

Intermediate-Term

Dermal 

(1-6 months)

Oral NOAEL = 4.38

mg/kg/day

(dermal-absorption 

rate = 10%)

Residential/ 

Occupational LOC for 

MOE = 100

90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on 

clinical chemistry (decreased 

hemoglobin, hematocrit, and RBC 

counts) and histopathology (increased 

hematopoiesis and hemosiderosis in 

spleen and liver).

Long-Term Oral NOAEL = 1.1 Residential/ Combined chronic 
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Table 3.1. Summary of Toxicological Dose and Endpoints for Novaluron.

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

FQPA SF and LOC 

for Risk Assessment Study and Toxicological Effects

Dermal 

(>6 months)

mg/kg/day

(dermal-absorption 

rate = 10%)

Occupational LOC for 

MOE = 100

toxicity/carcinogenicity feeding in rat

LOAEL = 30.6 mg/kg/day based on 

erythrocyte damage and turnover 

resulting in a regenerative anemia.

Short-Term

Inhalation 

(1-30 days)

Oral NOAEL = 4.38

mg/kg/day

(inhalationabsorption rate = 

100%)

Residential/ 

Occupational LOC for 

MOE = 100

90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on 

clinical chemistry (decreased 

hemoglobin, hematocrit, and RBC 

counts) and histopathology (increased 

hematopoiesis and hemosiderosis in 

spleen and liver).

Intermediate-Term

Inhalation 

(1-6 months)

Oral NOAEL = 4.38

mg/kg/day

(inhalationabsorption rate = 

100%)

Residential/ 

Occupational LOC for 

MOE = 100

90-day feeding study in rat

LOAEL = 8.64 mg/kg/day based on 

clinical chemistry (decreased 

hemoglobin, hematocrit, and RBC 

counts) and histopathology (increased 

hematopoiesis and hemosiderosis in 

spleen and liver).

Long-Term

Inhalation 

(>6 months)

Oral NOAEL = 1.1 

mg/kg/day

(inhalationabsorption rate = 

100%)

Residential/ 

Occupational LOC for 

MOE = 100 

Combined chronic 

toxicity/carcinogenicity feeding in rat

LOAEL = 30.6 mg/kg/day based on 

erythrocyte damage and turnover 

resulting in a regenerative anemia.

Cancer Not likely to be carcinogenic to humans.

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no-observed-adverse-effect-level, LOAEL = 

lowest-observed-adverse-effect-level, PAD = population-adjusted dose (a = acute, c = chronic), RfD = reference 

dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable.

3.2 Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to 

determine whether certain substances (including all pesticide active and other ingredients) “may 

have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, 

or other such endocrine effects as the Administrator may designate.” Following the 

recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee 

(EDSTAC), EPA determined that there were scientific bases for including, as part of the 

program, androgen and thyroid hormone systems, in addition to the estrogen hormone system. 

EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential 

effects in wildlife. When the appropriate screening and/or testing protocols being considered 

under the Agency’s Endocrine Disrupter Screening Program (EDSP) have been developed and 

vetted, novaluron may be subjected to additional screening and/or testing to better characterize 

effects related to endocrine disruption.
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4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION

The residue chemistry data submitted in support of the proposed uses are summarized in the 

pending HED memorandum by J. L. Van Alstine (D364237). The chronic dietary exposure 

assessment is summarized in the pending HED memorandum by J. L. Van Alstine (D364235).

4.1 Food Residue Profile

Nature of the Residue - Plants: HED previously concluded that the nature of the residue in 

plants is adequately understood based on acceptable metabolism studies conducted on apples, 

cabbage, cotton, and potatoes using [difluorophenyl-U14C]novaluron and [chlorophenyl-U14C]novaluron as the test substances (Memo, G. Kramer, 22-MAR-2004; D285474). These 

studies indicate that novaluron is not extensively metabolized in these crops. The parent 

compound, novaluron, was either the only residue component identified or was the predominant 

residue component in all analyzed plant matrices. The reviewed studies also indicate that 

novaluron, when foliarly applied during the vegetative growth stage, is not readily translocated 

to mature apple fruit, potato tubers, or cottonseed (Memo, G. Kramer, 22-MAR-2004; D285474). 

Based on these studies, the Metabolism Assessment and Review Committee (MARC) 

determined that the residue of concern in crops for purposes of tolerance enforcement and risk 

assessment is novaluron only (Memo, G. Kramer et al., 03-FEB-2004; D297646). 

Nature of the Residue - Livestock: HED also previously concluded that the nature of the residue 

in livestock is adequately understood based on the submitted goat and poultry metabolism 

studies (Memo, G. Kramer, 22-MAR-2004; D285474). The HED MARC determined that the 

residue of concern in livestock for purposes of tolerance enforcement and risk assessment is 

novaluron only (Memo, G. Kramer et al., 03-FEB-2004; D297646).

Residue Analytical Enforcement Method - Plant: MANA previously submitted a gas 

chromatography/electron-capture detection (GC/ECD) residue analytical method for the analysis 

of novaluron residues in/on pome fruit, cabbage, and potato commodities; HED concluded that 

the method was adequate for gathering data on novaluron. A second method, high-performance 

liquid chromatography/ultraviolet (HPLC/UV), was submitted for the analysis of novaluron 

residues only in/on cotton commodities. Both methods were adequately validated by the 

petitioner and by an independent laboratory. Acceptable radiovalidation data for the GC/ECD 

method have been submitted and reviewed in a previous HED memorandum (Memo, S. Levy, 

23-AUG-2006; D325183) and both methods were forwarded to the EPA Analytical Chemistry

Branch (ACB)/Biological and Economics Analysis Division (BEAD) for petition method 

validation (PMV). 

ACB concluded that based upon review of the submitted method validation data, without 

laboratory validation, that the GC/ECD and HPLC/UV methods appear suitable for food 

tolerance enforcement in plants (apples, cabbage, potatoes) and cotton. ACB recommended that 

the analytical methods do not need to be laboratory validated by EPA (Memo, S. Levy, 15-

SEPT-2004; D306998). Both methods have been forwarded to the Food and Drug 

Administration (FDA) for inclusion in the Pesticide Analytical Manual, Volume II (PAM II) as a 

Letter Method (S. Levy, 15-SEPT-2004; D307595). An interference study was requested and a 

specific single-analyte confirmatory method was submitted and considered acceptable (Memo, J. 

Langsdale, 21-OCT-2008; D355574).
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Magnitude of the Residue - Plants: The submitted field trial data for bell and non-bell pepper, 

cucumber, cantaloupe, summer squash, strawberry, snap bean, dry bean seed, and Swiss chard 

are adequate and will support the establishment of residue tolerances for novaluron in/on fruiting 

vegetables group 8 (1.0 ppm), cucurbit vegetable group 9 (0.15 ppm), low-growing berry

subgroup 13-07G (0.45 ppm), cocona (1.0 ppm), African eggplant (1.0 ppm), pea eggplant (1.0 

ppm), scarlet eggplant (1.0 ppm), goji berry (1.0 ppm), garden huckleberry (1.0 ppm), martynia 

(1.0 ppm), naranjilla (1.0 ppm), okra (1.0 ppm), roselle (1.0 ppm), sunberry (1.0 ppm), bush 

tomato (1.0 ppm), currant tomato (1.0 ppm), tree tomato (1.0 ppm), snap bean (0.60 ppm), dry

bean seed (0.30 ppm), and Swiss chard (12 ppm). 

Processed Food and Feed: HED does not require residue data for any processed commodities 

associated with the proposed crops. Therefore, data requirements for processed food and feed 

are not relevant to these commodities. 

Confined/Field Accumulation in Rotational Crops: The commodities associated with the 

current petitions may be rotated. The available confined rotational crop study is adequate. The 

HED MARC has determined that for tolerance assessment and risk assessment, parent only is the 

residue of concern (Memo, G. Kramer et al., 03-FEB-2004; D297646). Based on the results of a 

previously submitted confined rotational crop study (Memo, G. Kramer, 22-MAR-2004; 

D285474), the appropriate plantback interval (PBI) for all non-labeled crops is 30 days. The 

current and proposed labels include a restriction that only registered crops may be rotated to a 

treated field within 30 days of the final application, which is appropriate for this petition. 

Tolerance Summary: Permanent tolerances for novaluron have been established for a variety of 

commodities under 40 CFR §180.598. HED has determined that the residue of concern in plants 

for tolerance enforcement is novaluron only. The proposed tolerance expression for petition 

number 9E7546 is written in terms of “tolerances for combined residues of the insecticide

novaluron, 1-[3-chloro-4(1,1,2-trifluoro-2-trifluoro-methoxyethoxy)phenyl]-3-(2,6-

difluorobenzoyl)urea.” A revised Section F should be submitted to remove the word combined

and cite the appropriate CAS name for novaluron:

“Tolerances are established for residues of the insecticide novaluron, including its metabolites 

and degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only novaluron (N-[[[3-chloro-4-[1,1,2-

trifluoro-2-(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide) in or on 

the following raw agricultural commodities:”

A summary of the recommended tolerances for the current petition are listed in Table 4.1. A 

revised Section F is requested which reflects the recommended tolerances and commodity

definitions presented in Table 4.1. HED notes that cocona, African eggplant, pea eggplant, 

scarlet eggplant, goji berry, garden huckleberry, martynia, naranjilla, okra, roselle, sunberry, 

bush tomato, currant tomato, and tree tomato residue data have not been submitted and concludes 

that the fruiting vegetable crop group 8 tolerance (1.0 ppm) may be translated to the proposed 

commodities (see Reviewer's Guide and Summary of HED ChemSAC Approvals for Amending 

Commodity Definitions (40 CFR 180.1(h)) and Crop Group/Subgroups (40 CFR 180.41)). 

No Codex, Canadian, or Mexican MRLs have been established for novaluron in/on the proposed 

commodities. Canada is currently in the process of reviewing the use of novaluron on 

strawberries, snap beans, and bell and non-bell peppers. EPA and PMRA tolerance 
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recommendations have been harmonized at 0.45 ppm for low-growing berry subgroup 13-07G 

and 0.60 for edible-podded snap beans. The PMRA has not received petitions for the use of 

novaluron on fruiting vegetable group 8 and will be setting tolerances for bell and non-bell 

peppers at 0.80 ppm and 0.90 ppm, respectively (personal communication with Melissa 

Watchorn of PMRA, 30-NOV-2009).

The Agency’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized 

for determining appropriate tolerance levels.

Notes to RD: The currently established tomato tolerance and the time-limited tolerance for 

strawberry should be removed from 40 CFR §180.598. Additionally, the pending tolerance for 

bushberry subgroup 13-07B (7.0 ppm) should be amended to “bushberry subgroup 13-07B, 

except lowbush blueberry.”

Table 4.1. Tolerance Summary for Novaluron.

Commodity Proposed 

Tolerance (ppm)

HED Recommended 

Tolerance (ppm)

Comments; 

Correct Commodity Definition

Vegetable, fruiting, group 8 1.1 1.0 

Vegetable, cucurbit, group 9 0.25 0.15 

Berry, low growing, 

subgroup 13-07G 0.50 0.45 Berry, low-growing, subgroup 13-07G

Cocona 1.1 1.0 

Eggplant, African 1.1 1.0 

Eggplant, pea 1.1 1.0 

Eggplant, scarlet 1.1 1.0 

Goji berry 1.1 1.0 

Huckleberry, garden 1.1 1.0 

Martynia 1.1 1.0 

Naranjilla 1.1 1.0 

Okra 1.1 1.0 

Roselle 1.1 1.0 

Sunberry 1.1 1.0 

Tomato, bush 1.1 1.0 

Tomato, currant 1.1 1.0 

Tomato, tree 1.1 1.0 

Bean, snap, succulent 0.60 0.60 

Bean, dry 0.20 0.30 Bean, dry, seed

Swiss chard 12 12 

4.2 Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED (Memo, 

I. Maher, 16-JUL-09; D363989). Since the application rates for the proposed new uses are 

significantly lower than the use rates for pome fruits and stone fruits, the EDWCs provided in the 

previous drinking water assessments dated 10-MAR-2009 (D357061) and 11-FEB-2004 

(D285477) are applicable for the proposed uses. 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 
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chlorophenyl urea and chloroaniline degradates, in surface water or ground water. 

Concentrations in surface water and ground water were estimated using standard EFED drinking 

water models.

Tier II Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) 

modeling was performed to estimate drinking water concentrations for surface water for the 

parent novaluron. The scenarios were selected to provide high-end drinking water 

concentrations for each crop and represent the geographic locations where the specific crops are 

grown in large quantities. The most-conservative estimates were obtained for aerial applications 

to apples grown in PA at the maximum annual application rate of 0.96 lb ai/acre, applied three 

times at 0.32 lb ai/acre, with an interval between applications of ten days. For surface water, the 

1-in-10-year annual mean EDWC for the parent novaluron is 0.76 ppb. 

A Tier I drinking water analysis was performed for the chlorophenyl urea and chloroaniline 

degradates. The FQPA Index Reservoir Screening Tool (FIRST) model was used to obtain 

surface water estimates. For surface water, the annual average EDWC for chlorophenyl urea is 

0.89 ppb and the annual average EDWC for chloroaniline is 2.6 ppb. The chlorophenyl urea 

estimate is based upon the maximum application rate in peaches [0.32 lb ai/A applied 3 times per 

season every 7 days (0.96 lb ai/year)] and the chloroaniline estimate is based upon the maximum 

application rate in apples [0.32 lb ai/A applied 3 times per season every 10 days (0.96 lb 

ai/year)].

For ground water, the Screening Concentration in Ground Water (SCI-GROW) model was used 

to predict a ground water concentration for novaluron at the annual application rate of 0.96 lb 

ai/acre (i.e., three applications of 0.32 lb ai/acre). The estimate for the parent novaluron is 

0.0056 ppb in drinking water from shallow ground water sources. For the chlorophenyl urea 

degradate, the predicted ground water concentration is 0.0045 ppb, and for the chloroaniline 

degradate the concentration is 0.0090 ppb. These concentrations were estimated with the same 

assumptions used for surface water modeling, and may be considered as both the peak and 

annual average upper-bound exposures.

These EDWC values are meant to represent upper-bound estimates of the concentrations that 

might be found in surface water and ground water based upon existing and proposed uses. Of 

the three EDWC values, chronic estimates for the terminal chloroaniline metabolite are the 

highest (100% conversion from parent to aniline was assumed). This is consistent with the 

expected degradation pattern for novaluron. Therefore, the EDWC value for the chloroaniline 

degradate (2.6 ppb) was used to assess chronic aggregate risk.

4.3 Dietary Exposure and Risk

An acute dietary assessment was not conducted for novaluron because an endpoint of concern 

attributable to a single dose was not identified. A cancer dietary assessment was not conducted 

because novaluron was classified as “not likely to be carcinogenic to humans.”

A chronic dietary exposure and risk assessment was conducted using the DEEM-FCID, 

Version 2.03, which uses food consumption data from USDA’s CSFII from 1994-1996 and 

1998. The analysis was performed to support the request for use of novaluron fruiting vegetable 

group 8; cucurbit vegetable group 9; low-growing berry subgroup 13-07G; miscellaneous 

fruiting vegetables; snap bean; dry bean seed; and Swiss chard.
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The chronic dietary (food and drinking water) exposure and risk assessment was conducted for 

the proposed uses on fruiting vegetables group 8, cucurbit vegetable group 9, low-growing berry

subgroup 13-07G, miscellaneous fruiting vegetables, snap bean, dry bean seed, and Swiss chard;

all established uses; and drinking water. A partially refined assessment was conducted. EDWCs 

were provided by EFED. The chronic analysis assumed 100% crop treated for all commodities; 

incorporated average field trial residues for some commodities (pome fruit, sugarcane, 

bushberries, Brassica leafy greens, stone fruit, bell pepper, non-bell pepper, cucumber, summer 

squash, cantaloupe, strawberry, succulent snap bean, dry bean seed, and Swiss chard); average 

greenhouse trial residues for tomatoes; empirical processing factors for apple juice (translated to 

pear and stone fruit) and tomato paste and purée; and DEEM (ver. 7.81) default processing 

factors for the remaining processed commodities. Furthermore, ARs were used for meat, hog, 

and milk commodities.

The chronic dietary (food and drinking water) exposure to novaluron is below HED’s LOC for 

the general U.S. population and all population subgroups. The chronic dietary exposure results 

in a risk estimate that is 25% of the chronic population-adjusted dose (cPAD) for the general 

U.S. population and 84% of the cPAD for children 1-2 years old, the most highly exposed 

population subgroup. 

Table 4.3. Summary of Chronic Dietary Exposure (Food and Drinking Water) and Risk for Novaluron1.

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

0.002749 25

N/A N/A

All Infants (<1 year old) 0.004732 43

Children 1-2 years old 0.009204 84

Children 3-5 years old 0.007142 65

Children 6-12 years old 0.004307 39

Youth 13-19 years old 0.002365 22

Adults 20-49 years old 0.001944 18

Adults 50+ years old 0.001965 18

Females 13-49 years old 0.001856 17

1 The chronic RfD (cRfd= cPAD = 0.011 mg/kg/day).

5.0 Residential (Non-Occupational) Exposure/Risk Characterization

All uses for novaluron, either proposed or existing, are agricultural or commercial in nature. No 

residential uses are proposed, nor are any of the uses expected to result in residential exposure. 

Therefore, a residential exposure assessment was not performed for this action.

5.1 Spray Drift 

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application but, to a lesser extent, could also be a 

potential source of exposure from the ground application method additionally employed for 

novaluron. The Agency has been working with the Spray Drift Task Force, EPA Regional 

Offices and State Lead Agencies for pesticide regulation and other parties to develop the best 

spray drift management practices. The Agency is now requiring interim mitigation measures for 

aerial applications that must be placed on product labels/labeling. The Agency has completed its 
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evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data and the 

AgDRIFT®computer model to its risk assessments for pesticides applied by air, orchard airblast 

and ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray drift management practices to reduce off-target drift and risks associated 

with aerial as well as other application types where appropriate.

6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

Including all existing and proposed uses, a human-health aggregate risk assessment has been 

conducted for the following exposure scenario: chronic aggregate exposure (food + water only). 

An acute aggregate assessment was not conducted for novaluron because an endpoint of concern 

attributable to a single dose was not identified. A cancer aggregate assessment was not 

conducted because novaluron was classified as “not likely to be carcinogenic to humans.”

Because there are no uses of novaluron that could result in residential exposures, this aggregate 

risk assessment takes into consideration dietary food + water exposure only; therefore, the 

chronic aggregate estimates would be the same as the chronic dietary exposure results shown in 

Table 4.3. The chronic aggregate exposure and risk estimate is below HED’s LOC. 

7.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY

An occupational exposure assessment for novaluron was prepared in an HED memorandum 

dated 05-NOV-2009 (L. Venkateshwara; D364236). See Table 2.0 for a summary of the 

proposed use patterns. 

7.1 Occupational Pesticide Handler Exposure and Risk

There is potential for occupational handler exposure from the proposed uses on agricultural 

crops. Handler’s exposure and risk were estimated for the following scenarios: 

Mixer/Loader:

(1) Mixing/loading liquids for aerial application;

(2) Mixing/loading liquids for groundboom application;

Applicator:

(3) Applying sprays via aerial applications;

(4) Applying sprays via groundboom applications; and

Flagger:

(5) Flagging to support aerial applications

No chemical-specific data were available with which to assess potential exposure to pesticide 

handlers. The estimates of exposure to pesticide handlers are based upon surrogate study data 

available in the PHED (August, 1998). For pesticide handlers, HED presents estimates of 

dermal exposure for “baseline” (i.e., workers wearing a single layer of work clothing consisting 

of a long-sleeved shirt, long pants, shoes plus socks, and no protective gloves), as well as for 
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“baseline” and the use of protective gloves or other personal-protective equipment (PPE), as 

might be necessary. The novaluron product labels direct applicators and other handlers to wear a 

long-sleeved shirt, long pants, protective eyewear, chemical-resistant gloves, and shoes plus 

socks. 

Handler exposure is expected to be short- and intermediate-term based on information provided 

on proposed labels (e.g., depending on the crop, 3-6 applications per season are allowed ranging 

from 7-14 days apart). There is no short-term dermal point of departure; therefore, only 

intermediate-term dermal exposure has been assessed and is anticipated to be protective of shortterm dermal exposure. Short- and intermediate-term inhalation exposures have been assessed. 

In addition, the short- and intermediate-term inhalation toxicological points of departure are the 

same; therefore, the estimates of risk for short-term duration inhalation exposures are protective 

of those for intermediate-term inhalation duration exposures. The average adult body weight of 

70 kg was used for estimating inhalation and dermal dose. Long-term exposures are not 

expected, therefore, a long-term assessment was not conducted.

Daily dermal or inhalation handler exposures are estimated for each applicable handler task with 

the application rate, the area treated in a day, and the applicable dermal or inhalation unit 

exposure using the following formula:

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

Treated (area/day)

Where: 

Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is 

available for dermal absorption or amount inhaled that is available for 

inhalation absorption;

Unit Exposure = Unit exposure value (mg ai/lb ai) derived from August 1998 PHED 

data;

Application Rate = Normalized application rate based on a logical unit treatment, such as 

acres; and

Daily Area Treated = Normalized application area based on a logical unit treatment such as 

acres (A/day). 

The daily dermal or inhalation dose is calculated by normalizing the daily exposure by body

weight and adjusting, if necessary, with an appropriate dermal or inhalation absorption factor 

using the following formula:

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

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a 

given scenario (mg ai/kg body weight/day);

Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that 

is available for dermal absorption or amount inhaled that is 

available for inhalation absorption;

Absorption Factor = A measure of the amount of chemical that crosses a biological 

boundary such as the skin or lungs (% of the total available 

absorbed); and

Body Weight = Body weight determined to represent the population of interest 

in a risk assessment (kg).
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Non-cancer dermal and inhalation risks for each applicable handler scenario are calculated using 

an MOE, which is a ratio of the NOAEL to the daily dose. All MOE values were calculated 

using the formula below:

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

Dermal and inhalation risks were combined in this assessment, since the toxicological effects for 

these exposure routes were similar. Dermal and inhalation risks were combined using the 

following formula:

Total MOE = NOAEL / (Dermal + Inhalation Dose)

Table 7.1 presents the estimated risks for workers based on the intermediate-term dermal and 

short- and intermediate-term inhalation exposures at baseline and with PPE. HED has 

determined that risks are not of concern (i.e., MOEs ≥ 100), provided workers wear chemicalresistant gloves as recommended on the label. No short-term point of departure was selected 

for dermal exposure; therefore, the risks presented for handlers are representative of 

intermediate-term exposures and would be considered protective of short-term exposures.

It should be noted that only engineering control data are available to assess dermal and inhalation 

risks to handlers operating aircraft (enclosed cockpit). The risks are not of concern for pilots 

using enclosed cockpits.

Table 7.1. Occupational Handler Dermal and Inhalation Exposures and Risks.

Dermal and

Inhalation Unit 

Exposures

(mg/lb ai)

Application 

rate

(lb ai/A)1

Area 

Treated 

Daily (A)2

Short- and 

Intermediate-term

Doses (mg/kg/day)3

Total Dose

4

Short- and 

Intermediateterm MOETotal MOEs 5

(1) Mixer/Loader – Groundboom Application

Dermal

Baseline: 2.9 

Single layer 

w/gloves: 0.023

Inhalation

Baseline: 0.0012 

0.078 80

Dermal

Baseline6: 0.026

Single layer 

w/gloves8: 0.00021

Baseline 

Dermal + 

Inhalation

0.026

Single layer 

w/gloves + 

Inhalation

0.00032

Dermal

Baseline6: 

170

Single layer 

w/gloves8: 

21,000

Baseline 

Dermal + 

Inhalation

170

Single layer 

w/gloves + 

Baseline 

Inhalation

14,000

Inhalation

Baseline7: 0.00011

Inhalation 

Baseline7: 

41,000

(2) Mixer/Loader – Aerial Application

Dermal

Baseline: 2.9

Single layer 

w/gloves: 0.023

Inhalation

Baseline: 0.0012 

0.078 350

Dermal

Baseline: 0.11

Single layer 

w/gloves:

0.00090

Baseline 

Dermal + 

Inhalation

0.11

Single layer 

w/gloves + 

Inhalation

0.0014

Dermal

Baseline: 39

Single layer 

w/gloves:

13,000

Baseline 

Dermal + 

Inhalation

39

Single layer 

w/gloves + 

Baseline 

Inhalation

3,200

Inhalation

Baseline: 0.00047

Inhalation

Baseline: 9,400
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Table 7.1. Occupational Handler Dermal and Inhalation Exposures and Risks.

Dermal and

Inhalation Unit 

Exposures

(mg/lb ai)

Application 

rate

(lb ai/A)1

Area 

Treated 

Daily (A)2

Short- and 

Intermediate-term

Doses (mg/kg/day)3

Total Dose

4

Short- and 

Intermediateterm MOETotal MOEs 5

(3) Applicator –Groundboom Application

Dermal

Baseline: 0.014

Inhalation

Baseline: 0.00074

0.078 80

Dermal

Baseline: 0.00012 Baseline 

Dermal + 

Inhalation

0.0002

Dermal

Baseline: 

35,000

Baseline 

Dermal + 

Inhalation

Inhalation 23,000

Baseline: 0.000066

Inhalation

Baseline: 

66,000

(4) Applicator –Aerial Application

Dermal

Engineering 

Control: 0.0050

Inhalation

Engineering 

Control: 0.000068 

0.078 350

Dermal

Engineering control:

0.0002 Combined 

Engineering 

Control

0.00023

Dermal

Engineering 

control:

22,000

Combined 

Engineering 

Control

20,000 Inhalation

Engineering control: 

0.000027

Inhalation

Engineering 

control: 

170,000

(5) Flagger –Aerial Application

Dermal

Baseline: 0.011

Inhalation

Baseline: 0.00035 

0.078 350

Dermal

Baseline: 0.00043 Baseline 

Dermal + 

Inhalation

0.0006 

Dermal

Baseline: 

10,000 Baseline 

Dermal + 

Inhalation

Inhalation 7,700

Baseline: 0.00014 

Inhalation

Baseline: 

32,000

1 Application rates are the maximum recommended rates provided on the novaluron product labels.

2 Area treated per day values are HED estimates based on ExpoSAC Policy #9 “Standard Values for Daily Acres Treated in 

Agriculture,” industry sources, and HED estimates.

3 Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x % Absorption (10% dermal 

and 100% inhalation assumed) / Body weight. The body weight is 70 kg for the inhalation and dermal dose. 

4 Total Dose = Dermal + Inhalation Dose.

5 Total MOE = NOAEL (4.38 mg/kg/day)/Total Dose.

6 Baseline Dermal: long-sleeved shirt, long pants, no gloves.

7 Baseline Inhalation: no respirator.

8

Single layer with gloves: single layer baseline attire plus chemical-resistant gloves.

7.2 Occupational Post-Application Worker Exposure and Risk

HED assumes that inhalation exposures are minimal following outdoor applications of an active 

ingredient with low vapor pressure. Since novaluron is applied only in outdoor settings and has 

a low vapor pressure (1.2 x 10-7 mm Hg at 22o Celsius), a quantitative post-application inhalation 

exposure and risk assessment was not conducted.

The proposed use is for a postemergent application; therefore, a dermal post application exposure 

assessment was conducted. Since no post-application data were submitted in support of this 

registration action, dermal exposures during post-application activities were estimated using 

dermal transfer coefficients from the ExpoSAC Policy Number 3.1: Agricultural Transfer 

Coefficients, August 2000, summarized in Table 7.2 below and the following assumptions:
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 Application Rate = 0.078 lb ai/A; 

 Exposure Duration = 8 hours per day;

 Body Weight = 70 kg for adult male;

 Dermal Absorption = 10%; and

 Fraction of ai retained on foliage is assumed to be 20% (0.2) on day zero [= % 

dislodgeable-foliar residue (DFR) after initial treatment] for agricultural crops. This 

fraction is assumed to further dissipate at the rate of 10% (0.1) per day on following 

days. These are default values established by HED’s ExpoSAC.

Table 7.2. Anticipated Post-application Activities and Dermal Transfer Coefficients.

Proposed 

Crops

Policy Crop 

Group Category

Transfer 

Coefficients 

(cm2/hr)

Activities

Fruiting 

Vegetables

Fruiting 

Vegetables

500 Scouting (minimum foliage), hand weeding, thinning

700 Scouting (full foliage), irrigation

1000 Hand harvest, pruning, staking, tying

Swiss Chard Vegetable, leafy

500 Hand weeding, irrigation (minimum foliage), scouting (minimum 

foliage), thinning (minimum foliage)

1,500 Irrigation (full foliage), scouting (full foliage)

2500 Hand harvesting, hand pruning, thinning (full foliage)

Beans (snap 

and dry)

Field/row crop 

low/medium

100 Scouting (minimum foliage), irrigation (minimum foliage), hand 

weeding

1500 Scouting (full foliage), irrigation (full foliage)

2500 Hand harvesting

Cucurbit 

Vegetables

Vegetable, 

cucurbit

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

1500 Irrigation, scouting, hand weeding (full foliage)

2500 Hand harvest, thinning (full foliage), hand pruning

Lowgrowing 

Berries

Berry, low

400 Scouting, hand weeding, irrigation, hand pruning, thinning

1500 Hand harvest, hand pruning

Strawberry Berry, low

400 Irrigation, mulching, scouting, hand pruning and hand weeding

1500 Hand harvesting, pinching, hand pruning, training

The following equations were used to calculate risks for workers performing post-application 

activities:

DFRt (μg/cm2) = AR (lb ai/acre) x F x (1-D)tx 4.54E8 μg/lb x 2.47E-8 acre/cm2

Where:

DFRt = dislodgeable foliage residue on day “t” (μg/cm2);

AR = application rate (lb ai/acre);

F = fraction of ai retained on foliage (unitless); 
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D = fraction of residue that dissipates daily (unitless);

and

Daily dermal dose t (mg/kg-day) = [DFRt (μg/cm2) x 1E-3 mg/μg x Tc (cm2/hr) x DA x ET (hrs)] / BW (kg).

Where:

t = number of days after application day (days);

DFRt = dislodgeable foliage residue on day “t” (μg/cm2);

Tc = transfer coefficient (cm2/hr);

DA = dermal absorption factor (unitless);

ET = exposure time (hr/day);

BW = body weight (kg);

and

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

The post-application exposures associated with the proposed new use are summarized in Table 

7.3. The resulting MOEs are greater than 100 on day 0 (12 hours after application) for all crops 

and activities. Post-application dermal risks were calculated based on an intermediate-term 

endpoint and are considered highly conservative for the included activities.

Table 7.3. Post-application Risks for Novaluron.

Crop

Application 

Rate

(lb ai/A)

Transfer Coefficient

(cm2/hr)

DFR 

(ug/cm2)

Days After 

Treatment

Daily Dose1

(mg/kg/ay) MOE2

Fruiting 

Vegetables 0.078

500

0.18 12 hours (0 

days)

0.001 4,400

700 0.0014 3,100

1,000 0.002 2,200

Swiss Chard 0.078

500

0.18 12 hours (0 

days)

0.001 4,400

1,500 0.003 1,500

2,500 0.005 880

Beans (snap 

and dry) 0.078

100

0.18 12 hours (0 

days)

0.0002 22,000

1,500 0.003 1,500

2,500 0.005 880

Cucurbit 

Vegetables 0.078

500

0.18 12 hours (0 

days)

0.001 4,400

1,500 0.003 1,500

2,500 0.18 12 hours (0 

days) 0.005 880

Low-growing 

Berries 0.078

400

0.18 12 hours (0 

days)

0.0008 5,500

1,500 0.003 1,500

Strawberry 0.078 400 0.18 12 hours (0 0.0008 5,500
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Table 7.3. Post-application Risks for Novaluron.

Crop

Application 

Rate

(lb ai/A)

Transfer Coefficient

(cm2/hr)

DFR 

(ug/cm2)

Days After 

Treatment

Daily Dose1

(mg/kg/ay) MOE2

1,500 days) 0.003 1,500

1 Daily Dose = [DFR (ug/cm2

) x TC (cm2/hr) x 0.001 mg/μg x Dermal Absorption (10%) x 8 hrs/day] ÷ Body Weight (70 kg).

2 NOAEL/Daily Dose (Intermediate-term NOAEL = 4.38 mg/kg/day).

Since the post-application assessment is not a concern on Day 0 (12 hours following 

application), the REI is based on the acute toxicity of novaluron technical material. The 

proposed label for RIMON®has a 12-hour REI. The technical material has a Toxicity Category

III for acute dermal and a Toxicity Category IV for acute oral and inhalation and primary eye 

and skin irritation. It is not a dermal sensitizer. Per the WPS, a 12-hour REI is required for 

chemicals classified under Toxicity Category III and IV. 

8.0 DATA NEEDS AND LABEL RECOMMENDATIONS

8.1 Toxicology

 The HED HIARC requested a 28-day inhalation toxicity study as a condition of 

registration. However, based on the low volatility and low inhalation toxicity (Category

IV) of novaluron and inhalation MOEs >1000 for the proposed uses in this risk 

assessment, novaluron qualifies for a waiver of the 28-day inhalation toxicity study for 

the proposed uses [HED SOP 2002.01: Guidance: Waiver Criteria for Multiple-Exposure 

Inhalation Toxicity Studies, 15-AUG-2002]. The requirement for the 28-day inhalation 

toxicity study is waived for this action only. If in the future, requests for new uses or 

formulations are submitted that may result in a significant change in either the toxicity

profile or exposure scenarios, HED will reconsider this data requirement.

 An immunotoxicity study is required as specified in the new 40 CFR Part 158 data 

requirements.

8.2 Residue Chemistry

 860.1200 Directions for Use

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

 Specifies that the use of adjuvants/surfactants (including non-ionic 

surfactants) on fruiting vegetable group 8, cucurbit vegetable group 9, 

strawberry, and low-growing berry subgroup 13-07G is prohibited;

 Corrects “lowbush berry” to “lowbush blueberry” in the low-growing berry

subgroup 13-07G section of the label; and

 States that the use of novaluron on crops grown for food in greenhouses, 

except tomatoes, is prohibited. 

 860.1550 Proposed Tolerances

 The proposed tolerance expression for petition number 9E7546 is written in 

terms of “tolerances for combined residues of the insecticide novaluron, 1-[3-

chloro-4(1,1,2-trifluoro-2-trifluoro-methoxyethoxy)phenyl]-3-(2,6-

difluorobenzoyl)urea.” A revised Section F for petition number 9E7546 

should be submitted to remove the word combined and cite the appropriate 

CAS name for novaluron:
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“Tolerances are established for residues of the insecticide novaluron, 

including its metabolites and degradates, in or on the commodities in the table 

below. Compliance with the tolerance levels specified below is to be 

determined by measuring only novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro-2-

(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-difluorobenzamide) in 

or on the following raw agricultural commodities:”

 A revised Section F is requested which reflects the recommended tolerances 

and commodity definitions presented in Table 4.1. 

Notes to RD: The currently established tomato tolerance and the time-limited tolerance for 

strawberry should be removed from 40 CFR §180.598. Additionally, the pending tolerance for 

bushberry subgroup 13-07B (7.0 ppm) should be amended to “bushberry subgroup 13-07B, 

except lowbush blueberry.”

8.3 Occupational and Residential Exposure

 None. 

Attachments:

Appendix A: TOXICOLOGY ASSESSMENT

A.1 Acute Toxicity Profile.

A.2 Toxicity Profiles.

cc: J. Van Alstine, L. Venkateshwara, R. Mitkus

RDI: RAB1 Branch (11/18/09); G. Kramer (04/12/09); D. Vogel (04/12/09)

J. Van Alstine: S-10954: Potomac Yard 1 (PY1): (703)603-8866: 7509P: RAB1
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Appendix A: TOXICOLOGY ASSESSMENT

A.1. Acute Toxicity Profile

Table A.1. Acute Toxicity of Novaluron.

Guideline No. Study Type MRID #(s) Results Toxicity Category

870.1100

(81-1) Acute Oral (rat) 44961001 LD50 > 5000 mg/kg IV

870.1200

(81-2) Acute Dermal (rat) 45003201 LD50 > 2000 mg/kg III

870.1300

(81-3) Acute Inhalation (rat) 45003202 LC50 > 5.15 mg/L IV

870.2400

(81-4) Primary Eye Irritation (rabbit) 45003203 Not an eye irritant IV

870.2500

(81-5 ) Primary Skin Irritation (rabbit) 45003204 Not a dermal irritant IV

87.2600

(81-6) Dermal Sensitization (guinea pig) 45084001 Not a dermal sensitizer N/A

A.2 Toxicity Profiles

Table A.2. Toxicity Profile of Novaluron.

Guideline No/ 

Study type MRID No.(year)/Doses/Classification Results

870.3100

90-Day oral 

toxicity rodents

45651504/45651503 (1993/1990);

Acceptable/guideline

Study I: 0, 50, 100, 200, or 400 ppm 

(equivalent to 0, 3.52, 6.93, 13.03, and

27.77 mg/kg bw/day, respectively in 

males and 0, 4.38, 8.64, 17.54, and 

34.39 mg/kg bw/day, respectively in 

females)

Study II: 0, 10, 320, or 10,000

ppm (equivalent to 0, 0.7, 22.2, and 713 

mg/kg bw/day, respectively in males and 

0, 0.8, 24.3, and 754 mg/kg bw/day, 

respectively in females)

NOAEL = 320 ppm (22.2 mg/kg/day) in males 

and 50 ppm (4.38 mg/kg/day) in females.

LOAEL = 400 ppm (27.77 mg/kg/day) in males 

based on increased occurrence of extramedullary 

hematopoiesis and hemosiderosis in spleen; and

100 ppm (8.64 mg/kg/day) in females based on 

reduction in hemoglobin, hematocrit,

and RBC count; increased occurrence of 

extramedullary hematopoiesis in the

spleen and hemosiderosis in the spleen and liver.

870.3200

28-day Dermal 

Toxicity - rat

45288501 (1998);

0, 75, 400, 1000 mg/kg/day 

Acceptable/Guideline

Systemic NOAEL = 1000 mg/kg/day; LOAEL= 

not established.

Dermal NOAEL = 1000 mg/kg/day; LOAEL= not 

established.

870.3700

Prenatal 

Developmental 

in rodents-Rat

45082602 (1997); 

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

Acceptable/Guideline

Maternal NOAEL: >1000; LOAEL: not 

established.

Developmental NOAEL: >1000; LOAEL: not 

established.

870.3700

Prenatal 

Developmental 

in nonrodentsRabbit

45638316, 45638318, 45638317

(1997,1998);

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

Acceptable/Guideline

Maternal NOAEL: >1000; LOAEL: not 

established.

Developmental NOAEL: >1000; LOAEL: not 

established.
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Table A.2. Toxicity Profile of Novaluron.

Guideline No/ 

Study type MRID No.(year)/Doses/Classification Results

870.3800 

Reproduction 

and fertility- rat

45651505 (Main Study, 1999), 

45638319 (Preliminary Study, 1998);

0, 1000, 4000, or 12,000 ppm ;

M: 0, 74.2, 297.5, or 894.9 mg/kg/day 

F: 0, 84.0, 336.7, or 1009.8 mg/kg/day

Acceptable/Guideline

Parental NOAEL = Not established; LOAEL 

(M/F) = 74.2/84.0 mg/kg/day based on increased 

absolute and relative spleen weights.

Offspring NOAEL = Not established; LOAEL 

(M/F) = 74.2/84.0 mg/kg/day based on increased 

absolute and relative spleen weights.

Reproductive NOAEL (M/F) = 74.2/ 1009.8 

mg/kg/day; LOAEL = 297.5 mg/kg/day based on 

decreased epididymal sperm counts and increased 

age of preputial separation in the F1 generation, 

reproductive LOAEL for females was not 

established.

870.4100

Chronic 

toxicity - dog

45638320 (1999);

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

Acceptable/Guideline

NOAEL = 10 mg/kg/day.

LOAEL = 100 mg/kg/day based on hematologic 

changes associated with histopathological changes 

in liver and spleen.

870.4300 

Chronic/

Carcinogenicity

-rat

45651506 (1995);

0, 25, 700, or 20,000 ppm test material;

M: 0, 1.1, 30.6, and 884.2 mg/kg/day 

F: 0, 1.4, 39.5, and 1113.5 mg/kg/day

Acceptable/Guideline

NOAEL (M/F) =1.1/1.4 mg/kg/day.

LOAEL (M/F) =30.6/39.5 mg/kg/day based on 

erythrocyte damage and turnover resulting in a 

regenerative mild anemia.

870.4300 

Chronic/

Carcinogenicity

-mouse

45651507/45877901 (2000/2003);

0, 30, 450, or 7000 ppm test material;

M: 0, 3.6, 53.4, or 800.0 mg/kg/day 

F: 0, 4.3, 63.3, or 913.4 mg/kg/day

Acceptable/Guideline

NOAEL (M/F) =3.6/4.3 mg/kg/day.

LOAEL (M/F) =53.4/63.3 mg/kg/day based on 

increased erythrocyte turnover due to hemoglobin 

oxidation and resulting in a mild anemia.

870.5100

Salmonella 

typhimurium

and 

Escherichia 

coli Reverse 

Mutation Assay

44961013 (1997);

0, 312.5, 625, 1250, 2500, or 5000 

μg/plate in the presence and absence of 

metabolic activation (±S9)

Acceptable/Guideline

Novaluron, tested up to the limit of solubility 

(2500 μg/plate) and the limit dose (5000 μg/plate), 

was not cytotoxic with or without S9 activation in 

four S. typhimurium strains and one strain of E. 

coli, and did not induce a genotoxic response in 

any strain.

870.5100

Salmonella 

typhimuriumbacterial 

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 44961015 (1992); Novaluron produced no evidence of clastogenic 
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Table A.2. Toxicity Profile of Novaluron.

Guideline No/ 

Study type MRID No.(year)/Doses/Classification Results

In vitro

mammalian 

chromosome 

aberration test

40, 200, and 1000 μg/mL, with and 

without metabolic activation (±S9)

Acceptable/Guideline

activity in primary human lymphocytes, in the 

presence or absence of S9 activation.

870.5395

Mammalian 

erythrocyte 

micronucleus 

test in mice

45638322(1989);

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

weight

Acceptable/Guideline

There was no statistically significant increase in 

the frequency of micronucleated polychromatic 

erythrocytes in mouse bone marrow at any dose or 

harvest time.

870.5500

Mutagenicity–

Rec assay with 

Bacillus subtilis

44961014 (1998);

50, 150, 500, 1,500, or 5,000 μg/plate, 

with and without mammalian metabolic 

activation (±S9)

Acceptable/Guideline

Novaluron was equivocal for bacterial DNA 

damage in the absence of S9 activation, and 

negative for bacterial DNA damage in the 

presence of S9 activation.

870.5550

Unscheduled 

DNA Synthesis 

in HeLa S3 

Human 

Epitheliod cells

45030002 (1988);

0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 

128, or 256 μg/mL (±S9)

Acceptable/Guideline

Novaluron was considered not to show any

evidence of causing DNA damage to HeLa S3

epithelioid cells in this unscheduled DNA 

synthesis test for mutagenic potential.

870.6200

Acute 

Neurotoxicity 

screening 

battery- rat

45082601 (1999);

0, 200, 650, 2000 mg novaluron/kg

Acceptable/Guideline

NOAEL = 650 mg/kg/day; LOAEL =2000 

mg/kg/day based on clinical signs (piloerection, 

irregular breathing), FOB parameters (increased 

head swaying, abnormal gait) and neuropathology 

(sciatic and tibial nerve degeneration).

870.6200

Subchronic 

Neurotoxicity 

screening 

battery- rat

46086204 (2002);

0, 17.5, 174, 1752 mg/kg/day

Acceptable/Guideline

NOAEL (M/F) = >1752/>2000 mg/kg/day; 

LOAEL = not established.

870.7485

Metabolism-rat

45638401 (2000), 45638323 (1998);

single dose of 2 mg/kg or 1000 mg/kg, 

or 14 multiple 2 mg/kg/day doses of 

unlabeled 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 [chlorophenyl14C]novaluron or [difluorophenyl14C]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, 
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Table A.2. Toxicity Profile of Novaluron.

Guideline No/ 

Study type MRID No.(year)/Doses/Classification Results

and 1-[3-chloro-4-(1,1,2-trifluoro-2-

trifluoromethoxyethoxy)phenyl]urea. 

Quantitatively, these were minor components 

accounting for <2% of the dose. In the repeateddose group, some tissues such as fat contained 

measurable radioactivity at 168 hours post dose 

but did not appear to suggest significant potential 

for bioaccumulation or sequestration at the doses 

tested.

870.7600

Rat Dermal 

Penetration

45638415 (2000);

1.0, 0.067, 0.0048, or 0.0003 mg/cm2

Acceptable/Guideline 

Recovery of administered radioactivity was an 

acceptable 90.19-105.26%. The maximum total 

absorbed dose (expressed as per cent of 

administered dose and determined as the sum of 

radioactivity in excreta, cage wash, untreated skin, 

fat, blood, and residual carcass) ranged from 

about 0.5% to 10% of that administered.