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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

MEMORANDUM

Date: 23-FEB-2010

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

Grain Sorghum.

PC Code: 124002 DP Barcode: D364307

Decision No.: 407899 Registration No.: 66222-35

Petition No.: 9F7547 Regulatory Action: Section 3 Registration

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

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: John Hebert (RM 07)/ Jennifer Gaines

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).

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

the use of novaluron on fruiting vegetables group 8, cucurbit vegetable group 9, low growing 

berry subgroup 13-07G, miscellaneous fruiting vegetables, snap bean, dry bean seed, and Swiss 
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chard (Memo, J. Van Alstine, et al., 04-DEC-2009; D363988). A detailed hazard 

characterization for novaluron is presented in a previous HED risk assessment (Memo, S. Levy, 

et al., 03-NOV-2005; D313322). The following information from the 25-FEB-2008 risk 

assessment for the use of novaluron on tomato and sugarcane (Memo, G. Kramer, 25-FEB-2008; 

D347661) can be applied directly to this action:

 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 grain sorghum. 
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Table of Contents

1.0 EXECUTIVE SUMMARY ...............................................................................................4

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

3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS.............................10

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

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

4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION ...........................................13

4.1 Food Residue Profile................................................................................................... 13

4.2 Drinking Water Residue Profile................................................................................ 17

4.3 Dietary Exposure and Risk ........................................................................................ 18

4.4 Anticipated Residue and %CT Information ............................................................ 19

5.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION ................................................................................................19

5.1 Spray Drift................................................................................................................... 19

6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION ........20

7.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY...................................................20

7.1 Occupational Pesticide Handler Exposure and Risk............................................... 20

7.2 Occupational Post-Application Worker Exposure and Risk.................................. 23

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

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

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

Appendix A: TOXICOLOGY ASSESSMENT........................................................................27

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

A.2 Toxicity Profiles .......................................................................................................... 27
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1.0 EXECUTIVE SUMMARY

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

amended, Makhteshim-Agan of North America (MANA) has submitted a petition (PP# 9F7547)

to register the end-use product 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 grain sorghum. To support the submission 

for permanent tolerances for residues of novaluron in/on grain sorghum grain, forage, stover, and 

aspirated grain fractions (AGF), MANA proposes tolerance increases for residues of novaluron 

in/on the following livestock commodities: hog and poultry meat, liver, kidney, and fat; and 

eggs. End-use products containing novaluron as the ai are formulated as an EC, a suspension 

concentrate (SC), or a water-dispersible granular (WDG).

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

insecticides called insect-growth regulators (IGRs). Tolerances for residues of novaluron are 

established in/on cotton, Brassica head and stem vegetables (subgroup 5A), pome fruit (group 

11), tuberous and corm vegetables (subgroup 1C), tomatoes, sugarcane, bushberry subgroup 13-

07B, Brassica, leafy greens (subgroup 5B), turnip greens, and stone fruit (crop group 12) at 

levels ranging from 0.05 to 30 ppm. Tolerances for residues of novaluron are also established 

in/on the following livestock commodities: eggs, milk, milk fat, the meat, fat, kidney, liver, and 

meat byproducts (except kidney and liver) of cattle, goat, horse, and sheep, and the meat, fat, and 

meat byproducts of poultry and hog. A time-limited tolerance, with an expiration date of 31-

DEC-2011, is established in association with a Section 18 Emergency Exemption for 

strawberries at 0.50 ppm. Tolerances are pending for fruiting vegetables group 8, cucurbit 

vegetables group 9, low growing berry subgroup 13-07G (except lowbush blueberry), 

miscellaneous fruiting vegetables, snap bean, dry bean seed, and Swiss chard (Memo, J. Van 

Alstine et al., 04-DEC-2009; D363988).

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 (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 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
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in rats at similar doses, no evidence of neuropathology was observed in subchronic and chronic 

toxicity studies in rats, mice, or dogs, and novaluron is not considered acutely toxic (LD50>5000 

mg/kg). 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 

(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 developmental toxicity

studies at levels up to the limit dose in the rat or rabbit or in the 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 toxicity/carcinogenicity study in the rat. An uncertainty factor (UF) of 100 (10-fold for 

interspecies extrapolation and 10-fold for intraspecies variability) was applied to the 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 

toxicological endpoints have been selected and are the same; therefore, the estimates of risk for 

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

duration exposures. A 10% dermal-absorption factor was based on an acceptable dermalabsorption 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.
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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 

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

Intermediate-term inhalation

Dietary Exposure Estimate

An acute dietary assessment was not conducted for novaluron because an 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 (food and drinking water) exposure and risk assessment was conducted for the 

proposed new use on grain sorghum, all established uses, and drinking water. A partially refined 

assessment was conducted. EFED provided the estimated drinking water concentrations 

(EDWCs) which were incorporated into the analysis. A Screening Level Usage Analysis 

(SLUA) memorandum for existing uses and a percent crop treated for new use (PCTn) 

memorandum for sorghum were provided by the Biological and Economic Analysis Division 

(BEAD). The chronic analysis incorporated average percent crop treated (%CT) data for apples, 

cabbage, cotton, pears, and potatoes and PCTn data for grain sorghum. 100% CT was assumed 

for the remaining food commodities. Anticipated residues (ARs) for meat, milk, hog, and 

poultry commodities were calculated using PCTn for grain sorghum, average %CT for apple and 

cotton, and assumed 100% CT for sugarcane. The chronic analysis also incorporated average 

field trial residues for some commodities; average greenhouse trial residues for tomatoes; 

empirical processing factors for apple juice (translated to pear and stone fruit juice) and tomato 

paste and purée; and Dietary Exposure Evaluation Model (DEEMTM, ver. 7.81) default processing 

factors for the remaining processed commodities. In accordance with HED Standard Operating 

Procedure (SOP) 2000.1, average field trial residues were translated from representative 

commodities in the crop group to other commodities in that crop group as needed. 

For this action, the chronic dietary (food and drinking water) exposure to novaluron is below 

HED’s LOC for the general U.S. population and all population subgroups. The chronic dietary

exposure results in a risk estimate that is 11% of the cPAD for the general U.S. population and 

32% of the cPAD for children 1-2 years old, the most highly exposed population subgroup. 

Residential Exposure/Risk

There are no residential uses proposed or currently registered for novaluron. Therefore, a 

residential risk assessment is not required.

Aggregate Exposure Scenarios 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. 
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Occupational Exposure Estimates

Occupational handler and post-application exposure from the proposed uses of novaluron are 

anticipated. Based on label information, exposure is expected to occur for short- and 

intermediate-term exposure durations. No chemical-specific handler exposure data were 

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

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

Exposure Guide (AUG-1998) to assess handler exposures for regulatory actions when chemicalspecific monitoring data are not available [HED Science Advisory Council for Exposure 

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

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

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

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

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

exposures.

The MOEs for occupational post-application exposure are all greater than the target MOE of 100 

on day 0 (12 hours after application) for all crops and activities and are not of concern. Postapplication dermal risks were calculated based on an intermediate-term point of departure and 

are considered highly conservative for the included activities.

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 

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

Categories 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 
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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 issues that would preclude granting a

conditional registration for the use of novaluron on grain sorghum. 

The proposed uses and the submitted data support the permanent tolerances for residues of the 

insecticide novaluron, including its metabolites and degradates, in or on the commodities listed 

below. Compliance with the tolerance levels specified below is to be determined by measuring 

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

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

following raw agricultural commodities (RACs):

Grain, aspirated fractions 25 ppm Poultry, fat 7.0 ppm

Sorghum, grain, grain 3.0 ppm Egg 1.5 ppm

Sorghum, grain, forage 6.0 ppm Hog, meat 0.07 ppm

Sorghum, grain, stover 40 ppm Hog, liver 0.10 ppm

Poultry, meat 0.40 ppm Hog, kidney 0.10 ppm

Poultry, liver 0.80 ppm Hog, meat byproducts 0.10 ppm

Poultry, kidney 0.80 ppm Hog, fat 1.5 ppm

Poultry, meat byproducts 0.80 ppm

Data Needs and Label Recommendations

The residue chemistry, toxicology, and occupational and residential databases will support 

unconditional registration upon submission of data/information which adequately addresses the 

following issues: 

Toxicology

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

registration. However, based on the low volatility 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.
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 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 9F7547 should be submitted which:

 Specifies that the use of adjuvants/surfactants on grain sorghum is prohibited;

 Specifies that the label is for “grain sorghum” as opposed to “sorghum;” 

 Specifies separate preharvest interval (PHIs) for grain sorghum forage (7 days), grain (14 

days), and stover (14 days); and

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

is prohibited. 

860.1380 Storage Stability Data

Storage stability data on grain sorghum forage, grain, AGF, and stover for up to 275, 253, 237,

and 245 days, respectively, are required. 

860.1550 Proposed Tolerances

 A revised Section F for petition number 9F7547 should be submitted which cites the 

appropriate CAS name for novaluron:

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

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

with the tolerance levels specified below is to be 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. 

Occupational and Residential Exposure

 None. 

2.0 PROPOSED USE PATTERN

MANA submitted a draft label for Rimon

®

0.83EC Insecticide (EPA Reg. No. 66222-35) to 

include the proposed new use (see Table 2.0) on grain sorghum.
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Table 2.0. Summary of Proposed Use Pattern for Novaluron on Grain Sorghum.

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

Grain Sorghum

Aerial/ 

Groundboom

0.83 lb/gal 

EC

[66222-35]

0.058-

0.078 3 0.23 14

A 7 to 14 day retreatment 

interval (RTI) is specified to 

protect new growth. For the

most effective control, fields 

should be scouted twice 

weekly. REI = 12 hours.

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

the proposed new use on grain sorghum; however, a revised Section B is requested which: 

 specifies that the use of adjuvants/surfactants on grain sorghum is prohibited;

 specifies that the label is for “grain sorghum” as opposed to “sorghum;” 

 specifies separate PHIs for grain sorghum forage (7 days), grain (14 days), and stover (14 

days); and

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

is prohibited. 

3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS

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

(Memo, S. 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 (toxicity to blood) 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 similar doses (1752 mg/kg/day in males 

and 2000 mg/kg/day in females). In addition, novaluron is not considered acutely toxic 

(LD50>5000 mg/kg). Therefore, RAB1 toxicologists reaffirmed the HED HIARC conclusion 

that there is not a concern for neurotoxicity resulting from exposure to novaluron. There was no 

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 
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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 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, and novaluron is not considered acutely toxic (LD50>5000 mg/kg).

 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 in the 

reproduction study in rats. These findings were associated with the primary

hematotoxicity of novaluron, which caused secondary accumulation of damaged

erythrocytes in the spleen following removal from the blood. Therefore, these 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.
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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

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

Dermal 

(>6 months)

Oral NOAEL = 1.1 

mg/kg/day

(dermal-absorption 

rate = 10%)

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.

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

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

dose, MOE = margin of exposure, LOC = level of concern.

3.2 Endocrine Disruption

As required under Federal Food, Drug, and Cosmetic Act (FFDCA) section 408(p), EPA has 

developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain 

substances (including pesticide active and other ingredients) may have an effect in humans or 

wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine 

effects as the Administrator may designate.” The EDSP employs a two-tiered approach to 

making the statutorily required determinations. Tier 1 consists of a battery of 11 screening 

assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or 

thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are 

found to have the potential to interact with E, A, or T hormonal systems will proceed to the next 

stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary 

based on the available data. Tier 2 testing is designed to identify any adverse endocrine related 

effects caused by the substance, and establish a dose-response relationship between the dose and 

the E, A, or T effect.

Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Novaluron is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION

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

pending HED memorandum by J. L. Van Alstine (D374420). The chronic dietary exposure 

assessment is summarized in the pending HED memorandum by J. L. Van Alstine (D374419).

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 
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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 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).

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; Memo, G. Kramer, 05-DEC-2003; D296264).

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

laboratory validation, that the GC/ECD and 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).

Multiresidue Methods: Novaluron was tested through the FDA MRM Test guidelines in PAM I, 

Appendix II (JAN-1994). The results indicate that novaluron is not adequately recovered by any 

of the MRMs. This study was forwarded to FDA for further evaluation and updating of PAM 

Vol. I, Appendix I (Memo, S. Levy, 19-OCT-2005; D322359).

Magnitude of the Residue - Plants: MANA has submitted field trial data to support the 

proposed use of novaluron on grain sorghum. Twelve grain sorghum field trials were conducted 

in the U.S. during the 2007 growing season in North American Free Trade Agreement (NAFTA) 

Growing Zones 2 (NC; 1 trial), 4 (AR; 1 trial), 5 (IL, KS, and NE; 4 trials), 6 (OK and TX; 1 

trial each), 7 (NE, 1 trial), and 8 (KS, OK, and TX; 1 trial each).

Each trial site consisted of one untreated plot and one treated plot. The treated plots received 

three broadcast spray applications of a 0.83 lb/gal EC formulation of novaluron (EPA Reg. No. 

66222-35) at 0.076-0.081 lb ai/A per application, with 7- to 15-day RTIs, for a total rate of 

0.232-0.239 lb ai/A; forage samples were harvested after only two applications, for a total rate of 
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0.156-0.160 lb ai/A. Applications were made using ground equipment in approximately 20-34 

GPA spray volumes, without an adjuvant. Samples of grain sorghum forage, grain, and stover 

were taken at normal harvest times, 6 to 7 days after the second application for forage and 13 to 

14 days after the last application for grain and stover. To evaluate residue decline, additional 

treated samples were also collected at one trial 1, 3, 10, and 14 days after the second application 

(forage) and 10, 14, 17, and 21 days after the last application (grain and stover).

Residues of novaluron ranged from 0.620 to 4.82 ppm in/on 24 samples of treated sorghum 

forage harvested 6-7 days following foliar treatments with the 0.83 lb/gal EC formulation at a 

total rate of 0.156-0.160 lb ai/A. Novaluron residues ranged from 0.586 to 1.96 ppm in/on 22 

samples of treated sorghum grain, and from 3.62 to 26.0 ppm in/on 22 samples of treated 

sorghum stover (adjusted to 88% dry matter) harvested 13-14 days following foliar treatments at 

a total rate of 0.232-0.239 lb ai/A.

In the residue decline trial, average residues of novaluron generally decreased in/on forage, from 

4.0 ppm at the 1-day PHI to 2.0 ppm at the 14-day PHI, and stover, from 6.7 ppm at the 7-day

PHI to 3.8 ppm at the 21-day PHI; average residues in/on grain were approximately the same at 

all sampling intervals.

Conclusions: The submitted field trial data for grain sorghum commodities are classified as 

scientifically acceptable and will support the establishment of residue tolerances for novaluron 

in/on grain sorghum forage (6.0 ppm), grain (3.0 ppm), and stover (40 ppm), pending submission 

of freezer storage stability data for residues of novaluron in/on grain sorghum forage, grain, and 

stover for up to 275, 253, and 245 days, respectively. Although this is a deficiency, HED 

recommends a conditional registration for the use of novaluron on grain sorghum. This decision 

is based on previously submitted storage stability data for various commodities which 

demonstrates the stability of novaluron in/on food commodities for up to 15.3 months, which 

exceeds the longest storage time (9.0 months for grain sorghum forage) of the grain sorghum 

commodities in the field trials. The residue chemistry database will support an unconditional 

registration upon submission of adequate storage stability data along with revised Sections B and 

F. 

Processed Food and Feed: A processing study on grain sorghum AGF and flour was submitted

which indicated that residues of novaluron concentrate in AGF (13X) but do not concentrate in 

flour (processing factor of 0.66X). Sorghum flour is not considered to be a human food item in 

the U.S. A tolerance value of 25 ppm [i.e., 1.84 ppm (highest-average field trial (HAFT)) x 13 = 

24 ppm] was calculated for AGF. For grain sorghum AGF, the processed food data are classified 

as scientifically acceptable and will support the establishment of residue tolerances for novaluron 

in/on AGF (25 ppm) pending submission of freezer storage stability data for grain sorghum grain 

and AGF.

Confined/Field Accumulation in Rotational Crops: Based on the results of the submitted 

confined rotational crop study, the appropriate plantback interval (PBI) for all non-labeled crops 

is 30 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. The HED MARC 

has determined that for tolerance assessment and risk assessment, parent only is the residue of 

concern in rotational crops (Memo, G. Kramer et al., 03-FEB-2004; D297646).
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Magnitude of the Residue - Livestock: The potential for secondary transfer of novaluron

residues of concern in meat, milk, and eggs exists because there are livestock feedstuffs 

associated with the proposed/registered novaluron uses. Livestock dietary burdens of novaluron

were calculated, which incorporate the proposed/registered uses of novaluron. The calculations 

reflected the most recent guidance from HED (OPPTS 860.1000 Supplement, Table 1

Feedstuffs, 30-JUN-2008) concerning revisions of feedstuff percentages and constructing 

reasonably balanced dietary burdens (RBDBs). 

The currently established livestock tolerances are based on the following RBDBs for novaluron: 

5.9 ppm for beef cattle, 2.3 ppm for dairy cattle, 0.12 for poultry, and 0.09 for swine (Memo G. 

Kramer, 07-FEB-2008; D340137). Based on the proposed/registered uses, the revised RBDBs 

for novaluron are 9.6 ppm for beef cattle, 12.4 ppm for dairy cattle, 2.4 for poultry, and 2.5 for 

swine. This increase in the RBDBs necessitates an increase in the tolerances for secondary

residues in/on poultry and hog commodities; however, no changes are necessary for the 

tolerances for secondary residues in/on cattle, goat, horse, and sheep. The revised tolerances for 

residues of novaluron in hog and poultry are as follows: 0.07 ppm in hog meat; 0.10 ppm in hog 

liver, kidney, and meat byproducts; 1.5 ppm in hog fat; 1.5 ppm in eggs; 0.40 ppm in poultry

meat; 0.80 ppm in poultry liver, kidney, and meat byproducts; and 7.0 ppm in poultry fat. The 

petitioner is requested to submit a revised Section F reflecting these tolerances.

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

commodities under 40 CFR §180.598. The HED MARC determined that the residue of concern 

in plants (primary and rotational crops) and livestock for purposes of tolerance enforcement and 

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

Section F for petition number 9F7547 should be submitted which cites the 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 revised Section F is requested which reflects the HED-recommended tolerances and 

commodity definitions presented in Table 4.1. 

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

sorghum. 

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

for determining appropriate tolerance levels.
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Table 4.1. Tolerance Summary for Novaluron.

Commodity Proposed 

Tolerance (ppm)

HED-Recommended 

Tolerance (ppm)

Comments; 

Correct Commodity Definition

Grain sorghum, grain 3 3.0 Sorghum, grain, grain

Grain sorghum, aspirated 

grain fractions 25 25 Grain, aspirated fractions

Grain sorghum, forage 6 6.0 Sorghum, grain, forage

Grain sorghum, stover 40 40 Sorghum, grain, stover

Poultry, fat 7.0 7.0

Poultry, muscle 0.4 0.40 Poultry, meat

Poultry, liver 0.8 0.80

Poultry, kidney 0.8 0.80

-- -- 0.80 Poultry, meat byproducts

Hog, fat 1.5 1.5

Hog, muscle 0.07 0.07 Hog, meat

Hog, liver 0.15 0.10

Hog, kidney 0.15 0.10

-- -- 0.10 Hog, meat byproducts

Eggs 1.5 1.5 Egg

4.2 Drinking Water 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 

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 
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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 on grain sorghum.

The chronic analysis incorporated average %CT data for apples, cabbage, cotton, pears, and 

potatoes and PCTn data for grain sorghum. 100% CT was assumed for the remaining food 

commodities. ARs for meat, milk, hog, and poultry commodities which were calculated using 

PCTn for grain sorghum, average %CT for apple and cotton, and 100% CT for sugarcane were 

incorporated into the analysis. The chronic analysis also incorporated average field trial residues 

for some commodities (pome fruit, sugarcane, bushberries, Brassica leafy greens, stone fruit, 

bell pepper, non-bell pepper, cucumber, summer squash, cantaloupe, strawberry, succulent snap 

bean, dry bean seed, and Swiss chard); average greenhouse trial residues for tomatoes; empirical 

processing factors for apple juice (translated to pear and stone fruit juice) and tomato paste and 

purée; and DEEM (ver. 7.81) default processing factors for the remaining processed 

commodities. In accordance with HED SOP 2000.1, average field trial residues were translated 

from representative commodities in the crop group to other commodities in that crop group as 

needed. 

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

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

in a risk estimate that is 11% of the cPAD for the general U.S. population and 32% of the cPAD 

for children 1-2 years old, the most highly exposed population subgroup. 
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Table 4.3. Summary of Chronic Dietary Exposure (Food and Drinking Water) and Risk for Novaluron1,2.

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

0.001206 11

N/A N/A

All Infants (<1 year old) 0.001955 18

Children 1-2 years old 0.003537 32

Children 3-5 years old 0.002771 25

Children 6-12 years old 0.001700 16

Youth 13-19 years old 0.001021 9

Adults 20-49 years old 0.000884 8

Adults 50+ years old 0.001027 9

Females 13-49 years old 0.000874 8

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

2 The highest dietary exposure is bolded. 

4.4 Anticipated Residue and %CT Information

A SLUA memorandum and PCTn memorandum were provided by BEAD (A. Grube, 17-NOV2009, D371221; C. Doucoure et al., 29-DEC-2009, D371615). The SLUA memo included %CT

data for apples, cabbage, cotton, pears, and potatoes. The market leader approach was used by 

BEAD to determine the PCTn for sorghum. 

The chronic dietary analysis incorporated average %CT data for apples (15%), cabbage (10%), 

cotton (2.5%), pears (10%), and potatoes (2.5%) and PCTn data for grain sorghum (5%). 100% 

CT was assumed for the remaining food commodities. Livestock dietary burdens of novaluron

were calculated based on the proposed/registered uses, tolerance-level residues, and PCTn data 

for grain sorghum (5%), average %CT data for apple (15%) and cotton (2.5%), and 100% CT for 

sugarcane. 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. 

5.0 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 

evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. 
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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 a pending HED 

memorandum (L. Venkateshwara; D374418). See Table 2.0 for a summary of the proposed use 

patterns. 

7.1 Occupational Pesticide Handler Exposure and Risk

There is potential for occupational handler exposure from the proposed use on grain sorghum. 

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

Mixer/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 

“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 
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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 the proposed labels. 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. 

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).

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:
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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 Dose4

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

(3) Applicator –Groundboom Application
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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 Dose4

Short- and 

Intermediateterm MOETotal MOEs 5

Dermal

Baseline: 0.014

Inhalation

Baseline: 0.00074

0.078 80

Dermal

Baseline: 0.00012 Baseline 

Dermal + 

Inhalation

0.0002

Dermal

Baseline: 

35,000

Baseline 

Dermal + 

Inhalation

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 label.

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 C), a quantitative post-application inhalation 

exposure and risk assessment was not conducted.

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

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

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

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

Coefficients, August 2000, summarized in Table 7.2.1 below and the following assumptions:

 Application Rate = 0.078 lb ai/A; 
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 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 7.2.1. Anticipated Post-application Activities and Dermal Transfer Coefficients.

Proposed 

Crops

Policy Crop 

Group Category

Transfer Coefficients 

(cm2/hr) Activities

Grain 

Sorghum

Field/row crop 

tall

100 Scouting and hand weeding

1000 Irrigation and scouting

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

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 

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

crops and activities. Post-application dermal risks were calculated based on an intermediateterm endpoint and are considered highly conservative for the included activities.

Table 7.2.2. Post-application Risks for Novaluron.

Crop Application Rate

(lb ai/A)

Transfer Coefficient

(cm2/hr)

DFR 

(ug/cm2)

Days After 

Treatment

Daily Dose1

(mg/kg/ay) MOE2

Grain 

Sorghum

0.078 100

0.18 12 hours (0 

days)

0.0002 21,900

1,000 0.002 2,200

The information in the table is based on proprietary and non-proprietary data.

1 Daily Dose = [DFR (ug/cm2

) x 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).
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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 9F7547 should be submitted which:

 Specifies that the use of adjuvants/surfactants on grain sorghum is 

prohibited;

 Specifies that the label is for “grain sorghum” as opposed to “sorghum;” 

 Specifies separate PHIs for grain sorghum forage (7 days), grain (14 

days), and stover (14 days); and

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

except tomatoes, is prohibited. 

 860.1380 Storage Stability Data

Storage stability data on grain sorghum forage, grain, AGF, and stover for up to 

275, 253, 237, and 245 days, respectively, are required. 

 860.1550 Proposed Tolerances

 A revised Section F for petition number 9F7547 should be submitted 

which cites the appropriate CAS name for novaluron:

“Tolerances are established for residues of the insecticide novaluron, 

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

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

determined by measuring only novaluron (N-[[[3-chloro-4-[1,1,2-trifluoro2-(trifluoromethoxy)ethoxy]phenyl]amino]carbonyl]-2,6-

difluorobenzamide) in or on the following raw agricultural commodities:”
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 A revised Section F is requested which reflects the recommended 

tolerances and commodity definitions presented in Table 4.1.

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 (02/17/10); G. Kramer (02/5/10); D. Vogel (02/23/10)

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 mg/kg/day; LOAEL =

not established.

Developmental NOAEL = 1000 mg/kg/day; 

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 mg/kg/day; LOAEL = 

not established.

Developmental NOAEL = 1000 mg/kg/day; 

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 (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.

870.4100

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.
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Table A.2. Toxicity Profile of Novaluron.

Guideline No/ 

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

870.5375

In vitro

mammalian 

chromosome 

aberration test

44961015 (1992);

40, 200, and 1000 μg/mL, with and 

without metabolic activation (±S9)

Acceptable/Guideline

Novaluron produced no evidence of clastogenic 

activity in primary human lymphocytes, in the 

presence or absence of S9 activation.

870.5395

Mammalian 

erythrocyte 

micronucleus 

test in mice

45638322(1989);

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

weight

Acceptable/Guideline

There was no statistically significant increase in 

the frequency of micronucleated polychromatic 

erythrocytes in mouse bone marrow at any dose or 

harvest time.

870.5500

Mutagenicity–

Rec assay with 

Bacillus subtilis

44961014 (1998);

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

with and without mammalian metabolic 

activation (±S9)

Acceptable/Guideline

Novaluron was equivocal for bacterial DNA 

damage in the absence of S9 activation, and 

negative for bacterial DNA damage in the 

presence of S9 activation.

870.5550

Unscheduled 

DNA Synthesis 

in HeLa S3 

Human 

Epitheliod cells

45030002 (1988);

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

128, or 256 μg/mL (±S9)

Acceptable/Guideline

Novaluron was considered not to show any

evidence of causing DNA damage to HeLa S3 

epithelioid cells in this unscheduled DNA 

synthesis test for mutagenic potential.

870.6200

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, 17.5/20.5, 174/207, 1752/2000

mg/kg/day

(M/F)

Acceptable/Guideline

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

= not established.

870.7485

Metabolism-rat

45638401 (2000), 45638323 (1998);

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

or 14 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 
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Table A.2. Toxicity Profile of Novaluron.

Guideline No/ 

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

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 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.