UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: July 15,2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Noviflumuron. Human Health Assessment Scoping Document in Support of Registration 

Review. 

PC Code: 118204 

Decision No.: 48930 I 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: 0419013 

Registration No.: NA 

Regulatory Action: Registration Review Scoping Document 

Case No.: 7434 

CAS No.: 121451-02-3 

40CFR: NA 

FROM: Kristin Rury, Biologist ¥-~ 1 _, 

Vincent Chen, Toxicologist'· . ~_g Lc;.._---

Risk Assessment Branch III 

Health Effects Division (7509P) 

Office of Pesticide Programs 

THROUGH: Christine 

Risk Assessment 

Olinger, 

Branch 

Branch 

III 

Chi~e ,. 

Health Effects Division (750 

Office of Pesticide Programs 

TO: Dana Friedman, Chemical Review Manager 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

Attached is the Health Effects Division's (HED) human health Registration Review scoping 

document for the insecticide growth regulator, noviflumuron. 

Executive Summary 

HED has evaluated recent human health assessments for noviflumuron to determine whether 

sufficient data are available and whether any updates are needed to support Registration Review. 

To determine the scope of work necessary to support Registration Review, HED has considered 

updates to Agency science policy and risk assessment methodologies and to the noviflumuron 

toxicity, exposure, and usage databases. The most recent (qualitative) risk assessment for 

noviflumuron was conducted to evaluate the proposed use of noviflumuron as a gel bait for crack 

and crevice application to control cockroaches (J. Arthur, D307978, 09/29/2005). 

Page 1 of 14 
Noviflumuron is a benzoylphenylurea insect growth regulator used as bait around ornamental 

trees, buildings, wood decks, wood fences, and wood utility poles to control subterranean 

termites; and as an indoor crack and crevice treatment to control cockroaches. Noviflumuron 

products are formulated as ready-to-use gel baits in syringe applicators, and as impregnated bait 

stations. The labels specify that only pest management professionals licensed by the state to 

apply termite control products may use noviflumuron. 

Noviflumuron primarily targets the liver in rats and bone marrow in dogs as evidenced by 

hypertrophy of the liver and hyperplasia ofthe bone marrow. Adequate carcinogenicity studies 

have been submitted for noviflumuron, but are currently undergoing secondary review. 

Noviflumuron's carcinogenic potential will be evaluated Registration Review. There are no 

concerns for neurotoxicity, mutagenicity, immunotoxicity, and gen<;>toxicity. 

A new dietary exposure and risk assessment will not be needed during Registration Review 

because noviflumuron is considered a non-food use pesticide. A dietary exposure assessment 

has not been conducted previously for noviflumuron. Additionally, given the limited use pattern 

there currently is no need to calculate EDWCs. There are no outstanding residue chemistry 

database deficiencies at this time. 

A new occupational and residential exposure assessment will not be needed during Registration 

Review because the protected bait stations and syringe crack and crevice uses are expected to 

provide negligible handler and post-application exposure. The occupational and residential 

exposure databases are considered complete for noviflumuron. 

An updated aggregate risk assessment will not be required to support Registration Review 

because residential and drinking water exposures are considered negligible. 

HED does not believe that new data are needed for Registration Review. Because of the 

negligible exposure from the registered uses of noviflumuron, a quantitative risk assessment will 

not be conducted during Registration Review. 

Introduction 

Noviflumuron is a benzoylphenylurea insect growth regulator currently undergoing Registration 

Review. The most recent (qualitative) risk assessment for noviflumuron was conducted to 

evaluate the proposed use as a gel bait for crack and crevice application to control cockroaches 

(J. Arthur, D307978, 09/29/2005). The risk assessment was solely qualitative because exposure 

to noviflumuron is considered negligible via all routes. Noviflumuron products are only 

formulated as ready-to-use gel baits in syringe applicators, and as an impregnated bait station. It 

is registered for use as an indoor crack and crevice treatment to control cockroaches; and as 

above ground and in-ground baits around ornamental trees and buildings; and around wood 

decks, fences, and utility poles to control subterranean termites. The labels specify that only pest 

management professionals licensed by the state to apply termite control products may use 

noviflumuron. For information on the chemical identity of noviflumuron, see Attachment 1. 

Page 2 of 14 
Page 3 of 14

Hazard Identification/Toxicology

The toxicology database is adequate for human health risk assessment. The Hazard Science and 

Policy Council (HASPOC) considered all the available hazard and exposure information for 

noviflumuron and concluded, by weight of evidence, that the following studies are waived

immunotoxicity, acute and subchronic neurotoxicity, subchronic dermal, and subchronic 

inhalation toxicity studies (TXR# 0056966). In the repeated dietary exposure studies, 

noviflumuron appears to target the liver in rats and bone marrow in dogs. In rats, noviflumuron 

exposure leads to liver hypertrophy and histopathology (i.e., altered tinctorial properties of the 

hepatic lobules in males and hepatocellular vacuolation in both sexes). In dogs, noviflumuron 

exposure leads to bone marrow hyperplasia and changes in hematological parameters (i.e., 

decreased red blood count, hematocrit concentration, and hemoglobin concentration). There was 

no evidence of neurotoxicity following chronic oral exposures up to the highest dose tested (300 

mg/kg/day). No developmental toxicity was seen in the pre-natal toxicity studies in rats and 

rabbits. In the reproduction study, parental toxicity manifested as decreased liver weights in both 

generations; offspring toxicity consisted of convulsions and decreased survival and body 

weights; and reproductive toxicity included decreased mating and fertility indices. Adequate 

carcinogenicity studies have been submitted for noviflumuron, but are currently undergoing 

secondary review. Noviflumuron’s carcinogenic potential will be evaluated following 

completion of the secondary review of the carcinogenicity studies at the time of Registration 

Review. There is no evidence for mutagenicity.

Dietary (both acute and chronic), incidental oral, dermal, and inhalation exposure risk 

assessments were not conducted because exposure is not expected to occur from noviflumuron’s 

currently registered uses.

Noviflumuron’s acute toxicity studies were based on a formulation (containing 49.9% a.i.). 

Noviflumuron has low acute toxicity via the oral, dermal, and inhalation routes of exposure 

(Toxicity Categories III-IV); it is not an eye or skin irritant (Toxicity Category IV), nor a 

dermal sensitizer.

Conclusion: Based on the current use pattern, noviflumuron’s toxicity database is adequate for 

risk assessment and the carcinogenic potential of noviflumuron will be evaluated following 

completion of the secondary review of the carcinogenicity studies. This evaluation will be 

completed during Registration Review.

Dietary Exposure

Noviflumuron is considered a non-food use pesticide. HED considers protected baits as nonfood/non-feed uses per the Chemistry Science Advisory Council (ChemSAC). The non-food use 

designation criteria for bait stations applies if they: (1) will not leak or spill; (2) prevent (direct) 

contact with food/feed; and (3) are resistant to child tampering (ChemSAC Minutes, 

06/22/2005).

Furthermore, gel baits are considered non-food/non-feed provided the active ingredient has a low 

vapor pressure (vapor pressure <10-6or 10-7 mm Hg) and provided the use does not include 
Page 4 of 14

application to surfaces that might contact food (ChemSAC Minutes, 08/15/2007). The vapor 

pressure of the technical noviflumuron is 2.20 x 10 - 10 Pa at 20°C (or ~1.65 × 10-12 mm Hg at 

20oC), which means the technical qualifies as having a low vapor pressure. Therefore, all 

existing uses of noviflumuron are considered non-food/non-feed uses, and the residue chemistry 

database is considered complete. 

A dietary risk assessment is not required for noviflumuron during Registration Review as 

noviflumuron is considered a non-food use pesticide and given the limited use pattern, the 

Environmental Fate and Effects Division (EFED) does not anticipate calculating EDWCs. 

Conclusion: The dietary exposure database is adequate to support existing registrations of 

noviflumuron. A dietary exposure assessment will not be needed during Registration Review. 

Residential and Occupational Exposure

Noviflumuron is an insect growth regulator used to control subterranean termites and 

cockroaches. The labels specify that only pest management professionals licensed by the state to 

apply termite control products may use noviflumuron. There are no personal protective 

equipment (PPE) requirements listed on any of the registered labels containing noviflumuron.

Based on the use pattern, occupational handler and occupational and residential post-application 

exposure to noviflumuron is expected to be negligible. A qualitative risk assessment was 

completed previously. A qualitative risk assessment was conducted based on the following 

rationale for the registered bait stations (K. O’Rourke, D285861, 03/27/2003):

 The device is enclosed in a plastic station, except when the pest management professional

adds water for moisture and looks for termites; 

 The device contains impregnated material with 0.5% ai; 

 The vapor pressure is low; 

 The acute toxicity categories for all routes of exposure were low; and

 This is a reduced risk method for termite control, preferable to spray applications. 

The crack and crevice formulations direct users to only apply directly into cracks and crevices by 

placing the syringe applicator directly into cracks, crevices, holes, and other small openings and 

to apply the bait in cracks and crevices between different elements of construction; between 

equipment and floors; in openings leading into voids and hollow spaces in floors, walls, ceilings, 

equipment legs and bases; around plumbing pipes, doors and windows; and behind and under 

refrigerators, cabinets, sinks, closets, stoves, and other equipment where cockroaches hide. 

Therefore, because of the specific application directions and the delivery system through a 

syringe, the potential for occupational handler and occupational and residential post-application 

exposure is low. 

Residential bystander exposure and exposures resulting from spray drift are not expected because

there are no registered agricultural uses of noviflumuron or uses that would result in 

volatilization or drift. 
Page 5 of 14

Conclusions: A quantitative exposure assessment is not needed for noviflumuron at this time and 

the occupational and residential exposure databases are complete. 

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. 

Although noviflumuron is used in residential settings, the exposure from the registered uses is 

expected to be negligible. Noviflumuron is considered a non-food/non-feed use pesticide; 

therefore, a dietary (food and drinking water) exposure assessment is not required. 

Conclusions: An aggregate risk assessment will not be required during Registration Review. 

Public Health and Pesticide Epidemiology Data

Based on the low frequency and severity of incident cases reported for noviflumuron in both the 

OPP Incident Data System (IDS) and Centers for Disease Control and Prevention/National 

Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System 

for Occupational Risk (SENSOR)-Pesticides, there does not appear to be a concern at this time 

that would warrant further investigation. There was only one incident, of minor severity,

reported in the aggregate IDS from January 1, 2009 to March 5, 2014. A query of SENSORPesticides 1998-2010 did not identify any cases involving noviflumuron. 

The Agency will continue to monitor the incident information and if a concern is triggered, 

additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Noviflumuron is considered a non-food/non-feed pesticide; therefore, there are no existing 

noviflumuron tolerances. There are no Codex or Canadian maximum residue limits (MRLs) 

established for noviflumuron; therefore, there is no harmonization issue at this time. 

Environmental Justice

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

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

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

(http://www.eh.doe.gov/oepa/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 United States Department of 

Agriculture’s (USDA’s) National Health and Nutrition Examination Survey (NHANES), What 

We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, 
Page 6 of 14

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 children <6 years old, youths, 

and adults entering or playing on treated areas following 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.

Cumulative Risk Assessments 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to noviflumuron and any other substances, and noviflumuron does not appear to produce a toxic

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that noviflumuron has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s OPP concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Data Requirements

None.

References

Memoranda Relevant to Registration Review of Noviflumuron

Author DP/TXR# Date Title

Occupational Residential Exposure

K. O’Rourke D285861 03/27/2003 Noviflumuron [XDE-007]: Occupational and Residential Risk 

Assessment of a New Termiticide

J. Arthur D307878 09/29/2005 Noviflumuron: Occupational and Residential Risk Assessment of 

a New Bait Gel for Cockroaches

Toxicology

U. Habiba 0056966 05/27/2014 Noviflumuron HASPOC Report

W. Greer 0051752 04/04/2003 Noviflumuron (XDE-007): Report of the Hazard Identification 

Assessment Review Committee

Incident Report

E. Evans D420119 05/08/2014 Noviflumuron: Tier I Review of Human Incidents

Attachments

Attachment 1. Chemical Identity Table

Attachment 2. Noviflumuron Use Pattern

Attachment 3. Noviflumuron Toxicity Profiles
Page 7 of 14

Attachment 1: Chemical Identity 

Table A.1. Noviflumuron Nomenclature.

Chemical structure

Common name noviflumuron

PC Code 118204

Company experimental name XDE-007

IUPAC name 1-{3,5-dichloro-2-fluoro-4-[(RS)-1,1,2,3,3,3-hexafluoropropoxy]phenyl}-3-(2,6-

difluorobenzoyl)urea

CAS name N-[[[3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]amino]carbonyl]-2,6-

difluorobenzamide

CAS registry number 121451-02-3

End-use products (EPs) Recruit ® IV Termite Bait (0.5% Noviflumuron) ; EPA Reg. No. 62719-453

Recruit ® IV AG Termite Bait Station (0.5% Noviflumuron) ; EPA Reg. No. 62719-454

GF-1252 Gel Bait (0.5% Noviflumuron) ; EPA Reg. No. 62719-520

Recruit ® HED (0.5% Noviflumuron) : EPA Reg. No. 62719-608

Recruit® AD (0.5% Noviflumuron) ; EPA Reg. No. 62719-652

Table A1.2. Physicochemical Properties of the Technical Grade of Noviflumuron.

Parameter Value Reference

Melting point 156.2°C (range of 155-157°C) MRID 45516704

pH 6.31 at 23°C MRID 45516704

Density 1.88 g/cc at 20°C MRID 45516704

Water solubility 1.94 x 10 -4 g / L at 20°C MRID 45516704

Solvent solubility Acetone: 425; 

Acetonitrile: 44.9; 

1,2-dichloromethane: 20.7; 

Ethyl acetate: 290; 

Heptane: 0.068; 

Methanol” 48.9; 

n-octanol: 8.1;

p-xylene = 93.3

MRID 45516704

Vapor pressure 2.20 x 10 - 10 Pa at 20°C MRID 45516704

Dissociation constant, pKa Does not contain reversibly ionizable 

functional gr.

Octanol/water partition coefficient,

Log(KOW)

Kow = 4.94 ; Log 10 Ko/w = 86200 @ 

20oC

unbuffered water

MRID 45516704
Page 8 of 14

Attachment 2: Noviflumuron Use Pattern

Table A.2. Noviflumuron: Use Pattern.

Formulation Registration Number Target Pest Application 

Method(s)

Application information

Recruit® IV 

Termite Bait

(0.5% 

Noviflumuron)

62719-453 Subterranean 

Termites Ready-to-Use Termite Bait System

Recruit® IV AG 

Termite Bait 

Station (0.5% 

Noviflumuron)

62719-454

Subterranean 

Termites Above-Ground Delivery System

Termites in 

Food Handling 

Establishments

(FHEs)

Housing with the bait matrix packet the open side of the 

bait station allows termites to access the bait.

GF-1252 Gel Bait 

(0.5% 

Noviflurmuron)

62719-520

Cockroaches

In residential areas 

and non-food areas 

of institutional, 

warehouse and 

commercial facilities 

and in the non-food 

areas of FHEs.

1-3 grams per 100 ft2 or 4-12

grams per 100 ft2if population 

is inaccessible (in walls). For 

outdoor use, apply around 

eaves, sills, and in expansion 

joints. Reapply when bait is no 

longer visible. Can also be 

used in refillable bait stations 

(1 tsp gel bait per station)

Subterranean 

Termites

Recommended as a 

supplemental 

treatment to bait 

stations. 

Drill into the termite infected 

wood, and inject gel into the 

hole. 0.5 – 2 grams per 

treatment site

Recruit® HD 

(0.5% 

noviflumuron)

62719-608 Subterranean 

Termite Bait Bait Station

Install around the target site at 

intervals not to exceed 20 ft. 

The station consists of a 

housing containing the bait. 

Recruit® AD 

(0.5% 

noviflumuron)

62719-652

Above ground 

bait station for 

subterranean 

termites

Bait Station

The station consists of a 

housing containing the bait. 

May be installed in food and 

non-food areas of FHEs.
Page 9 of 14

Attachment 3: Toxicology Data Requirements and Profile Table

The requirements (40 CFR 158.500) for non-food uses are in the table below. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.5: Toxicology Data Requirements

Guideline Study Type Required Submitted Satisfied

870.1100 Acute Oral Toxicity yes yes yes

870.1200 Acute Dermal Toxicity yes yes yes

870.1300 Acute Inhalation Toxicity yes yes yes

870.2400 Acute Eye Irritation yes yes yes

870.2500 Acute Dermal Irritation yes yes yes

870.2600 Skin Sensitization yes yes yes

870.3100 90-Day Oral Toxicity in Rodents CR no NA

870.3150 90-Day Oral Toxicity in Non-Rodents CR yes NA

870.3200 21/28-Day Dermal Toxicity no no NA

870.3250 90-Day Dermal Toxicity yes no waived2

870.3465 90-Day Inhalation Toxicity CR no waived2

870.3700 Prenatal Developmental Toxicity Study (Rodent) yes yes yes

Prenatal Developmental Toxicity Study (Non-Rodent) yes yes yes

870.3800 Reproduction and Fertility Effects yes yes1 yes

870.4100 Chronic Toxicity (Rodent) CR yes1 NA

Chronic Toxicity (Non-Rodent) CR yes1 NA

870.4200 Carcinogenicity (Rat) CR yes1 NA

Carcinogenicity (Mouse) CR yes1 NA

870.5100 Bacterial Reverse Mutation Test yes yes yes

870.5300

870.5375

in vitro Mammalian Cell Gene Mutation Test

in vitro Mammalian Chromosome Aberration Test yes3 yesyes

yes

870.5385

870.5395

Mammalian Bone Marrow Chromosomal Aberration Test

Mammalian Erythrocyte Micronucleus Test yes3 noyes

yes

870.6100 Delayed Neurotoxicity of Organophosphorus Substances (Acute, Hen) CR no NA

Delayed Neurotoxicity of Organophosphorus Substances (28-Day, Hen) CR no NA

870.6200 Neurotoxicity Screening Battery (Acute, Rat) yes no waived2

Neurotoxicity Screening Battery (90-Day, Rat) yes no waived2

870.6300 Developmental Neurotoxicity Study CR no NA

870.7200 Companion Animal Safety CR no NA

870.7485 Metabolism and Pharmacokinetics CR yes1 NA

870.7600 Dermal Penetration CR no NA

870.7800 Immunotoxicity yes no waived2

CR: Conditionally Required

NA: Not Applicable

1 Studies pending review

2 Requirement waived by HASPOC - TXR#0056966

3 Either guideline study type may be used to satisfy the data requirement (e.g., 870.5300 or 870.5375)
Page 10 of 14

Toxicity Profiles

Table A.6: Acute Toxicity Profile

Guideline Study Type MRID Results Toxicity Category

870.1100 Acute Oral Toxicity 45516710 LD50 > 5000 mg/kg; the test material was 49.9% a.i. IV

870.1200 Acute Dermal Toxicity 45118305 LD50 > 5000 mg/kg; the test material was 49.9% a.i. IV

870.1300 Acute Inhalation Toxicity 45118308 LC50 > 0.92 mg/L; the test material was 49.9% a.i. III

870.2400 Primary Eye Irritation 45118311

“No signs of ocular irritation in any of the three 

rabbits during the 72-hour post dosing observation 

period.” The test material was 49.9% a.i.

IV

870.2500 Primary Dermal Irritation 45118314

Primary Dermal Irritation Index (PDII) = 0.0

“There were no signs of dermal irritation in any of 

the three rabbits during the study.” The test material 

was 49.9% a.i.

IV

870.2600 Dermal Sensitization 45118317 Not a dermal sensitizer. The test material was 49.9% 

a.i. N/A

Table A.7: Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

870.3050 Repeated Dose 

28-Day Oral 

Toxicity in 

Rodents (Rat)

45232416 (1997)

ppm:

0, 1, 10, 100, 500, 1000

mg/kg/day:

M: 0, 1.0, 10.4, 101, 513, 1029

F: 0, 1.1, 10.9, 105, 521, 1056

Acceptable / Guideline

NOAEL (mg/kg/day): M = 513 F = 521

LOAEL (mg/kg/day): M = 1029 F = 1056

Based on decreased food consumption in males. 

Repeated Dose 

28-Day Oral 

Toxicity in 

Rodents (Mice)

45516716 (2001)

ppm:

0, 10, 100, 500, 1000

mg/kg/day:

M: 0, 10.8, 110, 538, 1060

F: 0, 11.2, 113, 504, 1140

Acceptable / Guideline

NOAEL (mg/kg/day): M = 10.8 F = 11.2

LOAEL (mg/kg/day): M = 110 F = 113

Based on increased liver weights in both sexes and 

progressing to liver toxicity at higher dose levels.

870.3150 90-Day Oral 

Toxicity in NonRodents (Dog)

45784101 (2002)

ppm:

0, 30, 3000, 30000

mg/kg/day:

M: 0, 0.9, 115, 1040

F: 0, 1.1, 113, 1150

Acceptable / Guideline

Associated with an un-reviewed study 

MRID 46005501 (2003)

NOAEL (mg/kg/day): M = 1 F = 1

LOAEL (mg/kg/day): M = 115 F = 113

Based on changes in red blood cell parameters 

(hematocrit, hemoglobin, RBC, and MCV) and 

compensatory bone marrow hyperplasia. 

870.3250 90-Day Dermal 

Toxicity (NA)

NA Waived (TXR #0056966)

870.3465 90-Day Inhalation 

Toxicity (Rat)

NA Waived (TXR #0056966)

870.3700 Prenatal 

Developmental 

Toxicity Study 

(Rat)

45232419 (2000)

mg/kg/day:

F: 0, 250, 500, 1000

Acceptable / Guideline

Maternal

NOAEL (mg/kg/day) =1000

LOAEL (mg/kg/day) > 1000

Developmental

NOAEL (mg/kg/day) =1000

LOAEL (mg/kg/day) > 1000
Page 11 of 14

Table A.7: Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

Prenatal 

Developmental 

Toxicity Study 

(Rabbit)

45232418 (2000)

mg/kg/day:

F: 0, 250, 500, 1000

Acceptable / Guideline

Maternal

NOAEL (mg/kg/day) =1000

LOAEL (mg/kg/day) > 1000

Developmental

NOAEL (mg/kg/day) =1000

LOAEL (mg/kg/day) > 1000

870.3800 Reproduction and 

Fertility Effects 

(Rat)

46251901 (2004) Pending review

46277912 (2004)

46251902 (2004)

mg/kg/day:

M: 0, 0.5, 5, 25

F: 0, 0.5, 5, 25

Acceptable / Guideline

-pending secondary reviewParental

NOAEL (mg/kg/day): M = 5 F = 5

LOAEL (mg/kg/day): M = 25 F = 25

Based on increased absolute and relative (to body 

weight) liver weights in both generations

Reproductive

NOAEL (mg/kg/day): M = 0.5 F = 0.5

LOAEL (mg/kg/day): M = 5 F = 5

Based on decreased mating and fertility indices in 

the F1 parents.

Offspring

NOAEL (mg/kg/day): M = 5 F = 5

LOAEL (mg/kg/day): M = 25 F = 25

Based on convulsions and decreased survival and 

body weights in the F1 and F2 pups.

870.4100 Chronic Toxicity 

(Dog)

46227101 (2005)

ppm:

0, 30, 300, 2250

mg/kg/day:

M: 0, 0.7, 9.3, 69

F: 0, 0.9, 8.7, 70

Acceptable / Guideline

-pending secondary reviewNOAEL (mg/kg/day): M = 9.3 F = 8.7

LOAEL (mg/kg/day): M = 69 F = 70

Based on presence of erythroid cell hyperplasia of 

the bone marrow (males), and increased incidence of 

polychromasia and effects on hematology (males and 

females).

870.4200 Carcinogenicity 

(Mouse)

46539601 (2005)

mg/kg/day:

M: 0, 0.5, 3.0, 30.2

F: 0, 0.5, 30.5, 102.3

Acceptable / Guideline

-pending secondary reviewNOAEL (mg/kg/day): M = 30.2 F = 30.5

LOAEL (mg/kg/day): M > 30.2 F = 102

Based on increased mortality and tonoclonic 

convulsions in females.

870.4300 Combined Chronic 

Toxicity / 

Carcinogenicity 

(Rat)

46542901 (2005) Pending review
Page 12 of 14

Table A.7: Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

870.5100 Bacterial Reverse 

Mutation Test

(Salmonella 

typhimurium)

45516717 (2001)

μg/plate:

S9: 33.3, 100, 333, 1000, 3300, 

5000

Acceptable / Guideline

XDE-007 was tested up to concentrations where 

precipitation was observed (≥333 g/plate). 

However, in no test cultures up to the limit 

concentration (5000 g/mL) was a positive (and 

significant) increase found in mean number of 

revertants per plate, either in the present (+S9) or 

absence (-S9) of metabolic activation. Mutagentreated cultures responded with marked increased 

revertants.

870.5300 in vitro

Mammalian Cell 

Gene Mutation 

Test (Mouse 

Lymphoma Cells)

45516719 (2001)

μg/plate:

S9: 6.66, 12.5, 20, 25, 50, 66.6. 100, 

200

Acceptable / Guideline

In the presence or absence of S9, there was no clear 

evidence of cytotoxicity at any concentration. 

Precipitation of test material was observed in both 

assays in the presence and absence of S9 (≥20 

g/mL).

There was no increase in presumed forward 

mutations at any concentration in the presence or 

absence of S9, indicating no induction of a 

mutagenic response in this system.

870.5375 in vitro

Mammalian 

Chromosome 

Aberration Test

(Primary Rat 

Lymphocyte)

45232418 (2000)

μg/mL:

S9: 0.5, 1.67, 5.0, 16.7, 50, 167, 500

Acceptable / Guideline

XDE-007 was tested up to concentrations where 

precipitation was observed (≥16.7 g/mL). No 

significant increase in incidence of aberrant cells 

was found at any treatment level, in contrast to 

positive controls which showed marked increases in 

abnormal cells.

45516720 (2001)

μg/mL:

S9: 3.13, 6.25,12.5, 25, 50, 100, 200

Acceptable / Guideline

Increasing degrees of precipitation up to the asserted 

limit of solubility of the test compound (200 g/mL) 

were observed in the presence or absence of S9, 

accompanied by slight cytotoxicity (33% reduction 

in the mitotic indices at 200 g/mL –S9). At no 

concentration in the presence or absence of S9 was 

there any increased incidence of aberrant cells 

(structural or numerical) compared to the vehicle 

(DMSO) control.

Cultures treated with positive controls (i.e., 

mitomycin-C and cyclophosphamide) manifested the 

expected high incidence (p<0.05) of structural (but 

not numerical) chromosome abnormalities.

Therefore, XDE-007 is considered negative for in 

vitro chromosomal aberrations (clastogenesis).

870.5395 Mammalian 

Erythrocyte 

Micronucleus Test

(Mouse)

45516718 (2001)

mg/kg/day:

M: 500, 1000, 2000

Acceptable / Guideline

XDE-007 induced no clinical signs and was not 

cytotoxic to bone marrow (i.e., no significant 

decrease in the polychromatic erythrocytes to 

normochromatic erythrocytes ratio). Furthermore, no 

significant increase in micronucleated polychromatic 

erythrocytes (MPCEs) was observed at any dose 

level, in contrast to the marked increase in MPCEs 

from cyclophosphamide-treated animals.
Page 13 of 14

Table A.7: Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

Non

Guideline

Ex Vivo 

Developmental 

Toxicity Study 

(Rat)

45232417 (1988)

mg/kg/day:

F: 1000

Acceptable / Guideline

XR-007 was considered negative for teratogenic 

potential in this screening study.

870.6200 Acute 

Neurotoxicity 

Screening Battery

(Rat)

NA Waived (TXR # 0056966)

90-Day 

Neurotoxicity 

Screening Battery

(Rat)

NA Waived (TXR #0056966)

Non

Guideline

Chronic

Neurotoxicity 

Study

46277910 (2004)

mg/kg/day:

M: 0, 0.1, 1, 75, 300

F: 0, 0.1, 1, 75, 300

Acceptable / Guideline

-pending secondary reviewNeurotoxicity

NOAEL (mg/kg/day): M = 300 F = 300

LOAEL (mg/kg/day): M > 300 F > 300

Systemic

NOAEL (mg/kg/day): M = 300 F = 300

LOAEL (mg/kg/day): M > 300 F > 300
Page 14 of 14

Table A.7: Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

870.7485 Metabolism and 

Pharmacokinetics 

(Rat)

46277911 (2004)

mg/kg:

Single: 1, 100

Repeated: 1

Acceptable / Guideline

-pending secondary reviewAbsorption 

The test animals absorbed up to 56% of the 

administered dose (AD).

Distribution

The test animals contained up to 34% AD at the time 

of sacrifice (168 hours post-dosing). The majority of 

the radioactivity was located in the carcass. 

Radioactivity was also associated with the skin, 

liver, and kidneys. When radioactivity was 

normalized to tissue weight, the concentration of 

radioactivity was highest in the fat, generally 

followed by ovaries, adrenals, uterus, carcass, skin, 

liver, and kidneys.

Metabolites

The parent passed through largely unchanged and 

represented up to 54% AD, however several 

metabolic processes were represented: cleavage of 

the acyl urea moiety followed by conjugation with 

glycine with the corresponding aniline metabolite 

being hydroxylated and conjugated with either 

sulfate or glucuronic acid. The metabolic process 

yielded the following metabolites: a ringhydroxylated 2-fluoro-3,5-dichloro-4-

(hexafluoropropoxyl)aniline (12% AD); deschloroParent (9% AD); 2,6-difluorobenzoic acid (32% 

AD); sulfate conjugate of ring-hydroxylated 2-

fluoro-3,5-dichloro-4-(hexafluoropropoxyl)aniline 

(12% AD).

Elimination

At 168 hours post-dosing, the AD was excreted via 

urine (16% AD) and feces (64% AD). However, up 

to 29% AD was retained in tissues and carcass. A 

repeated-dose experiment indicates that the test 

article does not bioaccumulate beyond 19% AD.

870.7800 Immunotoxicity

(NA)

NA Waived (TXR #0056966)