## UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

DATE: July 15,2014 OFFICE OF CHEMICAL SAFETY
AND POLLUTION PRE V ENTIO N



## SUBJECT: Noviflum uron

. Human H ea lth Assessment Scoping Do cument in Support of Registration
Review.

PC Code: 118 204


### Decision No.: 48930 I


### Petition No.: NA
Risk Assessment Type: NA

TXRNo.: NA

MRIDNo

. : NA DP Barcode: 0419013 

### Registration No.: NA Regulatory Action: Registrat i on Review Sco p i ng Document


### Case No.: 7434


### CAS No.: 121451-02-3


### 40CFR: NA



## FROM: Kristin Rury, Biologist

# ¥-~ 1

_, 

## Vincent Chen, Toxico l ogist '·

.

# ~_g Lc;.._---

Risk Assessment Branch III

Health Effects Division (7509P)

Office of Pesticide Programs

THROUGH: Christine Olinger, Branch

# Chi~e Risk Assessment Branch III

,. Health Effects Division (750

Office of Pesticide Programs

TO: Dana Friedman, Chemical Review Manager

Pesticide Re

- Eval uation Division (7508P)

Office of Pesticide Pr ograms

Attached i s the Hea l th Effects Division 's ( H ED) human health Registration Review scoping

document for the insecticide growth regulator

, noviflumuron.

Execu tive Summary

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

suffic ient data are available and w hether any updates are needed to support Registration Re view.

To determine the scope of work necessary to support R eg i stration Review

, HED has considered updates to Agency science policy and risk assessment methodologies and to the noviflumuron toxicity, exposure , and usage databases. The most rece nt (qualitat iv e) risk assessme n t 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 /29/2 005).

Page 1 of 14

## Noviflumuron is a benzoylphenylurea insect growth regulator used as bait around ornamental

trees, bui ld ings, wood decks, wood fences, and wood utility poles to control subterranean termites; and as an indoor crack and crevice tr eatme n t to control cockroaches. Novi flumuron products are formulated as ready

- to-use gel baits in syringe applicators, and as impregnated bait

stations. The labe ls specify that only pest management professionals license d by t he state to apply termite control products may use noviflumuron

.

Nov iflumuron primarily targe ts the liver in rats and bone marrow in dogs as evidenced by hypertrophy of the liver and hyperplasia ofthe bone marrow. Adequate carcinogenicity st udie s have been submitted for noviflumuron, but are currently undergoing secondary review.

Noviflumuron's carcinogenic potential will be e valuated Registration Re view. There are no

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

.

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

because noviflumuron is considered a non-food use pes tici d e

. A dietary exposure assessment
has not been conducted previously fo r noviflumuron

. Additionally, given the lim i t ed use pattern
there currently is no need to calculate EDWCs. There are no outstanding re sidue chemistry

database deficiencies at this time.

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

Re v iew because the protected bait stations and syringe crack and crevice uses are expected to provide n eglig i b le handler and post

- application exposure. The occupational and residential

exposure databases are considered complete for noviflumuron.

An 

## u pdated aggregate risk assessment will not be required to support Registratio n Review

because residential and drinking water exposures are considered negligible.

HED does not believe that new data are needed for Registration Review. Becau se of the negligible expos ur e from the registered uses of noviflumuron, a quantitative risk assessment will

not be conducted during Registration Review.



## Introduction

Novifl umuron 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 beca use exposure

to noviflumuron is considered ne g li gible via all routes. Noviflumuron products are only

formulated as ready

- to

- use gel baits in syr inge applicators, and as an impregnated bait station

. It

is regis tered 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 u ti lity poles to control subterranean termites. The labels specify that only pest management professionals licensed by the state to apply termite control produc ts may use noviflumuron. For information on the chemical ident ity 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 stu dies are waived immunotoxicity, acute and subchronic neurotoxicity, subchronic dermal, and subchronic inhalation toxicity studies (TXR# 005696 6 ). 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 hy perplasia 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/d ay). 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 decreas ed 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 pot ential 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 a cute and chronic )

, incidental oral

, dermal

, and inhalation exposure risk
assessments were not conducted because exposure i s 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.

C onclusion : Based on the current use pattern, noviflumuron’s toxicity databa se 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 p rotected baits as non

food/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 tamperin g (ChemSAC Minutes, 06/22/2005)

.

F urther more, g el baits are considered non

- food/non

- feed provided the active ingredient has a low vapor pressure (vap or pressure <10

- 6 

## or 10

- 7 

## mm Hg ) and provided the use does not include

## Page 4 of 14

application to surface s that might contact food (Chem SAC 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

- 1 2 

## mm Hg at
20oC ) , w hich means the technical qualifies as having a low vapor pressure. The refore, 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 a n insect growth regulator used t o 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 list ed 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, D2 85861, 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 tox icity categories for all routes of exposure were low; and

 This is a reduced ris k 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 s yringe 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 flo ors, 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 dire ctions 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 exposu re 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 : A n 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 SENSOR

Pesticides 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.

E nvironmental 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 Minor ity 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 arou nd 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 A merica (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 pestic ide 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 re sources 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 pe sticides 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 che micals 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 h ave a common mechanism on
EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

Data Requirements

None.

R eferences

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 005696 6 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



## Attachment

s Attachment 1. Chemical Identity Table
Attachment 2. Noviflumuron Use Pattern
Attachment 3

. Noviflumuron Toxicity Profile s

## 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 product s (EP s ) Recruit ® IV Termite Bait (0.5% Noviflumuron) ; EPA R e g. 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. Phys icochemical 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;

A cetonitrile: 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, pK a D oes not contain reversibly ionizable functional gr.

Octanol/water partition coefficient, Log(K OW ) Kow = 4.94 ; Log 10 Ko/w = 86200 @

20 o C
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 ft 2 or 4

- 12

grams per 100 ft 2 if 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 Re commended 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 y es 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 waived 2

870.3465 90

- Day Inhalation Toxicity CR no waived 2

870.3700 Prenatal Developmental Toxicity Study (Rodent) y es yes yes

Prenatal Developmental Toxicity Study (Non

- Rodent) yes yes yes 870.3800 Reproduction and Fertility Effects yes yes 1 yes

870.4100 Chronic Toxicity (Rodent) CR yes 1 NA

Chronic Toxicity (Non

- Rodent) CR yes 1 NA

870.4200 Carcinogenicity ( Rat ) CR yes 1 NA

Carcinogenicity ( Mouse ) CR yes 1 NA

870.5100 Bacterial Reverse Mutation Test y es yes yes 870.5300

870.5375 i n vitro Mammalian Cell Gene Mutation Test

i n vitro Mammalian Chromosome Aberration Test yes 3 yes

yes yes

870.5385
870.5395 Mammalian Bone Marrow Chromosomal Aberration Test

Mammalian Erythrocyte Micronucleus Test yes 3 no

yes 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 waived 2

Neuro toxicity Screening Battery (90

- Day , Rat) yes no waived 2

870.6300 Developmental Neurotoxicity Study CR no NA

870.7200 Companion Animal Safety CR no NA

870.7485 Metabolism and Pharmacokinetics CR yes 1 NA

870.7600 Dermal Penetration CR no NA

870.7800 Immunotoxicity yes no waived 2

CR : Conditionally Required

NA: Not Applicable

1 Studies p ending 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 LD 50 > 5000 mg/kg; the test material was 49.9% a.i. IV

870.1200 Acute Dermal Toxicity 45118305 LD 50 > 5000 mg/kg; the test material was 49.9% a.i. IV

870.1300 Acute Inhalation Toxicity 45118308 LC 50 > 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, 50 0, 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, 50 0, 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 Non

Rodents (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 review

Parental 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 F 1 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 F 1 and F 2 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 review

NOAEL (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 review

NOAEL (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. Mutagen

treated 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

co ncentration 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: 50 0, 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). Furthermor e, 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 review

Neurotoxicity 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 review

Absorption 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, s kin, 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 correspondi ng aniline metabolite being hydroxylated and conjugated with either sulfate or glucuronic acid. The metabolic process yielded the following metabolites: a ring

hydroxylated 2

- fluoro

- 3,5

- dichloro

- 4

- (hexafluoropropoxyl)aniline (12% AD); deschloro

Parent (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)