VOLUME - OF OF SUBMISSION

syngenta

Norflurazon

Request for Waiver of Endocrine Disruption Screening Program Assays

Assessment

DATA REQUIREMENT(S): Not Applicable

AUTHOR(S): W. Thomas Beidler, Ph.D.

James T. Stevens, Ph.D.

Jonathan M. Akins, Ph.D., DABT

COMPLETION DATE: February 4, 2010

PERFORMING LABORATORY: Syngenta Crop Protection, Inc.

410 Swing Road

Greensboro, NC 27409 USA

LABORATORY PROJECT ID: Report Number: TK0023425

Task Number: TK0023425

SUBMITTER/SPONSOR: Syngenta Crop Protection, Inc. I J

410 Swing Road " a<> <

Post Office Box 18300 * *'

Greensboro, NC 27419-8300

VOLUME 1 OF 1 OF STUDY

PAGE 1 OF 43
STATEMENT OF DATA CONFIDENTIALITY CLAIMS

STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS

UNDER SPECIFIED FIFRA PROVISIONS

No claim of confidentiality is made for any information contained in this study on the basis

of its falling within the scope of FIFRA Section 10(d)(l)(A) (discloses manufacturing or

quality control processes), (B) (discloses the details of methods for testing, detecting or

measuring the quantity of any deliberately added inert ingredient of a pesticide), or (C)

(discloses the identity or percentage quantity of any deliberately added inert ingredient of a

pesticide).

Company:

Syngenta Crop Protection, Inc.

Company Agent: Jerry Wells, Ph.D.

U. S. Product Registration Manager Date

Syngenta is the owner of this study. Syngenta has submitted this material to the United

States Environmental Protection Agency specifically under the provisions contained in

FIFRA as amended and, hereby, consents to use and disclosure of this material by EPA

according to FIFRA. Notwithstanding the wording of our marking TRADE SECRET, this

marking, by itself, conveys no supplemental claims of confidentiality under FIFRA

Sections 10(a) or 10(b) (addressing protection of trade secrets and commercial and financial

information). In submitting this material to EPA according to method and format

requirements contained in PR Notice 86-5, we do not waive any protection or right involving

this material that would have been claimed by the company if this material had not been . J.

submitted to the EPA, nor do we waive any protection or right provided under FIFRA *

Section 3 (concerning data exclusivity and data compensation) or FIFRA Sectipn.lO(g) ; »0 *

(prohibiting disclosure to foreign and multinational pesticide companies or tjieirlagents). .

Report Number: TK0023425 Page 2 of 43
GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT

As this volume contains comments and assessments of information and data in reports

submitted separately, a Good Laboratory Practice Compliance Statement is not appropriate.

Study Director: There is no GLP Study Director for this volume.

W. Thomas Beidler, Ph.D. Date

 /

Author

Performing Laboratory: Syngenta Crop Protection, Inc.

410 Swing Road

Greensboro, NC 27409 USA

, 20 fO

JoWhan M. Akins, Ph.^J&BT Date

Representative of Submitter/Sponsor

Submitter/Sponsor: Syngenta Crop Protection, Inc.

410 Swing Road

Post Office Box 18300

Greensboro, NC 27419-8300 USA ' • •

•

> • • • *

Report Number: TK0023425 Page 3 of 43
TABLE OF CONTENTS

STATEMENT OF DATA CONFIDENTIALITY CLAIMS 1

GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT 2

TABLE OF CONTENTS 3

1.0 EXECUTIVE SUMMARY 5

2.0 INTRODUCTION 6

3.0 OTHER SCIENTIFICALLY RELEVANT INFORMATION (OSRI):

EXISTING NORFLURAZON STUDIES SATISFY EDSP TIER 1

ASSAY REQUIREMENTS 8

3.1 Reproduction Studies ......................................................................................... 9

3.2 Developmental Toxicity Studies ...................................................................... 10

3.3 Rodent Subchronic and Chronic Toxicity/Carcinogenicity Studies ................ 1 1

3.4 Fish and Amphibian Studies ............................................................................ 12

4.0 RATIONALE FOR ACCEPTANCE OF NORFLURAZON OSRI

FOR SPECIFIC TIER 1 ASSAYS 12

4.1 Estrogen Receptor Binding Assays (OPPTS 890.1250; OPPTS 890.1300) .... 12

4.2 Androgen Receptor Binding (OPPTS 890.1150) ............................................. 13

4.3 Aromatase -Human Recombinant (OPPTS 890.1200) .................................... 15

4.4 Steroidogenesis- Human Cell Line H295R (OPPTS 890.1550) .................... 16

4.5 Hershberger - Rat (OPPTS 890.1400) ............................................................. 17

4.6 Male Pubertal - Rat (OPPTS 890.1500) ........................................................... 18

4.7 Female Pubertal - Rat (OPPTS 890.1450) ....................................................... 20

4.8 Uterotrophic - Rat (OPPTS 890.1600) ............................................................ 22

4.9 Fish Short Term Reproduction (OPPTS 890.1350) .................................... .....23

4.10 Amphibian Metamorphosis (OPPTS 890. 11 00) ..................................... ..;.,.... 23

5.0 CONCLUSION ../.^ 23

6.0 REFERENCES I'Tl * "" 25

APPENDICES SECTION ••;••• •••"• 27

APPENDIX 1 Title Pages of Cited Studies ................................................. ".?•" ........ :.V..V.28 * ~ ^ ••*•&.._ -

• •

•

Report Number: TK0023425 Page 4 of 43
LIST OF TABLES

Table 1 Norflurazon OSRI Studies 8

Table 2 Functionally Equivalent Endpoints in FIFRA Guideline Studies Conducted

with Norflurazon which are Relevant to in vitro ER Binding and to the

Estrogenic Mode of Action 13

Table 3 Functionally Equivalent Endpoints in FIFRA Guideline Studies Conducted

with Norflurazon which are Relevant to in vitro AR Binding and to the

Androgenic Mode of Action 14

Table 4 Functionally Equivalent Endpoints in FIFRA Guideline Studies Conducted

with Norflurazon which are Relevant to Aromatase Inhibition 16

Table 5 Functionally Equivalent Endpoints in FIFRA Guideline Studies Conducted

with Norflurazon which are Relevant to the Steroids Alterations that might

be Detected in the Steroidogenesis Screen 17

Table 6 Functionally Equivalent Endpoints in FIFRA Guideline Studies Conducted

with Norflurazon Compared to those Measured hi the Hershberger Screen.... 18

Table 7 Functionally Equivalent Endpoints in FIFRA Guideline Studies Conducted

with Norflurazon Compared to those Measured in the Pubertal Male Screen. 19

•••••• * *,,*

••••• I *,.*

Report Number: TK0023425 Page 5 of 43
1.0 EXECUTIVE SUMMARY

This document provides the scientific justification towards a waiver for the majority of the

Endocrine Disruption Screening Program Tier 1 assays in the norflurazon test order based on

the existence of Other Scientifically Relevant Information (OSRI).

EPA developed and recently published the guidelines for the Endocrine Disruption Screening

Program (EDSP) Tier 1 Screening (T1S) assays to identify potential endocrine-modulating

chemicals, and EPA sent test orders to registrant of norflurazon. However, EPA also

indicated that "other scientifically relevant information ("OSRI") that is functionally

equivalent to the EDSP Tier 1 assays may be utilized in lieu of conducting the Tier 1 assays.

The objective of this document is to provide the OSRI that is available for norflurazon and to

obtain waivers for the following EDSP Tier 1 assays of the test order:

890.1150 - Androgen Receptor Binding (Rat Prostate)

890.1200 - Aromatase (Human Recombinant)

890.1250 - Estrogen Receptor Binding

890.1300 - Estrogen Receptor Transcriptional Activation (Human Cell Line HeLa-9903)

890.1400 - Hershberger (Rat)

890.1450 - Female Pubertal (Rat)

890.1500 - Male Pubertal (Rat)

890.1550 - Steroidogenesis (Human Cell Line - H295R)

890.1600 - Uterotrophic (Rat)

The OSRI for norflurazon is based on two different sources: the EPA's ToxCastTM program

results and the US EPA's 40CFR Part 158 guideline studies. Norflurazon was tested as part

of the EPA's ToxCastTM Phase 1 screen, where the NIH Chemical Genomics Center

conducted estrogen and androgen receptor binding assays and a Novascreen assay for

aromatase inhibition. In addition, endocrine-related endpoints have already been assessed in

existing EPA-required guideline studies for norflurazon, which provide further weight of

evidence that the OSRI provide "functionally equivalent" information to that obtained in the

proposed T1S battery.

In conclusion, norflurazon already has been thoroughly evaluated via critical apical endpoints

that correspond to the EDSP Tier 1 screens. Therefore, Syngenta Crop Protection, Inc.,

requests that the Environmental Protection Agency waive the requirement to conduct the

majority of the norflurazon EDSP test order assays based on the following scientific

justification.

1. US EPA has recently sponsored and produced OSRI for the following

studies/endpoints, therefore these studies should be waived from the EDSP Tier 1

screen requirements:

• 890.1150 - Androgen Receptor Binding (Rat Prostate)

• 890.1200 - Aromatase (Human Recombinant)

• 890.1250 - Estrogen Receptor Binding

• 890.1300 - Estrogen Receptor Transcriptional Activation (Human Cell Line HeLa-9903)

Report Number: TK0023425 Page 6 of 43
2. Tier 2 studies have been previously conducted for norflurazon as part of the 40CFR

Part 158 data requirements (e.g., rat reproduction study, developmental toxicity, 90-

day studies, chronic and oncogenicity studies). These EPA guideline studies serve as

OSRI for the following studies/endpoints, therefore these studies should be waived

from the EDSP Tier 1 screen requirements:

890.1400 - Hershberger (Rat)

890.1450 - Female Pubertal (Rat)

890.1500 - Male Pubertal (Rat)

890.1550 - Steroidogenesis (Human Cell Line - H295R)

890.1600 - Uterotrophic (Rat)

3. The existing database for norflurazon does not contain the specific OSRI for the fish

and amphibian studies, and Syngenta is not providing a rationale to waive these

specific assays. However, the existing mammalian toxicity database combined with

the fish early life stage studies provide significant information that may be judged as

adequate OSRI for a waiver or partial waiver of the following two studies:

• 890.1100 - Amphibian Metamorphosis (Frog)

• 890.1350 - Fish Short-Term Reproduction

2.0 INTRODUCTION

Norflurazon is a selective pre-emergent herbicide used to control germinating annual grasses

and broadleaf weeds in fruits, vegetables, nuts, cotton, peanuts, soybeans, and various

nonagricultural and industrial areas. Norflurazon was first registered as a pesticide in the

U.S. in 1974 and has undergone registration, with the latest Registration Eligibility Decision

occurring in or around 2002, and was judged to meet current data requirements and

regulatory standards.

The Federal Food Drug and Cosmetic Act required the U. S. Environmental Protection

Agency (EPA) to "develop a screening program, using appropriate validated test systems and

other scientifically relevant information to determine whether certain substances may have an

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

other effects as [EPA] may designate [21 U.S.C. 346a (p)]. Section 408(p) (3) specifically

required that the Administrator "shall provide for the testing of all pesticide chemicals." [21

U.S.C. 346a (p) (3)].

EPA developed and recently published the guidelines for the Endocrine Disruption Screening

Program (EDSP) Tier 1 Screening (T1S) assays to identify potential endocrine-modulating

chemicals, and EPA sent test orders for norflurazon to the registrant Syngenta Crop

Protection. However, EPA also indicated that "other scientifically relevant information

("OSRI") that is functionally equivalent to the EDSP Tier 1 assays may be utilized in lieu of

conducting the Tier 1 assays. EPA indicated the following criteria for OSRI.

Report Number: TK0023425 Page 7 of 43
1) The OSRI studies must follow accepted scientific methodology or protocol, including

but not limited to those presented in the EPA's harmonized test guideline

compendium (see http://www.epa.gov/endo), and:

a. Adhere to good laboratory practices

b. Are of high quality, achieving the objective to provide reasonable assurance

that a chemical does or does not have the potential to interact with estrogen,

androgen, or thyroid systems.

c. Include data or a reference to the data for each test that is required, along with

a rationale that explains how the existing study that is cited / submitted

satisfies part or all of the Order.

i. Deviations from the protocols validated for the Tier 1 assays must be

identified, along with an explanation for the deviations, including an

explanation as to why, notwithstanding the deviations, the protocol

used should still be considered as providing an accepted scientific

methodology or protocol.

2) Be classified by EPA as acceptable if it has been previously submitted.

a. Provide MRID number and copy of the title page (do not resubmit a study that

has previously been submitted to the Agency.

b. Identify any action taken by the Agency on the protocol, if it had been

previously reviewed by EPA. Identify manner in which all Agency

comments, concerns or issues were addressed in the final protocol and study.

c. Offer to pay compensation to original data submitter if you are citing a study

of which you are not the original data submitter.

The objective of this document is to provide the OSRI that is available for norflurazon and to

obtain waivers for the following EDSP Tier 1 assays:

890.1150 - Androgen Receptor Binding (Rat Prostate)

890.1200 - Aromatase (Human Recombinant)

890.1250 - Estrogen Receptor Binding

890.1300 - Estrogen Receptor Transcriptional Activation (Human Cell Line HeLa-9903)

890.1400 - Hershberger (Rat)

890.1450 - Female Pubertal (Rat)

890.1500 - Male Pubertal (Rat)

890.1550 - Steroidogenesis (Human Cell Line - H295R)

890.1600 - Uterotrophic (Rat)

This document reviews the endocrine-related endpoints already routinely assessed in existing

EPA-required FIFRA guideline studies and other testing of norflurazon by EPA (e.g., EPA

data generation for norflurazon from the ToxCastTM program), which provide weight of

evidence that the OSRI provide "functionally equivalent" information which fulfils the

requirement for the majority of the screens in the T1S battery.

Report Number: TK0023425 Page 8 of 43
3.0 OTHER SCIENTIFICALLY RELEVANT INFORMATION

(OSRI): EXISTING NORFLURAZON STUDIES SATISFY EDSP

TIER 1 ASSAY REQUIREMENTS

The OSRI for norflurazon is based on two different sources: the EPA's ToxCastTM program

results on norflurazon and the US EPA's 40CFR Part 158 guideline studies for norflurazon

registration (Table 1). The ToxCast data provides substantially similar methodology as the

EDSP Tier 1 screens with regard to estrogen, androgen, and aromatase activity. The USEPA

40CFR Part 158 data provides the Tier 2 assessment for potential effects on subchronic

toxicity, developmental toxicity, reproduction effects, chronic toxicity and other apical

endpoints of endocrine function effects.

Table 1 Norflurazon OSRI Studies

OSRI Data Source

US EPA ToxCast

The USEPA 40CFR

part 158 data

requirements

Study

Estrogen Binding

Androgen Binding

Aromatase

90-Day Subchronic Rat. (1971). FIFRA

§82-1.

6- Month Dog Chronic Toxicity.

(1973). FIFRA §83-1

Rat Chronic Toxicity/ Carcinogenicity.

(1975). FIFRA §83-1.

Rabbit Developmental Toxicity.

(1983). FIFRA §83-3.

Rat Developmental Toxicity. (1972).

FIFRA §83-3.

3-Generation Rat Reproduction.

(1975). FIFRA §83-4.

2-Generation Rat Reproduction.

(1994). FIFRA §83-4

MRID#

-

-

-

00091055

00111618.

0082019

and

00111649

00131152

00063621

0080750

43522301

OSRI Assessment

Substantially Similar

methodology by USEPA; GLP

Substantially Similar

methodology by USEPA; GLP

Substantially Similar

methodology by USEPA; GLP

USEPA Guideline study, PreGLP

USEPA Guideline study, PreGLP

USEPA Guideline study, PreGLP

USEPA Guideline study, GLP

USEPA Guideline study, PreGLP

USEPA Guideline study, PreGLP

USEPA Guideline study, GLP

The EPA's ToxCastTM program has already evaluated the norflurazon in assays similar to the

estrogen (OPPTS 890.1300 - Estrogen Receptor Transcriptional Activation), androgen

(OPPTS 890.1150 - Androgen Receptor Binding), and aromatase (OPPTS 890.1200 -

Aromatase - Human Recombinant) screens required by the EDSP Tier 1 battery (Kavlock et

al., 2009; Houck, 2009). The protocols for assays used in the ToxCastTM evaluation are not

currently available, however the assays were conducted by and for EPA. These EPAsupported assays apparently meet the quality standards of adherence to the spirit of good

laboratory practices and are of high quality, achieving the objective to provide reasonable

assurance that a chemical does or does not have the potential to interact with estrogen,

androgen and aromatase receptors (Eli Lilly and Company and NIH Chemical Genomics

Center, 2008).

Report Number: TK0023425 Page 9 of43
In addition the Reregistration Eligibility Decision (RED) Document for norflurazon was

issued in 2002 (USEPA, 2002); this Reregistration Eligibility Decision document reflects a

reassessment of all data which were submitted in response to the Registration Standard and

the subsequent DCIs. The toxicology database for norflurazon was considered complete.

Norflurazon is listed in the IEH REDIPED report (IEH, 2005) with the designation that no

data is available in regard to norflurazon potential to disrupt the endocrine system. No other

scientifically relevant information consistent with the EDSP Tier 1 assays was found for

norflurazon in the literature.

3.1 Reproduction Studies

The following reproduction studies have been conducted with norflurazon; a one-generation

study in the mouse (guideline 83-3; MRID 00080751), a two-generation reproduction study

in the rat (guideline 83-4; MRID 435223-01) and a three-generation study in the rat

(guideline 83-4; MRID 00080750). All of these studies were determined by the USEPA as

guideline acceptable except the one-generation mouse which was found to be supplemental.

A one-generation reproduction study was conducted in male and female CD-I (HaM/ICR

Swiss) mice. In this study (WARF, 1975b), norflurazon technical was administered in the

diet at nominal doses of 0, 85, 170, or 340 ppm (0, 12.1, 24.3, or 48.5 mg/kg/day). There

were no treatment-related effects reported in parental mice or in offspring at any of the dose

levels tested. The systemic and reproductive NOEL was determined to be 48.5 mg/kg/day,

and the systemic and reproductive LEL were determined to be > 48.5 mg/kg/day. This study

was classified as core supplementary data.

A three-generation reproductive toxicity study was conducted in male and female SpragueDawley rats (WARF, 11975b). In this study, norflurazon technical (98.8% a.i.) was

administered in the diet at nominal doses of 0, 125, 375, or 1025 ppm (0, 6.25, 18.75, or

51.25 mg/kg/day). The FQ generation of rats received norflurazon technical at nominal dose

levels of 0, 125, 250, or 500 ppm (0, 6.25, 12.5, or 25.0 mg/kg/day) for 18 weeks prior to

mating to produce the F]a and Fib generation. Subsequent to this, the Fja generation was used

for a two year feeding study, while the Fib generations received norflurazon technical at 0,

125, 375, or 1025 ppm for 13 weeks and were then mated to produce the p2a and F2b

generations. The F2a litter continued to receive test article and were sacrificed just prior to

delivery of a second litter (Fsb), which was examined for developmental effects. There were

no data presented for parental rats in this study. Reproductive data presented indicated no

apparent effects of norflurazon treatment on reproductive performance at any dose level

tested. The systemic toxicity NOEL was determined to be 18.75 mg/kg/day, and the

systemic toxicity LEL was determined to be 51.25 mg/kg/day. The reproductive toxicity

NOEL was determined to be 51.25 mg/kg/day and the reproductive toxicity LEL was

determined to be > 51.25 mg/kg/day. Due to the lack of parental toxicity data in this study,

the systemic toxicity NOEL and LEL were based on the results of subchronic and chronic

testing with norflurazon, in which an effect level of 25 mg/kg/day was indicated. However,

the Health Effects Division RfD/Quality Assurance Committee determined that it was not

Report Number: TK0023425 Page 10 of 43
appropriate to extrapolate a systemic NOEL/LEL to this study based on effects observed

from subchronic and chronic toxicity studies. Nonetheless, the Committee felt that the

conclusions drawn from the subchronic and chronic toxicity studies could be used to justify

that the dose levels were probably adequate. Therefore, the systemic toxicity NOEL and

LEL were considered appropriate.

A 2-generation reproductive toxicity study was conducted in male and female Wistar rats

(Eschbach et al., 1994). In this study, norflurazon technical was administered in the diet at

dose levels of 0,150, 750, or 1500 ppm over 2 generations (0, 10.2, 50.8, or 102.5 mg/kg/day

for F0males; 0, 12.1, 62.0, or 129.7 mg/kg/day for F0 females; 0, 13.2, 67.8, or 138.6

mg/kg/day for Fl males; 17.1, 81.7, and 173.0 mg/kg/day for FI females). The NOEL for

systemic toxicity was determined to be 150 ppm (10.2 mg/kg/day for males and 12.1

mg/kg/day for females), and the systemic toxicity LEL was determined to be 750 ppm (50.8

mg/kg/day for males and 62.0 mg/kg/day for females), based on significant increases in liver

and kidney weights observed in both generations of parental rats and the increased incidence

of hepatocellular hypertrophy in both generations of parental rats. The reproductive toxicity

NOEL was determined to be 750 ppm (50.8 mg/kg/day for males and 62.0 mg/kg/day for

females), and the reproductive toxicity LEL was determined to be 1500 ppm (102.5

mg/kg/day for males and 129.7 mg/kg/day for females), based on an increase in pup deaths,

an increase in stillborn pups in the Fib and Fia litters, and a decreased lactation index in the

F2b litter.

The studies examining developmental and reproductive toxicity of norflurazon were

considered by the Health Effects Division RfD/Peer Review Committee in a meeting held

March 16, 1995 (USEPA, 2002). The committee concluded that treatment with norflurazon

was associated with reproductive toxicity in the form of increased pup death, increased

stillborn pups, and increased pup deaths between days 5-14 of lactation at a dose of 1500

ppm [129 and 173 mg/kg/day for F0 and FI females, respectively] (USEPA, 2002).

3.2 Developmental Toxicity Studies

Developmental toxicity studies with norflurazon have been conducted in the rat (guideline

83-3; MRID 00063621) and the rabbit (guideline 83-3; MRID 00131151 and 00131152). All

of these studies were determined by the USEPA as guideline acceptable.

In a developmental toxicity (teratology) study (Hartman, 1972), rats of the Sprague-Dawley

strain received 0, 100, 200, or 400 mg/kg/day norflurazon technical by oral gavage on

gestation days 6 through 15 inclusive. The maternal toxicity NOEL was determined to be <

100 mg/kg/day, and the maternal toxicity LEL was determined to be < 100 mg/kg/day, based

on reductions in body weight gain for the period of dosing and for the dosing plus postdosing period. The developmental toxicity NOEL was determined to be > 400 mg/kg/day

and the developmental toxicity LEL was determined to be > 400 mg/kg/day. Developmental

toxicity was suggested at the 400 mg/kg/day dose level in the form of an increase in bipartite

thoracic vertebrae (10th-13th) and an increase in rudimentary 14th ribs. However, these

increases were not statistically significant and are believed to be secondary to maternal

effects at the high dose (USEPA, 2002).

Report Number: TK0023425 Page 11 of 43
A developmental toxicity study was conducted in New Zealand White rabbits, which

received 0, 10, 30, or 60 mg/kg /day norflurazon technical, by oral gavage on gestation days

7 through 19 inclusive. The maternal toxicity NOEL was determined to be 30 mg/kg/day,

and the maternal toxicity LEL was determined to be 60 mg/kg/day, based on decreased body

weight gain and clinical toxicity (abortion) at this dose level. The developmental toxicity

NOEL was determined to be 30 mg/kg/day, and the developmental toxicity LEL was

determined to be 60 mg/kg/day, based on statistically significant increases in the fetal

incidence of incompletely ossified frontal bones, caudal vertebrae, unossified first

metacarpal, unossified middle phalanx of the fifth digit of the forelimb, and unossified

proximal epiphysis of the tibia at the 60 mg/kg/day dose level. A 12% decrease in mean fetal

weight was also observed at the 60 mg/kg/day dose level.

Health Effects Division RfD/Peer Review Committee which met in March 16, 1995 and

concluded that developmental toxicity was not evident in treated rats, but developmental

toxicity in rabbits was evident at a dose of 60 mg/kg/day in the form of decreased mean fetal

weight, slight delays in ossification of the skull and limbs, and an increase in the incidence of

13th ribs. These developmental effects occurred at a dose that was maternally toxic

(USEPA, 2002).

3.3 Rodent Subchronic and Chronic Toxicity/Carcinogenicity Studies

In a 90-day rat feeding study (Fogleman, 1971), the systemic NOEL was determined to be

12.5 mg/kg/day in males, and 25 mg/kg/day in females. The 6-month dog feeding study

(Klotzche et al. 1973) had a systemic NOEL of 1.53 mg/kg/day for males and 1.58

mg/kg/day for females; the systemic LEL was determined to be 5.02 mg/kg/day for males

and 4.77 mg/kg/day for females based on increased absolute and relative liver weight and

increased cholesterol in both sexes, hi a 9-month rat feeding study (Harris, 1972), the

systemic NOEL was determined to be 12.5 mg/kg/day for both sexes, and the systemic LEL

was determined to be 25 mg/kg/day in both sexes based on the dose-related increase in liver

weight in male and female rats at 39 weeks, the increase in gonad weight of females, and the

microscopic changes observed in kidneys of both sexes.

Further, in the rat combined chronic toxicity/carcinogenicity study (Warf, 1975c), the

systemic NOEL was determined to be 18.75 mg/kg/day for both sexes. The systemic LEL

was determined to be 51.25 mg/kg/day in both sexes (HDT), based on the increased kidney

weight and accompanying microscopic pathologic changes, as well as the increase in liver

weight in male and female rats and the increase in thyroid weight in males. There was no

evidence of carcinogenicity for norflurazon. A two-year carcinogenicity study in mice

(WARF, 1975d), the systemic NOEL was determined to be 12.8 mg/kg/day for male mice,

and 58.7 mg/kg/day for female mice. The systemic LEL was determined to be 58.7

mg/kg/day for male mice, based on the increased incidence of enlarged spleen, increased

absolute and relative liver weight, and increased incidence of nephritis. The systemic LEL

was determined to be 218.8 mg/kg/day for female mice, based on the increased incidence of

enlarged liver and cystic ovaries, the increased absolute and relative liver weight, and the

increased incidence of pyelonephritis. Based upon statistically significant pair-wise

comparisons of the incidence of liver adenomas and combined liver adenomas/carcinomas as

Report Number: TK0023425 Page 12 of 43
well as statistically positive trends for these lesions in male CD-I mice receiving 218.8

mg/kg/day norflurazon technical in the diet for up to 104 weeks, the OPP/Health Effects

Division Carcinogenicity Peer Review Committee, norflurazon was classified as a non

quantifiable Group C - possible human carcinogen.

3.4 Fish and Amphibian Studies

Norflurazon has been tested in the guideline acute and chronic toxicity tests in fish. Fish

early life cycle studies were conducted with norflurazon in the rainbow trout (EG&G

Bionomics, 1982a) and fathead minnow (EG&G Bionomics, 1982b) and there were no

endocrine-mediated changes. To our knowledge, no norflurazon toxicity data has been

generated with amphibian species.

4.0 RATIONALE FOR ACCEPTANCE OF NORFLURAZON OSRI

FOR SPECIFIC TIER 1 ASSAYS

4.1 Estrogen Receptor Binding Assays (OPPTS 890.1250; OPPTS 890.1300)

The norflurazon OSRI for the Estrogen Receptor Binding Assay is based on two different

sources: the EPA ToxCastTM program results on norflurazon and the US EPA's 40CFR Part

158 guidelines studies supporting the norflurazon registration. The ToxCast data provides

substantially similar endpoints/methodology as the EDSP Tier 1 screen and the USEPA

40CFR Part 158 data provides the Tier 2 assessment for potential effects on subchronic

toxicity, developmental toxicity, reproduction effects, chronic toxicity and other apical

endpoints of endocrine function effects.

EPA's ToxCastTM program results: Norflurazon has been previously tested for estrogen

binding in the EPA ToxCast program (Kavlock et al, 2009; Houck, 2009). The protocol

utilized was deemed appropriate by US EPA for estrogen binding potential (see Eli Lilly and

Company and NIH Chemical Genomics Center, 2008). The protocols for the assays used in

the ToxCastTM evaluation are not currently available, however the assays were conducted by

and for EPA. These EPA-supported assays apparently meet the quality standards of

adherence to the spirit of good laboratory practices and are of high quality, achieving the

objective to provide reasonable assurance that a chemical does or does not have the potential

to interact with estrogen receptors (Eli Lilly and Company and NIH Chemical Genomics

Center, 2008).

Based on the existence of this data, Syngenta requests a waiver for the EDSP Tier 1 screen

for estrogen binding.

US EPA's 40CFR Part 158 data requirements: Norflurazon has an extensive toxicity

database, including the 2-generation reproduction study which has been designated by the

EPA as the Tier 2 study in the EDSP program for mammalian endocrine toxicity

characterization.

Report Number: TK0023425 Page 13 of 43
It is important to recognize in light of the use of other scientifically relevant information that

there are endpoints measured in the breadth of the EPA guideline studies which can detect

effects on the endocrine system. For example, an increase in uterine weight usually reflects a

response to estrogen, or a functionally-equivalent measure of estrogen acting through an

estrogen receptor-mediated reaction. The endpoints measured in the EPA guideline studies

for norflurazon which can detect a functionally equivalent response to in vitro estrogen

receptor binding (OPPTS 890.1250 and 890.1300), both agonism and antagonism, are

presented in Table 2.

Table 2 Functionally Equivalent Endpoints in FIFRA Guideline Studies

Conducted with Norflurazon which are Relevant to in vitro ER Binding

and to the Estrogenic Mode of Action

3-Generation Rat

Reproduction. FIFRA §83-4;

EPA MRID 0080750

2-Generation Rat

Reproduction. FIFRA §83-4;

EPA MRID 43522301

Organ weight: Uterus, Ovary,

Pituitary

Histopathology: Uterus, Vagina,

Cervix, Ovary, Pituitary,

Female Reproductive indices:

mating, conception, fertility,

gestation, and lactation

Dystocia

Pup sex ratio

No. pups "missexed "at birth

compare to sex at cull and

necropsy

Normality of external genitalia

in pups and Fl adults

Time to mating

Gross lesions

Rabbit Developmental

Toxicity. FIFRA §83-3.

EPA MRID 00131 152

Rat Developmental

Toxicity. FIFRA §83-3.

EPA MRID 00063621

Organ weight: Uterus

(gravid)

Number of corpora lutea,

implantation sites, fetuses

—

Fetal sex ratio

Fetal reproductive tract

anomalies

—_

90-Day Subchronic

Rat. FIFRA §82-1.

EPA MRID 00091055

Organ weight: Adrenals,

Ovary

Histopathology: Uterus,

Ovary, Adrenals,

Pituitary, Thyroid

~

—

—

—

Gross lesions

6- Month Dog Chronic

Toxicity. FIFRA §83-1.

EPA MRID 001 11 61 8.

Rat Chronic Toxicity/

Carcinogenicity. FIFRA

§83-1. EPA MRID's

0082019 and 00111649

Organ weight: Uterus, Ovary,

Pituitary, Thyroid, Adrenal

Histopathology: Uterus,

Ovary, Mammary gland,

Pituitary, Thyroid, Adrenal

—

—

— Gross lesions

If norflurazon were estrogenic or anti-estrogenic, changes in uterine and ovarian weights

should manifest themselves in not only FIFRA §83-4 and FIFRA §83-3, but also FIFRA

§82-1 and FIFRA §83-1 guideline studies. Likewise, changes in the histopathology of these

endocrine tissues and accessory sex tissues like the mammary gland should occur. Needless

to say, effects on reproductive indices would be observed in the EDSP Tier II gold standard

study, the 2-generation reproduction study in rats. Therefore, based on the available

norflurazon OSRI, Syngenta requests a waiver from this EDSP Tier 1 screen.

4.2 Androgen Receptor Binding (OPPTS 890.1150)

The norflurazon OSRI for the Androgen Receptor Binding Assay is based on two different

sources: the EPA ToxCastTM program results on norflurazon and the US EPA's 40CFR Part

158 guidelines studies supporting the norflurazon registration. The ToxCast data provides

substantially similar methodology/endpoints as the EDSP Tier 1 screen and the USEPA

Report Number: TK0023425 Page 14 of 43
40CFR Part 158 data provides the Tier 2 assessment for potential effects on subchronic

toxicity, developmental toxicity, reproduction effects, chronic toxicity and other apical

endpoints of endocrine function effects.

EPA's ToxCastTM program results: Norflurazon has been previously tested for androgen

binding in the EPA ToxCast program (Kavlock et al, 2009; Houck, 2009). The protocol

utilized was deemed appropriate by US EPA for androgen binding potential (see Eli Lilly and

Company and NIH Chemical Genomics Center, 2008). The protocols for assays used in the

ToxCastTM evaluation are not currently available; however, the assays were conducted by and

for EPA. These EPA-supported assays apparently meet the quality standards of adherence to

the spirit of good laboratory practices and are of high quality, achieving the objective to

provide reasonable assurance that a chemical does or does not have the potential to interact

with androgen receptors (Eli Lilly and Company and NIH Chemical Genomics Center,

2008). Based on the existence of this data, Syngenta requests a waiver for the EDSP Tier 1

screen for androgen binding.

US EPA's 40CFR Part 158 data requirements: Norflurazon has an extensive toxicity

database, including the 2-generation reproduction study which has been designated by the

EPA as the Tier 2 study in the EDSP program for mammalian endocrine toxicity

characterization. The endpoints measured in the existing FIFRA guideline studies provide

functional equivalents to in vitro androgen receptor binding (OPPTS 890.1150). These

parameters for studies with norflurazon are given in Table 3.

Table 3 Functionally Equivalent Endpoints in FIFRA Guideline Studies

Conducted with Norflurazon which are Relevant to in vitro AR Binding

and to the Androgenic Mode of Action

3-Generation Rat

Reproduction. FIFRA §83-4;

EPA MRID 0080750

2 -Generation Rat

Reproduction. FIFRA §83^»;

EPA MRID 43522301

Organ weight: Testes, Pituitary,

Thyroids, Adrenals

Histopathology: Testes,

Prostate, Seminal Vesicles,

Epididymides

Male Reproductive indices:

Mating, Fertility,

Conception

Time to mating

Normality of external genitalia

No. pups "missexed "at birth

compare to sex at cull and

necropsy

Pup sex ratio

Undescended testes in Fl males

Gross lesions

Rabbit Developmental

Toxicity. FIFRA §83-3.

EPA MRID 00131 152

Rat Developmental

Toxicity. FIFRA §83-3.

EPA MRID 00063621

—

Fetal Reproductive tract

anomalies

Fetal sex ratio

——

90-Day Subchronic

Rat. FIFRA §82-1.

EPA MRID 00091 055

Organ weight: Testes,

Epididymides

Histopathology: Testes,

Epididymides, Seminal

vesicles, Prostate

——

—

— Gross lesions

6- Month Dog Chronic

Toxicity. FIFRA §83-1.

EPA MRID 001 11 61 8.

Rat Chronic Toxicity/

Carcinogenicity. FIFRA

§83-1. EPA MRID's

0082019 and 00111649

Organ weight: Testes,

Epididymides, Prostate,

Thyroid, Adrenals, Pituitary

Histopathology: Testes,

Epididymides, Prostate,

Adrenals, Thyroid, Pituitary

—

—

—

— Gross lesions

Report Number: TK0023425 Page 15 of 43
If norflurazon were androgenic or anti-androgenic, these effects would be noted in the

existing FIFRA §83-4, FIFRA §82-1 and FIFRA §83-1 guideline studies through alterations

in endocrine and/or accessory sex tissue weight and/or pathology, alteration of reproduction

and fecundity in FIFRA §83-4 or sex ratio in FIFRA §83-3 studies.Therefore, based on the

available norflurazon OSRI, Syngenta requests a waiver from this EDSP Tier 1 Screen.

4.3 Aromatase -Human Recombinant (OPPTS 890.1200)

The norflurazon OSRI for the aromatase assay is based on two different sources: the EPA

ToxCastTM program results on norflurazon and the US EPA's 40CFR Part 158 guidelines

studies supporting the norflurazon registration. The ToxCast data provides substantially

similar methodology/endpoints as the EDSP Tier 1 screen and the USEPA 40CFR Part 158

data provides the Tier 2 assessment for potential effects on subchronic toxicity,

developmental toxicity, reproduction effects, chronic toxicity and other apical endpoints of

endocrine function effects.

EPA's ToxCastTM program results: Norflurazon has been previously tested for aromatase

assay in the EPA ToxCast program (Kavlock et al., Houck, 2009). The protocol utilized was

deemed appropriate by US EPA for assessing effects on aromatase. The protocols for assays

used in the ToxCastTM evaluation are not currently available; however the assays were

conducted by and for EPA. These EPA-supported assays apparently meet the quality

standards of adherence to the spirit of good laboratory practices and are of high quality,

achieving the objective to provide reasonable assurance that a chemical does or does not have

the potential to interact with aromatase activity (Eli Lilly and Company and NIH Chemical

Genomics Center, 2008). Based on the existence of this data, Syngenta requests a waiver for

the EDSP Tier 1 screen for assessing aromatase effects.

US EPA's 40CFR Part 158 data requirements: Norflurazon has an extensive toxicity

database, including the 2-generation reproduction study which has been designated by the

EPA as the Tier 2 study in the EDSP program for mammalian endocrine toxicity

characterization.

Although the measurement of inhibition of aromatase [Human Recombinant] (OPPTS

890.1200) is unlike direct alteration of binding of a steroid hormone with its receptor, the

aromatase focuses on the alteration of estrogen formation and therefore the endpoints that are

measured in the FIFRA guideline studies are functionally equivalent to those evaluated in

OPPTS 890.1250 and/or OPPTS 890.1300. These endpoints are presented in Table 4.

OPPTS 890.1200 will only detect a reduction in aromatase activity which will result in a

reduction in testosterone or an anti-androgenic response. Again this would be detected in

existing EPA guideline studies that were conducted using the FIFRA §83-4, FIFRA §83-3,

FIFRA §82-1 and FIFRA §83-1 guidelines. Therefore, based on the available norflurazon

OSRI, Syngenta requests a waiver from this EDSP Tier 1 Screen.

Report Number: TK0023425 Page 16 of 43
Table 4 Functionally Equivalent Endpoints in FIFRA Guideline Studies

Conducted with Norflurazon which are Relevant to Aromatase

Inhibition

3-Generation Rat

Reproduction. FIFRA §83-4;

EPA MRID 0080750

2 -Generation Rat

Reproduction. FIFRA §83-4;

EPA MRID 43522301

Organ weight: Pituitary, Testes,

Epididymides, Uterus, Ovary,

Adrenal, Thyroid

Histopathology: Pituitary,

Testes, Seminal Vesicle,

Epididymides, Prostate, Uterus,

Ovary

Reproductive indices:

Male and female , Mating,

Fertility, Conception, Female

Gestation and Lactation

No. pups "missexed "at birth

compare to sex at cull and

necropsy

Normality of external genitalia

Gross lesions

Rabbit Developmental

Toxicity. FIFRA §83-3.

EPA MRID 00131152

Rat Developmental

Toxicity. FIFRA §83-3.

EPA MRID 00063621

Organ weight: Uterus

Number of corpora lutea,

implantation sites, fetuses

Fetal reproductive tract

anomalies

—

90-Day Subchronic

Rat. FIFRA §82-1.

EPA MRID 00091055

Organ weight: Testes,

Uterus, Ovary, Thyroid,

Adrenal

Histopathology: Testes,

Epididymides, Prostate,

Seminal vesicles,

Uterus, Ovary,

Mammary gland,

Thyroid, Adrenal,

Pituitary

—

Gross lesions

6- Month Dog Chronic

Toxicity. FIFRA §83-1.

EPA MRID 00111618.

Rat Chronic Toxicity/

Carcinogcnicity. FIFRA

§83-1. EPA MRID's

0082019 and 001 11649

Organ weight: Testes, Uterus,

Ovary, Thyroid (non-rodent),

Adrenal

Histopathology: Testes,

Epididymides, Prostate,

Seminal vesicles, Uterus,

Ovary, Mammary gland,

Thyroid , Adrenal, Pituitary

—

Gross lesions

4.4 Steroidogenesis - Human Cell Line H295R (OPPTS 890.1550)

The norflurazon OSRI for Steroidogenesis assay is based on the exiting US EPA's 40CFR

Part 158 guideline studies that support the norflurazon registration. The USEPA 40CFR Part

158 data provides the Tier 2 assessment for potential effects on subchronic toxicity,

developmental toxicity, reproduction effects, chronic toxicity and other apical endpoints of

endocrine function effects.

As with aromatase inhibition, the endpoints measured in the H295R Steroidogenesis screen

(OPPTS 890. 1550) are alterations of estradiol and testosterone. Therefore, the relevant

endpoints measured in the FIFRA guideline studies encompass the organs and tissues that

would be potentially affected by the alteration of both steroids (Table 5). If norflurazon had

effects on Steroidogenesis, the EPA guideline studies, FIFRA §83-4, FIFRA §83-3, FIFRA

§82-1 and FIFRA §83-1, would be capable of detecting estrogenic, anti-estrogenic,

androgenic and anti-androgenic changes in the apical endpoints. Therefore, based on the

available norflurazon OSRI, Syngenta requests a waiver from this EDSP Tier 1 Screen.

Report Number: TK0023425 Page 17 of 43
Table 5 Functionally Equivalent Endpoints in FIFRA Guideline Studies

Conducted with Norflurazon which are Relevant to the Steroids

Alterations that might be Detected in the Steroidogenesis Screen

3-Generation Rat

Reproduction. FIFRA §83-4;

EPA MRID 0080750

2-Generation Rat

Reproduction. FIFRA §83-4;

EPA MRID 43522301

Organ weight: Pituitary,

Testes, Epididymides, Uterus,

Ovary, Adrenal, Thyroid

Histopathology: Pituitary,

Testes, Seminal Vesicle,

Epididymides, Prostate,

Uterus, Ovary

Reproductive indices

No. pups "missexed "at birth

compare to sex at cull and

necropsy

—

Corpora lutea

Normality of external genitalia

—

Gross lesions

Rabbit Developmental

Toxicity. FIFRA §83-3.

EPA MRID 001 31 152

Rat Developmental

Toxicity. FIFRA §83-3.

EPA MRID 00063621

Organ weight: Uterus

Number of corpora lutea,

implantation sites, fetuses

— Corpora lutea

Fetal reproductive tract

anomalies

Number of implantation

sites

—

90-Day Subchronic Rat.

FIFRA §82-1. EPA

MRID 00091055

Organ weight: Pituitary,

Testes, Ovary, Thyroid,

Adrenal

Histopathology: Testes,

Epididymides, Prostate, ,

Uterus, Ovary, Thyroid,

Adrenal, Pituitary

—

Serum cholesterol

—

—

—

Gross lesions

6- Month Dog Chronic

Toxicity. FIFRA §83-1. EPA

MRID 00111618.

Rat Chronic Toxicity/

Carcinogenicity. FIFRA

§83-1. EPA MRID's

008201 9 and 001 11 649

Organ weight: Testes, Uterus,

Ovary, Thyroid (non-rodent),

Adrenal

Histopathology: Testes,

Epididymides, Prostate,

Seminal vesicles, Uterus,

Ovary, Thyroid , Adrenal,

Pituitary, Mammary gland

—

—

—

—

Gross lesions

4.5 Hershberger - Rat (OPPTS 890.1400)

The norflurazon OSRI for Hershberger assay is based on the exiting US EPA's 40CFR Part

158 guideline studies that support the norflurazon registration. The USEPA 40CFR Part 158

data provides the Tier 2 assessment for potential effects on subchronic toxicity,

developmental toxicity, reproduction effects, chronic toxicity and other apical endpoints of

endocrine function effects.

In vivo EDSP screens focus on many of the apical endpoint that are measured in FIFRA

guideline studies for developmental, reproductive, subchronic and chronic toxicity. The

endpoints measured in the Hershberger screen (OPPTS 890.1400) are presented in Table 6

against the FIFRA guideline studies showing functional equivalence.

While the Hershberger assay has not been specifically conducted with norflurazon, the

FIFRA guideline studies conducted with norflurazon capture important parameters such as

change in testes weight and, in the case of FIFRA §83-4, prostate weight which are evaluated

in the Hershberger screen. However, the FIFRA studies also include the measurement of

more definitive endpoints such as histopathology of the testes (which has been removed in

the Hershberger) and reproductive and developmental parameters in models with an intact

hypothalamic-pituitary-gonadal axis. Therefore, based on the available norflurazon OSRI,

Syngenta requests a waiver from this EDSP Tier 1 Screen.

Report Number: TK0023425 Page 18 of 43
Table 6 Functionally Equivalent Endpoints in FIFRA Guideline Studies

Conducted with Norflurazon Compared to those Measured in the

Hershberger Screen

Hershberger Endpoints

Cowper's Gland Weight

Testes Weight

Epididymides Weight

Ventral prostate Weight

Seminal Vesicle Weight

Levator Anibulbocavernosus Muscle

Weight

Glans Penis Weight

(castrated male)

—

——

3-Generation Rat

Reproduction. FIFRA

§83-4; EPA MRID

0080750

2-Gcneration Rat

Reproduction. FIFRA

§83-4; EPA MRID

43522301

—X

X

X

X

~

—

Rabbit

Developmental

Toxicity. FIFRA

§83-3. EPA MRID

00131152

Rat Developmental

Toxicity. FIFRA

§83-3. EPA MRID

00063621

—

—

—

——

~

—

90-Day

Subchronic

Rat. FIFRA

§82-1. EPA

MRID

00091055

—X

X

X

—

"

—

6- Month Dog Chronic

Toxicity. FIFRA §83-

1. EPA MRID

00111618.

Rat Chronic Toxicity/

Carcinogenicity.

FIFRA §83-1. EPA

MRID's 0082019 and

00111649

—X

X

X

—

~

—

Additional Relevant Parameters in Existing Studies

Histopathology: Testes,

Epididymides, Prostate

Reproductive Indices

Pup sex ratio

Gross lesions

Normality of male

genitalia

Number of corpora

lutea, implantation

sites, fetuses

Fetal sex ratio

—

Histopathology:

Testes,

Epididymides,

Prostate,

Seminal vesicles

— Gross lesions

Histopathology: Testes,

Epididymides, Prostate,

Seminal vesicles

—

Gross lesions

4.6 Male Pubertal - Rat (OPPTS 890.1500)

The norflurazon OSRI for male pubertal assay is based on the exiting US EPA's 40CFR Part

158 guideline studies that are required for the norflurazon registration. The USEPA 40CFR

Part 158 data provides the Tier 2 assessment for potential effects on subchronic toxicity,

developmental toxicity, reproduction effects, chronic toxicity and other apical endpoints of

endocrine function effects.

Despite the age of the 3-generation rat reproduction study (WARF, 1975b), the study

measured body weights, food consumptions and the weights of the liver, kidneys, pituitary,

testes, thyroids and adrenals in all generations of males; further a histopathologic evaluation

was performed on these organs. In addition, a more modern 2-generation reproduction study

conducted with norflurazon (Eschbach et al., 1994) recorded the body weight and food

consumption for FQ and FI males throughout the study, the pup sex distribution, and the

examination of smears for spermatozoa and/or appearance mating period, which is not only

an assessment of male fertility but also that normal pubertal development has occurred. In

addition, the pituitary, prostate, seminal vesicles with coagulating gland, and testes with

Report Number: TK0023425 Page 19 of 43
epididymides were evaluated histopathologically for the FO and FI males. Therefore, these

FIFRA§83-4 guideline studies with norflurazon cover nearly all the endpoints measured in

OPPTS 890.1500 and the FIFRA §82-1 and §83-1 studies captures the clinical chemistry

(Tables 7).

Table 7 Functionally Equivalent Endpoints in FIFRA Guideline Studies

Conducted with Norflurazon Compared to those Measured in the

Pubertal Male Screen

Pubertal Male

Endpoints

Growth (daily body

weight)

Age and Weight at

Preputial Separation

Seminal Vesicle and

Coagulating gland

weight (with and

without fluid)

Ventral Prostate Weight

Dorsolateral Prostate

Weight

Levator Ani plus

Bulbocavernosus

Muscle Complex

(LABC)Weight

Epididymis Weight

Testes Weight

Thyroid Weight

Adrenal Weight

Pituitary Weight

Liver Weight

Kidney Weight

Blood Chemistry,

standard panel

Thyroid Hormone

Levels (T4, TSH)

Testosterone levels

Testes histopathology

(1)

Thyroid histopathology

Epididymides

histopathology (1)

Kidney histopathology

3-Generation Rat

Reproduction. FIFRA

§83-4; EPA MRID

0080750

2-Generation Rat

Reproduction. FIFRA

§83-4; EPA MRID

43522301

X

—

X

X

—

X

X

X

X

X

X

X

—

—

—

X

X

X

X

Rabbit Developmental

Toxicity. FIFRA §83-

3. EPA MRID

00131152

Rat Developmental

Toxicity. FIFRA §83-

3. EPA MRID

00063621

X

—

_.

—

X

X

—

,

—

—

—

—

—

—

X

-

X

—

90-Day

Subchronic

Rat. FIFRA

§82-1. EPA

MRID

00091055

X

—

...

—

X

X

X

X

X

X

X

X

—

—

X

X

X

X

6- Month Dog Chronic

Toxicity. FIFRA §83-1.

EPA MRID 00111618.

Rat Chronic Toxicity/

Carcinogenicity.

FIFRA §83-1. EPA

MRID's 0082019 and

00111649

X

—

...

—

X

X

X

X

X

X

X

X

—

—

X

X

X

X

Report Number: TK0023425 Page 20 of 43
Table 7 Functionally Equivalent Endpoints in FIFRA Guideline Studies

Conducted with Norflurazon Compared to those Measured in the

Pubertal Male Screen (continued)

Pubertal Male

Endpoints

3-Generation Rat

Reproduction.

FIFRA §83-4; EPA

MRID 0080750

2 -Generation Rat

Reproduction.

FIFRA §83-4; EPA

MRID 43522301

Rabbit

Developmental

Toxicity. FIFRA

§83-3. EPA MRID

00131152

Rat Developmental

Toxicity. FIFRA

§83-3. EPA MRID

00063621

90-Day

Subchronic Rat.

FIFRA §82-1.

EPA MRID

00091055

6- Month Dog Chronic

Toxicity. FIFRA §83-1.

EPA MRID 001 11 61 8.

Rat Chronic Toxicity/

Carcinogenicity. FIFRA

§83-1. EPA MRID's

0082019 and 00111649

Additional Relevant Parameters in Existing Studies

—

...

—

—

Reproductive Indices

Number of corpora

lutea, implantation

sites, fetuses

No. pups "missexed

"at birth compare to

sex at cull and

necropsy

Pup sex ratio

Normality of external

genitalia

Gross lesions

—

Fetal sex ratio

Fetal anomalies

—

—

Histopathology

Pituitary,

Adrenal,

Prostate, Seminal

vesicles, Liver,

Kidney

—

—

Gross lesions

—

Histopathology: Pituitary,

Adrenal, Prostate,

Seminal vesicles, Liver,

Kidney

—

—

Gross lesions

While the male pubertal assay has not been specifically conducted with norflurazon, the

FIFRA guideline studies conducted with norflurazon capture important parameters measured

in OPPTS 890.1500. Therefore, based on the available norflurazon OSRI, Syngenta requests

a waiver from this EDSP Tier 1 Screen.

4.7 Female Pubertal - Rat (OPPTS 890.1450)

The norflurazon OSRI for female pubertal assay is based on the exiting US EPA's 40CFR

Part 158 guideline studies that are required for the norflurazon registration. The USEPA

40CFR Part 158 data provides the Tier 2 assessment for potential effects on subchronic

toxicity, developmental toxicity, reproduction effects, chronic toxicity and other apical

endpoints of endocrine function effects.

For the females, the 3-generation rat reproduction study (WARF, 1975b) measured body

weights and major organs weights of kidneys, pituitary, ovaries, thyroids and adrenals for

females as defined in OPPTS 890.1450 as well as histopathologic evaluation of these organs.

In addition, the 2-generation reproduction study conducted with norflurazon (Eschbach et al.,

1994) recorded the body weight and food consumption for FQ and FI females throughout the

study, the pup sex distribution, and the assessment of mating, fertility, gestation, and

Report Number: TK0023425 Page 21 of 43
lactation indices which measure female development, fecundity and reproductive success. In

addition, the pituitary, ovaries, uterus, vagina and cervix were evaluated histopathologically

for the F0 and FI females. Therefore, these FIFRA§83-4 guideline studies with norflurazon

cover nearly all the endpoints measured in OPPTS 890.1450 and the FIFRA §82-1 and §83-1

studies captures the clinical chemistry (Table 8).

Table 8 Functionally Equivalent Endpoints in FIFRA Guideline Studies

Conducted with Norflurazon Compared to those Measured in the

Pubertal Female Screen

Pubertal Female

Endpoints

Growth (daily body

weight)

Age and Weight at

Vaginal opening

Uterus (blotted) Weight

Ovaries (paired) Weight

Thyroid Weight

Pituitary Weight

Adrenals (paired) Weight

Uterus histopathology

Ovary histopathology

Thyroid (colloid area and

follicular cell height)

histopathology

Blood Chemistry,

standard panel

Thyroid Hormone Levels

Estrous Cyclicity

—

—

—

3-Generarion Rat

Reproduction. FIFRA

§83-4; EPA MRID

0080750

2-Gcncration Rat

Reproduction. FIFRA

§83-4; EPA MRID

43522301

X

—

X

X

X

X

X

X

X

X

—

—X

Rabbit

Developmental

Toxicity. FIFRA

§83-3. EPA MRID

00131152

Rat Developmental

Toxicity. FIFRA

§83-3. EPA MRID

00063621

—

—

—

...

—

—

—

—

...

—

——

90-Day

Subchronic

Rat. FIFRA

§82-1. EPA

MRID

00091055

X

—

X

X

X

—X

X

X

X

X

——

6- Month Dog Chronic

Toxicity. FIFRA §83-1.

EPA MRID 001 11 61 8.

Rat Chronic Toxicity/

Carcinogenicity. FIFRA

§83-1. EPA MRID's

0082019 and 00111649

X

—

X

X

X

X

X

X

X

X

X

——

Additional Relevant Parameters in Existing Studies

Reproductive indices

Pup sex ratio

Normality of external

Genitalia

Gross lesions

Number of corpora

lutea, implantation

sites, fetuses

Fetal sex ratio

Fetal anomalies

Histopathology:

Pituitary,

Adrenal,

Mammary gland

Gross lesions

Histopathology:

Pituitary, Adrenal,

Mammary gland

Gross lesions, masses

While the female pubertal assay has not been specifically conducted with norflurazon, the

FIFRA guideline studies conducted with norflurazon capture the important parameters

measured in OPPTS 890.1450. Therefore, based on the available norflurazon OSRI,

Syngenta requests a waiver from this EDSP Tier 1 Screen.

Report Number: TK0023425 Page 22 of 43
4.8 Uterotrophic - Rat (OPPTS 890.1600)

The norflurazon OSRI for Uterotrophic assay is based on the exiting US EPA's 40CFR Part

158 guideline studies that are required for the norflurazon registration. The USEPA 40CFR

Part 158 data provides the Tier 2 assessment for potential effects on subchronic toxicity,

developmental toxicity, reproduction effects, chronic toxicity and other apical endpoints of

endocrine function effects.

Although the Uterotrophic Screen has only one functional endpoint, uterine weight as a

surrogate for measuring a response to a chemical which reflects on the mode of action of

estrogen, it falls short of measuring the suite of endpoints which could signal estrogenic

effects that are measured in the existing FIFRA§83-4, FIFRA §82-1 and §83-1 guideline

studies (Table 9).

Table 9 Functionally Equivalent Endpoints in FIFRA Guideline Studies

Conducted with Norflurazon Compared to those Measured in the

Uterotrophic Screen

Uterotrophic Screen

Endpoints

Uterus Weight

Uterine histopathology

(optional)

—

—

—

—

3-Generation Rat

Reproduction.

FIFRA §83-4; EPA

MRID 0080750

2-Generation Rat

Reproduction.

FIFRA §83-4; EPA

MRID 43522301

—

X

Rabbit

Developmental

Toxicity. FIFRA

§83-3. EPA MRID

00131152

Rat

Developmental

Toxicity. FIFRA

§83-3. EPA MRID

00063621

X (with placenta)

—

90-Day

Subchronic Rat.

FIFRA §82-1.

EPA MRID

00091055

—

X

6- Month Dog

Chronic Toxicity.

FIFRA §83-1. EPA

MRID 00111618.

Rat Chronic Toxicity/

Carcinogenicity.

FIFRA §83-1. EPA

MRlD's 0082019 and

00111649

X

—

Additional Relevant Parameters in Existing Studies

Organ weight:

Ovary

Histopathology:

Ovary, Uterus

Reproductive indices

Time to Mating

Pup sex ratio

Gross lesions

—

Number of

corpora lutea,

implantation

sites, fetuses

Fetal sex ratio

Organ weight:

Ovary

Histopathology:

Ovary, Uterus,

Mammary gland

—

—

Gross lesions

Organ weight:

Ovary

Histopathology:

Ovary, Uterus,

Mammary gland

—

—

—

While the Uterotrophic assay has not been specifically conducted with norflurazon, the

FIFRA guideline studies conducted with norflurazon capture important measuring endpoints

important in measuring estrogenic effects. Therefore, based on the available norflurazon

OSRI, Syngenta requests a waiver from this EDSP Tier 1 Screen.

Report Number: TK0023425 Page 23 of 43
4.9 Fish Short Term Reproduction (OPPTS 890.1350)

The norflurazon OSRI for the fish short term reproduction study is limited to the exiting US

EPA's 40CFR Part 158 guideline studies that are required for the norflurazon registration.

These studies include acute and chronic studies in fish and evidence from the mammalian

toxicity database. The chronic fish studies available for norflurazon are limited to the early

life stage tests, which do not include all of the study endpoints required by the fish short term

reproduction study. Therefore, Syngenta is not seeking a waiver at this time for this study.

4.10 Amphibian Metamorphosis (OPPTS 890.1100)

The norflurazon OSRI for the amphibian metamorphosis study is limited to the exiting US

EPA's 40CFR Part 158 guideline studies that are required for norflurazon registration. These

studies include acute and chronic studies in fish and evidence from the mammalian toxicity

database. Based on our review of the existing database, there are no existing amphibian studies

with norflurazon, and, therefore, Syngenta is not seeking a waiver at this time for this study.

5.0 CONCLUSION

The objective of this document is to provide the OSRI that is available for norflurazon in the

form of US EPA testing and FIFRA guideline (Tier 2) studies and to obtain waivers for

certain EDSP Tier 1 assays where scientifically justified.

In conclusion, norflurazon already has been thoroughly evaluated relative to the critical

apical endpoints covered by the EDSP Tier 1 screens. Therefore, Syngenta Crop Protection,

Inc., requests that the Environmental Protection Agency waive the requirement to conduct

the majority of the norflurazon EDSP test order assays based on the following scientific

justification.

1. US EPA has recently sponsored and produced OSRI for the following studies/endpoints,

therefore these studies should be waived from the EDSP Tier 1 screen requirements:

• 890.1150 - Androgen Receptor Binding (Rat Prostate)

• 890.1200 - Aromatase (Human Recombinant)

• 890.1250 - Estrogen Receptor Binding

• 890.1300 - Estrogen Receptor Transcriptional Activation (Human Cell Line HeLa-9903)

2. Tier 2 studies have been previously conducted for norflurazon as part of the 40CFR Part

158 data requirements (e.g., rat reproduction study, developmental toxicity, 90-day

studies, chronic and oncogenicity studies). These EPA guideline studies serve as OSRI

for the following studies/endpoints, therefore these studies should be waived from the

EDSP Tier 1 screen requirements:

890.1400 - Hershberger (Rat)

890.1450 - Female Pubertal (Rat)

890.1500 - Male Pubertal (Rat)

890.1550 - Steroidogenesis (Human Cell Line - H295R)

890.1600 - Uterotrophic (Rat)

Report Number: TK0023425 Page 24 of 43
The existing database for norflurazon does not contain the specific OSRI for the fish and

amphibian studies, and Syngenta is not providing a rationale to waive these specific assays.

However, the existing mammalian toxicity database combined with the fish early life stage

studies provide significant information that may be judged as adequate OSRI for a waiver or

partial waiver of the following two studies:

• 890.1100 - Amphibian Metamorphosis (Frog)

• 890.13 50 - Fish Short-Term Reproduction

Report Number: TK0023425 Page 25 of 43
6.0 REFERENCES

EG&G Bionomics (1982a): Early Life Cycle Study in Rainbow Trout. MRID 00218047.

EG&G Bionomics (1982b): Early Life Cycle Study in Fathead Minnows. MRID 0018048.

Eli Lilly and Company and NIH Chemical Genomics Center. (2008). Assay Guidance

Manual Version 5.0.'. http://www.ncgc.nih.gov/guidance/manual toc.html. (Last accessed

1/25/2010).

Eschbach, B.; Aerni, R.; Hertl, P.; et al. (1994): Two Generation Reproduction Study in Rats:

Norflurazon: Revised Final Report. Project No. 440R. (Unpublished study prepared by

Sandoz Agro, Ltd.). EPA MRID 43522301.

Fogleman, R.W. (1971) Evaluation of the Subchronic (90-day) Toxicity Effects of SAN9789 in Rats: Contract No. 120-546-9-70. Final rept. (Unpublished study received Nov 14,

1972 under 3G1310; prepared by Affiliated Medical Enterprises, Inc., submitted by Sandoz,

Inc., Homestead, Fla.; CDL:092233-F). EPA MRID 00091055.

Harris, D.L. (1972) 9 Month Feeding Study in Rats: FO Generation. Final rept. (Unpublished

study received Nov 14,1972 under 3G1310; prepared by WARF Institute, Inc., submitted by

Sandoz, Inc., Homestead, Fla.; CDL: 092233-G). EPA MRID 00091056.

Harris, D.; Nees, P. (1973) Long Term Feeding Study-Rat: 1 Year Report: Compound 9789.

(Unpublished study received May 13, 1974 under 4F1506; prepared by WARF Institute, Inc.,

submitted by Sandoz-Wander, Inc., Homestead, FL; CDL:093994-G; 093995). EPA MRID

00111617.

Hartman, H.A.; Hrab, R. (1972): Compound 9789: Investigation of Teratogenic Potential in

the Rat: Report No. T-1-8/7/72. (Unpublished study submitted by Sandoz, Inc.). EPA MRID

00063621.

Houck, K. (2009).What Can ToxCastTM Tell Us about Endocrine Disruption? Presented at

the International Society of Regulatory Toxicology and Pharmacology 2009 Endocrine

Workshop, September 9-10, 2009. National Institutes of Health, 8600 Rockville Pike,

Bethesda, MD.

Hrab, R.; De Raismes, M.; Yao, C. (1983a). Dose Range-finding Study of Norflurazon in

Pregnant Rabbits: Sandoz Project No. T-1793. (Unpublished study submitted by Sandoz,

Inc., Crop Protection). EPA MRID 00131151.

Hrab, R.; Halbert, F.; Quagliotti, M. et al. (1983b): Investigation of Teratogenic Potential of

Norflurazon in the Rabbit—Segment II: Sandoz Project T-1794. (Unpublished study

submitted by Sandoz, Inc., Crop Protection). EPA MRID 00131152.

Institute for Environment and Heath (IEH). (2005). Chemicals purported to be endocrine

disrupters: A compilation of published lists. IEH Web Report 20. March 2005.

Report Number: TK0023425 Page 26 of 43
http://www.cranfield.ac.uk/health/researchareas/environmenthealth/ieh/ieh%20publications/

w20.pdf

Kavlock, R.; Dix, D.; Houck, K.; Judson, R.; Knudsen, T.; Reif, D.; and Martin, M. (2009).

Biological Profiling of Endocrine Related Effects of Chemicals in ToxCastTM. Presented at

ToxCast Data Analysis Summit, RTP, NC, May 14-15,2009.

http://www.epa.gov/NCCT/toxcast/summit.html.

Klotzsche, C.; Carpy, S.; De Rijk; et al. (1973). San 9789 (Zorial), 6 Months Feeding Study

in Dogs: Report Nr. 56/73. (Unpublished study received May 13, 1974 under 4F1506;

prepared by Sandoz-Wander, Inc., Homestead, FL; CDL: 093995-A). EPA MRID 00111618.

USEPA. 2002. Reregistration Eligibility Decision (RED) Document for Norfiurazon. LIST

A. CASE 0229. May 31, 2002. http://www.epa.gov/oppsrrdl/REDs/0229.pdf

WARF Institute, Incorporated (1975a) Compound 9789: Reproduction Studies in Rats and

Mice: Volume I: Reproduction Studies on Rats. Final rept. (Unpublished study, including

submitter summary, received May 8, 1975 under 5F1602; submitted by Sandoz, Inc.,

Homestead, Fla.; CDL:094369-A). EPA MRID 00080750.

WARF Institute, Incorporated (1975b) Compound 9789: Reproduction Studies in Rats and

Mice: Volume 2: Reproduction Studies in Mice. Final rept. (Unpublished study, including

submitter summary, received May 8, 1975 under 5F1602; submitted by Sandoz, Inc.,

Homestead, Fla.; CDL:094368-A) EPA MRID 00080751.

WARF Institute, Incorporated (1975c) Compound 9789: Two Year Feeding Study in Rats.

Final rept. (Unpublished study received May 8, 1975 under 5F1602; submitted by Sandoz,

Inc., Homestead, Fla.; CDL: 094370-A; 094371; 094372; 094373; 094374). EPA MRID

00082019.

WARF Institute, Inc. (1975d): Compound 9789: Two Year Feeding Study in Mice. Final

Report. (Unpublished study submitted by Sandoz-Wander, Inc.). EPA MRID 00111649.

TK0023425-EDSPWaiver.doc sbh: 2/4/10 verl.O

Report Number: TK0023425 Page 27 of 43
APPENDICES SECTION

Report Number: TK0023425 Page 28 of 43
APPENDIX 1 Title Pages of Cited Studies

Report Number: TK0023425 Page 29 of 43
:GbNF.£DEMTIAI.-T.aSDE SECRET

OOM8047

o

)'.

? Guideline: requirement :is <-f iiljfeilled. CRED»

SUBMITTED; TO

"EAST,

REPORT *3W-82-5:-ll:6:6

Aquatic 7bxicoi-a:gy, Labo'ratoir?/-

790: Main Strs^-t

'fa-reh-aa; Massapause tcs

'

Report Number: TK0023425 Page 30 of 43
SECRET

SANDOZ, INC.

EAST HANOVER, NEW JERSEY

|filVTHE'SAINBQJfSROOT Oti NORFUJRAZON

......... . t:SftNDOZ:: J?;ROafEGT--T-i"t;J'3i;);i

MID: 00118048

Classified: Guideline requirement is fiilftiled (KED, 1996)

REPORT 1BW-82-5-1165

•EG&G, Bionomics

Aquatic Toxicology: Laboratory

790 Main Street

'Vfar.eham-, Ma$sachus,etl:s

May 2Q'.t 1932

Report Number: TK0023425 Page 31 of 43
S AN DO 2i A G R 0 LTD

DEVELOPMENT REGION BASLE

.OESiMt

Hiss)

? F&l

Glassif led: Acceptibl^/.Guidel ine

H 0 R P"L 0 R A Z 0 H.

REPORT: -W125

%DSX ::• $52556

TVO RKPROMJCTIOH STUDT

FIHALRKPOBT

Data Requirenentst

OEO) Guidelines 416 I?g3)

Sponsor : SANDOZ CROP PROTECTION CORPORATION

Des Plaines, U.S.A..

Authors:: B. Eschbach

R. Aerni

P. Bert!

P.

Performing Laboratory SANDOZ AGRO Ltd., Development Region

Basle, Pepar^fflcnt of toxicology,

Basle/Switzerland

Sandoz Project Number

Study initiated :

Report completed on :

440 R

October 1989

December 1991

Page 1 of 1376

Report Number: TK0023425 Page 32 of 43
MR10: 00091055

Clas«ified{: Gore supplementary/; registrant was -requested, to -verify

dose levels

-ftoport

o

OP Tti£. SUHCimOKICi

OF

Affilintod Miiilicisl Entori>iris<iS f Inc.

Priiicofeon, Jfew Jarsoy

July 20. 1971

Report Number: TK0023425 Page 33 of 43
MR1D: 60091056

Classified: Cote : Supplementary

•Fi'hal R:cport

h!i'clwt>»',. Tnc.

Midvson. 'V/ii5c"oni»s!h, U.S. A.

Report Number: TK0023425 Page 34 of 43
. Ssfoa biofe .

^ 00111617

Classified: G6re minimum and satisfies guideliiie r^quii:eine|ntsr

Sandoz-Wander, tec.

.Compound

Long "Term ;Fee<iing Stod^r

1 Year Report

WARF Institute, lac.

Madison, "Wisconsin; U.S.A.

Report Number: TK0023425 Page 35 of 43
, INC. EXE.-; #6.424

DEVELOPMENT

pSEARCH DEPARTMENT

EAST;HANOVER, NEW .JERSEY

MRID: 00063621

Classified: Core minimum and satisfies guideline requirements

9789

Ihyestigatipn of Teratogenic pqtehtiai: in tlie Rat

TOXICOLOGY-PATHOLOGY SECTION

DATE: August ?., 1972

Report Number: TK0023425 Page 36 of 43
OON|!1 OtNf I AL-TRADE SECRET

SANDOZ, INC.

PHARMACEUTICAL RESEARCH AND DEVELOPMENT

DEPARTMENT OF PRECLINICAL SAFETY ASSESSMENT (PSA)

EAST HANOVER, NEW JERSEY 07936

: 00131151

Classified? Core minimum and: satisfies^ guideline requirements

DOSE; RANGE-FIWP'ING; STUDY ;OP NPRFLURSZON; ;xtf SREISNANT ^RABBITS

(SANDQZ PROJECT T*1

: Co ri tgtbut <>r s '•';

-R;; -Hr.ab;;

Resgonsibie Technicians M. <3e Ralsme's

PSA Systems Leader: C. Yao, M.S.

Report Number: TK0023425 Page 37 of 43
CONFIDENTIAL-TRADE SECRET

PHARMACEUTICAI, RESEARCH AND DEVELOPMENT

DEPARTMENT OP PRBCLINICAL SAFETY ASSESSMENT (PSA)

EAST laSKWER, KfEW JESSE* 07?3i> .......... ' .....

MRID: 00131152

Core minimum ^nd satis* ies guideline

INVESTIGATION OF TERATOGENIC POTENTIAL OF NORFLDRA20N

IN THE ^Blt-SEGMEHT II { SANDOZ PROJECT T-17S4)

Cdntrtbutorst

Study Directoir:

Responsible Technicians:

PSA Systems Leader:

R. Hrab, H.S.

P. Halbert

M. Quagliotti

C. Yao, M.S.

. August 31> 1§83

Report Number: TK0023425 Page 38 of 43
00ll618,

GlassiMedi Core mittlmum and;

CROP OR; laARKET; Toxicology

EXPTNO,;.

TYPEREPORTL

CONTACT: (Name, Position. Organization and Location)

L'y Siiic: iaoivth JPigeaiqg Study 'in Docs reported

PREPARED RYit*

., _....San<ic>g- JLti3:. •. :-BasIe>. 'Switzerland::

" " " " ~ ~ " ^^^^^

10/9/73 APPROVED;!

"DATE><>g»ygfg

SUMMARY

\S

SAN 9789, the active ingredient of ZORIAL, was fed to

Beagle dogs at levels of 50, 150, and 450 ppm, respectively.

The actual average daily intake in mgAg/daily was higher

than calculated from the ppm-values (1.25, 3.75, and 11.25

rag/kg/dail^) :

A

^B

C

female

1.54

5i.02i

14.27

Male

1.59

4.77"

17.75

In all three doses, weight, behavior, hematology and

iiririalysis were within, normal ranges-. Gholesterbl showed

s'pjne higher values, but also in the controls. In ithe middle

and: high dose,, 'the- SAP:' activity -did' .not decrease in -the -^same

manner as thei controls and the; low dose, But there was no

increase in : -activity \ An: induction -of liver enzymes was not

observedi. 'No: 'increase of water or protein in this tissue

could b$ detected.

In the necropsy, no gross changes were seen. The liver

weights, both absolute and relative were increasing significantly in the high dose of both sexes. Histopathology showed

an iyticreased quantity of colloid vacuoles in the thyroid of

animals on the high dose level.

.—........ ,Thii¥a'ft/:fJ.-in'iHngH' rtasultea in a no-ef fec,t-J.e.VeJ-..O!f- ISO ppm...

VFB:sa

10/9/73

313H

Report Number: TK0023425 Page 39 of 43
MR1D: 0008075X)

Classified: UnaC'eep.tfllble; / Guideline fcedause ri6 parental tbxtblty

was found

SANDdZ-WANDER,

 ;

GOMPOITKI)

'IN'

 SRM!S .JtND MIJEE

VOLUME 1

REPRCiDUCTiON STUDIES ON RATS

WAliF INSTIT0TE> INC.

MADISON, WISCONSIN;

Report Number: TK0023425 Page 40 of 43
MRifi: 00080751

Classified: Supplementary

SANpOZ-WANDER,;: INC.:

^GOMEQUND 9^89

;

STSJDIEia IN 'RATS, -AND JHCCE-

'

: 2

STUDIES? IN 'MICE:

WARF INSTITUTED -INC.

, WISGONSIN

Report Number: TK0023425 Page 41 of 43
RE£(5RD

NOT REMOVE INDKWC STSIBi

s..

HRID: 00082019

iGlassif i6d: Gote niinlmum itid sstti^fies

guideline requiy exists .

SANDOZ~WANDER> ING,,

Thfe Record

has

COMPOUND

TWO; YEAR FEEDING; IN RATS

SUMMARY DATA

WARF INSTiTtJTE, INC.

MADISON, WISCONSIN

CONFIDENTIAL

Thfe is proprietary information of Sandoz Crop protection

CorpOraUon. The us« of this Information by other*,

without the permission of Sandoz C|P or without: just

compenaatlbii paid to Sondoz CjP to obtain govemm«nt

approval for to* sate of. competHive products 1$ i »lof»-

Don of this, pro'prtetary right. This Inlormallon sheuk)

not Be disclosed to anyone without Iha p«rmlssiori of

SawtorCrop: Protection Carporstion.

Report Number: TK0023425 Page 42 of 43
pfiNFiOENTlftt UUINr-V"-:.,. • . _• (Ojettoft MID, mum

 W9teiS^^SS

Classified: Gore minimum, and, satisfies 'Slf^ permission ^^^^SS*1^

guideline Tequirements 't&&*$^^$^*^'6«^k?^

,pp,ova:ior:tr»;^w^^. ^ ^^tswvW

, INC.

<TVK> ''&& 'J|EEiP>ING :SSOl>Y: 'IN. MICE;

•FIHAE

'STUiJV WRITE-UP

SUMMARY DATA

WARF INSTITUTE, INC.

MA0ISi6Nf WISCONSIN'

Report Number: TK0023425 Page 43 of 43