Dow AgroSciences LLC

9330 Zionsville Road

Indianapolis, IN 46268-1054

308/2E

February 5,2010

Dow AgroSciences

Document Processing Desk (PRD-EDSP)

Office of Pesticide Programs (7504P)

U. S. Environmental Protection Agency

One Potomac Yard

2777 S. Crystal Drive

Arlington, VA 22202

Attn: Jane Smith (7508P)

AI: BENFLURALIN

CHEMICAL CODE: 084301

CAS NUMBER: 1861-40-1 -

ORDER/DCINO.: EDSP-084301-15

RESPONSE TO ENDOCRINE DISRUPTOR SCREENING PROGRAM (EDSP)

In response to the Endocrine Disrupter Screening Program (EDSP), enclosed is Dow AgroSciences EDSP response form

and supporting scientifically relevant information (included in the enclosed study) for the active ingredient benfluralin.

Contents of Submission

Volume Contents

Volume 1 • Transmittal document (this letter)

(Administrative) • EDSP Response Form dated February 4, 2010 (1 page)

Volume MRID NO. Contents/Study

Guideline

Volume #2 Benfluralin: Scientific Rationale for Citation of Other

Scientifically Relevant Information in Fulfillment of OPPTS

890.1450 and OPPTS 890.1500 EDSP Tier I Assays

OPPTS Author: Sean Gehen Report Date: February 4,

890.1450 2010

890.1500

Study ID: AKH020510

Pages: 1-25 (3 copies)

If you require additional information, please contact Cathy Galvin, Registration Assistant for this product, at

317-337-4828 (clgalvin@dow.com).

Sincerely,

A FT J- •••••••*». *

Amy Hudson • * .

Regulatory Leader - Regulatory Affairs • •

317-337-3967 ...... .T.

317-337-4649 (FAX) J^5 *

akhudson@dow.com ••••, * * •

* •

• * . Enclosures . . • • •

.....0

AKH/clg ' _
Dow AgroSciences LLC

Report ID: AKH020510

Page 1 of 25

STUDY TITLE

Benfluralin: Scientific Rationale for Citation of Other Scientifically Relevant Information in

Fulfillment of OPPTS 890.1450 and OPPTS 890.1500 EDSP Tier I Assays

ORDER NUMBER: EDSP-084301-15

DATA REQUIREMENT

OPPTS 890.1450 and OPPTS 890.1500 EDSP Tier I Assays

AUTHOR

Sean Gehen

STUDY COMPLETED ON

February 4,2010

PERFORMING LABORATORY

Dow AgroSciences LLC

9330 Zionsville Road

Indianapolis, IN 46268 "'

REPORT ID

AKH020510

•

- • •
Dow AgroSciences LLC

Report ID: AKH020510

Page 2 of 25

STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS

Compound: Benfluralin

Title: Benfluralin: Scientific Rationale for Citation of Other Scientifically Relevant

Information in Fulfillment of OPPTS 890.1450 and OPPTS 890.1500 EDSPTier I Assays

No claim of confidentiality, on any basis whatsoever, is made for any information contained in

this document. I acknowledge that information not designated as within the scope of FIFRA

Section 10 (d)(l)(A)(B) or (C), and which pertains to a registered or previously registered

pesticide is not entitled to confidential treatment and may be released to the public, subject to

the provisions regarding disclosure to multinational entities under FIFRA Section 10(g).

Company: Dow AgroSciences LLC

Company Agent: Amv Hudson

Title: Regulatory Manager

Signature:

Date: February 4.2010

THIS DATA MAY BE CONSIDERED CONFIDENTIAL OUTSIDE THE UNITED

STATES.
Dow AgroSciences LLC

Report ID: AKH020510

Page 3 of 25

STATEMENT OF COMPLIANCE WITH GOOD LABORATORY PRACTICE

STANDARDS

Title: Benfluralin: Scientific Rationale for Citation of Other Scientifically Relevant

Information in Fulfillment of OPPTS 890.1450 and OPPTS 890.1500 EDSP Tier I Assays

Compound: Benfluralin

This report does not meet the definition of a GLP study as it appears in:

United States Environmental Protection Agency

Title 40 Code of Federal Regulations Part 160

Federal Register, 17 August 1989

Organization for Economic Cooperation and Development

ENV/LMC/CHEM(98)17, Paris - January 26,1998

NON-GLP STUDY

Amy Hudson

Sponsor

Dow Agrosciences LLC

February 4,2010

Amy Hudson

Submitter

Dow Agrosciences LLC

February 4,2010

Sean Gehen

Study Director/Author

Dow AgroSciences LLC

February 4,2010
Dow AgroSciences LLC

Report ID: AKH020510

Page 4 of 25

QUALITY ASSURANCE STATEMENT

Compound: Benfluralin

Title: Benfluralin: Scientific Rationale for Citation of Other Scientifically Relevant

Information in Fulfillment of OPPTS 890.1450 and OPPTS 890.1500 EDSP Tier I Assays

Report Completion Date: February 4,2010

NON-GLP STUDY
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Report ID: AKH020510

Page 5 of 25

1.1 Summary

The basis for this scientific rationale is that all of the critical endpoints defined in the OPPTS

890.1450 and OPPTS 890.1500 guidelines and the associated endocrine modes-of-action have

been evaluated in one or more of three ways: a) the endpoint has been directly assessed in

existing studies; b) in rare cases, surrogate endpoints have been evaluated; c) the relevant

endocrine mode-of-action will be assessed in other Tier IEDSP assays (See tables 7 and 8).

The stated purpose of the Endocrine Disrupter Screening Program is "to determine whether

certain substances may have an effect in humans that is similar to an effect produced by a

naturally occurring estrogen, or such other endocrine effect

as the Administrator may designate." Tier I "is to identify substances

that have the potential to interact with the estrogen, androgen, or thyroid hormone systems

using a battery of assays." Based on the information that will be presented in this rationale, it

is clear that the male and female pubertal assays are not required to make this determination.

Adequate information is available based on existing data and the other Tier I studies that will

be conducted. The pubertal assays are, therefore, redundant, not justified from an animal use

position, and should not be conducted per EPA's mandate to avoid duplicative testing.

We, therefore, encourage EPA to carefully examine the OSRI cited in this rationale and,

respectfully, request that the requirement for conducting the female and male pubertal assays

(OPPTS 890.1450, OPPTS 890.1500) be considered complete based on the submission of

OSRI and the fact that other EDSP assays will be conducted to also aid in evaluating the

specific endpoints relevant for these screening assays.

1.2 Background

The EPA document entitled: "EPA's Approach for Considering Other Scientifically Relevant

Information (OSRI) under the Endocrine Disrupter Screening Program" (EPA, March 2009)

provides guidance to registrants on how existing data or 'other scientifically relevant

information' (OSRI) is to be considered in full or partial fulfillment of Tier I EDSP data

requirements. OSRI is defined as: "information that informs the

determination as to whether the substance may have an effect that is similar to

an effect produced by a substance that interacts with the estrogen, androgen,

and/or thyroid hormonal systems." According to the EPA OSRI guidance document, the

following types of information may be useful as OSRI: studies that correspond to the assays in

Tier 1 or Tier 2; metabolism studies; or other vertebrate or invertebrate toxicity studies,

including, but not limited to, developmental toxicity tests, carcinogenicity tests,

toxicogenomic data, and reproductive toxicity tests.

In addition to the types of data defined above, the document gives specific mention to toxicity

studies conducted in fulfillment of the 40 CFR Part 158 data requirements for pesticide
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Page 6 of 25

registration. Allowing for the review and consideration of 40 CFR 158 data in fulfillment of

tier I data requirements is significant. These data requirements delineate a broad range of

robust toxicity studies that must be completed and critically assessed by the EPA prior to

approval and registration of a pesticide active ingredient in the United States. Among the

required data-set are multiple repeat-dose toxicity studies of various duration from 4-13 weeks

to those where exposure encompasses the majority of the lifespan of the test organism. In

addition, studies are conducted to determine any potential for treatment-related effects on

reproduction as well as pre- and post-natal development. In all of these studies, animals

receive dose-levels that appropriately challenge the test organisms and which are much higher

than anticipated human exposure levels. Examination of this complete data-set, which is

already available for all active ingredients, allows for determination of target organ toxicity

and any other adverse effects that may be elicited by exposure. These existing studies are

capable of detecting adverse biological effects of treatment that could be elicited by one or

more modes-of-action inclusive of the endocrine modes-of-action being addressed by the

EDSP. It is therefore a statement of fact that with rare exceptions, any potential adverse

effects resulting from modulation of the endocrine system have already been detected in the

exiting registration toxicity studies for a given active ingredient. The application of the

principles of risk assessment based on the no-effect levels from these studies allows for

appropriate margins of exposure in the use of these active ingredients.

On the basis of good scientific principles and particularly relative to the Scientific

Community's responsibly for judicious use of animal resources, it is appropriate to consider

existing data in the context of the EDSP requirements and EPA should grant exemptions from

screening where existing data already provide adequate information. In fact, according to

FFDCA section 408(p)(5)(B) EPA has a mandate to "... .minimize duplicative testing of the

same substance for the same endocrine effect." This policy is echoed by the OMB response to

EPA's EDSP Information Collection Response (ICR) which directs EPA to "promote and

encourage test order recipients to submit Other Scientifically Relevant Information (OSRI) in

lieu of performing all or some of the Tier I assays, and EPA should accept OSRI as sufficient

to satisfy the test orders to the greatest extent possible." Failure to appropriately consider and

accept existing data will result in duplicative testing and this scenario is not justified from an

animal use perspective.

In summary, for the pesticide active ingredients on the Tier I list for screening, there is a

wealth of existing information available that can reduce or eliminate the need for Tier I

screening. In particular, the multi-generation reproduction study which is already available for

pesticide active ingredients is a higher-tiered assessment for potential endocrine-mediated

toxicity, and EPA is in fact planning to utilize it as the mammalian Tier n testing requirement.

Logic therefore dictates that having the higher tiered study complete lessens or eliminates the

need for supplying lower-tiered screening assays of a less robust nature. With higher-tier data

available, the practical utility of performing screening studies is questionable. In addition,

EPA has already evaluated these existing studies for pesticide active ingredients, including any
Dow AgroSciences LLC

Report ID: AKH020510

Page 7 of 25

potential adverse effects resulting from modulation of the endocrine system, and made a

determination that these active ingredients can be used without undue risk to human health.

1.3 Benfluralin: Overview of Existing Data Set

As with other pesticide active ingredients, the 40 CFR Part 158 required studies have been

conducted for benfluralin. While the entire data set is much larger, the studies considered most

relevant for assessing any potential for interaction with the endocrine system are found in

Table 1 and include 2 multi-generation reproduction studies, 2 sub-chronic toxicity studies, 2

chronic toxicity/oncogenicity studies, and 1 teratology/developmental toxicity study. These

studies were conducted in accordance with internationally accepted test guidelines in place at

the time, and the more recent studies adhered to GLP standards. The studies utilized rats and,

therefore, are considered the most relevant to the mammalian Tier I data requirements. Where

appropriate, data in other species may also be cited when considered relevant. The multigeneration reproduction studies in particular provide the foundational data-set for benfluralin

relative to the Tier IEDSP assays. Additional end-points not specifically assessed in these two

studies but requested by the OPPTS guideline have been assessed in other repeat-dose studies

that make up the core registration data-package for benfluralin. Taken together, these studies

provide a robust determination of any potential effects on general toxicity, development and

maturation, as well as other end-points that could be impacted through an effect on the

endocrine system.

Examination of the existing benfluralin data-set did not reveal any potential for specific

modulation of the estrogen or androgen systems in the test organisms. Consistent with other

dinitroaniline herbicides, benfluralin targets the liver, kidneys and thyroid gland. As will be

shown in the tables below, the effects of benfluralin on the thyroid have been well

characterized in existing studies where thyroid weight and histopathology have been

examined.

A mode-of-action (MOA) study is currently being conducted with benfluralin to further

elucidate the high-dose thyroid effects; results so far appear consistent with an expected MOA

involving induction of UDP-GT, increased clearance of thyroid hormones (T3 and T4),

increased production of TSH, chronic stimulation of follicular cells and increased neoplasia

(Fischer, 1991,1993; Saghir, 2005). The key events responsible for thyroid toxicity in rats do

not occur in humans due to the presence of high-affinity thyroxine binding protein (TBG) in

humans and a lack of it in rats (Hill et al., 1989,1998). Due to the lack of TBG in rats, free T4

is much larger in rats than in humans and is much more susceptible to removal from the blood,

which triggers the cycle of TSH stimulation and follicular cell stimulation.
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Table 1- Existing Studies (OSRI) Cited in fulfillment of Tier I data requirements

Citation Code Study Citation GLP Study MRID Number

A Trutter,J.( 1995) TwoGeneration

Reproduction Study in

Rats with Benefin: Final

Report: Lab Project

Number: HWA 174-

136. Unpublished study

prepared by

Hazleton Washington,

Inc.

Yes 43628701

B Adams, E. R. et al.

(1973) A MultiGeneration Rat

Reproduction Study

with Benefin, R0305,

R0795, R0057, R0657,

R0316. Unpublished

study prepared by Lilly

Research Labs.

Study Conducted

Prior to GLP

Regulations

00037676

Adams, E.; Jordan, W.

(1996) Subchronic

Toxicity Studies of

Benefin (Compound

054521) Administered

Orally in the Diet to

Fischer 344 Rats for 3

Months: Lab

Project Number:

R33989: R44089:

R29990. Unpublished

study prepared by Lilly

Research Labs.

Yes 44050001
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Citation Code Study Citation GLP Study MRID Number

D Moore, M.( 1996)

Benefin: Two-Year

Dietary Chronic

Toxicity/Oncogenicity

Study

in Fischer 344 Rats:

Final Report: Lab

Project Number: CHV

174-133: DR-0097-

3397-005. Unpublished

study prepared by

Corning Hazleton Inc.

Yes 44050002

Worth, H. M., et al.

(1966)Subacute

Toxicity of Benefin to

Rats. Unpublished study

prepared by Lilly

Research Labs.

Study Conducted

Prior to GLP

Regulations

00024651

Gibson, W. R. et al.

(1973) A Study of the

Effects on Rats from the

Ingestion of Benefin for

Two Years. Unpublished

study prepared by Lilly

Research Labs.

Study Conducted

Prior to GLP

Regulations

00037675

Dalgard, D. (1993)

Benefin: 13-Week Oral

Toxicity Study in Beagle

Dogs: Lab

Project Number: HWA

174-135: DR-0097-

3397-003. Unpublished

study prepared by

Hazleton Washington,

Inc.

Yes 43072301
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GLP Study MRID Number

Yes 43628702

Yes 00147535

Citation Code

H

Study Citation

Walker, M.( 1995)

Benefin: One-Year Oral

Chronic Toxicity Study

in Beagle Dogs:

Final Report: Lab

Project Number: CHV

174-143: DR-0097-

3397-004. Unpublished

study prepared by

Corning Hazleton Inc.

381 p.

MacKenzie,K.(l985)

Rat Teratology Study

with Benefin: Study No.

6180-101.

Unpublished study

prepared by Hazleton

Laboratories America,

Inc.
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1.4 Benfluralin: Scientific Rationale for Sufficiency of OSRI in

Fulfillment of OPPTS 890.1450 and OPPTS 890.1500

In preparing this scientific rationale, the following process was adhered to:

1. Collect appropriate existing benfluralin data (OSRI), including primarily guideline

toxicity studies

2. Examine existing data for endpoints relevant to EDSP Tier I

3. Determine which Tier I endpoints are adequately addressed by OSRI

4. Determine which if any EDSP Tier I assays are sufficiently addressed by OSRI

therefore making them redundant

The conclusion from this process, after careful consideration of the weight of the evidence

provided by the individual toxicity studies available for benfluralin combined with the EDSP

studies that will be conducted, is that the female and male pubertal assays are essentially

redundant and are, therefore, not justified from an animal use perspective. In granting an

exemption from performing these studies. EPA will prevent the unnecessary use of at least 90

animals.

The data available for the specific endpoints defined in the OPPTS 890.1450 and OPPTS

890.1500 guidelines are summarized in Tables 5 and 6 respectively. For any endpoints where

the requested data are not available, other OPPTS EDSP Tier I assays may be performed to

provide the missing data-points since there is significant overlap in the Tier I testing program

for the various endocrine-mediated modes-of-action. In addition, Other Scientifically

Relevant Information (OSRI) may be available to help determine the relative significance of

the missing endpoints (i.e. if a preponderance of other endpoints are available which

essentially address the same endrocrine MO A). For registered active ingredients, there is an

abundance of available information that is relevant to determining if any endocrine-mediated

effects occur with treatment. Studies submitted as OSRI in fulfillment of Tier I requirements

should be carefully considered and not dismissed if only one or a few specific endpoints

requested by the Tier I screening studies were not evaluated. Further to this, it should be noted

that in the case of the pubertal assays, many of the endpoints are not specific to the endocrine

system and can also be altered by as the result of general systemic toxicity (Stoker, 2000). For

example, endpoints evaluated in the pubertal assays can be altered secondary to effects on

body weight (Carney, 2004). This is significant as the guidelines for pubertal assays define

reduced body weight as evidence for having achieved an appropriate high dose-level for

testing. Given the lack of specificity for many of the apical pubertal endpoints, it is

appropriate to consider surrogate endpoints in place of these less-specific endpoints which

may not have been examined in the existing data base for a given chemical. This approach

will allow for a robust weight of evidence determination based upon the totality of the

available data. While all of these endpoints may not be of equal sensitivity, consistent results

found across multiple studies and end-points will often provide a high degree of confidence in

the conclusion without the need for conducting additional testing. Tables 2-4 below provide
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Page 12 of 25

examples of end-points commonly assessed in 40 CFR 158 guideline studies that can serve as

surrogates for other endpoints that assess estrogenicity, anti-estrogenicity, and antiandrogenicity (androgenicity not included as xenobiotic androgen agonists are rare). If a

pattern consistent with the effects presented in these tables is not observed, then a test

chemical can be considered negative for adverse effects elicited through the endocrine modesof-action. The conduct of special endocrine mode-of-action studies (i.e ER binding, AR

binding, steroidogenesis, aromatose) may not be necessary, but can further support the weight

of evidence conclusions.

Table 2- Adverse Effects Elicited by Estrogenic Substances

Endpoint

Estrous cyclicity

Time to mating

Uterine weight

Vaginal patency

PPS

Ovarian follicle count

Fertility

Mating index

Corpora lutea

Implantations

Gestational length

Litter size

Anogenital distance

Epidydimis sperm count

Testis Histopathology

Epidydimis histopathology

Prostate histopathology

Ovary weight

Ovary histopathology

Mammary histopathology

Expected Change

Decrease frequency;

anestrous

Increase

Increase

Accelerated

Delayed

Decrease

Decrease

Decrease

Decrease

Increase

increase

Decrease

Decrease

Decrease

Atrophy

Lesions, decreased sperm

content

Involution of ventral prostate

epithelium; stromal

proliferation

Decrease

Stromal hyperplasia;

follicular cysts

Increased

References

Terry, 2004; Abbott, 2006;

Delia Seta, 2008; Sawaki,

2003
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Table 3- Adverse Effects Elicited by Anti-Estrogenic Substances

Endpoint

Estrous cyclicity

Time to mating

Testis weight

Vaginal patency

Corpora lutea

Litter size

Testis Histopathology

Epidydimis histopathology

Prostate histopathology

Seminal Vesicle

histopathology

Ovary histopathology

Expected Change

Decrease frequency;

unestrous

Increase

Decrease

Delayed

Decrease or absent

Decrease

Leydig cell atrophy

Degenerative changes

Degenerative changes

Degenerative changes

Decrease primordial follicles;

hemorrhagic follicles;

interstitial/stromal

hyperplasia

References

Vanage, 1997; Abbott, 2006;
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Table 4- Adverse Effects Elicited by Anti-Androgenic Substances

Endpoint

Preputial separation

Sperm count, motility

Testis Weight

Vaginal patency

Epididymis weight

Prostate weight

Seminal Vesicles Weight

Testis histopathology

Epididymis histopathology

Prostate histopathology

Seminal Vesicle

histopathology

Anogenital distance

Uterine histopathology

Mammary gland

Estrous cyclicity

Time to mating

Fertility..

Ovary histopathology

Uterine histopathology

Expected Change

Delayed

Decrease

Generally Decrease

Delayed

Decrease

Decrease

Decrease

Carcinoma; leydig cell

hypertrophy/hyperplasia;

germinal degeneration

Agenesis; spermatic

depletion

Fibrosis, cellular infiltration;

epithelial hyperplasia;

agenesis

Fibrosis, cellular infiltration;

epithelial hyperplasia

Decrease

Cystic endometrial

hyperplasia

Decrease adenomas,

adenocarcinomas

Persistent estrus

Increase

decrease

Hypertrophy

Cystic endometrial

hyperplasia

References

Gray, 2001; Shin, 2002;

Lund, 2004; Van Der School,

1992; York, 2006; Bowman,

2005; Horsley, 2005; Rider,

2008; O'Connor, 2002;
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Dow AgroSciences LLC

Report ID: AKH020510

Page 21

1.7 Summary and Conclusions

Potential effects of treatment on growth and development are evaluated in multi-generation

reproduction studies. As this is also essentially the purpose of the EDSP pubertal assays, it is logical to

conclude that data from multi-generation studies should be carefully evaluated prior to conducting the

pubertal assays. When the multi-generation study results are combined with other existing data and

perhaps supplemented with EDSP Tier I screening data, it may be concluded that the pubertal assays

would be redundant and, therefore, not necessary to make a robust determination of any potential

effects on the endocrine system.

This is in fact the case for benflurlin where all of the critical endpoints defined in the OPPTS

890.1450 and OPPTS 890.1500 guidelines and the associated endocrine modes-of-action have been

evaluated in one or more of three ways: a) the endpoint has been directly assessed in existing studies;

b) in rare cases, surrogate endpoints have been evaluated; c) the relevant endocrine mode-of-action

will be assessed in other Tier I EDSP assays (See tables 7 and 8). It is clear from these tables that no

critical information will be gained by conducting the pubertal assays.

Table 7- Summary of OSRI for Female Pubertal

OPPTS 890.1450

Endpoint

Growth

Age at Vaginal

Opening

Uterine Weight

Ovarian Weight

Thyroid Weight

Liver Weight

Kidney Weight

Pituitary Weight

Adrenal Weight

Uterine

Histopathology

Ovarian

Histopathology

Thyroid

Histopathology

Kidney

Histopathology

TSHandT4

Estrous cyclicity

Clinical Chemistry

Endpoint assessed

in existing studies

X

X

X

X

X

X

X

X

X

X

X

X

X*

X

Surrogate endpoints

assessed in existing

studies

X

X

Mode-of-Action to

be assessed in other

Tier I EDSP assays

X

X

X

X

X

X

X

*current data for trifluralin; benfluralin data being developed
Dow AgroSciences LLC

Report ID: AKH020510

Page 22

Table 8- Summary of OSRI for Male Pubertal

OPPTS 890.1500

Endpoint

Growth

Age at preputial

separation

SV Weight

VP Weight

DLP Weight

Levator ani- weight

Epididymides

Weight

Testes weight

Thyroid weight

Liver Weight

Kidney Weight

Pituitary Weight

Adrenal Weight

Epididymis

Histopathology

Testes

Histopathology

Thyroid

Histopathology

Kidney

Histopathology

TSHandT4

Testosterone

Clinical Chemistry

Endpoint assessed

in existing studies

X

X

X

X

X

X

X

X

X

X

X

X

X

X*

X

Surrogate endpoints

assessed in existing

studies

X

X

Mode-of-Action to

be assessed in other

Tier I EDSP assays

X

X

X

X

X

X

X

X (optional)

X (optional)

X (optional)

X

X (optional)

X

*current data for trifluralin; benfluralin data being developed

The confidence that one has in the existing studies cited in this rationale and ability to use them in leiu

of performing new studies is increased by examining the totality of available information and

performing a weight of evidence evaluation. The existing database for benfluralin does not

demonstrate any pattern of effects consistent with adverse endocrine-mediated effects on reproductive

organs or processes. The thyroid is a target for benfluralin and further studies are being conducted to

further understand how benfluralin affects the thyroid.

The stated purpose of the Endocrine Disrupter Screening Program is "to determine whether certain

substances may have an effect in humans that is similar to an effect produced by a naturally occurring

estrogen, or such other endocrine effect
Dow AgroSciences LLC

Report ID: AKH020510

Page 23

as the Administrator may designate." Tier I "is to identify substances

that have the potential to interact with the estrogen, androgen, or thyroid hormone systems using a

battery of assays." Based on the information presented above, it is clear that the male and female

pubertal assays are not required to make this determination. Adequate information is available based

on existing data and the other Tier I studies that will be conducted. The pubertal assays are, therefore,

redundant, not justified from an animal use position, and should not be conducted per EPA's mandate

to avoid duplicative testing.

We, therefore, encourage EPA to carefully examine the OSRI that was cited in this rationale and,

respectfully, request that the requirement for conducting the female and male pubertal assays (OPPTS

890.1450, OPPTS 890.1500) be considered complete based on the submission of OSRI and the fact

that other Tier IEDSP sceening assays will be conducted to also aid in evaluating the specific

endpoints and relevant for these assays.
Dow AgroSciences LLC

Report ID: AKH020510

Page 24

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