MGK: MCLAUGHLIN GORMLEY KING COMPAIVY

8810 Tenth Avenue North • Minneapolis, MN 55427-4319 U.S.A.

763-544-0341 • 800-645-6466 • Fax 763-544-6437 • www.m^.com

SENT BY COURIER

April 22, 2010

Jane Smith

Document Processing Desk (PRD-EDSP)

Office of Pesticide Programs (OPP), Mail Code 7508P

U.S. Environmental Protection Agency

One Potomac Yard (South Bldg)

2777 S. Crystal Drive

Arlington, VA 22202-4501

Dear Jane,

Enclosed is the 90-day response form for the EDSP Test Order for MGK-264, PC Code 057001

CAS No. 113-48-4. Also attached are three copies of our Other Scientifically Relevant

Information (OSRI), 6 pages).

If you have any questions, please feel free to contact me at 763-593-3410, or via email at

ian.sharp@mgk.com.

Thank you.

Best Regards,

Janice K. Sharp, Ph.D.

Regulatory Department Manager

CC: Regulatory File

Enclosures

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Quality Products Since 19O2
McLaughlin Gormley King Co.

Submission of Other Scientific Relevant Information

In Response to EDSP Testing Order # EDSP-057001

For MGK-264 (PC Code 057001)

Submitted April 22, 2010

In response to the above-cited EDSP Testing order, McLaughlin Gormley

King Co. (MGK) submits the following "Other Scientific Relevant Information"

(OSRI) to satisfy part of the testing order. Specifically, MGK cites as OSRI two

studies:

1) A recently conducted two-generation rat study that examined the

entire reproduction process in Wistar rats (the "2-gen study"). The

2-gen study, which is discussed in detail in the attachment to this

submission and is appended to this submission, is a well-conducted

GLP study that utilized current EPA protocols.

2) A Combined Chronic Toxicity/Carcinogenicity Study in Rats

(MRID No.43005301). This was a comprehensive guideline study

that examined all lexicologically relevant organ systems including

the thyroid-liver-pituitary axis.

The 2-gen Study

The 2-gen study adequately informs the determination as to whether

MGK-264 "may have an effect that is similar to an effect produced by a substance

that interacts with the [estrogen and androgen] hormonal systems." Order

#EDSP-057001 at 5; 74 Fed.Reg. 17560, 17566. Specifically, the 2-gen study

provides "information on a potential consequence or effect that could be due to

effects on the [estrogen and androgen] systems." Id. The study demonstrates that

MGK-264 produces mild effects on endocrine-related parameters only at 6400

ppm (the highest dose tested), far above the NOAEL for parental systemic ••••

toxicity of 400 ppm. J " * J * J ****

. • • • • .

Because the 2-gen study provides adequate information as to th» potential •*•,*•

consequences of MGK-264 or effects on the estrogen and androgen system^.* .. .

MGK is submitting the 2-gen study to satisfy the requirement to submit«date»for t *••*

the following screening assays:

Androgen Receptor Binding ••••••

Aromatase

Estrogen Receptor Binding

Estrogen Receptor Transcriptional Activation

Hershberger
• Female Pubertal

• Male Pubertal

• Steroidogenesis

• Uterotropic

MGK believes that conducting the above-listed screening assays for

MGK-264 when a well conducted, recent, relevant and apical 2-gen study is

already available, is unnecessary and unlikely to generate additional information

that will assist EPA in making regulatory determinations. MGK also believes that

to the extent EPA requires unnecessary screening, the Agency exceeds the

authority granted EPA by the Food Quality Act (FQPA). The purpose of FQPA is

clear: "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

effects as [EPA] may designate." 21 U.S.C. 346a(p)(l). This language must be

read in light of the FQPA directive that the Agency shall take actions (e.g.,

regulate) to ensure the protection of public health. 21 U.S.C. 346a(p)(6). There is

no evidence Congress intended that EPA require generation of unnecessary data

or data the Agency couldn't use to protect human health. Indeed, Congress

directed EPA to minimize duplicative testing.

The Combined Chronic Toxicitv/Carcinogenicity Study

The Combined Chronic Toxicity/Carcinogenicity Study in Rats in

combination with the 2-gen study adequately informs the determination as to

whether MGK-264 "may have an effect that is similar to an effect produced by a

substance that interacts with the [thyroid] hormonal system." Order #EDSP057001 at 5; 74 Fed.Reg. 17560, 17566. Specifically, together the Combined

Chronic Toxicity/Carcinogenicity Study in Rats and the 2-gen study provide

"information on a potential consequence or effect that could be due to effects on

the [thyroid] system." In the Combined Chronic Toxicity/Carcinogenicity Study

in Rats, MGK-264 was shown to cause dose-dependent increases in benign

thyroid follicular tumors in male rats. In the 2-gen study, follicular cell

hypertrophy and/or colloidal alteration were increased in males beginning partly

at 1600 ppm in both FO and Fl, and in FO and Fl females at 6400 ppm.

With respect to the thyroid, EPA states in its recent Reregistratiew..

Eligibility Decision (RED) for MGK-264: • '

"It is noted, however, that the rat carcinogenicity study J

demonstrated increased thyroid tumors that may have been.related

to perturbation of the thyroid/liver/pituitary axis to alter thjroitl ,

hormone metabolism. EPA believes the endpoints and risfc"* * J...J.

scenarios evaluated are protective of this potential endocrine • effect." .;;:;.

Clearly, the existing database provides sufficient information to assess

potential thyroid effect and EPA has already made the required assessment with
respect to MGK-264. The proposed Amphibian Metamorphosis Assay will

provide no additional information on which to base regulatory decisions. The

Combined Chronic Toxicity/Carcinogenicity Study in Rats and the 2-gen study

together provide adequate information as to the potential consequences of MGK264 or effects on the thyroid system, For that reason, MGK cites the Combined

Chronic Toxicity/Carcinogenicity Study in Rats along with the 2-gen study to

satisfy the requirement to submit data for the Amphibian Metamorphosis Assay.

Discussion

Tier 1 data, by itself, will not determine whether a substance will have an

endocrine effect in humans. As EPA admits, the Tier 1 screens will not determine

whether a substance causes adverse human health effects and, if it does, at what

level of exposure. That information (hazard and dose-response) is determined

using more apical testing, such as EDSP Tier 2 tests, and forms the bases for

science-based regulation. Tier 1 screening can be useful, nonetheless, for

determining when additional, more apical testing is warranted. Because recent,

relevant and well-conducted apical tests have already been conducted for MGK264, screening assays are not necessary to determine whether apical testing is

warranted for the substance. Indeed, EPA should have adequate information from

the available apical testing to determine whether any regulatory actions

concerning MGK 264 are necessary to protect public health.

Simply put, the Tier 1 screens will not determine whether MGK-264 will

have an estrogenic, androgenic or thyroid effect in humans. Significantly, those

screens will not determine whether MGK-264 causes adverse human health

effects at typical levels of exposure. Conversely, the apical studies MGK cites as

OSRI can inform hazard and dose-response determinations and can form the basis

for Agency regulation. Therefore, in the case of MGK-264, the Tier 1 screens

listed above are not necessary to determine if more apical tests are warranted -

those tests have already been conducted. While, those screens may produce new

data, those data cannot form the basis of regulation and, in any event, are not

necessary for making regulatory decisions for MGK-264.

In sum, MGK believes that requiring screening data when relevant apical

data are available will result in "duplicative testing," which Congress e^xj^ljcijly .

directed the Agency to minimize. See, 21 U.S.C 346a(p)(5)(b). MGKImaJntains

that when relevant apical data are available, screening level data become$^* j

unnecessary or duplicative for purposes of serving the goals of FQPA: tojgerlerate

data that determine whether substances have an adverse hormonal effect in"

humans and to inform regulatory decisions. While screening data may b£ •

interesting they do not directly serve the ultimate goals of the EDSP. AVSfriatter.

of policy, EPA should not require screening that wastes limited resources and

leads to the unnecessary use of laboratory animals when that screening will not

directly benefit public health.

•*•
Attachment #1 - Summary of Combined Chronic Toxicity/Carcinogenicity

Study in Rats (MRID No.: 43005301)

Five groups of 60/sex Charles River CDs. strain rats were dosed in the diet

for 24 months as 0, 50, 150 or 450 mg/kg bw/day of MGK-264. The 50 mg/kg

bw/day dose group males had marginally increased (14% p < 0.05) terminal liver

weights. Higher dose levels had higher increases (maximum 45% for the 450

mg/kg bw/day high dose male and 59% for the female groups). At dose levels of

150 mg/kg bw/day and above pathological changes in the liver (hepatocyte

hypertrophy in both sexes and portal bile duct proliferation and bile stasis,

spongiosis hepatitis and cysts in females) and kidney (brown pigment in females)

were noted. Additional liver pathology (bile duct proliferation, cysts and altered

eosinophilic foci in males and spongiosis hepatitis in males) and kidney (brown

pigment and cysts in males) were also noted at 450 mg/kg as well as increases in

kidney, heart, and brain weights.

Dose-depended increases in the incidence of thyroid follicular tumors

occurred only in males: adenomas - 3/105 (3%), 4/56 (7%), 5/53 (9%) and 6/55

(11%) and carcinomas - 2/78 (3%), 2/38 (5%), 1/36 (3%) and 3/45 (7%);

combined - 5/105 (5%), 6/56 (11%), 6/53 (11%) and 9/55 (16%) for the two

combined control groups, the 50, 150 and 450 mg/kg/day dose groups,

respectively.

The thyroid changes are most likely an induction of oxidative enzymes in

the liver resulting in decreased serum levels of triiodothyronine (T3) and

thyroxine (T4) and a compensatory increase in serum levels of thyroid stimulating

hormone (TSH). The chronic stimulation of the thyroid gland by TSH is known to

result in follicular cell tumors in rodents. Because of the known species

differences between rodents and humans in the effects of inducers of hepatic

xenobiotic metabolism on the thyroid gland, these effects are considered ratspecific and have no relevance for the protection of human health.

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Attachment #2 - Two-generation Reproduction Study on MGK-264

[MGK is submitting this study along with this OSRI submission.]

MGK recently completed a Two-generation Reproduction Study on MGK

264. Conducted at the Bayer Schering Pharma AG laboratory in Wuppertal,

Germany, the study followed the OPPTS Series 870 Health Effects Test

Guidelines (1998). Doses tested included: 0, 400, 1600, 6400 ppm (the highest

dose tested - HDT).

The following endocrine-related parameters were evaluated and are worth noting:

1. Sperm analysis - showed no substance-related effects at any dose

including the HDT (FO and Fl).

2. Thyroid - Follicular cell hypertrophy and/or colloidal alteration

increased in males beginning partly at 1600 ppm in both FO and Fl, and in

FO and Fl females at 6400 ppm. As was the case for the thyroid changes

observed in the rat carcinogenicity study and evaluated in the RED, these

changes are most likely an induction of oxidative enzymes in the liver

resulting in a decrease decreased serum levels of triiodothyronine (T3) and

thyroxine (T4) and a compensatory increase in serum levels of thyroid

stimulating hormone (TSH). The chronic stimulation of the thyroid gland

by TSH is known to result in follicular cell tumors in rodents. Because of

the known species differences between rodents and humans in the effects

of inducers of hepatic xenobiotic metabolism on the thyroid gland, these

effects are considered rat-specific and have no relevance for the protection

of public health.

3. Ovaries/oviducts - The absolute and relative weights of

ovaries/oviducts were decreased in the FO females at 6400 ppm (the

HDT).

4. Ovarian function - Altered luteinization of the corpora lutea (FO and Fl

females) and/or an increased incidence of Fl females benign met-/diestrus

cycle were observed only at 6400 ppm (the HDT).

5. Seminal vesicles/coagulation glands - The absolute and relativ«*vsight •

of the seminal vesicles/coagulation glands were increased and ($400 ppm

(the HDT). No accompanying morphological changes were noted*t»» •

6. Reproductive Performance - No changes in insemination, fertili^, |

gestation, or rearing indices as well at gestation length and numbe)" o£

litters born were noted at any dose including the HDT. • • • • • (

<

7. Litter data - No changes in liver birth index, prenatal loss, number of (

pups born, or sex ratio were noted at any dose including the HDT. An

additional observation was that of a reduction in the mean litter size of Fl

pups at the HDT, resulting from small reduction in the number
implantation sites. The cause of this effect is unknown, but one possibility

is altered ovarian function.

8. Viability and lactation indices -No changes were noted up 6400 ppm

(the HOT).

9. Pup weights - A decrease in F2 pup weights at 1600 ppm beginning at

day 14 post-partum was noted, coinciding with an onset of ingestion of a

solid diet containing the test article. A consistent depression in pup weight

was noted in most generations was 6400 ppm (the HDT).

10. Vaginal opening - A delay was noted at 6400 ppm (the HDT) likely

secondary to the observed body weight depression at this high dose.

11. Ano-genital distance - No effects at any dose including the HDT.

12. Uterine weights in offspring - Absolute weights decreased in Fl

weanlings at 6400 ppm (the HDT) and in F2a weanlings at 1660 and 6400

ppm (not dose-dependent). Uterine weights relative to body weights were

not changed, reflecting the likelihood that the depressed body weights

were responsible for the observation of lower absolute uterine weights.

In summary, the parental systemic NOAEL from this study was 400 ppm, based

on the onset of liver and kidney effects at the next highest dose (1600 ppm). The

NOAEL for reproductive parameters was 1600 ppm. Potentially endocrine

related effects were only noted as indicated above and only at the highest dose

tested far greater (16X) than the NOAEL for systemic toxicity.

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