[Federal Register: April 6, 2009 (Volume 74, Number 64)]
[Notices]
[Page 15528-15530]
[DOCID:fr06ap09-129]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-59667; File No. SR-CBOE-2009-022]

Self-Regulatory Organizations; Chicago Board Options Exchange,
Incorporated; Notice of Filing of Proposal To List and Trade S&P 500
Dividend Index Options

March 31, 2009.
    Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934
(the ``Act''),\1\ and Rule 19b-4 thereunder,\2\ notice is hereby given
that on March 25, 2009, the Chicago Board Options Exchange,
Incorporated (``Exchange'' or ``CBOE'') filed with the Securities and
Exchange Commission (``Commission'') the proposed rule change as
described in Items I, II, and III below, which Items have been prepared
by the Exchange. The Commission is publishing this notice to solicit
comments on the proposal from interested persons.
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    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
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I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange proposes to amend certain of its rules to provide for
the listing and trading of options that overlie the S&P 500 Dividend
Index, which will be cash-settled and will have European-style
exercise. The text of the rule proposal is available on the Exchange's
Web site (http://www.cboe.org/legal), at the Exchange's Office of the
Secretary and at the Commission.

II. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

    In its filing with the Commission, the self-regulatory organization
included statements concerning the purpose of and basis for the
proposed rule change and discussed any comments it received on the
proposed rule change. The text of those statements may be examined at
the places specified in Item IV below. The Exchange has prepared
summaries, set forth in sections A, B, and C below, of the most
significant parts of such statements.

A. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

1. Purpose
    The purpose of the proposed rule change is to permit the Exchange
to list and trade cash-settled options that overlie the S&P 500
Dividend Index, which will be cash-settled and will have European-style
exercise.
Index Design
    The S&P 500 Dividend Index, which is currently being calculated,
represents the accumulated ex-dividend amounts of all S&P 500 Index
component securities over a specified quarterly accrual period. Each
day Standard & Poor's calculates the aggregate daily dividend totals
for the S&P 500 Index component securities, which are summed over any
given calendar quarter and are the basis of the S&P 500 Dividend Index.
On any given day, the index dividend is calculated as the total
dividend value for all constituents of the S&P 500 Index divided by the
S&P 500 Index divisor. The total dividend value is calculated as the
sum of dividends per share multiplied by the shares outstanding for all
constituents of the S&P 500 Index that are trading ``ex-dividend'' on
that day.
    Each accrual period will run from the business day after the third
Friday of a quarterly expiration month (March, June, September or
December) through the third Friday of the next quarterly expiration
month. An example of a quarterly accrual period is one that will run
from Monday, March 23, 2009 through Friday, June 19, 2009. The S&P 500
Dividend Index is expressed in S&P 500 Index points and is reset to
zero at the end of each quarterly accrual period.
    The S&P 500 Dividend Index is currently calculated by Standard &
Poor's and is disseminated by Standard and Poor's once per day.\3\ The
S&P 500 Dividend Index is reported in absolute numbers (e.g., 3, 5, 7),
and the Exchange proposes to trade option contracts on the S&P 500
Dividend Index level with an applied scaling factor of 10. To
illustrate, where the S&P 500 Dividend Index is 3, the underlying will
have an index value of 30 (3 x 10). Once daily, CBOE will disseminate
the underlying S&P 500 Dividend Index value with the applied scaling
factor of 10 through the Options Price Reporting Authority (``OPRA'')
and/or one or more major market data vendors.
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    \3\ The daily values can be accessed on Bloomberg under the
symbol: SPXDIV .
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Options Trading
    The exercise-settlement value for S&P 500 Dividend Index options
will be the S&P 500 Dividend Index that is calculated by Standard &
Poor's with an applied scaling factor that will be set by the Exchange
at listing. The underlying S&P Dividend Index will be quoted in
decimals and one point will be equal to $100.\4\ The minimum tick size
for options trading at or below 3.00 be 0.05 point ($5.00) and for all
other series, 0.10 ($10.00). Exhibit 3 presents proposed contract
specifications for S&P 500 Dividend Index options.
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    \4\ The contract multiplier will be $100.
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    The Exchange is proposing to list series at 1 point ($1.00) or
greater strike price intervals if the strike price is equal to or less
than 200 scaled index points on S&P 500 Dividend Index options.\5\
Because the S&P 500 Dividend Index will fluctuate around a limited
index value range, the Exchange believes that a granular strike price
increment will provide investors with greater flexibility by allowing
them to establish positions that are better tailored to meet their
investment objectives.
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    \5\ When the strike price exceeds 200 scaled index points,
strike price intervals will be no less than 2.5 points.
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    Initially, the Exchange will list in-, at- and out-of-the-money
strike prices and may open for trading up to five series above and five
series below the price of the related S&P 500 Dividend Index futures
contract. The Exchange is

proposing to use the forward index level rather than the current index
for setting strikes because the current index level is reset to zero at
the end of each quarterly accrual period. The Exchange believes that
the related S&P 500 Dividend Index futures price is a good proxy for
the forward index level.
    As for additional series, either in response to customer demand or
as the price of the related S&P 500 Dividend Index futures contract
moves from the initial exercise prices of options and LEAPs series that
have been opened for trading, the Exchange may open for trading up to
an additional twenty series. The Exchange will not be permitted to open
for trading series with 1 point ($1.00) intervals within 0.50 of an
existing 2.5 point ($2.50) strike price with the same expiration month.
The Exchange will not be permitted to list LEAPS on S&P 500 Dividend
Index options at intervals less than 1 point.
    The Exchange also proposes to add new Interpretation and Policy .13
to Rule 5.5, Series of Option Contracts Open for Trading, which will be
an internal cross reference stating that the intervals between strike
prices for S&P 500 Dividend Index option series will be determined in
accordance with proposed new Interpretation and Policy .01(h) to Rule
24.9.
Exercise and Settlement
    The proposed options will expire on the Saturday following the
third Friday of the expiring month. Trading in the expiring contract
month will normally cease at 3:15 p.m. Chicago time on the last day of
trading (ordinarily the Thursday before expiration Saturday, unless
there is an intervening holiday). When the last trading day is moved
because of an Exchange holiday (such as when CBOE is closed on the
Friday before expiration), the last trading day for expiring options
will be Wednesday.
    Exercise will result in delivery of cash on the business day
following expiration. S&P 500 Dividend Index options will be A.M.-
settled. The exercise-settlement amount will be equal to the difference
between the exercise-settlement value and the exercise price of the
option, multiplied by the contract multiplier ($100).
    If the exercise settlement value is not available or the normal
settlement procedure cannot be utilized due to a trading disruption or
other unusual circumstance, the settlement value will be determined in
accordance with the rules and bylaws of the OCC.
Surveillance
    The Exchange will use the same surveillance procedures currently
utilized for each of the Exchange's other index options to monitor
trading in S&P 500 Dividend Index options. The Exchange further
represents that these surveillance procedures shall be adequate to
monitor trading in options on these option products. For surveillance
purposes, the Exchange will have complete access to information
regarding trading activity in the pertinent underlying securities
(i.e., S&P 500 Index component securities).
Position Limits
    The Exchange is not proposing to establish any position limits for
S&P 500 Dividend Index options. Because the S&P 500 Dividend Index
represents the accumulated ``ex-dividend'' amounts of all S&P 500 Index
component securities, the Exchange believes that the position and
exercise limits for these new products should be the same as those for
other broad-based index options, e.g., SPX, for which there are no
position limits. S&P 500 Dividend Index options will be subject to the
same reporting and other requirements triggered for other options dealt
in on the Exchange.\6\
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    \6\ See Rule 4.13, Reports Related to Position Limits.
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Exchange Rules Applicable
    Except as modified herein, the rules in Chapters I through XIX,
XXIV, XXIVA, and XXIVB will equally apply to S&P 500 Dividend Index
options.
    S&P 500 Dividend Index options will be margined as ``broad-based
index'' options, and under CBOE rules, especially, Rule 12.3(c)(5)(A),
the margin requirement for a short put or call shall be 100% of the
current market value of the contract plus up to 15% of the aggregate
contract value. Additional margin may be required pursuant to Exchange
Rule 12.10.
    The Exchange hereby designates S&P 500 Dividend Index options as
eligible for trading as Flexible Exchange Options as provided for in
Chapters XXIVA (Flexible Exchange Options) and XXIVB (FLEX Hybrid
Trading System).
Capacity
    CBOE has analyzed its capacity and represents that it believes the
Exchange and OPRA have the necessary systems capacity to handle the
additional traffic associated with the listing of new series that will
result from the introduction of S&P 500 Dividend Index options.
2. Statutory Basis
    The proposed rule change is consistent with Section 6(b) of the Act
in general and furthers the objectives of Section 6(b)(5) in particular
in that it will permit trading in options based on the index pursuant
to rules designed to prevent fraudulent and manipulative acts and
practices and to promote just and equitable principles of trade, and
thereby will provide investors with the ability to invest in options
that settle to an index that represents the accumulated ex-dividend
amounts of all S&P 500 Index component securities over a specified
quarterly accrual period.

B. Self-Regulatory Organization's Statement on Burden on Competition

    CBOE does not believe that the proposed rule change will impose any
burden on competition not necessary or appropriate in furtherance of
the purposes of the Act.

C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants or Others

    The Exchange neither solicited nor received comments on the
proposal.

III. Date of Effectiveness of the Proposed Rule Change and Timing for
Commission Action

    Within 35 days of the date of publication of this notice in the
Federal Register or within such longer period (i) as the Commission may
designate up to 90 days of such date if it finds such longer period to
be appropriate and publishes its reasons for so finding or (ii) as to
which the self-regulatory organization consents, the Commission will:
    (A) By order approve such proposed rule change, or
    (B) Institute proceedings to determine whether the proposed rule
change should be disapproved.

IV. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed rule
change is consistent with the Act. Comments may be submitted by any of
the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://
www.sec.gov/rules/sro.shtml); or
     Send an e-mail to<EMAIL_ADDRESS>Please include
File Number SR-CBOE-2009-022 on the subject line.

Paper Comments

     Send paper comments in triplicate to Elizabeth M. Murphy,
Secretary, Securities and Exchange Commission,

100 F Street, NE., Washington, DC 20549-1090.

All submissions should refer to File Number SR-CBOE-2009-022. This file
number should be included on the subject line if e-mail is used. To
help the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's Internet Web site (http://www.sec.gov/rules/
sro.shtml). Copies of the submission, all subsequent amendments, all
written statements with respect to the proposed rule change that are
filed with the Commission, and all written communications relating to
the proposed rule change between the Commission and any person, other
than those that may be withheld from the public in accordance with the
provisions of 5 U.S.C. 552, will be available for inspection and
copying in the Commission's Public Reference Room, 100 F Street, NE.,
Washington, DC 20549, on official business days between the hours of 10
a.m. and 3 p.m. Copies of the filing also will be available for
inspection and copying at the principal office of the Exchange. All
comments received will be posted without change; the Commission does
not edit personal identifying information from submissions. You should
submit only information that you wish to make available publicly. All
submissions should refer to File Number SR-CBOE-2009-022 and should be
submitted on or before April 27, 2009.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\7\

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    \7\ 17 CFR 200.30-3(a)(12).
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Florence E. Harmon,
Deputy Secretary.
[FR Doc. E9-7663 Filed 4-3-09; 8:45 am]

BILLING CODE 8010-01-P


Very recent data have indicated that male perinatal reproductive development is regulated not just by testosterone ( and DHT; made by the Leydig cells) and Mdllerian inhibiting substance ( MIS; made by the Sertoli cells) which cause the Mdllerian ducts, which form female reproductive structures to regress in males, but also by a peptide hormone, now designated as insulin like factor 3 ( ISNL3) produced by the Leydig cells ( Kubota et al., 2002). ISNL13 was discovered in the 1980s, but its function in regulating the development of the gubernaculum ( which attaches to the caudal portion of the testis and epididymis and is responsible, in whole or part, for testis descent into the lower abdomen to the inguinal ring in utero and into the scrotal sacs during late lactation in rodents) was not identified until ISNL13 knockout mice were constructed ( with normal T and MIS), which exhibited bilateral cryptorchidism ( Nef and Parada, 1999; Zimmermann et al., 1999). ISNL13 has also been shown to play a role in DES induced cryptorchidism in mice ( Emmen et al., 2000a), which implies estrogen involvement. The role of ISNL13 in human cryptorchidism is not clear, with evidence both for its role ( Tomboc et al., 2000) and against any role ( Baker et al., 2002). Emmen et al. ( 2000b) have shown that both androgen and Ins13 are required for rodent gubernuclear outgrowth in vitro. 080555.001.012 46 5/ 5/ 03 46 Dr. L. Early Gray's laboratory at U. S. EPA ( NHEERL) ( Gray et al., 2000; Gray and Foster, 2002; Wilson et al., 2003) has reported that gavage administration to rats of DBP ( or DEHP or BBP) at 750 mg/ kg/ day on gd 14 to pnd 3 results in male reproductive system malformations, including cryptorchidism associated with abnormalities of the gubernaculum. In addition, examination of fetal testes from dams exposed to DEHP at 750 mg/ kg/ day on gd 14 18 indicated that not only was testosterone production reduced, but also that Ins13 mRNA was inhibited by approximately 80% ( Wilson et al., 2003). When both DBP and BBP, each by gavage at 500 mg/ kg/ day, on gd 14 18 ( Gray et al., in preparation) were administered to rat dams, no offspring males in the combination group exhibited normal gubernacula, and a few males exhibited retained cranial suspensory ligaments, which normally maintain the ovaries in the upper abdomen in females. In some cases, only the gubernaculum was affected, with no other male reproductive system malformations or vice versa, indicating an effect of the phthalates at high oral doses on both testosterone and ISNL13 synthesis. Consistent with this interpretation, DBP administered by gavage at a high oral dose ( 500 mg/ kg/ day) to dams in the present study during gestation and lactation, produced a small but biologically significant incidence of undescended testes, as well as other male reproductive system malformations in male offspring on pnd 21 and 95.

Therefore, the cryptorchidism observed by Imagima et al. ( 1997), Shono et al. ( 2000), Gray and Foster ( 2002), Wilson et al. ( 2003), and in this study from administration of various phthalates ( monobutyl phthalate, DBP, DEHP, BBP, etc.) resulted only from very high oral " bolus" doses during the sensitive period.

In the present study, the presence of cranial suspensory ligaments in males and the reduced number of males with at least one gubernaculum on pnd 21, were observed at the low and high doses of DBP ( and in one male at the low dose VIN on pnd 21). Cranial suspensory ligaments were also observed on pnd 95 at the high dose of VIN ( one male) and at the high dose of DBP ( six males); cranial suspensory ligaments are normally observed only in females, attached to the ovaries and the under side of the diaphragm. Undescended testes were observed on pnd 21 at the high dose VIN ( three) and at the high dose DBP ( four); and on pnd 95 at the low dose VIN ( one), the high dose VIN ( 15), and at the high dose DBP ( 10) but not in the low dose DBP. Of the males with undescended testes at the high VIN and the high DBP doses, eight of 15 at 100 mg/ kg/ day VIN and two at 500 mg/ kg/ day DBP exhibited testes imbedded subcutaneously in the abdominal wall, strong evidence for abnormal/ absent gubernacula.

The diagnostic offspring male reproductive malformations observed after in utero exposure to VIN are hypospadias and agenesis ( absence) of the ventral prostate. In Text Table 6, which compares the percentage and incidence of malformations at pnd 21 and 95, the incidence of hypospadias was increased on pnd 95 over the incidence on pnd 21 for both doses of VIN ( and for the high dose of DBP). Agenesis of the ventral prostate exhibited a higher incidence on pnd 95 than on pnd 21 for the high dose of VIN; it was not detected at either time point for the low dose of VIN. It was also detected at the high ( but not the low) dose of DBP at both time points at approximately equal incidences. When one separates the data on missing ventral prostate lobe 080555.001.012 47 5/ 5/ 03 47 from data on ventral prostate lobe " reduced in size/ abnormal," the sensitivity of the pnd 95 necropsy ( over the pnd 21 necropsy) becomes very clear for the latter finding. In Text Table 6 on pnd 21, there were no incidences of ventral prostate lobe reduced in size/ abnormal. However, on pnd 95, the incidences were increased at the low ( 7.4%) and at the high dose ( 60.8%) on VIN and at the low ( 2.5% and high ( 10.8%) doses of DBP. Therefore, this effect was missed entirely on pnd 21.

Also for Text Table 6, those male malformations observed on pnd 95 but not on pnd 21 in either or both test chemicals or in both dose groups per chemical include the following:

° epididimydes reduced in size/ abnormal ( not observed in either VIN groups on pnd 21)

° epispadias ( not detected in any group on pnd 21)

° levator ani bulbocavernosus ( LABC) complex, missing/ reduced in size ( not observed in the low dose of VIN or either dose of DBP on pnd 21)

° cleft phalllus ( not observed in the low dose of DBP on pnd 21)

° dorsal and/ or ventral lobes of prostate reduced in size/ abnormal ( not detected in any group on pnd 21)

° seminal vesicles missing/ reduced in size/ abnormal ( not observed in the low dose of VIN on pnd 21)

° undescended testes ( not observed in the low dose of VIN on pnd 21)

° testes reduced in size or flaccid/ soft ( not detected in any group on pnd 21)

° and vaginal pouch ( not detected in any group on pnd 21)

An approach to determining whether effects observed on pnd 95 would have been observed if we only examined one adult male per litter in each group is presented in Text Table 7. In this table, the number ( and %) of male reproductive system malformations and the number( and %) of males with one or more reproductive system malformations are presented for pnd 21 and 95. Then, the incidence, based on the number of males with one or more reproductive system malformations ( taken from the individual animal data tables; Appendix I, Tables A 26 and A 28) and on the number of litters in each group, with > 1 male with > 1 reproductive malformations, is presented. These numbers are used to detemine whether one male randomly selected to represent his litter on pnd 95 would have been malformed. 080555.001.012 48 5/ 5/ 03 48 Text Table 6. Comparison of the Incidence of Male Reproductive System Malformations on pnd 21 Versus pnd 95 Vehicle Control ( mg/ kg/ day) VIN ( mg/ kg/ day) DBP ( mg/ kg/ day)

Parameter 0 50 100 100 500 No. males, pnd 21 74 82 65 71 65 No. males, pnd 95 82 95 74 81 74 Cowper's gland missing/ reduced in size:

Pnd 21 0 ( 0.0) a 9 ( 11.0) 47 ( 72.3) 1 ( 1.4) 7 ( 10.8)

Pnd 95 1 ( 1.2) 7 ( 7.4) 63 ( 85.1) 0 ( 0.0) 8 ( 10.8)

Epididymides missing Pnd 21 0 ( 0.0) 0 ( 0.0) 2 ( 3.1) 0 ( 0.0) 14 ( 21.5)

Pnd 95 0 ( 0.0) 0 ( 0.0) 4 ( 5.4) 0 ( 0.0) 33 ( 44.6)

Epididymides reduced in size/ abnormal Pnd 21 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 4 ( 6.2)

Pnd 95 1 ( 1.2) 0 ( 0.0) 19 ( 25.7) 0 ( 0.0) 52 ( 71.6)

Epispadias:

Pnd 21 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Pnd 95 0 ( 0.0) 4 ( 4.3) 11 ( 14.9) 0 ( 0.0) 0 ( 0.0)

Hypospadias:

Pnd 21 0 ( 0.0) 8.0 ( 9.7) 52 ( 80.0) 0 ( 0.0) 2 ( 3.1)

Pnd 95 0 ( 0.0) 15 ( 15.8) 73 ( 98.6) 0 ( 0.0) 12 ( 16.2)

LABC missing/ reduced in size:

Pnd 21 0 ( 0.0) 0 ( 0.0) 1 ( 1.5) 0 ( 0.0) 0 ( 0.0)

Pnd 95 0 ( 0.0) 2 ( 2.1) 40 ( 54.0) 0 ( 0.0) 4 ( 5.4)

( Continued) 080555.001.012 49 5/ 5/ 03 49 Vehicle Control ( mg/ kg/ day) VIN ( mg/ kg/ day) DBP ( mg/ kg/ day)

Parameter 0 50 100 100 500 Phallus, cleft:

Pnd 21 0 ( 0.0) 4 ( 4.9) 25 ( 38.5) 0 ( 0.0) 2 ( 3.1)

Pnd 95 1 ( 1.2) 41 ( 43.15) 74 ( 100.0) 2.0 ( 2.47) 26 ( 35.14)

Prostate dorsal lobe missing Pnd 21 0 ( 0.0) 0 ( 0.0) 21 ( 32.3) 0 ( 0.0) 1 ( 1.5)

Pnd 95 0 ( 0.0) 0 ( 0.0) 17 ( 23.0) 0 ( 0.0) 3 ( 4.0)

Prostate dorsal lobe reduced in size/ abnormal Pnd 21 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Pnd 95 0 ( 0.0) 3 ( 3.2) 20 ( 27.0) 2 ( 2.5) 8 ( 10.8)

Prostate ventral lobe missing Pnd 21 0 ( 0.0) 0 ( 0.0) 5 ( 7.7) 0 ( 0.0) 2 ( 3.1)

Pnd 95 0 ( 0.0) 0 ( 0.0) 12 ( 16.2) 0 ( 0.0) 3 ( 4.0)

Prostate ventral lobe reduced in size/ abnormal Pnd 21 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Pnd 95 1 ( 1.2) 7 ( 7.4) 45 ( 60.8) 2 ( 2.5) 8 ( 10.8)

Seminal vesicles missing/ reduced in size/ abnormal Pnd 21 0 ( 0.0) 0 ( 0.0) 8 ( 12.3) 0 ( 0.0) 7 ( 10.8)

Pnd 95 0 ( 0.0) 5 ( 6.1) 63 ( 85.1) 0 ( 0.0) 39 ( 52.7)

Testes undescended Pnd 21 0 ( 0.0) 0 ( 0.0) 3 ( 4.6) 0 ( 0.0) 4 ( 6.1)

Pnd 95 0 ( 0.0) 1 ( 1.0) 15 ( 20.3) 0 ( 0.0) 10 ( 13.3)

Testes reduced in size Pnd 21 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Pnd 95 1 ( 1.2) 1 ( 1.0) 17 ( 23.0) 0 ( 0.0) 45 ( 60.8)

( Continued) 080555.001.012 50 5/ 5/ 03 50 Vehicle Control ( mg/ kg/ day) VIN ( mg/ kg/ day) DBP ( mg/ kg/ day)

Parameter 0 50 100 100 500 Testes flaccid/ soft Pnd 21 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Pnd 95 0 ( 0.0) 0 ( 0.0) 1 ( 1.4) 0 ( 0.0) 32 ( 43.2)

Males with > 1 gubernuclear wt. b Pnd 21 74 ( 100.0) 82 ( 100.0) 65 ( 100.0) 69 ( 97.2) 59 ( 90.8)

Pnd 95 5.5 ( 6.2) 11 ( 11.6) 13 ( 17.6) 1.0 ( 1.2) 6 ( 8.1)

Males with > 1 cranial suspensory ligamentb Pnd 21 0 ( 0.0) 1 ( 1.32) 0 ( 0.0) 2.2 ( 3.1) 2.2 ( 3.4)

Pnd 95 0 ( 0.0) 0 ( 0.0) 1 ( 1.4) 0 ( 0.0) 6.2 ( 8.1)

Vaginal pouch Pnd 21 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Pnd 95 0 ( 0.0) 2 ( 2.4) 43 ( 58.1) 0 ( 0.0) 1 ( 1.4)

a Data presented as number (%) of males exhibiting the finding. Males may be counted more than once if they exhibited more than one finding.

b The incidences of these findings are taken from Summary Task 13 ( and Text Table 3) for pnd 21, and from Summary Task 20 ( and Text Table 4) for pnd 95.

For the pnd 95 necropsy, approximately 50% of the males and 84% of the litters at the low dose of VIN and all of the males in all of the litters at the high dose of VIN exhibited at least one reproductive malformation. Approximately 90% of the males and 30% of the litters at the low dose of DBP and 92% of the males and 96% of the litters at the high dose of DBP also exhibited at least one reproductive malformation. These values indicate that the number of affected males per affected litter would be 1.0, 2.2, 3.4, 1.0, and 3.1 at 0, 50, and 100 VIN and at 100 and 500 DBP, respectively ( Text Table 7). This information is interpreted to mean that affected males in the low and high dose VIN and the high dose DBP would have been detected at either the pnd 21 or 95 necropsies ( under the current testing guidelines). The incidence at the low dose DBP ( 1.0 affected males per affected litter) implies that detection of males with reproductive system malformations on pnd 21 ( three males examined out of five males present at weaning in the current guidelines) and at pnd 95 ( one male examined out of two males remaining after the pnd 21 necropsy in the 080555.001.012 51 5/ 5/ 03 51 current guidelines) would likely be detected but at an erroneously lower incidence. Since approximately three males/ litter were examined on pnd 21 ( as specified by the 1998 OPPTS testing guideline), the likelihood of detecting effects on pnd 21 is not changed, and the calculation for results on pnd 21 for this protocol, versus the current testing guidelines, was not performed.

The best approach to determine whether examination of more male pups at weaning, and, more importantly, retention of more male offspring to adulthood ( versus the one/ sex/ litter in the standard two generation study design) would allow detection of more male reproductive malformations and higher incidences of these malformations, would be to start with the full offspring data set from this study. Then, repeated random samples of three pups/ litter on pnd 21 and one male/ litter on pnd 95 would be selected ( using mathematical random number generators from SAS ® ) . Approximately 1000 such random samples would be obtained and then analyzed to determine whether retention of more pups/ litter would result in smaller variances ( increased precision) for estimated differences and therefore more significant p values. This repeated analysis is basically a Monte Carlo simulations assessment ( and use of a one tailed t test). The results should provide the probability of detecting significant effects ( for the parameters selected) with the randomly selected three male pups/ litter on pnd 21 and with the randomly selected one male/ litter on pnd 95 versus the probability of detection with the entire data set from this study.

6. Were there differences in the effects on weights of various male reproductive system organs between the two chemicals at the same time point, and within each chemical at the two different time points? Text Table 8 presents the absolute and adjusted ( adjusted for body weight as covariate) weights of all the reproductive organ weights on pnd 21 and 95 for all groups.

For testis weights, effects were more profound from DBP with significant reductions at the low dose DBP ( but not at the low dose VIN) on pnd 21 and greater reductions at the high dose DBP than at the high dose VIN for both pnd 21 and pnd 95.

For epididymal corpus plus caput together and for cauda epididymis, reductions were greater at the high dose DBP than at the high dose VIN for both pnd 21 and pnd 95. Interestingly, the weight of the corpus plus caput was reduced for both the low dose VIN and DBP for pnd 21 but not for pnd 95. The cauda epididymis weight was reduced for the right ( but not left) cauda for the low dose VIN only on pnd 95. The adjusted ( but not the absolute) weight of the right ( but not the left) cauda was also reduced for the low dose DBP only for pnd 95.

Seminal vesicle plus coagulating gland weights were more profoundly reduced at the high dose VIN than at the high dose DBP for both pnd 21 and 95. In addition, the absolute weights were significantly reduced at the low dose VIN ( but not DBP) for pnd 21, but not for pnd 95. 080555.001.012 52 5/ 5/ 03 52 Text Table 7. Evaluation of Detection of Male Reproductive System Malformations in this Protocol Versus in the OPPTS Testing Guidelines Vehicle Control ( mg/ kg/ day) VIN ( mg/ kg/ day) DBP ( mg/ kg/ day)

Parameter 0 50 100 100 500 Pnd 21a No. males examined 74 82 65 71 65 No. litters examined 23 25 22 23 23 Mean number of F1 male offspring examined per litter 3.22 3.28 3.38 3.24 3.54 Pnd 95b No. males examined 82 95 74 81 74 No. litters examined 23 25 22 23 23 Mean number of F1 male offspring examined per litter 3.56 3.80 3.36 3.52 3.22 Incidence of total no. of malformations based on no. F1 males examined Pnd 21 c, d 0 ( 0.0) 21 ( 256) 169 ( 260.0) 1 ( 1.4) 43 ( 66.2)

Pnd 95 c, e 8 ( 9.8) f 95 ( 100.0) 532 ( 718.9) 11 ( 13.6) 237 ( 320.3)

Total number of F1 males with > 1 malformation on pnd 95 c 7 ( 8.5) f 47 ( 49.5) 74 ( 100.0) 7 ( 8.6) 68 ( 91.9)

Total no. of F1 litters with > 1 male with > 1 malformations on pnd 95 c 7 ( 30.4) f 21 ( 84.0) 22 ( 100.0) 7 ( 30.4) 22 ( 95.7)

No. malformed males per affected litters on pnd 95 1.0f 2.24 3.36 1.0 3.09 a The number of F1 male weanlings/ litter examined in this protocol versus the numbers from the 1998 OPPTS testing guideline are approximately equivalent.

b The OPPTS testing guideline specifies one male/ litter retained to adulthood. Therefore, this protocol provides at least three times the power to detect adult male malformations.

c Data presented as number (%).

d Pnd 21 data taken from Summary Table 14 and Individual Animal Tables A 15 and A 17.

e Pnd 95 data taken from Summary Table 21 and Individual Animal Tables A 26 and A 28.

f Predominantly minor effects ( e. g., epididymis and testis reduced in size, prostate abnormal [ hard and brown], etc.) 080555.001.012 53 5/ 5/ 03 53 The whole prostate weight was more profoundly reduced for the high dose VIN than for the high dose DBP for both pnd 21 and 95; it was also significantly reduced as absolute and adjusted weights at the low dose VIN on pnd 21 but not on pnd 95. The ventral lobe weights paralleled the intact gland weights exactly. The dorsal lobe weight was significantly reduced only at the high dose of both VIN and DBP, with the weights at the high dose VIN more reduced than the weights at the high dose DBP on both pnd 21 and 95.

The levator ani bulbocavernosus ( LABC) weights ( absolute and adjusted) were significantly reduced at the low and high dose VIN, and at the high dose ( but not the low dose) DBP, with the reductions greater for VIN than for DBP at both pnd 21 and 95.

Cowper's gland weights were unaffected at the low dose VIN and significantly reduced for absolute weights on both pnd 21 and pnd 95, and for adjusted weights only for pnd 95 at the high dose VIN. For DBP groups, absolute and adjusted Cowper's gland weights were reduced at the high and low doses only for pnd 21 ( and not for pnd 95).

In summary, testes and epididymides weights were more affected ( reduced) by DBP. Seminal vesicle and coagulating gland, prostate, LABC, and Cowper's gland weights were more affected ( reduced) by VIN ( Text Table 8).

In addition to addressing the specific objectives stated above, the data in this study invite comparison of the effects of these two dissimilar antiandrogens.

As an example of this, the kinds and incidences of F1 male reproductive malformations observed at pnd 95 in the low and high dose groups of VIN versus DBP are presented in Text Table 9. The enhanced pnd 95 data resulting from the present study design provide an opportunity to compare male reproductive anomalies that are most likely persistent. There were dose related incidences in both chemicals, with the low dose of VIN more effective ( more malformations observed) than the low dose of DBP ( incidence of specific malformations was less or none). This assessment is obviously related to the doses selected for each chemical and the different mechanisms of action of the two chemicals. VIN is a dicarboximide fungicide, considered an androgen receptor antagonist ( Gray et al., 1994). DBP is an industrial chemical used as a coalescing agent in latex adhesives, as a plasticizer in cellulose plastics, and as a solvent for dyes ( Kavlock et al., 2002). DBP or its monoester, mBuP, does not bind to the androgen receptor ( Kavlock et al., 2002), and it does not act on reproductive development via its peroxisomal proliferating activity ( Ward et al., 1998). Its developmental anti androgenic mechanism is via inhibition of fetal testicular testosterone biosynthesis in the fetal interstital Leydig cells, perhaps by delaying Leydig cell differentiation and resulting in Leydig cell hyperplasia in utero ( Parks et al., 2000). DBP may also act by its inhibition of the transcription of the Insl3 gene also in the Leydig cells ( Kubota et al., 2002). The peptide hormone Insl3 is responsible for the normal development and function of the gubernaculum in fetal male rats. Knockout mice with normal T and MIS 080555.001.012 54 5/ 5/ 03 54 Text Table 8. Comparison of Male Reproductive System Organ Weights on pnd 21 versus pnd 95a Vehicle Control ( mg/ kg/ day) VIN ( mg/ kg/ day) DBP ( mg/ kg/ day)

Parameter 0 50 100 100 500 Testis Right Ab pnd 21   ( 0.1323)   99 ( 0.1198)   999 ( 0.1017)

Right Ab pnd 95   ( 1.7702)   999 ( 1.5284)   999 ( 1.2383)

Right Aj pnd 21   ( 0.1295) 8 ( 0.1334)   9 ( 0.1221) 999 ( 0.1105)

Right Aj pnd 95   ( 1.7680)   999 ( 1.5335)   999 ( 1.2416)

Left Ab pnd 21   ( 0.1305)   99 ( 0.1186)   999 ( 0.0983)

Left Ab pnd 95   ( 1.7688)   999 ( 1.4970)   999 ( 1.3982)

Left Aj pnd 21   ( 0.1281)     99 ( 0.1189) 999 ( 0.1078)

Left Aj pnd 95   ( 1.7649)   999 ( 1.5056)   999 ( 1.4089)

Corpus and Caput Epididymis Right Ab pnd 21   ( 0.0139) 9 ( 0.0125) 999 ( 0.0100) 9 ( 0.0123) 999 ( 0.0088)

Right Ab pnd 95   ( 0.3623)   999 ( 0.3267)   999 ( 0.2405)

Right Aj pnd 21   ( 0.0137) 9 ( 0.0123) 999 ( 0.0105) 9 ( 0.0121) 999 ( 0.0094)

Right Aj pnd 95   ( 0.3617)   999 ( 0.3282)   999 ( 0.2402)

Left Ab pnd 21   ( 0.0137)   999 ( 0.0099) 999 ( 0.0111) 999 ( 0.0084)

Left Ab pnd 95   ( 0.3563)   99 ( 0.3329)   999 ( 0.2548)

Left Aj pnd 21   ( 0.0130)   999 ( 0.0103) 999 ( 0.0108) 999 ( 0.0092)

Left Aj pnd 95   ( 0.3617)   9 ( 0.3282)   999 ( 0.2543)

( Continued) 080555.001.012 55 5/ 5/ 03 55 Cauda Epididymis Right Ab pnd 21   ( 0.0099)   999 ( 0.0069)   999 ( 0.0062)

Right Ab pnd 95   ( 0.2857) 9 ( 0.2719) 999 ( 0.2309)   999 ( 0.1128)

Right Aj pnd 21   ( 0.0097)   999 ( 0.0072)   999 ( 0.0069)

Right Aj pnd 95   ( 0.2854) 9 ( 0.2716) 999 ( 0.2316) 9 ( 0.2735) 999 ( 0.1143)

Left Ab pnd 21   ( 0.0096)   999 ( 0.0076)   999 ( 0.0064)

Left Ab pnd 95   ( 0.2720)   999 ( 0.2263)   999 ( 0.1362)

Left Aj pnd 21   ( 0.0095)   999 ( 0.0079)   999( 0.0070)

Left Aj pnd 95   ( 0.2714)   999 ( 0.2277)   999 ( 0.1363)

Seminal vesicles plus coagulating glands Ab pnd 21   ( 0.0180) 999 ( 0.0145) 999 ( 0.0082)   999 ( 0.0097)

Ab pnd 95   ( 1.4707)   999 ( 0.7097)   999 ( 1.1111)

Aj pnd 21   ( 0.0178) 999 ( 0.0143) 999 ( 0.0085)   999 ( 0.0102)

Aj pnd 95   ( 1.4585)   999 ( 0.7378)   999 ( 1.1186)

Prostate Whole Gland Ab pnd 21   ( 0.0483) 9 ( 0.0441) 999 ( 0.0235)   999 ( 0.0292)

Ab pnd 95   ( 1.0810)   999 ( 0.4226)   999 ( 0.8601)

Aj pnd 21   ( 0.0478) 9 ( 0.0436) 999 ( 0.0249)   999 ( 0.0322)

Aj pnd 95   ( 1.0799)   999 ( 0.4261)   999 ( 0.8689)

Ventral lobe Ab pnd 21   ( 0.0251) 9 ( 0.0225) 999 ( 0.0117)   999 ( 0.0163)

Ab pnd 95   ( 0.6418)   999 ( 0.1897)   999 ( 0.4762)

( Continued)

Aj pnd 21   ( 0.0246) 9 ( 0.0220) 999 ( 0.0127)   999 ( 0.0178)

Aj pnd 95   ( 0.6417)   999 ( 0.1899)   999 ( 0.4812) 080555.001.012 56 5/ 5/ 03 56 Dorsal lobe Ab pnd 21   ( 0.0232)   999 ( 0.0118)   999 ( 0.0126)

Ab pnd 95   ( 0.4393)   999 ( 0.2303)   99 ( 0.3791)

Aj pnd 21   ( 0.0229)   999 ( 0.0126)   999 ( 0.0139)

Aj pnd 95   ( 0.4381)   999 ( 0.2337)   9 ( 0.3829)

LABC Ab pnd 21   ( 0.0562) 99 ( 0.0474) 999 ( 0.0313)   999 ( 0.0419)

Ab pnd 95   ( 1.3577) 999 ( 1.1463) 999 ( 0.5539)   999 ( 0.9411)

Aj pnd 21   ( 0.0551) 99 ( 0.0459) 999 ( 0.0337)   99 ( 0.0456)

Aj pnd 95   ( 1.3508) 999 ( 1.1400) 999 ( 0.5703)   999 ( 0.9547)

Cowper's glands Ab pnd 21   ( 0.0036)   99 ( 0.0021) 9 ( 0.0030) 99 ( 0.0027)

Ab pnd 95   ( 0.1480)   999 ( 0.0688)     Aj pnd 21   ( 0.0035)     9 ( 0.0030) 9 ( 0.0029)

Aj pnd 95   ( 0.1479)   999 ( 0.0697)     a The control values are presented ( in parentheses) for comparison with the values from the treated groups; if there is a statistically significant change, the degree of significance is presented by up/ down arrows and the value is in parentheses. pnd 21 organ weights in grams from Summary Table 13 pnd 95 organ weights in grams from Summary Table 20 Ab = Absolute organ weight in grams Aj = Adjusted organ weight in grams ( adjusted for body weight as covariate). LABC = Levator ani bulbocavernosus ( LABC) muscle 9, 99, 999, statistically significantly reduced at p < 0.05, p< 0.01 and p< 0.001, respectively, by appropriate statistical tests ( see summary tables and text for details).

8, statistically significantly increased at p< 0.05 by appropriate statistical tests ( see summary tables and text for details).   , no statistically significant difference from the control group value. 080555.001.012 57 5/ 5/ 03 57 exhibited bilateral cryptorchidism ( Nef and Parada, 1999; Zimmerman et al., 1999). The gubernaculum attaches to the caudal portion of the testis and the caudal epididymis and to the inguinal ring ( and scrotal sac). It is responsible for the descent of the testis to the inguinal ring in utero and, with androgen, for testicular descent into the scrotal sac during later lactation. When it is absent or abnormal ( e. g., threadlike), the testis( es) do not descend to the inguinal ring during gestation and do not normally descend into the scrotal sacs postnatally. DBP at high oral doses ( 750 mg/ kg/ day, gd 14 pnd 3; Gray et al., 2000) has been shown to cause cryptorchidism with abnormal gubernacula ( Gray and Foster, 2002) in rats. Both VIN ( at both doses) and DBP ( at the high dose) in the present study caused undescended testes, with some of these males exhibiting testes embedded in the abdominal wall at the high doses of VIN ( eight males) and DBP ( two males).

Additionally, differences between the range and severity of effects caused by the two test chemicals are evident ( Text Table 9). VIN causes a low incidence of flaccid/ soft testes or retention of cranial suspensory ligaments in males, while DBP causes a midrange incidence. In contrast, VIN causes a higher incidence of epispadias, hypospadias, missing or small ventral prostate, or vaginal pouch than DBP does. It appears as if VIN more strongly affects those structures under DHT control ( lower reproductive tract, prostate, seminal vesicles, external genitalia). The other findings on Text Table 9 occurred with approximately equal incidences in the high dose groups of both chemicals ( and with a slightly less concordance in the low dose groups of both chemicals).

Text Table 9. Comparison of the Kinds and Incidences of F1 Male Reproductive Malformations by Chemical and by Dose Observed on pnd 95a VIN Dose DBP Dose Finding Low High Low High Cowpers gland missing/ reduced in size ## ##   # #

Epididymides, missing/ reduced in size   # #   # #

LABCb missing/ reduced in size/ malformed   #   #

Hypospadias ## ###   # #

Cleft phallus ## ### # ##

Prostate: Dorsal # ## # ##

Ventral # ###   # #

Seminal vesicles, missing/ misshapen # ###   # #

Epispadias # ##     Vaginal pouch # ##    Testes undescended # ##   # #

Testes embedded in abdominal wall   # #   #

Testes reduced in size # ##   # # 080555.001.012 58 5/ 5/ 03 VIN Dose DBP Dose Finding Low High Low High 58 Testes flaccid/ soft   #   # #

Glans penis not completely detached # ##   # #

Males with > 1 cranial suspensory ligament   #   # #

  = no incidence # = small incidence ( 1 5%), ## = mid range incidence ( 6 74%), ### = high incidence (> 75%)

a PND 95 data taken from Individual Animal Tables 20 and 21.

b LABC = Levator Ani plus Bulbocavernosus Complex 080555.001.012 59 5/ 5/ 03 59 CONCLUSIONS 1. Specific male offspring malformations were detected on pnd 95 but not on pnd 21. Examples include prostate dorsal lobe abnormal/ reduced in size ( VIN, both doses; DBP, high dose), prostate ventral lobe abnormal/ reduced in size ( both compounds, both doses), and epispadias ( VIN, both doses).

2. The incidence of specific male offspring malformations detected on pnd 95 was higher than the incidence of the same malformation observed on pnd 21. Examples include agenesis of all or parts of the epididymis( des) ( high dose of both VIN and DBP), hypospadias ( low dose VIN), and missing/ reduced in size/ abnormal seminal vesicles ( high dose of both VIN and DBP).

3. The effects of VIN on the incidence of hypospadias and ventral prostate agenesis were more obvious at pnd 95 than at pnd 21. This effect was more apparent at the low dose than at the high dose. Specifically, hypospadias was observed in 9.7% vs 15.8% of the animals on pnd 21 and 95, respectively, whereas high dose animals exhibited hypospadias at 80.0% vs 98.6% on pnd 21 and 95, respectively.

4. The effects of DBP ( high dose) on the incidence of epididymal agenesis on pnd 95 was approximately twice that observed on pnd 21, and thus were more obvious on pnd 95 than on pnd 21.

5. Adverse effects on the weight of some male reproductive tissues were more apparent at pnd 95 than on pnd 21. Examples include adjusted right or left testis weight ( high dose VIN), absolute right cauda epididymis weight ( low dose VIN), adjusted right cauda epididymis weight ( low dose VIN and DBP), absolute LABC weight ( low dose VIN), adjusted LABC weight ( high dose VIN and DBP), and absolute and adjusted Cowper's gland weight ( high dose VIN).

6. Adverse reproductive system effects in toto ( structural malformations and other abnormalities) of the low and high doses of VIN and the high dose of DBP on F1 adult male offspring would most likely be statistically significant with either one or three adult males/ litter, and would have been detected with either study design.

7. Adverse reproductive system structural effects in toto at the low dose of DBP on F1 adult male offspring were clearly biologically significant but not necessarily or likely statistically significant, with either one or three adult males/ litter, and provide an example of effects that would not be detected with either study design.

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Zeger, S., K. Y. Liang, and P. S. Albert ( 1988). Models for longitudinal data: a generalized estimating equation approach. Biometrics 44, 1049 1060.

Zimmermann, S., G. Steding, J. M. Emmen, A. O. Brinkman, K. Nayernia, A. F. Holstein, W. Engel, and I. M. Adham ( 1999). Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol. Endocrinol. 13( 5), 681 691. 080555.001.012 64 5/ 5/ 03 64 PROTOCOL DEVIATIONS 1. Nine instances of deviations from the protocol were noted, all involving relative humidity levels in the animal rooms, as follows:

Room Date % RH Duration 303 8/ 15/ 02 71.0 1 hour 303 9/ 17/ 02 85.5 1 hour 403 9/ 17/ 02 80.4 1 hour 403 10/ 9/ 02 85.0 1 hour 404 9/ 17/ 02 85.3 1 hour 404 10/ 9/ 02 78.9 1 hour 503 9/ 17/ 02 78.4 1 hour 503 10/ 9/ 02 76.1 1 hour 407 10/ 9/ 02 79.9 1 hour 2. On 8/ 2/ 02, the lights in the ARF did not go off at 8 pm as scheduled. The lights were turned off manually at 9: 30 pm. Thus, the lights were on 15.5 hours instead of 14. This deviation occurred during the gestational period. Based on the pregnancy rates, successful deliveries, and subsequent rearing of the young, this deviation in the light cycle did not appear to have an adverse effect on the study.

3. Samples of the dose formulations were scheduled to be taken on the first day of dosing on gd 6, pnd 0, 7, 14, and 21. Due to an oversight by the laboratory staff, the samples for pnd 0 and 20 were not taken until the second day of dosing for those time points. Results of the analysis ( see Appendix II) suggest that the dosing formulation had not been compromised by this oversight, and that it did not adversely affect the results of the analysis or the study.

4. The post dosing time for Animal # 98, Rx Code 31036 was inadvertently not recorded on 8/ 16/ 02.

5. The post dosing observation time for 4 females in Rx 01822 was from 1 5 minutes over the 2 hours post dosing time on 8/ 5/ 03.

6. On 8/ 15/ 02, two female pups were found dead and one male pup. External and visceral findings were recorded for one female and one male. Documentation for external and visceral exam for one female was inadvertently not recorded.

7. Presence or absence of cranial suspensory ligament was inadvertently not recorded at necropsy for Male 1348, Rx Code 77491, and Male 1038, Rx Code 31038.

8. Weight of Glans Penis inadvertently not recorded at necropsy for Male # 1044, Rx Code 31038.

9. The presence or absence of gubernacular cords was not recorded at necropsy for Male # 1158, Rx Code 31038.

10. The weight of the Glans Penis was taken at necropsy even though the Glans Penis was noted as partially detached for Male 1156, Rx Code 31038. The weight was not entered. 080555.001.012 65 5/ 5/ 03 65 11. The presence or absence of cranial suspensory ligaments was not recorded at pnd 21 necropsy for 6 pups in Rx Code 77491, for 6 pups in Rx Code 31036, for 9 pups in Rx Code 01822, for 6 pups in Rx Code 24038, and for 7 pups in Rx Code 17225.

12. Animals were ordered at 10 11 weeks of age with a weight range of 200 300 g and should have been ordered at age of 9 10 weeks with a weight range of 200 225 g.

13. Presence or absence of hypospadias not recorded for: dam 10 pup 2, dam 21 pup 2 in Rx 77491; dam 12 pup 5, dam 41 pup 2 in Rx 31036; dam 42 pup 1, dam 23 pup 5 in Rx 01822; dam 7 pup 2, dam 84, pup 4 in Rx 24038; dam 6 pup 1, dam 16 pup 2 in Rx 17725.

14. Presence or absence of epispadias not recorded for: dam 10 pup 2, dam 21 pup 2 in Rx 77491; dam 12 pup 5, dam 41 pup 2 in Rx 31036; dam 3 pup 1, dam 8 pup 3, dam 8 pup 4, dam 13 pup 3, dam 23 pup 3, dam 23 pup 5, dam 42 pup 1, dam 51 pup 3 in Rx 01822; dam 7 pup 2 dam 84 pup 4 in Rx 24038; dam 6 pup 1, dam 16 pup 2, dam 114 pup 2 in Rx 17725.

15. Presence or absence of cleft phallus not recorded for: dam 10 pup 2, dam 21 pup 2 in Rx 77491; dam 12 pup 5, dam 41 pup 2 in Rx 31036; dam 3 pup 1, dam 8 pup 3, dam 8 pup 4, dam 13 pup 3, dam 23 pup 3, dam 23 pup 5, dam 42 pup 1, dam 42 pup 2 in Rx 01822; dam 7 pup 2, dam 84 pup 4 in Rx 24038; dam 6 pup 1, dam 16 pup 2 in Rx 17725.

16. Inguinal regions soiled with urine not recorded for: dam 10 pup 2 in Rx 77491; dam 41 pup 2 in Rx 31036; dam 13 pup 2, dam 13 pup 3, dam 23 pup 5, dam 42 pup 1, dam 51 pup 3 in Rx 01822; dam 7 pup 2, dam 84 pup 4 in Rx 24038; dam 16 pup 2, dam 77 pup 1 in Rx 17725.

17. The length of the right gubernacular cord was not recorded because the cord was inadvertently cut for dam 23 pup 2 in Rx 01822. The length of neither gubernacular cord was not recorded because both were inadvertently cut for dam 115 pup 2 in Rx 17725.

18. F1 males 1266 through 1323 were weighed on 9/ 15/ 02 instead of 9/ 14/ 02 as required. Note: neither body or feed weights were done on 9/ 15/ 02.

19. Presence or absence of gross necropsy findings not recorded for: dam 3 pup 1, dam 42 pup 1 in Rx 01822; dam 24 pup 1 in Rx 24038; dam 6 pup 1, dam 15 pup 2 in Rx 17725.

20. Seminal vesicles were lost prior to weighing for dam 52 pup 1 in Rx 31036.

21. Number of nipples and number of areola not recorded for: dam 23 pup 5 in Rx 01822; dam 34 pup 3 in Rx 24038.

22. Levator ani plus bulbocavernosus lost prior to weighing for dam 109 pup 1 in Rx 24038.

23. One cowpers gland lost prior to weighing for dam 16 pup 1 in Rx 17725.

In the Study Director's professional opinion, these deviations did not affect the study design, performance, or interpretation and are presented for completeness.

____________________________________ ___________________

Julia D. George, Ph. D. Date Study Director 080555.001.012 66 5/ 5/ 03 66 Table 1. Analyses of Dose Formulationsa Test chemical RTI Rx Code RTI Color Code Battelle Sample Code Sample Typeb Nominal Concentration ( mg/ ml) Analytical Concentration ( mg/ ml) c Mean % of Nominal + RSDd vehicle NA NA 2 10 A preship 0 NDe

DBP NA NA 2 10 b preship 20 18.8 94.1 ± 2.52 2 10 c preship 100 94.2 94.3 ± 2.09 Vinclozolin NA NA 2 10 d preship 10 9.77 97.7 ± 2.28 NA NA 2 10 e preship 20 19.5 97.5 ± 1.89 DBP 24038 GD6 purple 1778 12 1 first dosing day 20 19.0 94.4 ± 2.01 20438 PND0 purple 1778 12 2 first dosing day 20 18.3 20438 PND7 purple 1778 12 3 first dosing day 20 18.7 20438 PND14 purple 1778 12 4 first dosing day 20 19.0 20438 PND21 purple 1778 12 5 first dosing day 20 19.3 17725 GD6 red 1778 13 1 first dosing day 100 93.8 94.5 ± 2.16 17725 PND0 red 1778 13 2 first dosing day 100 93.6 17725 PND7 red 1778 13 3 first dosing day 100 97.7 17725 PND14 red 1778 13 4 first dosing day 100 92.3 17725 PND21 red 1778 13 5 first dosing day 100 95.0 Vinclozolin 31036 GD6 green 1779 86 1 first dosing day 10 9.48 94.6 ± 1.26 31036 PND0 green 1779 86 2 first dosing day 10 9.27 31036 PND7 green 1779 86 3 first dosing day 10 9.58 31036 PND14 green 1779 86 4 first dosing day 10 9.47 31036 PND21 green 1779 86 5 first dosing day 10 9.51 01822 GD6 orange 1779 87 1 first dosing day 20 18.7 93.6 ± 1.76 01822 PND0 orange 1779 87 2 first dosing day 20 18.9 01822 PND7 orange 1779 87 3 first dosing day 20 18.8 ( Continued) 080555.001.012 67 5/ 5/ 03 67 Test Chemical RTI Rx Code RTI Color Code Battelle Sample Code Sample Typeb Nominal Concentration ( mg/ ml) Analytical Concentration ( mg/ ml) c Mean % of Nominal + RSDd 01822 PND14 orange 1779 87 4 first dosing day 20 18.1 01822 PND21 orange 1779 87 5 first dosing day 20 19.0 DBP 10303 05 01 NA 1778 10 1 postdose 20 18.8 94.3 ± 0.49 10303 05 01 NA 1778 10 2 postdose 20 18.9 10303 06 01 NA 1778 11 1 postdose 100 83.5 94.1 ± 1.36 10303 06 01 NA 1778 11 1 R 1f postdose 100 93.8 10303 06 01 NA 1778 11 1 R 2 postdose 100 95.2 10303 06 01 NA 1778 11 1 R 3 postdose 100 95.9 10303 06 01 NA 1778 11 2 postdose 100 93.2 Vinclozolin 10303 07 01 NA 1779 84 1 postdose 10 8.79 95.8 ± 3.34 10303 07 01 NA 1779 84 1 R 1 postdose 10 9.75 10303 07 01 NA 1779 84 1 R 2 postdose 10 9.95 10303 07 01 NA 1779 84 1 R 3 postdose 10 9.71 10303 07 01 NA 1779 84 2 postdose 10 9.35 10303 08 01 NA 1779 85 1 postdose 20 18.2 94.8 ± 5.79 10303 08 01 NA 1779 85 2 postdose 20 17.7 10303 08 01 NA 1779 85 2 R 1 postdose 20 19.5 10303 08 01 NA 1779 85 2 R 2 postdose 20 19.5 10303 08 01 NA 1779 85 2 R 3 postdose 20 20.1 ( Continued) 080555.001.012 68 5/ 5/ 03 68 a Dosing solutions were formulated on 7/ 9/ 02 in corn oil vehicle for administration at 5.0 ml/ kg. The doses were therefore 0, 50, and 100 mg/ kg/ day vinclozolin, and 100, and 500 mg/ kg/ day DBP.

b Samples were taken prior to shipping from Battelle to RTI ( preship), on the first day dosing for gd 6 and pnd 7 and 14, on the second day of dosing on pnd 0 and 20, and after dosing was completed ( postdose).

c n= 3 for individual determinations.

d Data are presented as mean % (% relative standard deviation).

e ND = not detected; estimated limit of detection is 0.57 microg/ ml for DBP and 0.11 microg/ ml for vinclozolin.

f Analyses labeled " R" were reanalyses of samples for which less than 90% of the nominal concentration was recovered.


[Federal Register Volume 85, Number 247 (Wednesday, December 23, 2020)]
[Notices]
[Pages 83968-83971]
[FR Doc No: 2020-28353]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2010-N-0155]

Agency Information Collection Activities; Proposed Collection;
Comment Request; Veterinary Feed Directive

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
an opportunity for public comment on the proposed collection of certain
information by the Agency. Under the Paperwork Reduction Act of 1995
(PRA), Federal Agencies are required to publish notice in the Federal
Register concerning each proposed collection of information, including
each proposed extension of an existing collection of information, and
to allow 60 days for public comment in response to the notice. This
notice solicits comments on veterinary feed directive regulation.

DATES: Submit either electronic or written comments on the collection
of information by February 22, 2021.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before February 22, 2021. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of February 22, 2021. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2010-N-0155 for ``Veterinary Feed Directive.'' Received comments,
those filed in a timely manner (see ADDRESSES), will be placed in the
docket and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management

Staff. If you do not wish your name and contact information to be made
publicly available, you can provide this information on the cover sheet
and not in the body of your comments and you must identify this
information as ``confidential.'' Any information marked as
``confidential'' will not be disclosed except in accordance with 21 CFR
10.20 and other applicable disclosure law. For more information about
FDA's posting of comments to public dockets, see 80 FR 56469, September
18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: JonnaLynn Capezzuto, Office of
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852,<PHONE_NUMBER>,
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3521), Federal
Agencies must obtain approval from the Office of Management and Budget
(OMB) for each collection of information they conduct or sponsor.
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes Agency requests or requirements that members of
the public submit reports, keep records, or provide information to a
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A))
requires Federal Agencies to provide a 60-day notice in the Federal
Register concerning each proposed collection of information, including
each proposed extension of an existing collection of information,
before submitting the collection to OMB for approval. To comply with
this requirement, FDA is publishing notice of the proposed collection
of information set forth in this document.
    With respect to the following collection of information, FDA
invites comments on these topics: (1) Whether the proposed collection
of information is necessary for the proper performance of FDA's
functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.

Veterinary Feed Directive

OMB Control Number 0910-0363--Extension

    Section 504 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
354) establishes a regulatory category for certain new animal drugs
called veterinary feed directive (VFD) drugs. The VFD regulation is set
forth at Sec.  558.6 (21 CFR 558.6). VFD drugs are new animal drugs,
intended for use in or on animal feed, which are limited to use under
the professional supervision of a licensed veterinarian in the course
of the veterinarian's professional practice (Sec.  558.6(b)(6)). An
animal feed containing a VFD drug or a combination VFD drug may be fed
to animals only by or upon a lawful VFD issued by a licensed
veterinarian (Sec.  558.6(a)(1)).
    Veterinarians issue three copies of the VFD: One for their own
records, one for their client, and one to the client's VFD feed
distributor (Sec.  558.6(a)(4) and (b)(8) and (9)). The VFD includes
information about the number and species of animals to receive feed
containing one or more of the VFD drugs (Sec.  558.6(b)(3)), along with
other information required under Sec.  558.6. All distributors of
medicated feed containing VFD drugs must notify FDA of their intent to
distribute such feed and must maintain records of the receipt and
distribution of all medicated feeds containing VFD drugs.
    The VFD regulation ensures the protection of public health while
enabling animal producers to obtain and use needed drugs as efficiently
and cost effectively as possible. The VFD regulation is tailored to the
unique circumstances relating to the distribution and use of animal
feeds containing a VFD drug.
    We will use the information collected to assess compliance with the
VFD regulation. The required recordkeeping and third-party disclosures
provide assurance that the medicated feeds will be safe and effective
for their labeled conditions of use and that edible products from
treated animals will be free of unsafe drug residues.

A. Reporting Requirements

    Description of Respondents: VFD Feed Distributors and VFD Drug
Sponsors.
    A distributor of animal feed containing a VFD drug must notify FDA
prior to the first time it distributes the VFD feed (Sec.
558.6(c)(5)). This notification is required one time per distributor
and must include the information set forth in Sec.  558.6(c)(5). In
addition, a distributor must notify FDA within 30 days of any change in
ownership, business name, or business address (Sec.  558.6(c)(6)).
Additional reporting burdens for current VFD drug sponsors are approved
under OMB control numbers 0910-0032 (New Animal Drug Application) and
0910-0669 (Abbreviated New Animal Drug Applications).

                                 Table 1--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                   Number of
    21 CFR section/activity        Number of     responses per   Total annual    Average burden     Total hours
                                  respondents     respondent       responses      per response
----------------------------------------------------------------------------------------------------------------
558.6(c)(5) requires a                     188               1             188  0.125 (7                      24
 distributor to notify FDA                                                       minutes).
 prior to the first time it
 distributes a VFD feed.
558.6(c)(6) requires a                     192               1             192  0.125 (7                      24
 distributor to notify FDA                                                       minutes).
 within 30 days of any change
 in ownership, business name,
 or business address.
                               ---------------------------------------------------------------------------------
Total.........................  ..............  ..............  ..............  ................              48
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

B. Recordkeeping Requirements

    Description of Respondents: VFD Feed Distributors, Food Animal
Veterinarians, and Clients (Food Animal Producers).
    As stated previously, veterinarians issue three copies of the VFD:
one for their own records, one for their client, and one to the
client's VFD feed distributor. All involved parties (veterinarian,
distributor, and client) must retain a copy of the VFD for 2 years
(Sec.  558.6(a)(4)). In addition, VFD feed distributors must also keep
receipt and distribution records of VFD feeds they manufacture and make
them available for inspection by FDA for 2 years (Sec.  558.6(c)(3)).
If a distributor manufactures the VFD feed, the distributor must also
keep VFD manufacturing records for 1 year in accordance with 21 CFR
part 225 and such records must be made available for inspection and
copying by FDA upon request (Sec.  558.6(c)(4)). These record
requirements are currently approved under OMB control number 0910-0152,
``Current Good Manufacturing Practice Regulations for Medicated Feed.
'' Distributors may distribute VFD feeds to another distributor only if
the originating distributor (consignor) first obtains a written
acknowledgment letter from the receiving distributor (consignee) before
the feed is shipped. Such letters, like VFDs, are also subject to a 2-
year record retention requirement (Sec.  558.6(c)(8)).

                               Table 2--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                   Number of                     Average burden
    21 CFR section/activity        Number of      records per    Total annual          per          Total hours
                                 recordkeepers   recordkeeper       records       recordkeeping
----------------------------------------------------------------------------------------------------------------
558.6(a)(4); required                   13,050           114.9       1,500,000  0.0167 (1                 25,050
 recordkeeping by                                                                minute).
 veterinarians and producers.
558.6(a)(4), (c)(3), (4), and            9,635           545.1       5,252,038  0.0167 (1                 87,709
 (8); required recordkeeping                                                     minute).
 by distributors.
                               ---------------------------------------------------------------------------------
Total.........................  ..............  ..............  ..............  ................         112,759
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

C. Third-Party Disclosure Requirements

    Description of Respondents: VFD Drug Sponsors, Food Animal
Veterinarians, VFD Feed Distributors, and Clients.
    FDA regulation requires that veterinarians include the information
specified at Sec.  558.6(b)(3) through (5) on the VFD. Additional
requirements relating to the VFD are specified at Sec.  558.6(b)(7)
through (9). A distributor may only distribute a VFD feed to another
distributor for further distribution if the originating distributor
(consignor) first obtains a written acknowledgment letter from the
receiving distributor (consignee) before the feed is shipped (Sec.
558.6(c)(8)).

                           Table 3--Estimated Annual Third-Party Disclosure Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                  Number of
   21 CFR section/activity        Number of    disclosures per   Total annual    Average burden     Total hours
                                 respondents      respondent      disclosures    per disclosure
----------------------------------------------------------------------------------------------------------------
558.6(b)(3)-(5) and (b)(7)-             3,050              246         750,000  0.125 (7                  93,750
 (9); required disclosures                                                       minutes).
 when a veterinarian issues a
 VFD.
558.6(c)(8); required                   1,000                5           5,000  0.125 (7                     625
 disclosure (acknowledgment                                                      minutes).
 letter) from one distributor
 to another.
                              ----------------------------------------------------------------------------------
Total........................  ..............  ...............  ..............  ................          94,375
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    The VFD regulation also contains several labeling provisions that
are exempt from OMB review and approval under the PRA because they are
a ``public disclosure of information originally supplied by the Federal
government to the recipient for the purpose of disclosure to the
public'' (5 CFR 1320.3(c)(2)) and therefore do not constitute a
``collection of information'' under the PRA (44 U.S.C. 3501, et seq.).
All labeling and advertising for VFD drugs, combination VFD drugs, and
feeds containing VFD drugs or combination VFD drugs must prominently
and conspicuously display the following cautionary statement:
``Caution: Federal law restricts medicated feed containing this
veterinary feed directive (VFD) drug to use by or on the order of a
licensed veterinarian'' (Sec.  558.6(a)(6)). In addition, the
veterinarian must ensure that the following statement is included on
the VFD (Sec.  558.6(b)(3)(xiii)): ``Use of feed containing this
veterinary feed directive (VFD) drug in a manner other than as directed
on the labeling (extralabel use) is not permitted. ``
    The veterinarian may restrict VFD authorization to only include the
VFD drug(s) cited on the VFD or such authorization may be expanded to
allow the use of the cited VFD drug(s) along with one or more over-the-
counter animal drugs in an approved, conditionally approved, or indexed
combination VFD drug (Sec.  558.6(b)(6)). The veterinarian must affirm
his or her intent regarding combination VFD drugs by including one of
the following statements on the VFD:
    1. ``This VFD only authorizes the use of the VFD drug(s) cited in
this order and is not intended to authorize the use of such drug(s) in
combination with any other animal drugs'' (Sec.  558.6(b)(6)(i)).

    2. ``This VFD authorizes the use of the VFD drug(s) cited in this
order in the following FDA-approved, conditionally approved, or indexed
combination(s) in medicated feed that contains the VFD drug(s) as a
component. '' (List specific approved, conditionally approved, or
indexed combination medicated feeds following this statement.) (Sec.
558.6(b)(6)(ii)).
    3. ``This VFD authorizes the use of the VFD drug(s) cited in this
order in any FDA-approved, conditionally approved, or indexed
combination(s) in medicated feed that contains the VFD drug(s) as a
component'' (Sec.  558.6(b)(6)(iii)).
    These labeling statements are not subject to review by OMB because,
as stated previously, they are a ``public disclosure of information
originally supplied by the Federal government to the recipient for the
purpose of disclosure to the public'' (5 CFR 1320.3(c)(2)) and
therefore do not constitute a ``collection of information'' under the
PRA (44 U.S.C. 3501, et seq.).
    Based on a review of the information collection since our last
request for OMB approval, there has been a significant increase in the
number of VFD distributors due to changes to the VFD regulations that
were implemented in 2017. Since implementation, the number of approved
VFD drugs has increased.

    Dated: December 17, 2020.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2020-28353 Filed 12-22-20; 8:45 am]
BILLING CODE 4164-01-P