[Federal Register Volume 79, Number 117 (Wednesday, June 18, 2014)]
[Notices]
[Pages 34744-34746]
[FR Doc No: 2014-14250]

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ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OPP-2013-0049; FRL-9912-14]

Notice of Receipt of a Request To Voluntarily Cancel Certain
Pesticide Registrations

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: In accordance with the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA), EPA is issuing a notice of receipt of a
request by a registrant to voluntarily cancel certain pesticide
registrations. EPA intends to issue a cancellation order granting this
request at the close of the comment period for this announcement. If
this request is granted, any sale, distribution, or use of products
listed in this notice will be permitted after the registrations have
been cancelled only if such sale, distribution, or use is consistent
with the terms as described in the cancellation order.

DATES: Comments must be received on or before July 18, 2014.

ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2013-0049, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the online instructions for submitting comments. Do not submit
electronically any information you consider to be Confidential Business
Information (CBI) or other information whose disclosure is restricted
by statute.
     Mail: OPP Docket, Environmental Protection Agency Docket
Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC
20460-0001.
    Submit written withdrawal request by mail to: Pesticide Re-
Evaluation Division (7508P), Office of Pesticide Programs,
Environmental Protection Agency, 1200 Pennsylvania Ave. NW.,
Washington, DC 20460-0001. ATTN: Rusty Wasem.
     Hand Delivery: To make special arrangements for hand
delivery or delivery of boxed information, please follow the
instructions at http://www.epa.gov/dockets/contacts.html. Additional
instructions on commenting or visiting the docket, along with more
information about dockets generally, is available at http://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Rusty Wasem, Pesticide Re-Evaluation
Division (7508P), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460-
0001; telephone number:<PHONE_NUMBER>; email address:
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    This action is directed to the public in general, and may be of
interest to a wide range of stakeholders including environmental, human
health, and agricultural advocates; the chemical industry; pesticide
users; and members of the public interested in the sale, distribution,
or use of pesticides.

B. What should I consider as I prepare my comments for EPA?

    1. Submitting CBI. Do not submit this information to EPA through
regulations.gov or email. Clearly mark the part or all of the
information that you claim to be CBI. For CBI information in a disk or
CD-ROM that you mail to EPA, mark the outside of the disk or CD-ROM as
CBI and then identify electronically within the disk or CD-ROM the
specific information that

is claimed as CBI. In addition to one complete version of the comment
that includes information claimed as CBI, a copy of the comment that
does not contain the information claimed as CBI must be submitted for
inclusion in the public docket. Information so marked will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2.
    2. Tips for preparing your comments. When submitting comments,
remember to:
    i. Identify the document by docket ID number and other identifying
information (subject heading, Federal Register date and page number).
    ii. Follow directions. The Agency may ask you to respond to
specific questions or organize comments by referencing a Code of
Federal Regulations (CFR) part or section number.
    iii. Explain why you agree or disagree; suggest alternatives and
substitute language for your requested changes.
    iv. Describe any assumptions and provide any technical information
and/or data that you used.
    v. If you estimate potential costs or burdens, explain how you
arrived at your estimate in sufficient detail to allow for it to be
reproduced.
    vi. Provide specific examples to illustrate your concerns and
suggest alternatives.
    vii. Explain your views as clearly as possible, avoiding the use of
profanity or personal threats.
    viii. Make sure to submit your comments by the comment period
deadline identified.

II. What action is the Agency taking?

    This notice announces receipt by the Agency of a request from
Reckitt Benckiser LLC (Reckitt) to cancel 12 pesticide products
registered under FIFRA section 3. These registrations are listed in
sequence by registration number in Table 1 of this unit. The request
for voluntary cancellation was conditioned on January 1, 2015 being the
earliest effective date of cancellation, the Agency allowing certain
sale and distribution of existing stocks of canceled product, and the
Agency approving an alternative inert ingredient in the products prior
to cancellation. EPA agreed to these conditions contingent upon:
    1. Reckitt limiting further production of the 12 pesticide
products, in the period prior to the effective date of cancellation, to
filling orders from existing customers in accordance with shelf-set
agreements and other contracts already in effect as of May 29, 2014;
    2. Quantity limits on Reckitt's production of the 12 pesticide
products; and
    3. Reckitt submitting periodic reports on its production, sales and
inventory of the 12 pesticide products.
    At the end of the 30-day comment period, EPA intends to issue an
order in the Federal Register canceling all of the affected
registrations in a manner consistent with the conditional nature of the
request for cancellation. Reckitt will be permitted to sell and
distribute existing stocks to its existing customers until March 31,
2015. During this time period, Reckitt will also be permitted to ship
product for the purpose of returning material back to Reckitt or for
the purpose of disposal. Reckitt will be permitted to sell and
distribute existing stocks after March 31, 2015 only for the limited
purposes of returning material back to Reckitt or for disposal. The
sale and distribution of existing stocks by persons other than Reckitt
(e.g., distributors, retailers) will be permitted until such stocks are
exhausted. Users will be allowed to use existing stocks until such
stocks are exhausted, provided that such use is consistent with the
terms of the previously approved labeling on, or that accompanied, the
canceled product.

                          Table 1--Registrations With Pending Requests for Cancellation
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           Registration No.                           Product name                         Chemical name
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3282-3................................  D-Con Concentrate Kills Rats & Mice.....  Warfarin.
3282-4................................  D-Con Ready Mixed Kills Rats & Mice.....  Warfarin.
3282-9................................  D-Con Mouse Prufe Kills Mice............  Warfarin.
3282-15...............................  D-Con Pellets Kills Rats & Mice.........  Warfarin.
3282-65...............................  D-Con Mouse Prufe II....................  Brodifacoum.
3282-66...............................  D-Con Pellets Generation II.............  Brodifacoum.
3282-74...............................  D-Con Bait Pellets II...................  Brodifacoum.
3282-81...............................  D-Con Ready Mixed Generation II.........  Brodifacoum.
3282-85...............................  D-Con Mouse-Prufe III...................  Difethialone.
3282-86...............................  D-Con Bait Pellets III..................  Difethialone.
3282-87...............................  D-Con II Ready Mix Baitbits III.........  Difethialone.
3282-88...............................  D-Con Bait Packs III....................  Difethialone.
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    Table 2 of this unit includes the address of Reckitt.

          Table 2--Registrant Requesting Voluntary Cancellation
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          EPA company No.                 Company name and  address
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3282..............................  Reckitt Benckiser LLC,
                                    399 Interpace Parkway,
                                    Parsippany, NJ 07054.
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III. What is the Agency's authority for taking this action?

    Section 6(f)(1) of FIFRA provides that a registrant of a pesticide
product may at any time request that any of its pesticide registrations
be canceled. FIFRA further provides that, before acting on the request,
EPA must publish a notice of receipt of any such request in the Federal
Register.
    Section 6(f)(1)(B) of FIFRA requires that before acting on a
request for voluntary cancellation, EPA must provide a 30-day public
comment period on the request for voluntary cancellation or use
termination. In addition, FIFRA section 6(f)(1)(C) requires that EPA
provide a 180-day comment period on a request for voluntary
cancellation or termination of any minor agricultural use before
granting the request, unless:
    1. The registrants request a waiver of the comment period, or
    2. The EPA Administrator determines that continued use of the
pesticide would pose an unreasonable adverse effect on the environment.
    The products listed in Table 1 of Unit II. do not represent minor
agricultural uses. Therefore, the requests are not eligible for a 180-
day comment period.

Accordingly, EPA will provide a 30-day comment period on the requests.

IV. Provisions for Disposition of Existing Stocks

    Existing stocks are those stocks of canceled pesticide products
that are in the United States and that were appropriately packaged,
labeled, and released for shipment prior to the effective date of
cancellation of the underlying registration. It is EPA's intention to
issue a cancellation order treating existing stocks after cancellation
of the registrations identified in Table 1 of Unit II. as follows:
    1. Cancellation of the registrations will not become effective
before January 1, 2015.
    2. Reckitt will be permitted to sell and distribute existing stocks
to its existing customers until March 31, 2015. During this time
period, Reckitt will also be permitted to ship product for the purpose
of returning material back to Reckitt or for the purpose of disposal.
    3. Reckitt will be permitted to sell and distribute existing stocks
after March 31, 2015 only for the limited purposes of returning
material back to Reckitt or for disposal.
    4. The sale and distribution of existing stocks by persons other
than Reckitt (e.g., distributors, retailers) will be permitted until
such stocks are exhausted. Users will be allowed to use existing stocks
until such stocks are exhausted, provided that such use is consistent
with the terms of the previously approved labeling on, or that
accompanied, the canceled product.

List of Subjects

    Environmental protection, Pesticides and pests.

    Dated: June 11, 2014.
Richard P. Keigwin, Jr.,
Director, Pesticide Re-Evaluation Division, Office of Pesticide
Programs.
[FR Doc. 2014-14250 Filed 6-17-14; 8:45 am]
BILLING CODE 6560-50-P


1 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM TXR#: 0051477 DATE: February 19, 2003 SUBJECT: Imazalil: Report of the Mechanism of Toxicity Assessment Review Committee ( MTRAC)

FROM: Abdallah Khasawinah, Ph. D., Toxicologist Reregistration Branch 4 Health Effects Division ( 7509C)

THROUGH: Pauline Wagner, Co Chair and Karl Baetcke, Co Chair Mechanism of Toxicity Assessment Review Committee ( MTRAC) Health Effects Division ( 7509C)

TO: Ray Kent, Branch Chief Reregistration Branch 4 Health Effects Division ( 7509C)

PC Code: 111901 cc: Anna Lowit ( RRB2), Susan Hummel ( RRB4), Cecelia Watson ( SRRD)

On January 21, 2003, the Health Effects Division ( HED) Mechanism of Toxicity Science Assessment Review Committee ( MTRAC) reviewed the recommendations of the toxicology reviewer for imazalil with regard to the proposed mechanism of action in causing liver tumors in male mice. The conclusions drawn at this meeting are presented in this report. 2 Action: The Mechanism of Toxicity Assessment Review Committee ( MTRAC) met on January 21, 2003 to evaluate the mechanistic and other relevant data to determine whether the liver tumorigenic effects of imazalil in the mouse liver are related to its effects on hepatic cell proliferation. The mechanistic data included a cell proliferation study in male CD 1 mice submitted by the Registrant ( MRID 45713701 and its addendums).

Conclusions: Based on the weight of evidence and MRID 45713701 findings, the committee concluded that the new data does not support a mechanism of action to explain the tumorigenic effects of imazalil in the rodent liver. The committee explained its decision on the following:

( 1) No hepatic cell proliferation was demonstrated in rat or the new mouse study. In the mouse, there was a decline of cell proliferation as measured by Bromo deoxyuridine ( BrdU) or Proliferating Cell Nuclear Antigen ( PCNA) staining.

( 2) BrdU is the preferred method for measuring cell proliferation. The mouse study findings were variable. BrdU staining occurred only in the control and the high dose animals but none in the intermediate doses.

( 3) PCNA staining ( not the best method for measuring cell proliferation) yielded also variable results with a declining trend suggesting inhibition of cell proliferation.

( 4) Even if hepatic cell proliferation was demonstrated, there is currently no scientific support to link it to tumorigenic effects.

The Committee concluded, therefore, that the new data in the mouse does not demonstrate a mechanism of action to explain the tumoregeinc effects of imazalil in rodents. 3 Committee Members in Attendance Members who were present and gave concurrence to this report were Karl Baetcke, Pauline Wagner, William Burnam and Anna Lowit.

Members in Absentia: Vicki Dellarco Also in Attendance were: Ray Kent Data Evaluation / Report Presentation Abdallah Khasawinah, Ph. D. Toxicologist Reregistration Branch 4 Health Effects Division ( HED) 4 Cl Cl O N N CH 2 I. BACKGROUND INFORMATION A. Introduction: Imazalil [ 1( 2( 2,4 dichlorophenyl) 2( 2 propenyloxy) ethyl) 1H imidazole] is a systemic fungicide registered for post harvest treatment of citrus fruits and bananas ( import tolearance only) and for seed treatment of barley and wheat prior to planting. Imazalil is also used in egg handling facilities. Imazalil is known as Enilconazole in veterinary medicine. The reregistration of imazalil is being supported by Janssen Pharmaceutica and Makhteshim Agan of North America Inc.

Imazalil is used to prevent, treat and control diseases caused by a variety of pathogenic organisms ( fungi), which include ( but are not limited to) Aspergillus in egg handling facilities and equipment, blue mold in citrus fruits and Fusarium in wheat and barley seeds. imazalil inhibits cytochrome P 450 dependent biosynthesis of ergosterol, an essential component of the cell membrane of the fungi cells.

B. Chemical Identification Chemical Structure:

Molecular formula: C 14 H 14 Cl 2 N 2 O Molecular weight: 297.18 Synonyms: ( R23979), Enilconazole, Fungaflor, Fecundal, Fungazil Melting point: 52.7

C Vapor pressure ( 20

C): 1.2x10 6 mm Hg Water solubility ( 20

C): 180  293 ppm Log K ow: 3.82 Solubility: very soluble in methanol, ethanol, 2 propanol, xylene, benzene, toluene, and solutions of mineral and organic acids. Soluble in n heptane, hexane, and petroleum ether CAS Registry No.: 35554 44 0 PC Code: 111901 5 C. Toxicity Summary:

Imazalil is placed in Category II, III, and IV for oral, dermal and inhalation toxicity, respectively. It is highly irritating to rabbit eye ( Category I), but is not a skin irritant ( Category IV) or a dermal sensitizer. Imazalil ( EC formulation) is readily absorbed by the rat skin with a 41 % absorption of the applied dose within 10 hours of application.

The thyroid and the liver are primary target organ for Imazalil toxicity. Enlarged livers were seen in rabbits after 6 days of dermal application at 250 mg/ kg/ day ( MRID 42085201), increased liver weights and liver to body weight ratios, increased centrilobular swollen hepatocytes and increased vacuolization in hepatocytes after one month of dietary treatment at 32.1 mg/ kg/ day in rats ( MRID 43965704), and similar histopathologic effects in mice ( at 38.6 mg/ kg/ day in the diet ( MRID 43222601). In a chronic dietary rat study, there was an increased incidence of intra cytoplasmic inclusion bodies of hepatocytes, increased severity of hepatocyte vacuolization as well as bile duct proliferation at 15.5 mg/ kg/ day ( MRID 47026101). Liver histopathologic lesions were also seen in a 23 month study in mice at 28.0 mg/ kg/ day ( 42972001). Increased liver vacuolization was also seen in male rats in a 2 generation reproduction study at 80 mg/ kg/ day ( MRID 42570701 & 42949402). Increased liver weights were seen in dogs treated for one year at 20 mg/ kg/ day ( 41328802). The absolute and relative weight of thyroid glands was increased in male rats fed Imazalil for two years at  65.8 mg/ kg/ day ( MRID 44858001). Microscopic changes were also seen in the affected thyroids.

Carcinogenicity studies in rodents indicate that Imazalil was carcinogenic to male Swiss albino mice and Wistar rats, based on significant increase in liver adenomas and combined adenomas/ carcinomas. In rats there was also increased incidence of combined thyroid follicular cell adenomas/ carcinomas. The HED CPRC ( 1994) and CARC ( 1998) classified Imazalil a Group C carcinogen and recommended a linear low dose approach ( Q 1 *) for quantification of human cancer risk. The CARC ( 1999) reclassified imazalil under the July 1999 Draft Guidelines for Carcinogenic Assessment into the category " Likely to be carcinogenic in humans". The Committee reaffirmed its earlier decision by recommending a linear low dose ( Q 1 *) extrapolation for quantification of human cancer risk. This extrapolation is supported by the lack of confirmation of the mode of action. The most potent unit risk , Q 1 *( mg/ kg/ day) 1 for imazalil based on male mouse liver adenoma and/ or carcinoma combined tumor rates is 6.2 x 10 2 in human equivalents ( HED Doc 013842).

Imazalil was non mutagenic both in vivo and in vitro mutagenicity assays ( Salmonella test, chromosomal aberration using hyman lymphocytes or Chinese hamster V79 cells, micronucleus test, Unscheduled DVA synthesis assay).

The registrant has conducted several non guideline studies on the enzyme induction properties of imazalil and its BrdU immunostaining and PCNA staining of hepatocytes. These studies are summarized in the following table. 6 MRID Study Summary 45160101 ; male rats 0, 400, 1200 or 3200 ppm dietary; ( 0, 40.8, 123 or 328 mg/ kg/ day); phenobarbital 1200 ppm ( 126 mg/ kg/ day), in the diet for 4 weeks followed by a 4 or 9 week recovery. The study authors contend that the primary effect of imazalil is on the liver causing microsomal enzyme induction resulting in hepatocellular hypertrophy. Enhanced hepatic metabolism of the thyroid hormone ( T4) was demonstrated in this study by increased hepatic UDP glucuronyl transferase activity with Lthyroxine which caused decreased serum levels. The decreased serum levels of the T4 hormone causes an increased release of TSH. The higher serum TSH levels, in turn may lead to thyroid follicular cell hypertrophy, hyperplasia and neoplasia.

45376801 Supplement to 45160101 Same conditions Imazalil affected the thyroid peroxidase and liver enzyme activities in a similar way as phenobarbital. Liver aniline hydroxylase, N ethylmorphine N demethylase, 7 pentoxyresorufin O dealkylase, and UDP glucuronyltransferase, and thyroid peroxidase activities were all induced during the imazalil treatment. The largest inductive effect of both imazalil and phenobarbital was observed on the 7 Pentoxyresorufin O dealkylase activity ( 1,600  2,700% of the control for imazalil and 43,500% of the control for phenobarbital at week 4 of treatment). The 5

monodeiodinase was not induced and was slightly depressed by either the imazalil or the phenobarbital treatment.

The supplementary information demonstrated that imazalil had a clear inductive effect on 7 ethoxyresorufin O dealkylase activity in a dose related manner ( 157%, 296% 400% relative to the control at 400, 1200 and 3200 ppm dietary feeding levels of imazalil for 4 weeks, respectively) in a fashion similar to phenobarbital ( positive control used in the study). However, the lauric acid hydroxylase activity was only slightly induced by both imazalil and phenobarbital.

The enzyme activities in the imazalil and phenobarbital treated rats returned to normal during the 4  9 week recovery periods.

45362602 supplement to 45160101 same conditions evaluated for the percentage of labeled cells stained immunocytochemically for Proliferating Cell Nuclear Antigen ( PCNA). Liver sections from ten rats per group were examined at the end of the treatment period and from ten per group after a 4 week recovery period. No treatment effect was observed at either time point; therefore, administration of imazalil had no effect on cell proliferating potential of the rat liver.

43222601, Swiss mice 0, 50, 200 or 600 ppm for 1 or 3 months The LOAEL in this study is 200 ppm ( 38.6 and 45.6 mg/ kg/ day in males and females respectively) and is based on increased incidence and severity of histopathologic effects, increased microsomal protein and increased microsomal cytochrome P450 content in the livers of both males and females. The NOAEL in this study is 50 ppm ( 9.5 and 11.3 mg/ kg/ day in males and females, respectively).

45362601 Supplement to 43222601, Hepatocytes were evaluated for the percentage of labeled cells stained immunochemically for Proliferating Cell Nuclear Antigen ( PCNA). At the end of the 13 week treatment period, the labeling index for all treated groups was similar to that of controls. These results show that treatment with imazalil for up to 13 weeks had no effect on cell proliferation in the liver as measured by PCNA. MRID Study Summary 7 45713701; 45708401; 45783801; 45822503; non guideline hepatocellular proliferation study; male mice; 0, 100, 200, 400, 600 or 1200 ppm ( 0, 18.7, 38.3, 73.4, 110.4, or 233.2 mg/ kg/ day) in the diet, for 2 or 13 weeks followed by 2 week recovery or 4 week recovery. At sacrifice, liver sections prepared for BrdU immunohistochemical and PCNA staining of hepatocytes. Liver enzymes levels ALD and SDH were elevated but not LDH. With the exception of a single hepatocellular nucleus in a 200 ppm animal positive for BrdU labeling, none was positive in all the 100, 200, 400, and 600 ppm groups. BrdU labeling in the high dose group of 1200 ppm was lower than in the control group at both the interim sacrifice of two weeks or the 13 week primary sacrifice. The 4 week and 17 week recovery sacrifices were negative for any BrdU labeling in both the control and 1200 ppm groups. PCNA labeling index as an indicator of hepatic cell proliferation was ( statistically significant) lower in the imazalil tested dose groups than in the control group. " There was a decreased proportion of PCNA labeled hepatocyte nuclei and fewer hepatocyte nuclei overall in like sized total areas of the livers of the 200, 400, 600 and 1200 ppm group mice compared to mice in the control group", suggesting an inhibition of cell proliferation in the imazalil treated mice. The LOAEL for imazalil in the male mice is 200 ppm ( 38.3 ± 2.7 mg/ kg/ day) based on its hepatotoxicity ( centrilobular hepatocellular hypertrophy and hepatocellular vacuolation, and hepatocellualr necrosis and elevated sorbitol dehydrogenase levels). The NOAEL is 100 ppm ( 18.7 ± 1.1 mg/ kg/ day)

The Registrant, in an Overview Summary ( MRID 45822502) suggests that imazalil might be acting as a mitogen inhibiting cell proliferation. However, mitogens stimulate cell proliferation in the absence of cytotoxicity/ necrosis/ regeneration. The Registrant also argues that the collective evidence from various studies on imazalil ( previously reviewed by HED) suggests that imazalil effects on the liver, including tumorigenic effects, are threshold based and reversible.

II. DATA PRESENTATION A. Available Data:

1. 1999 CARC Report: EXECUTIVE SUMMARY Previously, the Cancer Peer Review Committee ( CPRC; August 24, 1994) classified Imazalil as a Group C possible human carcinogen and recommended the low dose linear extrapolation ( Q 1*) approach for quantification of human cancer risk. This decision was based on an increased incidence of hepatocellular adenomas and combined adenomas and carcinomas in male Swiss albino mice at the high dose. The increase was statistically significant by pair wise comparison, with a statistically significant trend. Females had a significant dose related trend for hepatocellular carcinomas and combined adenomas/ carcinomas. No apparent increase in tumors was noted in Wistar rats. The Committee determined that the dosing was not adequate for assessing the carcinogenic potential in the rat and therefore, recommended that a new 2 year chronic feeding/ carcinogenicity study in rats using higher dose levels be performed.

At the July 22, 1998 CARC meeting, the Committee ( September, 4, 1998) reaffirmed the CPRC's previous decision in classifying Imazalil as a Group C carcinogen and the use of a linear low dose extrapolation approach for quantification of human cancer risk based on liver tumors in male mice. 8 On October 27, 1999, the CARC met to evaluate the newly completed rat chronic/ carcinogenicity study. The CARC concluded that Imazalil was carcinogenic to male rats because: 1) There was a significant increase by pair wise comparison of the 2400 ppm ( 134.8 mg/ kg/ day) group with the controls for hepatocellular adenoma and combined adenomas/ carcinomas. 2) The incidence of hepatocellular adenomas was outside the range of the historical control data and the combined incidence was driven by the adenomas. 3) There were also significant increasing trends for hepatocellular adenomas and combined adenomas/ carcinomas ; and 4) There was a significant increase by pair wise comparisons of the 1200 and 2400 ppm ( 65.8 and 134.8 mg/ kg/ day, respectively) groups with the controls for thyroid follicular cell combined adenomas/ carcinomas. There was also a significant increasing trend for thyroid follicular cell combined adenomas/ carcinomas. The incidence of combined thyroid tumors was outside the historical control. No increases in liver and thyroid tumors were noted in females. The dosing at the highest dose in both sexes was considered to be adequate and not excessive based on decreases in body weight gains and non neoplastic changes in the liver ( both sexes) and thyroid ( males only). The CARC considered the liver and thyroid tumors in males to be treatment related.

Under the Draft Guidelines for Carcinogen Risk Assessment ( July, 1999), Imazalil is classified in the category " Likely to be carcinogenic in humans". The CARC's decision was based on the following:

1. There were increases in hepatocellular adenomas and combined liver adenomas/ carcinomas in male Swiss albino mice and Wistar rats. In male rats, there was also an increased incidence of combined thyroid follicular cell adenomas/ carcinomas. 2. Imazalil was non mutagenic in in vitro and in vivo mutagenicity assays.

3. It is structurally related to triazole compounds, which are hepatocarcinogens in mice.

The CARC recommended a linear low dose ( Q 1*) extrapolation approach for the quantification of human cancer risk based on the most potent liver tumors in mice. This approach is supported by the lack of confirmation of the mode of action.

2. Thyroid Effects Study in Rats: In a one month oral toxicity study ( MRID 45160101), imazalil ( 50% a. i. premix) was administered in the diet to groups of 50 male SPF Wistar rats, substrain Hannover, at concentrations of 0 ( vehicle control), 400, 1200, or 3200 ppm ( 0, 40.8, 123, or 328 mg/ kg/ day) for up to 4 weeks followed by a recovery period of 4 or 9 weeks ( 13 weeks total study duration). A total of 50 rats fed 1200 ppm ( 126 mg/ kg/ day) phenobarbital under the same conditions as the test animals served as a positive control. Ten rats per group were sacrificed at weeks 1, 2, 4, 8, and 13 for evaluation of all parameters. 9 The only clinical sign noted was food wastage by a few high dose rats during weeks 1 to 8 of the study; the positive controls showed signs of sedation during weeks 1 and 2. Midand high dose male rats, respectively, weighed up to 8% ( p< 0.01) and 19% ( p< 0.01) less than vehicle controls, gained 15% ( p< 0.01) and 36% ( p< 0.01) less weight, and consumed 7% ( p< 0.01) and 15% ( p< 0.01) less food during the 4 week treatment period. Consequently, the food conversion ratio was not significantly affected by treatment with the test material. Compensatory weight gain was observed during the recovery period. Positive controls showed no effects on weight gain or food consumption during the 4 week treatment period.

Both imazalil and phenobarbital ( positive control) induced P 450 dependent activities and UDP glucuronyltransferase activity. Imazalil affected the thyroid peroxidase and 5' monodeiodinase activities in a similar way as phenobarbital. Most enzyme activities in the imazalil and phenobarbital treated rats returned to normal during recovery period.

Absolute and/ or relative liver weights were significantly ( p< 0.01 or < 0.05) increased by 7 27% at all doses after treatment for 1 or 4 weeks and at the mid and high dose levels after 2 weeks. Absolute and relative liver weights in positive controls were 30% to 39% ( p< 0.01) greater than that of controls throughout the treatment period. Relative thyroid weight in high dose rats was significantly increased ( 19%, p< 0.01) only at week 2, whereas absolute and relative thyroid weights in positive controls were increased by 18 21% ( p< 0.01) at weeks 2 and 4. Associated gross findings included swollen liver in 50 70% ( p< 0.01 or < 0.05) of high dose rats at weeks 1, 2, and 4 and in 40% ( N. S.) of middose rats at week 4 and a dark liver in 70% ( p< 0.01) of high dose rats at week 4. The liver was swollen in 70 100% of positive controls during the treatment period. No effect was observed on labeling index in the liver or thyroid gland at any dose of imazalil.

Treatment related microscopic findings occurring at incidences significantly greater ( p< 0.01 or < 0.05 unless otherwise noted) than those of controls included centrilobular and periportal hepatocyte hypertrophy and hepatocyte vacuolation. The incidence of centrilobular hypertrophy was 20% ( N. S.), 50%, and 50% in low dose rats; 60, 90, and 100% in mid dose rats; and 90 100% in high dose rats at weeks 1, 2, and 4, respectively, compared with 0% in controls. Periportal hypertrophy did not occur in controls or lowdose rats, but the incidence was 10% ( N. S.), 60%, and 60% in mid dose rats and 90, 80, and 100% in high dose rats at weeks 1, 2, and 4, respectively. Hepatocyte vacuolation occurred in 0, 0, and 10% ( N. S.) of low dose rats, 40% ( N. S.), 20% ( N. S.), and 10% ( N. S.) of mid dose rats, and 80 90% of high dose rats at weeks 1, 2, and 4, respectively, compared with 0% of controls. The severity of the liver lesions also increased with dose and duration of treatment. Except for one mid dose rat at week 8, none of these liver lesions were observed in any rat during the recovery period. The incidences of all three liver lesions and thyroid follicular hypertrophy were significantly increased in positive control rats at two or all three time points during treatment. 10 Serum thyroxine ( T4) and thyroid stimulating hormone ( TSH) levels were generally correlated with each other at weeks 1, 2, 4, and 8, particularly in mid and high dose rats. Although T4 and TSH levels in low dose rats fluctuated during treatment and recovery, the pattern did not show the consistency as observed for mid and high dose rats. One week after treatment started, serum T4 levels were decreased by 12% ( p< 0.05) and 17% ( p< 0.01) in mid and high dose rats, respectively, compared with controls, whereas TSH levels were increased by 15% ( N. S.) and 19% ( N. S.). With continued treatment, at week 4, serum T4 levels in mid and high dose rats, respectively, rose dramatically to levels 88% and 52% greater than that of controls and TSH levels decreased to 10% ( N. S.) and 20% ( N. S.) below that of controls. After treatment was terminated, T4 levels decreased to levels that were only 11% ( p< 0.05) and 5% ( N. S.) higher than that of controls in midand high dose rats, respectively, at week 8, and serum TSH levels again increased to 53% ( p< 0.01) and 42% ( p< 0.05), respectively, greater than that of controls. At week 13, T4 levels in mid and high dose remained comparable to those observed at week 8, but TSH levels decreased relative to those observed at week 8. A statistically significant serum triiodothyronine ( T3) level was noted in the high dose group at week 4 only.

In conclusion, this study was not conducted to determine a no observed adverse effect level ( NOAEL) and none was established, because liver lesions were observed at all dose levels. The study authors contend that the primary effect of imazalil is on the liver causing microsomal enzyme induction resulting in hepatocellular hypertrophy. Enhanced hepatic metabolism of the thyroid hormone ( T4) was demonstrated in this study by increased hepatic UDP glucuronyl transferase activity with L thyroxine, which caused decreased serum levels.

3. Hepatic Enzyme Induction/ Inhibition Study in Rats: In a one month oral toxicity study ( MRID 45160101), imazalil ( 50% a. i. premix) was administered in the diet to groups of 50 male SPF Wistar rats, substrain Hannover, at concentrations of 0 ( vehicle control), 400, 1200, or 3200 ppm ( 0, 40.8, 123, or 328 mg/ kg/ day) for up to 4 weeks followed by a recovery period of 4 or 9 weeks ( 13 weeks total study duration). A total of 50 rats fed 1200 ppm ( 126 mg/ kg/ day) phenobarbital under the same conditions as the test animals served as a positive control. Ten rats per group were sacrificed at weeks 1, 2, 4, 8, and 13 for evaluation of all parameters.

In the study supplement ( MRID 45376801), a final report of the hepatic drug metabolizing and thyroid enzymes is presented. Liver and thyroid microsomes were prepared from liver and thyroid pieces and assayed for protein and cytochrome P 450 contents ( liver microsomes). Liver aniline hydroxylase, N ethylmorphine N demethylase, 7 ethoxyresorufin O deethylase, 7 pentoxyresorufin O dealkylase, lauric acid hydroxylase, UDP glucuronyltransferase, and 5  monodeiodinase and thyroid peroxidase activities were analyzed. With the exception of the 7 ethoxyresorufin O deethylase and lauric acid hydroxylase, these enzyme activities were reported in MRID 45160101. 11 Both imazalil and phenobarbital induced P 450 dependent activities and UDP glucuronyltransferase activity. Imazalil affected the thyroid peroxidase and liver enzyme activities in a similar way as phenobarbital. Liver aniline hydroxylase, N ethylmorphine N demethylase, 7 pentoxyresorufin O dealkylase, and UDP glucuronyltransferase, and thyroid peroxidase activities were all induced during the imazalil treatment. The largest inductive effect of both imazalil and phenobarbital was observed on the 7 Pentoxyresorufin O dealkylase activity ( 1,600  2,700% of the control for imazalil and 43,500% of the control for phenobarbital at week 4 of treatment). The 5  monodeiodinase was not induced and was slightly depressed by either the imazalil or the phenobarbital treatment.

The supplementary information demonstrated that imazalil had a clear inductive effect on 7 ethoxyresorufin O dealkylase activity in a dose related manner ( 157%, 296% 400% relative to the control at 400, 1200 and 3200 ppm dietary feeding levels of imazalil for 4 weeks, respectively) in a fashion similar to phenobarbital ( positive control used in the study). However, the lauric acid hydroxylase activity was only slightly induced by both imazalil and phenobarbital.

The enzyme activities in the imazalil and phenobarbital treated rats returned to normal during the 4  9 week recovery periods.

This additional information supplements the original report does not affect the conclusions stated in the DER of MRID # 45160101.

This study was conducted to determine the effects of imazalil administration to male rats on the induction of the hepatic drug metabolizing enzymes and the related thyroid enzymes to explain the hepatocellular hypertrophy and the thyroid follicular cell hypertrophy seen in long term studies with imazalil. As stated previously in the DER of MRID 45160101, these findings may provide the mechanism by which imazalil induced thyroid neoplasms in long term studies.

4. PCNA Quantitative Analysis of Livers  Rats: This study ( MRID 45362602) is a supplement to MRID 45160101. Livers from 20 male rats administered imazalil base, technical ( 96.9%) at dietary concentrations of 0, 400, 1200, or 3200 ppm of imazalil ( 0, 40.8, 123, or 328 mg/ kg/ day) or 1200 phenobarbital ( 126 mg/ kg/ day; positive control) for 4 weeks were evaluated for the percentage of labeled cells stained immunocytochemically for Proliferating Cell Nuclear Antigen ( PCNA). Liver sections from ten rats per group were examined at the end of the treatment period and from ten per group after a 4 week recovery period. No treatment effect was observed at either time point; therefore, administration of imazalil had no effect on cell proliferating potential of the rat liver.

5. Subchronic Oral Hepatotoxicity Study in Mice: In a 3 month oral mechanistic toxicity study ( MRID 43222601, 43292402) designed to study effects on the liver, 12 Imazalil Base ( 96.9%) was administered in the diet to 25 male and 25 female Swiss mice for 3 months at nominal dosage levels of 0, 50, 200 or 600 ppm ( approximate doses of 0, 9.5, 38.6 or 115 mg/ kg/ day for males and 0, 11.3, 45.6 or 138 mg/ kg/ day for females, as adjusted for actual achieved concentrations of about 83% of nominal). Additional groups of 15 mice/ sex/ group were also given Imazalil base in the diet at 0, 50, 200 or 600 ppm, but were sacrificed at 1 month. The following parameters were evaluated: clinical signs, body weights, food consumption, clinical chemistries ( 3 liver enzymes only), gross necropsy, organ, weights, histopathology ( gall bladder and liver only), electron microscopy of liver, liver microsomal protein and cytochrome P450 content, liver enzymatic activities of 7 P450 isoenzymes, liver testosterone metabolism and serum concentrations of Imazalil.

No treatment related effects on mortality, clinical signs, body weights, body weight gains or food consumption were observed. At 200 ppm, the following treatment related effects were observed: increased incidence of dark liver at gross necropsy in males, increased incidence and severity of " centrilobular clearer aspect" and of large and/ or small vacuoles in the hepatocytes of males and females, increased liver microsomal protein in males and females, and increased microsomal cytochrome P450 content in males and females. At 600 ppm, the following treatment related effects were observed: increased incidence of dark livers at gross necropsy in males and females, increased absolute liver weights and relative liver/ body weight ratios in males and females, increased incidence and severity of " centrilobular clearer aspect" and of large and/ or small vacuoles in the hepatocytes of males and females, increased individual cell necrosis in hepatocytes of males, increased diffuse swelling of hepatocytes in females, increased liver microsomal protein in males and females, and increased microsomal cytochrome P450 content in males and females. Electron microscopy revealed increased numbers of lipid droplets in hepatocytes, which corresponded with the increased vacuolization observed by light microscopy, and a morphologically changed rough endoplasmic reticulum ( RER) in the hepatocytes of 600 ppm males and females. Regarding liver enzymatic activities of 7 P450 isoenzymes., dosing with Imazalil at 200 ppm and 600 ppm significantly induced certain enzymatic activities but also had an inhibitory effect on other metabolic activities. At 600 ppm, the total activity of testosterone hydroxylases was increased in both males and females. Low levels of Imazalil were detected in the serum of some males and females at 600 ppm only.

The LOEL in this study is 200 ppm ( 38.6 and 45.6 mg/ kg/ day in males and females respectively) and is based on increased incidence and severity of histopathologic effects, increased microsomal protein and increased microsomal cytochrome P450 content in the livers of both males and females. The NOEL in this study is 50 ppm ( 9.5 and 11.3 mg/ kg/ day in males and females, respectively). 13 6. PCNA Quantitative Analysis of Livers  Mouse: This study ( MRID 45362601) is a supplement to MRID 43222601. Liver sections from 20 male and 20 female mice administered Imazalil base, technical ( 96.9% purity) at dietary concentrations of 0, 50, 200, or 600 ppm ( approximate doses of 0, 9.5, 38.6 or 115 mg/ kg/ day for males and 0, 11.3, 45.6 or 138 mg/ kg/ day for females, as adjusted for actual achieved concentrations of about 83% of nominal) for 13 weeks were evaluated for the percentage of labeled cells stained immunochemically for Proliferating Cell Nuclear Antigen ( PCNA). No treatmenteffect was observed; therefore, oral administration of imazalil had no effect on cell proliferating potential of the rat liver.

7. Hepatocellular Proliferation Study  Mouse: In a nonguideline hepatocellular proliferation study ( MRID 45713701, 45708401, 45783801 & 45822503) conducted to investigate the mechanism of liver tumor induction observed at same dosage levels in oncogenicity studies, groups of male Crl: CD 1R( ICR) BR mice ( 10/ dose/ sacrifice time) were given imazalil ( purity 96.2%, Lot. No. ZR023979G3H771) in the diet ad libitum at concentrations of 0.0, 100, 200, 400, 600 or 1200 ppm ( 0, 18.7 ± 1.1, 38.3 ± 2.7, 73.4 ± 5.13, 110.4 ± 11.7, 233.2 ± 24.5 mg/ kg/ day) for 2 or 13 weeks. Bromo deoxyuridine ( BrdU) in sterile phosphate buffered saline ( 30 mg/ mL) was administered subcutaneously ( through an implanted osmotic minipump) seven days prior to the appropriate mice sacrifice period. Animals were sacrificed after 2 week interim period; 4 week recovery period ( the 0 and 1200 ppm group only); 13 week primary sacrifice; 17 week recovery period ( the 0 and 1200 ppm group only). At sacrifice, the animals were weighed and the liver removed, weighed, and sections prepared for serial review by Hematoxylin and Eosin or BrdU immunohistochemical and Proliferating Cell Nuclear Antigen ( PCNA) staining of hepatocytes.

Administration of imazalil to male mice in their diets for up to 13 weeks affected survival and body weight only at the 1200 ppm level. Clinical findings, food consumption and macroscopic changes were not affected by the imazalil treatment. The primary organ of imazalil toxicity in this test was the liver. Imazalil produced microscopic changes ( centrilobular hepatocellular hypertrophy and hepatocellular vacuolation, and hepatocellualr necrosis) in a dose related manner. Liver enzymes levels ALD and SDH were elevated but not LDH. With the exception of a single hepatocellular nucleus in a 200 ppm animal positive for BrdU labeling, none was positive in all the 100, 200, 400, and 600 ppm groups. BrdU labeling in the high dose group of 1200 ppm was lower than in the control group at both the interim sacrifice of two weeks or the 13 week primary sacrifice. The 4 week and 17 week recovery sacrifices were negative for any BrdU labeling in both the control and 1200 ppm groups. This was confirmed by repeating the staining procedure for the control and high dose groups at the interim and 13 week sacrifices. The BrdU staining procedure was also verified by producing positive results in cells taken from duodenum sections. It was observed that control animals had a higher labeling percentage than the highest imazalil dose tested. 14 PCNA labeling index as an indicator of hepatic cell proliferation was ( statistically significant) lower in the imazalil tested dose groups than in the control group. This demonstrates the lack of induction of hepatic cell proliferation by imazalil. " There was a decreased proportion of PCNA labeled hepatocyte nuclei and fewer hepatocyte nuclei overall in like sized total areas of the livers of the 200, 400, 600 and 1200 ppm group mice compared to mice in the control group", suggesting an inhibition of cell proliferation in the imazalil treated mice.

The LOAEL for imazalil in the male mice is 200 ppm ( 38.3 ± 2.7 mg/ kg/ day) based on its hepatotoxicity ( centrilobular hepatocellular hypertrophy and hepatocellular vacuolation, and hepatocellualr necrosis and elevated sorbitol dehydrogenase levels). The NOAEL is 100 ppm ( 18.7 ± 1.1 mg/ kg/ day).

8. Overview of Liver Effects and Cell Cycle Changes in Mice: In this overview prepared by the Registrant ( MRID 45822502), concludes that the effects of imazalil on the liver are nongenotoxic, threshold based and reversible. Cell proliferation data indicate that imazalil inhibits the cell proliferation at dietary concentrations of 200 ppm and greater. According to this review, the tumoregenic response may be related to the inhibition of cell proliferation which permits altered liver cell population that escape the cell cycle to have a selective growth advantage.

III. CONCLUSIONS Based on the weight of evidence and MRID 45713701 findings, the committee concluded that the new data does not support a mechanism of action to explain the tumorigenic effects of imazalil in the rodent liver. The committee explained its decision on the following:

( 1) NO hepatic cell proliferation was demonstrated in rat or the new mouse study. In the mouse, there was a decline of cell proliferation as measured by Bromo deoxyuridine ( BrdU) or Proliferating Cell Nuclear Antigen ( PCNA) staining.

( 2) BrdU is the preferred method for measuring cell proliferation. The mouse study findings were variable. BrdU staining occurred only in the control and the high dose animals but none in the intermediate doses.

( 3) PCNA staining ( not the best method for measuring cell proliferation) yielded also variable results with a declining trend suggesting inhibition of cell proliferation.

( 4) Even if hepatic cell proliferation was demonstrated, there is currently no scientific support to link it to tumorigenic effects.

The Committee concluded, therefore, that the new data in the mouse does not demonstrate a mechanism of action to explain the tumorigenic effects of imazalil in rodents.


[Federal Register Volume 77, Number 180 (Monday, September 17, 2012)]
[Notices]
[Pages 57092-57094]
[FR Doc No: 2012-22795]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-N-0020]

Agency Information Collection Activities; Submission for Office
of Management and Budget Review; Comment Request; Experimental Study of
Consumer Response to Health Claims and Disclaimers About the
Relationship Between Selenium and Risk of Various Cancers

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration (FDA) is announcing that a
proposed collection of information has been submitted to the Office of
Management and Budget (OMB) for review and clearance under the
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by October
17, 2012.

ADDRESSES: To ensure that comments on the information collection are
received, OMB recommends that written comments be faxed to the Office
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer,
FAX:<PHONE_NUMBER>, or emailed to<EMAIL_ADDRESS>All
comments should be identified with the OMB control number 0910--New and
title ``Experimental Study of Consumer Response to Health Claims and
Disclaimers About the Relationship Between Selenium and Risk of Various
Cancers.'' Also include the FDA docket number found in brackets in the
heading of this document.

FOR FURTHER INFORMATION CONTACT: Domini Bean, Office of Information
Management, Food and Drug Administration, 1350 Piccard Dr., PI50-400T,
Rockville, MD 20850<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has
submitted the following proposed collection of information to OMB for
review and clearance.

Experimental Study of Consumer Response to Health Claims and
Disclaimers About the Relationship Between Selenium and Risk of Various
Cancers--(OMB Control Number 0910--New)

I. Background

    FDA regulates the labeling of food products under the Federal Food,
Drug, and Cosmetic Act, as amended by the Nutrition Labeling and
Education Act of 1990 (NLEA). NLEA regulations establish general
requirements for voluntary health claims in food labeling; health
claims are labeling statements that characterize the relationship
between a food substance and a disease or health-related condition (21
CFR 101.14(a)(1)). Under the petition process for new health claims (21
CFR 101.70), the petitioner must submit the scientific evidence
supporting a proposed health claim to FDA for review. If FDA determines
that there is significant scientific agreement (SSA) among experts that
the proposed health claim is supported by the totality of publicly
available evidence, FDA issues a regulation authorizing the claim (21
CFR 101.14(c) and (d)). Health claims must be ``complete, truthful, and
not misleading'' (21 CFR 101.14(d)(2)(iii)) and must ``enable the
public to comprehend the information provided and to understand the
relative significance of such information in the context of a total
daily diet'' (21 CFR 101.14(d)(2)(v)).
    In a court challenge to FDA's decision not to authorize four
dietary supplement health claims that failed to meet the SSA standard,
the U.S. Court of Appeals for the DC Circuit held that the First
Amendment does not permit FDA to prohibit health claims that the Agency
determines to be potentially misleading unless the Agency also
reasonably determines that a disclaimer would not eliminate the
potential deception (Pearson v. Shalala, 164 F.3d 650 (DC Cir. 1999)).
Because the court also held that a health claim is not inherently
misleading simply because the evidence supporting it does not reach the
SSA level, the decision effectively requires FDA to permit health
claims that are backed by credible scientific evidence unless the
Agency can demonstrate that the claim would mislead consumers. In
response to the court's decision, FDA issued guidance on an interim
review process for health claims that do not meet the SSA standard for
the issuance of a regulation authorizing the claim (Ref. 1). These
claims, referred to as ``qualified health claims'' (QHCs), include a
disclaimer or other qualifying language to distinguish them from claims
that meet the SSA standard and to prevent consumers from being misled
about the level of scientific evidence supporting the claim (Ref. 2).
When FDA reviews a QHC petition and determines that the proposed claim
is supported by credible evidence and that it can be qualified to
prevent consumers from being misled, the Agency issues a letter stating
its intent to exercise enforcement discretion for the use of the QHC in
food labeling.
    In 2003, FDA issued a letter of enforcement discretion for two QHCs
for dietary supplements containing selenium (Ref. 3):

    Claim 1: ``Selenium may reduce the risk of certain cancers. Some
scientific evidence suggests that consumption of selenium may reduce
the risk of certain forms of cancer. However, FDA has determined
that this evidence is limited and not conclusive.''
    Claim 2: ``Selenium may produce anticarcinogenic effects in the
body. Some scientific evidence suggests that consumption of selenium
may produce anticarcinogenic effects in the body. However, FDA has
determined that this evidence is limited and not conclusive.''

    In 2007, FDA published a notice in the Federal Register (72 FR
72738; December 21, 2007) (the 2007 notice) announcing the Agency's
intent to reevaluate these two QHCs, among other health claims. One of
the other health claims being reevaluated is the authorized health
claim for dietary fat and cancer risk in Sec.  101.73 (21 CFR 101.73).
The model health claims in Sec.  101.73(e) use language similar to the
``certain cancers'' language used in Claim 1 for selenium, as they
state that low-fat diets may reduce the risk of ``some cancers'' or
``some types of cancers.'' The 2007 notice explained that, during FDA's
reevaluation of the scientific evidence underlying these claims, the
Agency also planned to consider whether the claims should be revised to
replace generic references to ``certain cancers'' (or similar language)
with the names of specific cancers (e.g., prostate cancer, breast
cancer) because each type of cancer is a separate disease with
different causes and risk factors (72 FR at 72740).
    In 2008, FDA received a petition requesting enforcement discretion
for two additional QHCs similar to the ones for which FDA had issued a
letter of enforcement discretion in 2003. The basic claim in the first
sentence of each proposed QHC was the same as the claim in the first
sentence of the corresponding 2003 QHC (``selenium may reduce the risk
of certain cancers'' and ``selenium may produce anticarcinogenic
effects in the body,'' respectively), but the 2008 petition

requested enforcement discretion for the use of the following
disclaimer with each claim: ``Scientific evidence supporting this claim
is convincing but not yet conclusive.'' The 2008 petition also
requested enforcement discretion for a number of other QHCs about
selenium and reduced risk of specific cancers. In 2009, FDA issued a
response to the 2008 petition in which the Agency stated its intent to
exercise enforcement discretion for QHCs about selenium and reduced
risk of prostate, thyroid, and bladder cancers (Ref. 4). The Agency
declined to exercise enforcement discretion for QHCs about selenium and
several other site-specific cancers because there was no credible
evidence that selenium reduces the risk of those cancers. The Agency
also declined to exercise enforcement discretion for the two QHCs that
were similar to the 2003 ``certain cancers'' and ``anticarcinogenic
effects'' QHCs because it concluded that the proposed claims were
misleading and could not be cured with a disclaimer.
    Several of the petitioners filed suit in the U.S. District Court
for the District of Columbia, challenging FDA's 2009 petition response
under the First Amendment. On cross-motions for summary judgment, the
court ruled for the plaintiffs on the ``certain cancers'' and
``anticarcinogenic effects'' claims, as well as three of the site-
specific cancer claims (Alliance for Natural Health v. Sebelius, 714 F.
Supp. 2d 48 (D.D.C. 2010)). With respect to the ``certain cancers'' and
``anticarcinogenic effects'' QHCs, the court found that FDA had failed
to show with empirical evidence that the claims were misleading and
could not be corrected with disclaimers. The court also concluded that
the Agency's scientific decisions regarding three QHCs for site-
specific cancers were not supported by the record and remanded the case
to FDA for reconsideration of those claims, along with the ``certain
cancers'' and ``anticarcinogenic effects'' QHCs. FDA and the plaintiffs
then reached a settlement whereby FDA agreed to exercise enforcement
discretion for QHCs for selenium and reduced risk of bladder, prostate,
colon, rectal, and thyroid cancers (Ref. 5). In lieu of the ``certain
cancers'' and ``anticarcinogenic effects'' QHCs, plaintiffs agreed to
accept a QHC that listed all five site-specific cancers.

II. Purpose and Methodology of Proposed Study

    The objective of FDA's proposed study is to collect quantitative
data to examine consumer interpretations of two dietary supplement
labeling claims, ``selenium may reduce the risk of certain cancers''
and ``selenium may produce anticarcinogenic effects in the body,'' with
and without various disclaimers. Previous studies conducted by FDA and
others have examined consumer understanding of hypothetical QHCs and
QHCs that are the subject of a letter of enforcement discretion. The
primary goal of the previous studies was to evaluate ways to
communicate the strength of scientific evidence supporting a claim
(Refs. 6 to 9). None of these studies, however, has investigated
whether labeling claims using phrases such as ``certain cancers'' and
``anticarcinogenic effects'' may mislead consumers into having
unjustified perceptions about the effects of a dietary supplement or
food and how such misperceptions may affect behavioral intentions. The
Agency therefore proposes to use selenium QHCs in this case study to
examine consumer reactions to health claims using those phrases, with
and without various disclaimers.
    Specifically, the study plans to examine: (1) Whether one or both
of the selenium claims quoted in this document would lead consumers to
have the impression that selenium reduces the risk of all forms of
cancer (``cancer in general''); (2) whether one or both of these claims
would lead consumers to have the impression that selenium reduces the
risk of a cancer for which there is no credible evidence of risk
reduction, and, if so, whether a disclaimer specifying the names of the
cancers for which there is such evidence (bladder, prostate, colon,
rectal, and thyroid cancers) can communicate to consumers that the
claimed risk reduction effect is only for the named cancers; (3)
whether the ``anticarcinogenic effects'' claim would lead consumers to
believe that selenium not only reduces the risk of cancer, but also
treats or completely prevents cancer; (4) whether various disclaimer
options for the two claims would correct potential consumer
misperceptions about the nature of the relationship between selenium
and various cancers or the scope of the claims; and (5) whether either
of the claims leads consumers to have other erroneous perceptions, such
as that all cancers are alike.
    The proposed study will use a Web-based survey to collect
information from approximately 1,200 adults, including 800 men who are
55 years or older and 400 women who are 50 years or older, who belong
to online consumer panels maintained by a contractor. Data provided by
the nationally representative Health Information National Trends Survey
(HINTS; Ref. 10) suggest that individuals in the age groups proposed
for this study have a higher overall prevalence of cancer in general,
and a higher prevalence of most of the specific cancers that are the
subject of an existing QHC for selenium (see list in I. Background
section), but do not systematically differ from individuals in other
age groups with respect to their patterns of cancer-related
perceptions. By targeting participants in this age range and with these
characteristics, the study is expected to maximize efficient use of the
limited resources allocated to the project by yielding a greater amount
of information pertinent to people who are more likely to take a
selenium supplement. To that end, the study will aim for increased
representation of potential selenium users by targeting a sample that
includes at least 400 participants who have taken a selenium supplement
at least once. Because the rate of selenium use in the general
population is estimated to be low overall, but somewhat higher among
men than women (Refs. 11 and 12), the sample will consist of a greater
proportion of men. In addition, the screening process for the online
consumer panel will limit female participants to those who report being
married, and women enrolled in the study will be asked to provide
information about their spouses' use of selenium in addition to their
own.
    On a computer screen, participants will view a label image and
answer questions about their perceptions and behavioral intentions in
response to the label they view. Each participant will be randomly
assigned to an experimental condition in which he or she will view one
of the following: (a) A selenium product label containing no claim; (b)
a selenium product label containing the claim that ``selenium may
reduce the risk of certain cancers''; (c) a selenium product label
containing the claim that ``selenium may produce anticarcinogenic
effects in the body''; (d) a selenium product label containing one of
the claims from (b) or (c) plus a selected disclaimer statement. To
help understand the data, the study will also collect information on
each participant's background, including, but not limited to, health
status, race/ethnicity, education, and income.
    The proposed study is part of FDA's continuing effort to enable
consumers to make informed dietary choices and eat healthful diets.
Results of this case study will be used to further the Agency's
understanding of how consumers may interpret ``certain cancers'' and
``anticarcinogenic effects,''

phrases that appear in a number of health claims that are authorized by
regulation, as well as in some QHCs for which the Agency has issued a
letter of enforcement discretion. Results of the study will not be used
to develop population estimates.
    In the Federal Register of January 27, 2012 (77 FR 4329), FDA
published a 60-day notice requesting public comment on the proposed
collection of information. The Agency received one comment that dealt
with topics outside the scope of the proposed collection of information
described in the 60-day notice. Therefore, the comment is not addressed
here.
    FDA estimates the burden of this collection of information as
follows:

                                 Table 1--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                    No. of
           Activity                 No. of       responses per   Total annual    Average burden     Total hours
                                  respondents     respondent       responses      per response
----------------------------------------------------------------------------------------------------------------
Cognitive interview screener..             350               1             350  0.083 (5                      29
                                                                                minutes).
Cognitive interview...........               9               1               9  1 hour..........               9
Pretest invitation............           1,700               1           1,700  0.033 (2                      56
                                                                                minutes).
Pretest.......................              60               1              60  0.167 (10                     10
                                                                                minutes).
Survey invitation.............          45,000               1          45,000  0.033 (2                   1,485
                                                                                minutes).
Survey........................           1,200               1           1,200  0.167 (10                    200
                                                                                minutes).
                               ---------------------------------------------------------------------------------
    Total.....................  ..............  ..............  ..............  ................           1,789
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    This burden estimate is 94 hours lower than the estimate published
in the 60-day notice and includes 23 more hours for the cognitive
interview screener, 48 more hours for the pretest invitation, and 165
fewer hours for the survey invitation. These estimates were adjusted to
better reflect the anticipated effort required to recruit, conduct
cognitive interviews, pretest, and survey participants with the desired
characteristics. FDA's burden estimate is based on prior experience
with research that is similar to this proposed study.

III. References

    The following references have been placed on display in the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852, and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday,
and are available electronically at http://www.regulations.gov. (FDA
has verified the Web site addresses, but we are not responsible for any
subsequent changes to the Web sites after this document publishes in
the Federal Register.)

    1. U.S. Food and Drug Administration, ``Guidance for Industry:
Interim Procedures for Qualified Health Claims in the Labeling of
Conventional Human Foods and Human Dietary Supplements,'' 2003,
available at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodLabelingNutrition/ucm053832.htm.
    2. U.S. Food and Drug Administration, ``Guidance for Industry:
Evidence-Based Review System for the Scientific Evaluation of Health
Claims,'' 2009, available at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodLabelingNutrition/ucm073332.htm.
    3. U.S. Food and Drug Administration, ``Selenium and Certain
Cancers (Qualified Health Claim: Final Decision Letter) (Docket No.
02P-0457),'' 2003, available at http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/ucm072780.htm.
    4. U.S. Food and Drug Administration, ``Selenium and a Reduced
Risk of Site-Specific Cancers (FDA-2008-Q-04323),'' 2009, available
at http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/ucm168527.htm.
    5. U.S. Food and Drug Administration, ``Settlement Reached for
Qualified Health Claims Relating Selenium to Reduced Risk of
Prostate, Colon, Rectal, Bladder, and Thyroid Cancers,'' 2011,
available at http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/ucm256940.htm.
    6. Derby, B.M. and A.S. Levy, ``Effects of Strength of Science
Disclaimers on the Communication Impacts of Health Claims,'' 2005,
available at http://www.fda.gov/OHRMS/dockets/dockets/03N0496/03N-0496-rpt0001.pdf.
    7. Choini[egrave]re, C. and L. Verrill, ``Experimental Study of
Qualified Health Claims: Consumer Inferences About Monounsaturated
Fatty Acids From Olive Oil, EPA and DHA Omega-3 Fatty Acids, and
Green Tea,'' 2009, available at http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/ucm207549.htm.
    8. Hooker, N.H. and R. Teratanavat, ``Dissecting Qualified
Health Claims: Evidence From Experimental Studies,'' Critical
Reviews in Food Science and Nutrition, vol. 48, pp. 160-176, 2008.
    9. Kapsak, W.R., D. Schmidt, N.M. Childs, et al., ``Consumer
Perceptions of Graded, Graphic and Text Label Presentations for
Qualified Health Claims,'' Critical Reviews in Food Science and
Nutrition, vol. 48, pp. 248-256, 2008.
    10. National Cancer Institute, ``Health Information National
Trends Survey,'' 2007, available at http://hints.cancer.gov/.
    11. Bailey, R.L., J.J. Gahche, C.V. Lentino, et al., ``Dietary
Supplement Use in the United States, 2003-2006,'' Journal of
Nutrition, vol. 141, pp. 261-266, 2011.
    12. Radimer, K., B. Bindewald, J. Hughes, et al., ``Dietary
Supplement Use by US Adults: Data From the National Health and
Nutrition Examination Survey, 1999-2000,'' American Journal of
Epidemiology, vol. 160, pp. 339-349, 2004.

    Dated: September 7, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-22795 Filed 9-14-12; 8:45 am]
BILLING CODE 4160-01-P


Telephone log  5/30/2007

Steve Adams, UPACo Adhesives<PHONE_NUMBER>

Where to get published rule?  www.gpoaccess.gov/fr

Article in the Clarion

Furniture Today

A jury awarded $9.5 million in damages to 4 workers.

UPACo will do an article

They intend to update their paper with new information.

He may want to send a personal comment, wouldn’t necessarily represent
his company.

Flammable still around $7/gal

Need ventilation for any option, flammable or not.  They will work on
this with customers.  People are listening.


[Federal Register Volume 84, Number 247 (Thursday, December 26, 2019)]
[Rules and Regulations]
[Page 70893]
[FR Doc No: 2019-27625]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 165

[Docket No. USCG-2019-0942]

Safety Zone, Brandon Road Lock and Dam to Lake Michigan Including
Des Plaines River, Chicago Sanitary and Ship Canal, Chicago River, and
Calumet-Saganashkee Channel, Chicago, IL

AGENCY: Coast Guard, DHS.

ACTION: Notice of enforcement of regulation.

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

SUMMARY: The Coast Guard will enforce a segment of the Safety Zone;
Brandon Road Lock and Dam to Lake Michigan including Des Plaines River,
Chicago Sanitary and Ship Canal, Chicago River, Calumet-Saganashkee
Channel on all waters of the Main Branch of the Chicago River 600 feet
west of the N Orleans Street Bridge and 1000 feet east of the N
Columbus Street Bridge. This action is necessary and intended to
protect the safety of life and property on navigable waters prior to,
during, and immediately after firework displays. During the enforcement
periods listed below, entry into, transiting, or anchoring within the
safety zone is prohibited unless authorized by the Captain of the Port
Lake Michigan or a designated representative.

DATES: The regulation in 33 CFR 165.930 will be enforced from 11:30
p.m. on December 31, 2019 through 12:15 a.m. on January 1, 2020.

FOR FURTHER INFORMATION CONTACT: If you have questions about this
notice of enforcement, call or email LT Tiziana C. Garner, Waterways
Management Division, Marine Safety Unit Chicago, U.S. Coast Guard;
telephone<PHONE_NUMBER>, email<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: The Coast Guard will enforce a segment of
the Safety Zone; Brandon Road Lock and Dam to Lake Michigan including
Des Plaines River, Chicago Sanitary and Ship Canal, Chicago River,
Calumet-Saganashkee Channel on all waters of the main branch of the
Chicago River 600 feet west of the N Orleans Street Bridge and 1000
feet east of the N Columbus Street bridge. During the enforcement
period, no vessel may transit this regulated area without approval from
the Captain of the Port Lake Michigan or a designated representative.
Vessels and persons granted permission to enter the safety zone shall
obey all lawful orders or directions of the Captain of the Port Lake
Michigan, or an on-scene representative.
    This notice of enforcement is issued under authority of 33 CFR
165.930 and 5 U.S.C. 552(a). In addition to this notice in the Federal
Register, the Coast Guard will also provide notice through other means,
which will include Broadcast Notice to Mariners, Local Notice to
Mariners, distribution in leaflet form, and on-scene oral notice. The
Captain of the Port Lake Michigan or a designated on-scene
representative may be contacted via Channel 16, VHF-FM or at (414) 747-
7182.

    Dated: December 17, 2019.
Thomas J. Stuhlreyer,
Captain, U.S. Coast Guard, Captain of the Port, Lake Michigan.
[FR Doc. 2019-27625 Filed 12-23-19; 8:45 am]
BILLING CODE 9110-04-P