[Federal Register: October 22, 2003 (Volume 68, Number 204)]
[Notices]
[Page 60383-60386]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr22oc03-92]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2003-0309; FRL-7326-1]
Phosphomannose Isomerase and the Genetic Material Necessary for
Its Production in All Plants; Notice of Filing a Pesticide Petition to
Establish a Tolerance for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by docket identification (ID) number OPP-
2003-0309, must be received on or before November 21, 2003.
ADDRESSES: Comments may be submitted electronically, by mail, or
through hand delivery/courier. Follow the detailed instructions as
provided in Unit I. of the SUPPLEMENTARY INFORMATION.
FOR FURTHER INFORMATION CONTACT: Mike Mendelsohn, Biopesticides and
Pollution Prevention Division (7511C), Office of Pesticide Programs,
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001; telephone number: (703) 308-8715; e-mail address: mendelsohn.mike@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to:
[sbull] Crop production (NAICS 111)
[sbull] Animal production (NAICS 112)
[sbull] Food manufacturing (NAICS 311)
[sbull] Pesticide manufacturing (NAICS 32532)
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. If you have any
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.
B. How Can I Get Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket ID number OPP-2003-0309. The official public docket
consists of the documents specifically referenced in this action, any
public comments received, and other information related to this action.
Although a part of the official docket, the public docket does not
include Confidential Business Information (CBI) or other information
whose disclosure is restricted by statute. The official public docket
is the collection of materials that is available for public viewing at
the Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall 2, 1921 Jefferson Davis Hwy., Arlington, VA. This
docket facility is open from 8:30 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays. The docket telephone number is (703)
305-5805.
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/.
An electronic version of the public docket is available through
EPA's electronic public docket and comment system, EPA Dockets. You may
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public
comments, access the index listing of the contents of the official
public docket, and to access those documents in the public docket that
are available electronically. Although not all docket materials may be
available electronically, you may still access any of the publicly
available docket materials through the docket facility identified in
Unit I.B.1. Once in the system, select ``search,'' then key in the
appropriate docket ID number.
Certain types of information will not be placed in EPA's Dockets.
Information claimed as CBI and other information whose disclosure is
restricted by statute, which is not included in the official public
docket, will not be available for public viewing in EPA's electronic
public docket. EPA's policy is that copyrighted material will not be
placed in EPA's electronic public docket but will be available only in
printed, paper form in the official public docket. To the extent
feasible, publicly available docket materials will be made available in
EPA's electronic public docket. When a document is selected from the
index list in EPA Dockets, the system will identify whether the
document is available for viewing in EPA's electronic public docket.
Although not all docket materials may be available electronically, you
may still access any of the publicly available docket materials through
the docket facility identified in Unit I.B.1. EPA intends to work
towards providing electronic access to all of the publicly available
docket materials through EPA's electronic public docket.
For public commenters, it is important to note that EPA's policy is
that public comments, whether submitted electronically or in paper,
will be made available for public viewing in EPA's electronic public
docket as EPA receives them and without change, unless the comment
contains copyrighted material, CBI, or other information whose
disclosure is restricted by statute. When EPA identifies a comment
containing copyrighted material, EPA will provide a reference to that
material in the version of the comment that is placed in EPA's
electronic public docket. The entire printed comment, including the
copyrighted material, will be available in the public docket.
Public comments submitted on computer disks that are mailed or
delivered to the docket will be transferred to EPA's electronic public
docket. Public comments that are mailed or delivered to the docket will
be scanned and placed in EPA's electronic public docket. Where
practical, physical objects will be photographed, and the photograph
will be placed in EPA's electronic public docket along with a brief
description written by the docket staff.
C. How and to Whom Do I Submit Comments?
You may submit comments electronically, by mail, or through hand
delivery/courier. To ensure proper receipt by EPA, identify the
appropriate docket ID number in the subject line on the first page of
your comment. Please ensure that your comments are submitted within the
specified comment period. Comments received after the close of the
comment period will be marked ``late.'' EPA is not required to consider
these late comments. If you wish to submit CBI or information that is
otherwise protected by statute, please follow the instructions in Unit
I.D. Do not use EPA Dockets or e-mail to submit CBI or information
protected by statute.
1. Electronically. If you submit an electronic comment as
prescribed in this unit, EPA recommends that you include your name,
mailing address, and an e-mail address or other contact
[[Page 60384]]
information in the body of your comment. Also include this contact
information on the outside of any disk or CD ROM you submit, and in any
cover letter accompanying the disk or CD ROM. This ensures that you can
be identified as the submitter of the comment and allows EPA to contact
you in case EPA cannot read your comment due to technical difficulties
or needs further information on the substance of your comment. EPA's
policy is that EPA will not edit your comment, and any identifying or
contact information provided in the body of a comment will be included
as part of the comment that is placed in the official public docket,
and made available in EPA's electronic public docket. If EPA cannot
read your comment due to technical difficulties and cannot contact you
for clarification, EPA may not be able to consider your comment.
i. EPA dockets. Your use of EPA's electronic public docket to
submit comments to EPA electronically is EPA's preferred method for
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket/
, and follow the online instructions for submitting comments.
Once in the system, select ``search,'' and then key in docket ID number
OPP-2003-0309. The system is an ``anonymous access'' system, which
means EPA will not know your identity, e-mail address, or other contact
information unless you provide it in the body of your comment. ii. E-mail. Comments may be sent by e-mail to opp-docket@epa.gov,
Attention: Docket ID Number OPP-2003-0309. In contrast to EPA's
electronic public docket, EPA's e-mail system is not an ``anonymous
access'' system. If you send an e-mail comment directly to the docket
without going through EPA's electronic public docket, EPA's e-mail
system automatically captures your e-mail address. E-mail addresses
that are automatically captured by EPA's e-mail system are included as
part of the comment that is placed in the official public docket, and
made available in EPA's electronic public docket.
iii. Disk or CD ROM. You may submit comments on a disk or CD ROM
that you mail to the mailing address identified in Unit I.C.2. These
electronic submissions will be accepted in WordPerfect or ASCII file
format. Avoid the use of special characters and any form of encryption.
2. By mail. Send your comments to: Public Information and Records
Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001, Attention: Docket ID Number OPP-2003-0309.
3. By hand delivery or courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Office of Pesticide
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall
2, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket
ID Number OPP-2003-0309. Such deliveries are only accepted during the
docket's normal hours of operation as identified in Unit I.B.1.
D. How Should I Submit CBI to the Agency?
Do not submit information that you consider to be CBI
electronically through EPA's electronic public docket or by e-mail. You
may claim information that you submit to EPA as CBI by marking any part
or all of that information as CBI (if you submit CBI on disk or CD ROM,
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 CBI). Information so marked will not be disclosed except in
accordance with procedures set forth in 40 CFR part 2.
In addition to one complete version of the comment that includes
any 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 and EPA's electronic public docket. If you submit
the copy that does not contain CBI on disk or CD ROM, mark the outside
of the disk or CD ROM clearly that it does not contain CBI. Information
not marked as CBI will be included in the public docket and EPA's
electronic public docket without prior notice. If you have any
questions about CBI or the procedures for claiming CBI, please consult
the person listed under FOR FURTHER INFORMATION CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
ID number assigned to this action in the subject line on the first page
of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in FFDCA section 408(d)(2); however,
EPA has not fully evaluated the sufficiency of the submitted data at
this time or whether the data support granting of the petition.
Additional data may be needed before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: October 9, 2003.
Janet L. Andersen,
Director, Biopesticides and Pollution Prevention Division, Office of
Pesticide Programs.
Summary of Petition
The petitioner's summary of the pesticide petition is printed below
as required by FFDCA section 408(d)(3). The summary of the petition was
prepared by the petitioner and represents the view of the petitioner.
The petition summary announces the availability of a description of the
analytical methods available to EPA for the detection and measurement
of the pesticide chemical residues or an explanation of why no such
method is needed.
Syngenta Seeds, Inc.
PP 3E6748
EPA has received a pesticide petition (PP 3E6748) from Syngenta
Seeds, Inc., P.O. Box 12257, 3054 Cornwallis Road, Research Triangle
Park, NC 27709-2257, proposing pursuant to section 408(d) of the FFDCA,
21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish an exemption
from the requirement of a tolerance for the plant-incorporated
protectant inert ingredient phosphomannose isomerase (PMI) marker
protein and the genetic material
[[Page 60385]]
necessary for its production in all plants in or on all food
commodities.
Pursuant to section 408(d)(2)(A)(i) of the FFDCA, as amended,
Syngenta Seeds, Inc. has submitted the following summary of
information, data, and arguments in support of their pesticide
petition. This summary was prepared by Syngenta Seeds, Inc. and EPA has
not fully evaluated the merits of the pesticide petition. The summary
may have been edited by EPA if the terminology used was unclear, the
summary contained extraneous material, or the summary unintentionally
made the reader conclude that the findings reflected EPA's position and
not the position of the petitioner.
A. Product Name and Proposed Use Practices
Phosphomannose isomerase (PMI) and the genetic material necessary
for its production is proposed for use as an inert ingredient in plants
producing a plant-incorporated protectant active ingredient. Production
of PMI in plant cells allows for selection and growth of genetically
transformed plant cells in the presence of mannose as the sole or
primary carbon source. PMI has no pesticidal activity. Its use allows
the identification of plant cells that have successfully acquired the
genetic material necessary to produce a plant-incorporated protectant.
B. Product Identity/Chemistry
1. Identity of the pesticide and corresponding residues. PMI is a
ubiquitous enzyme that catalyzes the reversible interconversion of
mannose-6-phosphate and fructose-6-phosphate. No other natural
substrates for PMI are known. The pmi gene (also known as the manA
gene) that encodes the PMI enzyme in transformed plants was derived
from E. coli strain K-12. The gene encodes a 391-amino acid protein
with an apparent of molecular weight of ca. 45,000. Functionally
equivalent PMI enzymes with significant amino acid homology to this PMI
protein have been identified among many diverse organisms including
other bacteria, plants, fungi, insects, nematodes, mammals, and
including humans. Unlike the traditional selectable markers used in
plant cell transformation, PMI does not confer resistance to an
antibiotic or herbicide.
2. Magnitude of residue at the time of harvest and method used to
determine the residue. A determination of the magnitude of residue at
harvest is not required for residues exempt from tolerances. However,
the petitioner has provided data on the quantity of PMI protein
measured in various plant parts representing an initial line of
transformed corn plants. PMI was detected in grain from these corn
plants at ca. 1-2 parts per million (ppm) on a dry- or fresh-weight
basis, as measured by enzyme-linked immunosorbent assay (ELISA).
Average PMI levels measured in chopped whole transformed corn plants
were less than or equal to ca. 5 ppm on a dry-weight basis and less
than or equal to ca. 1 ppm on a fresh-weight basis. In silage prepared
from the same line of transformed corn plants, no PMI was detectable
after 29 days.
3. A statement of why an analytical method for detecting and
measuring the levels of the pesticide residue are not needed. An
analytical method is not required because this petition requests an
exemption from tolerances. However, the petitioner has submitted an
analytical method for detection of the PMI protein by ELISA.
C. Mammalian Toxicological Profile
Syngenta Seeds, Inc. is providing the results of a mammalian
toxicology study, in vitro digestibility study, heat stability study
and bioinformatics evaluations conducted on the selectable marker
protein PMI. These studies, summarized herein, demonstrate the lack of
toxicity of the PMI protein following acute oral exposure to mice,
rapid degradation of PMI upon exposure to simulated gastric and
intestinal fluids, instability of the PMI protein upon heating, and the
lack of significant amino acid sequence homology of the PMI protein to
proteins known to be mammalian toxins or human allergens.
When proteins are toxic, they are known to act via acute mechanisms
and at very low doses (Sjoblad, R.D., J.T. McClintock, and R. Engler
(1992) Toxicological considerations for protein components of
biological pesticide products. Regulatory Toxicol. Pharmacol. 15: 3-9).
Therefore, when a protein demonstrates no acute oral toxicity in high-
dose testing using a standard laboratory mammalian test species, this
supports the determination that the protein will be non-toxic to humans
and other mammals, and will not present a hazard under any realistic
exposure scenario, including long-term exposures.
Because it is not feasible to extract sufficient PMI protein from
transformed plants for toxicology studies, PMI protein was produced in
recombinant E. coli by over-expressing the same pmi gene that was
introduced into transformed corn plants. The PMI protein encoded in
this E. coli system was identical in amino acid sequence to that
encoded in the transformed plants, except for additional N-terminal
amino acids representing 13 amino acids from the T7 Tag\TM\ and 3 amino
acids from the vector polylinker. Following purification from E. coli,
dialysis and lyophilization, the resulting sample, designated test
substance PMI-0198, was estimated by ELISA to contain ca. 61% PMI
protein by weight. PMI as contained in this test substance was
enzymatically active, had the predicted apparent molecular weight, and
immunoreacted with anti-PMI antibody. Side-by-side comparisons of PMI
in test substance PMI-0198 with PMI extracted from transformed corn
plants indicated that the proteins are substantially equivalent, as
measured by enzymatic activity, apparent molecular weight, and immuno-
crossreactivity with anti-PMI antibody. This justified the use of test
substance PMI-0198 in safety studies as a surrogate for PMI as produced
in transformed plants.
An acute mouse oral toxicity study was conducted according to EPA
Harmonized Test Guideline OPPTS 870.1100. Test substance PMI-0198 was
administered to seven male and six female mice via a gavage dose of
5,050 milligrams/kilogram body weight (mg/kg bwt), representing ca.
3,080 mg of pure PMI protein/kg bwt. A negative control group (six
males and five females) concurrently received the dosing vehicle alone,
a suspension of 0.5% carboxymethylcellulose, at the same dosing volume
used for the test substance mixture. No test substance-related
mortalities or clinical signs of toxicity occurred during the study.
One male in the control group and two males in the test group died as a
result of a perforated esophagus due to dosing error. Gross necropsy of
the remaining mice at study termination revealed no observable
abnormalities. Body weight, body weight gain, and organ weights (brain,
liver, kidneys, and spleen) were comparable in the control and test
groups. There was no evidence of toxicity. Accordingly, the lethal dose
(LD)50 value for PMI-0198 in male and female mice is greater
than 5,050 mg/kg bwt, and the LD50 value for pure PMI
protein is greater than 3,080 mg/kg bwt, the single dose tested.
Extensive bioinformatics searches of public protein data bases
revealed that the PMI protein shows no significant amino acid homology
to proteins known to be mammalian toxins or known or suspected to be
human allergens. Additional information and testing indicate that the
PMI protein does not have properties that would suggest it has the
potential to become a food allergen. The source of PMI (E. coli) is not
known to produce allergens. Unlike
[[Page 60386]]
allergenic proteins, which typically are present at 1-80% of the total
protein in an offending food, the average PMI concentration measured in
raw grain derived from a line of transformed corn plants represents
less than 0.00002% of the total protein. (This calculation is based on
corn grain containing 10% total protein by weight, and assumes 2 ppm
PMI in the grain.) Additionally, due to degradation via food processing
methods, PMI will not likely be present in processed food products, or
will be present in only trace quantities. PMI produced in transformed
plants is not targeted to a cellular pathway for glycosylation. PMI
activity, and therefore tertiary protein structure, is lost upon
heating at 65 degrees C for 30 minutes. PMI rapidly degrades upon
exposure to simulated mammalian gastric and intestinal fluids.
The genetic material occurring in the subject inert ingredient has
been adequately characterized. This genetic material (i.e., the nucleic
acids deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)),
including regulatory regions, necessary for the production of PMI as an
inert ingredient in all crops will not present a dietary safety
concern. ``Regulatory regions'' are the DNA sequences such as
promoters, terminators, and enhancers that control the expression of
the genetic material encoding the protein. Based on the ubiquitous
occurrence and established safety of nucleic acids in the food supply,
a tolerance exemption under the FFDCA regulations has been established
for residues of nucleic acids that are part of plant-incorporated
protectants or associated inert ingredients 40 CFR 174.475 (66 FR
37817) (FRL-6057-5). Therefore, no mammalian toxicity is anticipated
from dietary exposure to the genetic material necessary for the
production of PMI protein in all crops.
D. Aggregate Exposure
1. Dietary exposure--i. Food. Due to the ubiquitous occurrence of
PMI in nature, it is conceivable that the human diet has always
contained small amounts of PMI proteins that are similar to that
produced in plants transformed with the E. coli pmi gene. The levels of
PMI measured in raw grain from a line of transformed corn plants
averaged ca. 1-2 ppm. Processed plant products or by-products used in
food are unlikely to have measurable PMI protein, or will have only
trace amounts. Oral exposure is not expected to result in adverse
health effects, because of a demonstrated lack of toxicity to mammals
and the rapid digestibility of the PMI protein. It is expected that any
PMI protein consumed will be digested as conventional dietary protein.
ii. Drinking water. Little to no exposure via drinking water is
anticipated. Due to the demonstrated mammalian safety profile of PMI,
such exposure would not present a risk.
2. Non-dietary exposure. Non-dietary exposure is not anticipated,
due to the proposed use pattern of the product. Exposure via dermal or
inhalation routes is unlikely because the inert ingredient is contained
within plant cells. However, if exposure were to occur by non-dietary
routes, no risk would be expected because the PMI protein is not toxic
to mammals.
E. Cumulative Exposure
Because there is no indication of mammalian toxicity of the PMI
protein or the genetic material necessary for its production, it is
reasonable to conclude that there will be no cumulative effects for
this inert ingredient.
F. Safety Determination
1. U.S. population. The lack of mammalian toxicity at high levels
of exposure to the PMI protein demonstrates the safety of the product
at levels well above possible maximum exposure levels anticipated via
consumption of food products produced from pmi-transformed plants.
Moreover, little to no human dietary exposure to PMI protein is
expected to occur via pmi-transformed food crops. Due to the
digestibility and lack of toxicity of the PMI protein, and its very low
potential to become an allergen in food, dietary exposure is not
anticipated to pose any harm for the U.S. population. No special safety
provisions are applicable for consumption patterns or for any
population sub-groups.
2. Infants and children. Based on the mammalian safety profile of
the inert ingredient and the proposed use pattern, there is ample
evidence to conclude a reasonable certainty of no harm to infants and
children.
G. Effects on the Immune and Endocrine Systems
The inert ingredient is derived from sources that are not known to
exert an influence on the endocrine or immune systems.
H. Existing Tolerances
The registrant is not aware of any known existing tolerances or
exemptions for PMI and the genetic material necessary for its
production as an inert ingredient.
I. International Tolerances
The registrant is not aware that any Codex maximum residue levels
exist for the PMI protein and the genetic material necessary for its
production.
[FR Doc. 03-26412 Filed 10-21-03; 8:45 am]
BILLING CODE 6560-50-S