[Federal Register Volume 68, Number 204 (Wednesday, October 22, 2003)]
[Notices]
[Pages 60383-60386]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-26412]



[[Page 60383]]

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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: [email protected].

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

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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 [email protected], 
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

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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

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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