[Federal Register Volume 62, Number 195 (Wednesday, October 8, 1997)]
[Rules and Regulations]
[Pages 52505-52509]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-26190]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300552; FRL-5745-2]
RIN 2070-AB78
Glyphosate Oxidoreductase and the Genetic Material Necessary for
Its Production in All Plants; Exemption From Tolerance Requirement On
All Raw Agricultural Commodities
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This document establishes an exemption from the requirement
of a tolerance for residues of the plant-pesticide inert ingredients
glyphosate oxidoreductase (GOX) and the genetic material necessary for
its production in all plants when used as plant-pesticides in or on all
raw agricultural commodities (RACs). Monsanto Company submitted a
petition to EPA under the Federal Food, Drug, and Cosmetic Act (FFDCA)
as amended by the Food Quality Protection Act of l996 (FQPA) requesting
the exemption from the requirement of a tolerance. This regulation
eliminates the need to establish a maximum permissible level for
residues of this plant-pesticides in or on all RACS.
DATES: This regulation is effective on October 8, 1997. Written
objections and requests for hearings must be received by EPA on or
before December 8, 1997.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number OPP-300552, may be submitted to: Hearing Clerk
(1900), Environmental Protection Agency, Rm. M3708, 401 M St., SW.,
Washington, DC 20460. Fees accompanying objections and hearing requests
shall be labeled ``Tolerance Petition Fees'' and forwarded to: EPA
Headquarters Accounting Operations Branch, OPP (Tolerance Fees), P.O.
Box 360277M, Pittsburgh, PA 15251. A copy of any objections and hearing
requests filed with the Hearing Clerk should be identified by the
docket control number OPP-300552 and submitted to: Public Information
and Records Integrity Branch, Information Resources and Services
Division (7506C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. In person,
bring a copy of objections and hearing requests to: Rm. 1132, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by sending electronic mail
(e-mail) to:
opp-docket@epamail.epa.gov.
Copies of objections and hearing requests must be submitted as an
ASCII file avoiding the use of special characters and any form of
encryption. Copies of objections and hearing requests will also be
accepted on disks in WordPerfect in 5.1 file format or ASCII file
format. All copies of objections and hearing requests in electronic
form must be identified by the docket control number OPP-300552. No
Confidential Business Information (CBI) should be submitted through e-
mail. Additional information on CBI can be found in VII. of this
document. Electronic copies of objections and hearing requests on this
rule may be filed online at many Federal Depository Libraries.
Additional information on electronic submissions can be found in Unit
VIII. of this document.
FOR FURTHER INFORMATION CONTACT: By mail: Mike Mendelsohn,
Biopesticides and Pollution Prevention Division, Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location, telephone number, and
[[Page 52506]]
e-mail address: 5th Floor Crystal Station, 2800 Crystal Drive,
Arlington, VA , (703) 308-8715); e-mail:
mendelsohn.mike@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: In the Federal Register of January 24, 1997
(62 FR 3682) (FRL-5380-2), EPA issued a notice pursuant to section
408(d) of FFDCA, 21 U.S.C. 346a(d) announcing the filing of a pesticide
petition for an exemption from the requirement for a tolerance by
Monsanto Company, 700 Chesterfield Parkway, North St. Louis, MO 63198.
The notice contained a summary of the petition prepared by the
petitioner and this summary contained conclusions and arguments to
support its conclusion that the petition complied with the FQPA (Pub.
L. 104-170). The petition requested that an exemption from the
requirement of a tolerance be established for the plant-pesticides GOX
and the genetic material necessary for its production in plants in or
on all RACS. There were no comments or requests for referral to an
advisory committee received in response to the notice of filing. The
data submitted in the petition and other relevant material have been
evaluated. The toxicology and other data listed below were considered
in support of this exemption from the requirement of a tolerance.
I. Risk Assessment and Statutory Findings
New section 408(c)(2)(A)(I) of FFDCA allows EPA to establish an
exemption from the requirement of a tolerance (the legal limit for a
pesticide chemical residue in or on a food) only if EPA determines that
the tolerance is ``safe'' to mean that ``there is a reasonable
certainty that no harm will result from aggregate exposure to the
pesticide chemical residue, including all anticipated dietary exposures
and all other exposures for which there is reliable information.'' This
includes exposure through drinking water and in residential settings,
but does not include occupational exposure. Section 408(c)(2)(B) of
FFDCA requires EPA to give special consideration to exposure of infants
and children to the pesticide chemical residue in establishing a
tolerance and to ``ensure that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to the
pesticide chemical residue...'' EPA performs a number of analyses to
determine the risks from aggregate exposure to pesticide residues.
First, EPA determines the toxicity of pesticides. Second, EPA examines
exposure to the pesticide through food, drinking water, and through
other exposures that occur as a result of pesticide use in residential
settings.
II. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D) of FFDCA, EPA has reviewed the
available scientific data and other relevant information in support of
this action and considered its validity, completeness, and reliablitiy
and the relationship of this information to human risk. EPA has
sufficient data to assess the hazards of glyphosate oxidoreductase
(GOX), and to make a determination on aggregate exposure, consistent
with section 408(c)(2) of FFDCA, for an exemption from the requirement
of a tolerance for residues GOX in or on all RACS. EPA's assessment of
the dietary exposures and risks associated with establishing the
exemption follows.
A. Toxicological Profile
Glyphosate oxidoreductase (GOX) catalyzes the conversion of
glyphosate to aminomethylphosphonic acid (AMPA) and glyoxylate in a 1:1
stoichiometry while consuming \1/2\ mole of oxygen as a cosubstrate.
GOX requires flavin adenine dinucleotide (FAD) and magnesium for
activity; therefore, it is more appropriately designated an apoenzyme.
The gene for Gox was originally isolated from Achromobacter sp.
Strain LBAA. The GOX protein was then sequenced and the gene was
synthesized with an added signal sequence and the codons modified in
the guanine and cytosine nucleic acid (GC) content to yield higher
plant expression. Two modified GOX proteins are specified in this rule.
They are designated GOX and GOXv247. Both versions have an identifier
of ``(M4-C1)'' in the data submissions which indicates that the protein
was expressed in E. coli for testing purposes. The GOX protein retains
the same amino acid sequence as the native protein and has additional
four amino acid sequence N-terminus (reminanats of an added signal
sequence). In GOXv247, the gene sequence of the native protein was
altered resulting in changes to three amino acids in the sequence of
the resulting protein along with the remains of the added signal
sequence mentioned previously. These changes did not negatively affect
the enzymatic activity of either protein.
The GOX variants GOX and GOXv247, expressed in E. coli and
originating from the synthetic GOX gene optimized for protein
expression in plants, showed similarity to the native GOX protein when
expressed in E. coli. These similarities are seen as comparable
molecular weights, immunoreactivity, amino acid sequence and enzymatic
activity.
The data submitted regarding potential health effects of GOX and
GOXv247 includes information on the characterization of the expression
of GOX in corn, the acute oral toxicity of GOX and GOXv247, and in
vitro digestibility studies of the proteins. The applicability of the
results of these studies to evaluate human risk and the validity,
completeness, and reliability of the available data from the studies
were considered.
Both variants of the GOX protein (GOX and GOXv247) are rapidly
degraded in simulated gastric fluid (GF) and simulated intestinal fluid
(IF). After a fifteen-second incubation in GF, both variants have less
than 90% of their initial protein epitopes by western blot analysis.
Enzyme activity loss is also greater than 90% in both GOX variants when
assayed after a 1-minute incubation in GF. Similar results are seen in
simulated IF. Western blot assays show that both variants are greater
than 90% degraded by 30-second incubation in IF. However, the enzyme
activity assays show that the GOX activity lasts longer in IF than
variant GOXv247. After a 10-minute IF incubation, the activity
decreased to about 48% of initial for GOX whereas GOXv247 was already
greater than 90% inactive.
Two findings, found in the in vitro digestibility studies, that are
remarkable are: GOXv247 displays a more rapid degradation in the IF
compared to unaltered GOX, apparently due to the single amino acid
substitutions; and antibody recognition is lost prior to a significant
loss of enzyme activity indicating that western blots may not always
accurately track functional protein degradation.
None of the amino acid sequences of known allergens or proteins
involved in coeliac disease were shown to have similarity to the GOX
protein as defined by eight identical and contiguous amino acids in a
sequence. However, the assertion that a lack of allergenicity can be
established by comparison of sequences to known allergens is
questionable. While this is the best approximation at present, there is
no scientific basis to assume that the presence of eight contiguous and
homologous amino acids in a protein will predict its allergenicity. The
assumption is based on the finding that the presence of an eight amino
acid sequence in one allergen was associated with the epitope
responsible for IgE recognition. Alteration of this sequence
[[Page 52507]]
reduced IgE binding and hence allergenicity. The converse experiment,
to introduce the sequence into a non-allergenic protein and create an
allergen, has not been attempted experimentally.
The acute oral toxicity test of bacterially-derived GOX and GOXv247
proteins showed no test substance related deaths at doses of 91.3
milligrams per kilogram (mg/kg) and 104 g/kg respectively.
Expression data on the GOX protein expressed in corn grains ranges from
undetectable levels to a high of 11.70 micro grams per gram (mg/g)
freshweight. This indicates that it would require 8,547 kg corn grain
per kg bodyweight to receive the 100 mg/kg dose that was administered
to the mice.
However, residue chemistry data were not required for a human
health effects assessment of the subject plant-pesticide inert
ingredients because of the lack of mammalian toxicity. Both available
information concerning the dietary consumption patterns of consumers
(and major identifiable subgroups of consumers including infants and
children) and safety factors which, in the opinion of experts qualified
by scientific training and experience to evaluate the safety of food
additives, are generally recognized as appropriate for the use of
animal experimentation data were not evaluated because the lack of
mammalian toxicity at high levels of exposure demonstrate the safety of
the product at levels above possible maximum exposure levels. This is
similar to the Agency position regarding toxicity and the requirement
of residue data for the microbial Bacillus thuringiensis. [See 40 CFR
158.740(b).] For microbial products, further toxicity testing to verify
the observed effects and clarify the source of the effects (Tiers II
and III) and residue data are triggered by significant acute effects in
studies such as the mouse oral toxicity study.
The acute oral toxicity data submitted support the prediction that
the GOX proteins would be non-toxic to humans. When proteins are toxic,
they are known to act via acute mechanisms and at very low dose levels
[Sjoblad, Roy D., et al. ``Toxicological Considerations for Protein
Components of Biological Pesticide Products,'' Regulatory Toxicology
and Pharmacology 15, 3-9 (1992)]. Therefore, since no effects were
shown to be caused by the plant-pesticides, even at relatively high
dose levels, the GOX protein is not considered toxic.
Adequate information was submitted to show that the GOX test
materials derived from microbial cultures was biochemically and,
functionally similar to the proteins produced by the plant-pesticide
inert ingredient in corn. Production of microbially produced protein
was chosen in order to obtain sufficient material for testing. In
addition, the in vitro digestibility studies indicate the proteins
would be rapidly degraded following ingestion.
The genetic material necessary for the production of the plant-
pesticides active and inert ingredients are the nucleic acids (DNA)
which comprise genetic material encoding these proteins and) their
regulatory regions. ``Regulatory regions'' are the genetic material
that control the expression of the genetic material encoding the
proteins, such as promoters, terminators, and enhancers. DNA is common
to all forms of plant and animal life and the Agency knows of no
instance where these nucleic acids have been associated with toxic
effects related to their consumption as a component of food. These
ubiquitous nucleic acids as they appear in the subject plant-pesticide
inert ingredient have been adequately characterized by the applicant.
Therefore, no mammalian toxicity is anticipated from dietary exposure
to the genetic material necessary for the production of the subject
active and inert plant pesticidal ingredients.
B. Sensitivity of Subgroups
The Agency has considered available information on the variability
of the sensitivities of major identifiable subgroups of consumers
including infants and children and the physiological differences
between infants and children and adults and effects of in utero
exposure to the plant-pesticides. Since GOX is a protein, allergenic
sensitivities were considered. Current scientific knowledge suggests
that common food allergens tend to be resistant to degradation by heat,
acid, and proteases, are glycosylated and are present at high
concentrations in the food. Data has been submitted which demonstrate
that the GOX proteins are rapidly degraded by gastric fluid in vitro
and are non-glycosylated. Thus, the potential for the GOX proteins to
be a food allergens is minimal.
C. Cumulative Effects
The Agency has considered available information on the cumulative
effects of such residues and other substances that have a common mode
toxicity. These considerations included the cumulative effects on
infants and children of such residues and other substances with a
common mechanism of toxicity. Because there is no indication of
mammalian toxicity to these plant-pesticides, there are no cumulative
effects.
D. Aggregate Exposures
The Agency has considered available information on the aggregate
exposure levels of consumers (and major identifiable subgroups of
consumers) to the pesticide chemical residue and to other related
substances. These considerations include dietary exposure under the
tolerance exemption and all other tolerances or exemptions in effect
for the plant-pesticides chemical residue, and exposure from non-
occupational sources. Exposure via the skin or inhalation is not likely
since the plant-pesticides are contained within plant cells which
essentially eliminates these exposure routes or reduces these exposure
routes to negligible. Oral exposure, at very low levels, may occur from
ingestion of processed food products and drinking water. However a lack
of mammalian toxicity and the digestibility of the plant-pesticides has
been demonstrated. Regarding exposure via residential or lawn use to
infants and children, the Agency concludes that such exposure would
present no risk due to the lack of toxicity.
Section 408 of FFDCA provides that EPA shall apply an additional
10-fold margin of exposure (MOE) (safety) for infants and children in
the case of threshold effects to account for pre- and post-natal
toxicity and the completeness of the database unless EPA determines
that a different MOE (safety) will be safe for infants and children. In
this instance EPA believes there is reliable data to support the
conclusion that the plant-pesticides are not toxic to mammals,
including infants and children, and thus there are no threshold effects
of concern. As a result, the provision requiring an additional MOE does
not apply.
III. Endocrine Effects
EPA does not have any information regarding endocrine effects for
these kinds of pesticides at this time. The Agency is not requiring
information on the endocrine effects of these plant-pesticides at this
time; and Congress allowed 3 years after August 3, 1996, for the Agency
to implement a screening and testing program with respect to endocrine
effects.
IV. Analytical Method
The Agency is establishing an exemption from the requirement of a
tolerance without numerical limitation; therefore, it has concluded
that an analytical method is not required for enforcement purposes for
GOX and the genetic material necessary for their production.
[[Page 52508]]
V. Conclusion
There is a reasonable certainty that no harm will result from
aggregate exposure to the U.S. population, including infants and
children, to the GOX protein and the genetic material necessary for
that production. This includes all anticipated dietary exposures and
all other exposures for which there is reliable information. The Agency
has arrived at this conclusion because, as discussed above, no toxicity
to mammals has been observed for the plant-pesticides. As a result, EPA
establishes an exemption from tolerance requirements pursuant to
section 408(j)(3) of FFDCA for GOX and the genetic material necessary
for their production in all plants.
Glyphosate Oxidoreductase [GOX or GOXv247] and the genetic
material necessary for its production in all plants are exempt from the
requirement of a tolerance when used as plant-pesticide inert
ingredients in all plant RACs. ``Genetic material necessary for its
production'' means the genetic material which comprise genetic material
encoding the GOX proteins and their regulatory regions. ``Regulatory
regions'' are the genetic material that control the expression of the
genetic material encoding the GOX proteins, such as promoters,
terminators, and enhancers.
VI. Objections and Hearing Requests
The new FFDCA section 408(g) provides essentially the same process
for persons to ``object'' to a regulation for an exemption from the
requirement of a tolerance issued by EPA under new section 408(d) of
FFDCA as was provided in the old section 408 and in section 409 of
FFDCA. However, the period for filing objections is 60 days, rather
than 30 days. EPA currently has procedural regulations which governs
the submission of objections and hearing requests. These regulations
will require some modification to reflect the new law. However, until
those modifications can be made, EPA will continue to use those
procedural regulations with appropriate adjustments to reflect the new
law.
Any person may, by December 8, 1997 file written objections to any
aspect of this regulation and may also request a hearing on those
objections. Objections and hearing requests must be filed with the
Hearing Clerk, at the address given under the ``ADDRESSES'' section (40
CFR 178.20). A copy of the objections and/or hearing requests filed
with the Hearing Clerk should be submitted to the OPP docket for this
rulemaking. The objections submitted must specify the provisions of the
regulation deemed objectionable and the grounds for the objections (40
CFR 178.25). Each objection must be accompanied by the fee prescribed
by 40 CFR 180.33(i). If a hearing is requested, the objections must
include a statement of the factual issue(s) on which a hearing is
requested, the requestor's contentions on such issues, and a summary of
any evidence relied upon by the objector (40 CFR 178.27). A request for
a hearing will be granted if the Administrator determines that the
material submitted shows the following: There is a genuine and
substantial issue of fact; there is a reasonable possibility that
available evidence identified by the requestor would, if established,
resolve one or more of such issues in favor of the requestor, taking
into account uncontested claims or facts to the contrary; and
resolution of the factual issue(s) in the manner sought by the
requestor would be adequate to justify the action requested (40 CFR
178.32).
VII. Confidential Business Information
Information submitted in connection with an objection or hearing
request may be claimed confidential by marking any part or all of that
information as CBI. Information so marked will not be disclosed except
in accordance with procedures set forth in 40 CFR part 2. A copy not
contain CBI must be submitted for inclusion in the public record.
Information not marked confidential may be disclosed publicly by EPA
without prior notice.
VIII. Public Record and Electronic Submissions
EPA has established a record for this rulemaking under docket
control number OPP-300552 (including any comments and data submitted
electronically). A public version of this record, including printed,
paperversions of electronic comments, which does not in include any
information claimed as CBI, is available for inspection from 8:30 a.m.
to 4 p.m., Monday through Friday, excluding legal holidays. The public
record is located in Room 1132 of the Public Information and Records
Integrity Branch, Information Resources and Services Division (7506C),
Office of Pesticide Programs, Environmental Protection Agency, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.
Electronic comments may be sent directly to EPA at:
opp-docket@epamail.epa.gov.
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above, will be kept in paper form. Accordingly,
EPA will transfer any copies of objections and hearing requests
received electronically into printed, paper form as they are received
and will place the paper copies in the official rulemaking record. The
official rulemaking record is the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
IX. Regulatory Assessment
This final rule establishes an exemption from the tolerance
requirement under FFDCA section 408(d) in response to a petition
submitted to the Agency. The Office of Management and Budget (OMB) has
exempted these types of actions from review under Executive Order
12866, entitled Regulatory Planning and Review (58 FR 51735, October 4,
1993). This final rule does not contain any information collections
subject to OMB approval under the Paperwork Reduction Act (PRA),
44U.S.C. 3501 et seq., or impose any enforceable duty or contain any
unfunded mandate as described under Title II of the Unfunded Mandates
Reform Act of 1995 (UMRA) (P.L. 104-4). Nor does it require any prior
consultation as specified by Executive Order 12875, entitled Enhancing
the Intergovernmental Partnership (58 FR 58093, October 28, 1993), or
special considerations as required by Executive Order 12898, entitled
Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations (59 FR 7629, February 16, 1994),
or require OMB review in accordance with Executive Order 13045,
entitled Protection of Children from Environmental Health Risks and
Safety Risks (62 FR 19885, April 23, 1997).
In addition, since tolerances and exemptions that are established
on the basis of a petition under FFDCA section 408(d), such as the
exemption in this final rule, do not require the issuance of a proposed
rule, the requirements of the Regulatory Flexibility Act (RFA) (5
U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency previously
assessed whether establishing tolerances, exemptions from tolerances,
raising tolerance levels or expanding exemptions might adversely impact
small entities and concluded, as a generic matter, that there is no
adverse economic impact. The factual basis for the Agency's generic
certification for tolerance actions published on May 4, 1981 (46 FR
24950), and was provided
[[Page 52509]]
to the Chief Counsel for Advocacy of the Small Business Administration.
X. Submission to Congress and the General Accounting Office
Under 5 U.S.C. 801(a)(1)(A), as added by the Small Business
Regulatory Enforcement Fairness Act of 1996, the Agency has submitted a
report containing this rule and other required information to the U.S.
Senate, the U.S. House of Representatives, and the Comptroller General
of the General Accounting Office prior to publication of this rule in
today's Federal Register. This is not a ``major rule'' as defined by 5
U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: September 25, 1997.
Stephen L. Johnson,
Acting Director, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180--[AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
2. Section 180.1190 is added to subpart D to read as follows:
Sec. 180.1190 Glyphosate Oxidoreductase [GOX or GOXv247] and the
genetic material necessary for its production in all plants; exemption
from the requirement of a tolerance.
Glyphosate Oxidoreductase [GOX or GOXv247] and the genetic
material necessary for its production in all plants are exempt from the
requirement of a tolerance when used as plant-pesticide inert
ingredients in all plant RACs. Genetic material necessary for its
production means the genetic material which comprise genetic material
encoding the GOX proteins and their regulatory regions. Regulatory
regions are the genetic material that control the expression of the
genetic material encoding the GOX proteins, such as promoters,
terminators, and enhancers.
[FR Doc. 97-26190 Filed 10-7-97; 8:45 am]
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