Document ID: EPA-HQ-OPP-2007-0346-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-01T04:00Z

EPA BIOPESTICIDES AND POLLUTION PREVENTION DIVISION COMPANY NOTICE OF
FILING TEMPLATE FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL
REGISTER 

(03/09/07)

EPA Biopesticides and Pollution Prevention Division contact:  Mike
Mendelsohn, telephone number:  703-308-8715 PRIVATE  

COMMENT 1] 	[Comment 1] PRIVATE  Monsanto Company tc  \l 1 "Monsanto
Company" 

[COMMENT 2] 	[Insert petition number]

	

[COMMENT 3] 	EPA has received a pesticide petition [insert petition
number] from Monsanto Company, 800 North Lindbergh Blvd., St. Louis, MO
63167, proposing pursuant to section 408(d) of the Federal  Food, Drug,
and Cosmetic Act (FFDCA),  21 U.S.C. 346a(d), to amend 40 CFR part 180 

[COMMENT 4]	NA-Remove

[COMMENT 5]	 NA-Remove

[COMMENT 6]	to remove time limitation from the temporary exemption from
the requirement of a tolerance for the 

[COMMENT 7]	NA-Remove

[COMMENT 8]	NA-Remove

[COMMENT 9]	plant-incorporated protectant Bacillus thuringiensis Cry2Ab2
protein and the genetic material necessary for its production in all
crops and agricultural commodities.  EPA is being petitioned to
establish a permanent tolerance exemption as part of the registration of
insect-protected corn MON 89034. 

	

[COMMENT 10]	Pursuant to section 408(d)(2)(A)(i) of the FFDCA, as
amended, Monsanto Company has submitted the following summary of
information, data, and arguments in support of their pesticide petition.
 This summary was prepared by Monsanto Company; The summary may have
been edited by EPA to clarify terminology, remove extraneous material,
or if the summary unintentionally made the reader conclude that the
findings reflected EPA’s position and not the position of the
petitioner. 

[COMMENT 11]	I.  Monsanto Company Petition Summary

    

[COMMENT 12]	[Insert petition number]

[COMMENT 13]	A.  Product name and Proposed Use Practices 

	

[COMMENT 14]	Corn has been genetically modified to produce Bacillus
thuringiensis (Bt) Cry1A.105 and Cry2Ab2 proteins.  Plants producing
these proteins are derived from transformation events that contain the
insecticidal proteins and the genetic material necessary for their
expression in corn (vector ZMIR245).  The combination of Cry2Ab2 and
Cry1A.105 proteins provides a broad spectrum of activity against
lepidopteran insect pests and a tool for management of potential insect
resistance.  Both the Cry1A.105 and Cry2Ab2 proteins have been fully
characterized and no adverse effects were observed for human health and
environmental safety.

[COMMENT 15]	B.  Product Identity/Chemistry 

	

[COMMENT 17]	Identity of the pesticide and corresponding residues.  

[COMMENT 18]	The Cry2Ab2 protein is derived from Bacillus thuringiensis
subsp. kurstaki and has greater than 99% sequence identity to the wild
type Cry2Ab.  The Cry2Ab2 protein has been previously expressed in corn
(MON 84006) and cotton (MON 15985); the protein's safety has been fully
characterized.  The Cry2Ab2 safety assessment has been reviewed by EPA. 
An exemption from the requirement of a tolerance was issued for cotton
in 2004 (40 CFR §180.1215).  A temporary tolerance exemption was
granted for the Cry2Ab2 protein produced in corn in June 2006 (40 CFR
§174.454).

[COMMENT 20]	Magnitude of residue at the time of harvest and method used
to determine the residue.

[COMMENT 21]	Cry2Ab2 residue data are not required for an assessment of
human health effects because of the lack of mammalian toxicity.

	

 [COMMENT 23]	 A statement of why an analytical method for detecting and
measuring the levels of the pesticide residue is not needed.

[COMMENT 24]	 An analytical method is not required because this petition
requests an exemption from tolerances.  A validated ELISA method and an
analytical method for detection of the Cry2Ab2 protein are available and
allow for identification of MON 89034 corn.

[COMMENT 25]	C.  Mammalian Toxicological Profile	

Cry proteins have been used safely and effectively as pest control
agents in microbial Bt formulations for more than 45 years.  The
numerous toxicology studies conducted with these microbial products show
no significant adverse effects, and demonstrate that the products are
nontoxic to mammals.  

Data have been submitted demonstrating the lack of mammalian toxicity at
high levels of exposure to purified Cry2Ab2 protein.  These data
demonstrate the safety of the protein at levels well above maximum
possible exposure levels that are reasonably anticipated in crops.  This
conclusion is consistent with the Agency position regarding toxicity and
residue data requirements for the microbial Bt products which utilize
the same proteins as these plant-incorporated protectants (40 CFR
§158.740(b)(2)(i)).  For microbial products, further toxicity and
residue testing are only triggered by significant acute effects in
studies such as the mouse oral toxicity study.  

When proteins are toxic, they are known to act via acute mechanisms and
at very low levels (Sjoblad et al. “Toxicological Considerations for
Protein Components of Biological Pesticide Products.”  Reg. Toxicol.
Pharmacol. 15:3-9, 1992).  Acute oral toxicity studies have been
evaluated for Cry2Ab2 protein.  Cry2Ab2 protein with evaluated safety
has been placed in toxicity category IV due to the lack of any evidence
of toxicity.  Furthermore, amino acid sequence comparisons of the
Cry2Ab2 protein to known toxic proteins showed no similarities.

Because Cry2Ab2 is a protein, the potential for allergic sensitivities
was evaluated.  Common food allergens are present at high concentrations
in food, are resistant to pepsin digestion, may be resistant to acid or
heat, and can be glycosylated.  Data have been submitted demonstrating
that the Cry2Ab2 protein is rapidly degraded by simulated gastric fluid
in vitro.  In a solution of simulated gastric fluid, complete
degradation of the detectable Cry2Ab2 protein occurred within 30 seconds
of incubation.  

An analysis of amino acid sequences of known allergens uncovered no
evidence of sequence homology with the Cry2Ab2 protein, even at the
level of eight contiguous amino acid residues.  

The genetic material encoding the Cry2Ab2 proteins and the regulatory
regions controlling expression of the cry2Ab2 gene are nucleic acids
(DNA and RNA).  DNA and RNA occur in all forms of plant and animal life
and there is no documented instance of nucleic acids being associated
with toxic effects when consumed as a component of food.  DNA and RNA
are in the category of substances generally considered as safe (GRAS). 
EPA exempts nucleic acids from the FFDCA Section 408 requirements.  Data
characterizing the genetic material necessary for the production of
Cry2Ab2 in corn were provided to the Agency.  No mammalian toxicity is
anticipated from dietary exposure to the genetic material necessary for
production of the subject plant-incorporated protectant.  

[COMMENT 26]	D.  Aggregate Exposure

[COMMENT 28]	Dietary exposure

[COMMENT 29]	Cry2Ab2 is a plant-incorporated protectant in corn, thus
dietary exposure is deemed to be the most relevant route for assessing
human risk.

	

[COMMENT 31]	Food

[COMMENT 32]	Monsanto has considered available information on the
aggregate exposure levels to consumers and major identifiable groups of
consumers to the protein residue and related substances.  These
considerations include dietary exposure under the tolerance exemptions
in effect for the plant-incorporated protectant residue, and exposure
from non-occupational sources.  Oral exposure may occur at very low
levels from ingestion of processed corn products.  However, a lack of
mammalian toxicity and the rapid digestibility of the plant-incorporated
protectants have been demonstrated.

	

[COMMENT 34]	Drinking water

[COMMENT 35]	Oral exposure from ingestion of drinking water is unlikely
because the proteins are present at low levels within the plant and
previously submitted studies demonstrate that Cry2Ab2 protein are
rapidly degraded in soil and, therefore, are not present in drinking
water. 

	

[COMMENT 37]	Non-dietary exposure

[COMMENT 38]	Exposure via skin or inhalation is not likely because the
plant-incorporated protectants are contained within plant cells, which
essentially eliminates these exposure routes or reduces them to
negligible levels.  The use sites for the Cry2Ab2 protein are all
agricultural for control of insects.  Exposure to workers and bystanders
resulting from plant pesticides will be negligible and unlikely to add
measurably to any exposure resulting from microbial or other Bacillus
thuringiensis formulations.  Exposure to infants and children via
residential or lawn use is not expected.

[COMMENT 39]	E.  Cumulative Exposure  

	

[COMMENT 40]	Because there is no indication of mammalian toxicity to the
plant-incorporated protectants there will be no opportunity for
cumulative toxic effects.

[COMMENT 41]	F.  Safety Determination 

	

 [COMMENT 43] 	U.S. population

[COMMENT 44]	Sufficient data have been submitted to assess the health
risk of Cry2Ab2 protein and the genetic material necessary for their
production in all raw agricultural commodities.  The absence of toxicity
in high dose acute oral studies, the lack of sequence homology with
known protein toxins, rapid digestion in a gastric matrix, and minimal
allergenicity potential provide a reasonable certainty of no harm for
the U.S. general population potentially exposed to the Cry2Ab2 protein.

		

[COMMENT 46]	Infants and children

[COMMENT 47]	Non-dietary exposure to infants and children is not
anticipated due to the patterns of use for these plant-incorporated
protectants.  The submitted data provide no evidence of adverse
threshold effects for the Cry2Ab2 protein that would warrant application
of an additional safety factor for the protection of infants and
children.  Furthermore, the provisions for consumption patterns, special
susceptibility, and cumulative effects do not apply.

[COMMENT 48]	G.  Effects on the Immune and Endocrine Systems

[COMMENT 49]	The lack of Cry2Ab2 homology to known toxins and allergens
and their rapid degradation in a mammalian digestive system suggests
minimal risk for adverse effects on the immune system.  These pesticidal
active ingredients are proteins derived from sources that are not known
to exert an influence on the endocrine system.

[COMMENT 50]	H.  Existing Tolerances

	

[COMMENT 51]	 The Bacillus thuringiensis Cry2Ab2 protein and the genetic
material necessary for its production in corn is exempt from the
requirement of a tolerance when used as a plant incorporated protectant
in food and feed commodities of field corn, sweet corn, and popcorn
until June 30, 2009 (40 CFR §174.454). 

[COMMENT 52]	I.  International Tolerances

[COMMENT 53]	No Codex maximum residue levels have been established for
these plant-incorporated protectants at this time.

Monsanto Company	04-CR-138E-3	Page   PAGE  1  of   NUMPAGES  5 

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