Syngenta ECRY3.1AB

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- 2 Page 9 of 13 EPA BIOPESTICIDES AND POLLUTION PREVENTION DIVISION COMPANY

NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE

FEDE RAL REGISTER

EPA Biopesticides and Pollution Prevention Division contact: hollis.linda@epa.gov ;

Syngenta Seeds, Inc.

[Insert petition number]

EPA has received a pesticide petition ( [insert petition number] ) from Syngenta Seeds, Inc.

, P.O. Box 12257, 3054 E. Cornwallis Road, Research Triangle Park, NC

27709

- 2257 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 174 .532

1. NA

- Remov e

2. NA

- Remove

3. to establish an amendment/exp ansion of an existing tolerance exemption for

the

1. NA

- Remove

2. NA

- Remove

3. plant

- pesticide Bacillus thuringiensis eCry3.1Ab insect control protein in or

on corn.

Pursuant to section 408(d)(2)(A)(i) of the FFDCA, as ame nded, 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 petitio n. 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 petiti oner.

I. Syngenta Seeds, Inc. Petition Summary

[Insert petition number]

A. Product Name and Proposed Use PracticesSyngenta ECRY3.1AB

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- 2 Page 10 of 13 This notice of filing summarizes the information submitted and cited by Syngenta

Seeds in support of a request for a temporary exempti on from the requirement of a

tolerance for the Bacillus thuringiensis eCry3.1Ab protein and the genetic material necessary for its production in corn

. The eCry3.1Ab protein is highly specific to the targeted coleopteran species, and is nontoxic to mammali an species.

Upon commercial introduction as a plant

- incorporated protectant, eCry3.1Ab corn will offer growers a new option for corn rootworm pest control and integrated pest
management. eCry3.1Ab corn will be an attractive and more effective alternativ e to
conventional insecticides. eCry3.1Ab corn also offers environmental and work er safety benefits over conventional insecticide control options for control of coleopteran pests.

B. Product Identity/Chemistry

1. Identity of the pesticide and correspon ding residues. The Bacillus thuringiensis eCry3.1Ab protein has been incorporated into corn plants to provide control of some coleopteran insect pests , for example Western corn rootworm. It is a chimeric protein of Bacillus thuringiensis modified Cry3A a nd Cry1Ab proteins. The e c ry3.1Ab transformed plants are derived from transformation event 5307 that contain the eCry3.1Ab protein via Agrobacterium mediated transformation

.

2. Magnitude of residues at the time of harvest and method used to determine the

residue

. A determination of the magnitude of residues at harvest is not required for

residues that are temporarily exempt from tolerances

.

3. A statement of why an analytical method of detecting and measuring the levels of the pesticide residue are not needed. Th is petition is a request for a temporary exemption from the requirement of a tolerance without numerical limitation, thus an analytical detection method should not be required. However, in response to an Agency request the P etitioner has submit ted an immunoassay method for determination of eCry3.1Ab in corn tissues.

C. Mammalian Toxicological Profile

The eCry3.1Ab protein is derived from Bacillus thuringiensis

. It is a chimeric protein of Bacillus thuringiensis modi fied Cry3A and Cry1Ab prote ins. Bacillus thuringiensis proteins have been used as safe and effective pest control agents in

microbial formulations for many years. The numerous toxicology studies conducted with these microbial products show no significant adverse effects, and demons trate that the products are practically nontoxic to mammals.

It has been demonstrated that eCry3.1Ab p rotein display insect

- specific toxicity following ingestion by sensitive coleopteran species . In the insect digestive tract, partially digested eCry3. 1Ab protein can bind to specific receptors which are then inserted into the gut membrane to form ion

- specific pores. The formation of membraneSyngenta ECRY3.1AB

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- 2 Page 11 of 13 pores results in electrolyte imbalances that cause death of the insect. This mode of action

is not active in hu mans and other mammals as demonstrated in an acute mouse toxicology study where results confirmed that eCry3.1Ab is nontoxic to mice

.

The mammalian safety of eCry3.1Ab has been confirmed in studies summarized herein, that demonstrate the lack of toxicit y of the eCry3.1Ab protein following high

- dose acute oral exposures to mice, rapid degradation of eCry3.1Ab upon exposure to simulated mammalian gastric f luid

, and the lack of amino acid sequence similarity of the eCry3.1Ab protein to proteins known to be mammalian toxins or human allergens. These studies all support that eCry3.1Ab will be nontoxic to humans.

Single high dose exposures to eCry3.1Ab in mice produced no measurable

adverse effects. The eCry3.1Ab protein, produced in a heterologous fermenta tion system

, was administered orally to male and female mice; a no observable effect level of 2000 mg eCry3.1Ab/kg body weight was indicated and the LD 50 can be estimated as >2000 mg eCry3.1Ab/kg body weight. No mortality or clinical signs attributable to the test substance were observed during the study

. Plant and microbially

- produced eCry3.1Ab proteins have been shown to be equivalent in terms of biological activity, molecular weight, immunoreactivity, and lack of post

- translational modifications.

Whe n 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). Therefore, when a protein displays no acute oral toxicity in high

- dose testing using a standard laboratory

mamm alian test species, a determination can be made that the protein will be nontoxic to humans and other mammals, and will not present a hazard under any realistic exposure scenario, including long

- term exposures.

The amino acid sequence of eCry3.1Ab is not homologous to any non

- B.t. proteins identified as, or known to be, toxins described in public databases. The amino acid sequence of eCry3.1Ab is not homologous to that of any known or putative allergens described in public databases

. In addition, t he eC ry3.1Ab protein is not derived from a known source of allergens and does not display characteristics commonly associated with allergens, including post

- translational glycosylation. Additionally, eCry3.1Ab is readily digested in simulated gastric fluid in the presence of pepsin at pH 1.2

.

D. Aggregate Exposure

1. Dietary exposure. Information is available to estimate aggregate exposure levels for consumers and major identifiable subgroups of consumers to the plant

incorporated protectant and related sub stances. Possible sources of exposure include dietary exposure under the tolerance exemption and all other tolerances or exemptions in

effect for eCry3.1Ab protein residues, and exposure from other nonoccupational sources.

i. Food. Oral exposure, at very low levels m ay occur from ingestion of corn and processed corn products ; h owever, a lack of mammalian toxicity and the digestibility ofSyngenta ECRY3.1AB

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- 2 Page 12 of 13 eCry3.1Ab protein have been demonstrated. The u se sites for eCry3.1Ab proteins are all agricultural for the control of insects.

ii. Drinking Water Exposure. Oral exposure, at very low levels, may occur through drinking water ; however, a lack of mammalian toxicity and the digestibility of eCry3.1Ab protein have been demonstrated. The use sites for eCry3.1Ab proteins are all agricultural for the control of insects.

2. Non

- dietary exposure

. Exposure via the skin or inhalation is not likely since eCry3.1Ab is contained within plant cells, which essentially eliminates these exposure routes or reduces them to negligible leve ls.

E. Cumulative Effects

There is no indication of mammalian toxicity potential for eCry3.1Ab protein.

T he Cry class of proteins class display toxicity towards a narrow spectrum of insect species. It is reasonable to conclude that there will be no cum ulative effects for this protein.

F

. Safety Determination

1. U.S. population. Based on available data for eCry3.1Ab proteins there are no indications of mammalian toxicological effects and no threshold effects of concern. Due to its digestibility, lac k of toxicity and unlikely potential for allergenicity, eCry3.1Ab dietary exposure is not anticipated to pose any harm to the U.S. population. T here is no need for application o f an additional safety factor for establishing an adequate margin of

exposure. Furthermore, special provisions pertaining to unique consumption patterns, special susceptibility, and cumulative effects do not apply.

2. Infants and children

. Based on available data for eCry3.1Ab protein there are

no indications of mammalian toxicol ogical effects and no threshold effects of concern. Due to its digestibility, lack of toxicity, and unlikely potential for allergenicity, eCry3.1Ab dietary exposure is not anticipated to pose any harm to infants and children.

T here is no need for appli cation o f an additional safety factor for establishing an adequate margin of exposure. Furthermore, special provisions pertaining to unique consumption patterns, special susceptibility, and cumulative effects do not apply.

G. Effects on the Immune and En docrine Systems

The available safety data for eCry3.1Ab protein show no adverse effects in mammals at high levels of exposure ; thus , n o effects on mammalian immune or endocrine systems are predicted. Furthermore, the eCry3.1Ab protein is derived from

Bac illus thuringiensis and Bacillus thuringiensis is known not to exert an influence on the endocrine system.Syngenta ECRY3.1AB

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- 2 Page 13 of 13 H. Existing Tolerances

There are no existing tolerances or exemptions from the requirement of a

tolerance for the eCry3.1Ab protein granted to Syng enta Seeds

.

I

. International Tolerances

N o Codex maximum residue levels exist for the eCry3.1Ab protein and the genetic material necessary for their production in plants.