Source: https://www.federalregister.gov/documents/2008/07/02/E8-14794/bacillus-thuringiensis-cry2ab2-protein-exemption-from-the-requirement-of-a-tolerance
Timestamp: 2017-09-21 21:43:37
Document Index: 461387018

Matched Legal Cases: ['art 178', 'art 174', 'art 178', 'art 178', 'art 178', 'art 2', 'art 174']

Federal Register :: Bacillus thuringiensis Cry2Ab2 protein; Exemption from the Requirement of a Tolerance
Bacillus thuringiensis Cry2Ab2 protein; Exemption from the Requirement of a Tolerance
A Rule by the Environmental Protection Agency on 07/02/2008
This regulation is effective July 2, 2008. Objections and requests for hearings must be received on or before September 2, 2008, and must be filed in accordance with the instructions provided in 40 CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).
73 FR 37846
37846-37850 (5 pages)
EPA-HQ-OPP-2007-0346
FRL-8369-4
E8-14794
https://www.federalregister.gov/d/E8-14794 https://www.federalregister.gov/d/E8-14794
This regulation establishes an exemption from the requirement of a tolerance for residues of the Bacillus thuringiensis Cry2Ab2 protein in or on corn when used as plant-incorporated protectant in the food and feed commodities of corn; corn, field; corn, sweet; and corn, pop. 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 1996 (FQPA), requesting to amend the existing temporary tolerance(s) in 40 CFR 174.503 for the Bacillus thuringiensis Cry2Ab2 protein to establish a permanent exemption from the requirement of a tolerance for residues of the Bacillus thuringiensis Cry2Ab2 protein in or on all food commodities when used as a plant-incorporated protectant in all food commodities. This regulation eliminates the need to establish a maximum permissible level for residues of the Bacillus thuringiensis Cry2Ab2 insecticidal protein in or on the food and feed commodities of corn; corn, field; corn, sweet; and corn, pop.
EPA has established a docket for this action under docket identification (ID) number EPA-HQ-OPP-2007-0346. To access the electronic docket, go to http://www.regulations.gov, select “Advanced Search,” then “Docket Search.” Insert the docket ID number where indicated and select the “Submit” button. Follow the instructions on the regulations.gov website to view the docket index or access available documents. All documents in the docket are listed in the docket index available in regulations.gov. Although listed in the index, some information is not publicly available, e.g., Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. Certain other material, such as copyrighted material, is not placed on the Internet and will be publicly available only in hard copy form. Publicly available docket materials are available in the electronic docket at http://www.regulations.gov, or, if only available in hard copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The Docket Facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The Docket Facility telephone number is (703) 305-5805.
Susanne Cerrelli, Biopesticides and Pollution Prevention Division (7511P), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone number: (703) 308-8077; e-mail address: cerrelli.susanne@epa.gov.
In addition to accessing an electronic copy of this Federal Register document through the electronic docket at http://www.regulations.gov, you may access this “Federal Register” document electronically through the EPA Internet under the “Federal Register” listings at http://www.epa.gov/​fedrgstr. You may also access a frequently updated electronic version of 40 CFR part 174 through the Government Printing Office's pilot e-CFR site at http://www.gpoaccess.gov/​ecfr.
Under section 408(g) of FFDCA, as amended by FQPA, any person may file an objection to any aspect of this regulation and may also request a hearing on those objections. The EPA procedural regulations which govern the submission of objections and requests for hearings appear in 40 CFR part 178. You must file your objection or request a hearing on this regulation in accordance with the instructions provided in 40 CFR part 178. To ensure proper receipt by EPA, you must identify docket ID number EPA-HQ-OPP-2007-0346 in the subject line on the first page of your submission. All requests must be in writing, and must be mailed or delivered to the Hearing Clerk on or before September 2, 2008.
In addition to filing an objection or hearing request with the Hearing Clerk as described in 40 CFR part 178, please submit a copy of the filing that does not contain any CBI for inclusion in the public docket that is described in ADDRESSES. Information not marked confidential pursuant to 40 CFR part 2 may be disclosed publicly by EPA without prior notice. Submit your copies, identified by docket ID number EPA-HQ-OPP-2007-0346, by one of the following methods.
Delivery: OPP Regulatory Public Docket (7502P), Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only accepted during the Docket's normal hours of operation (8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays). Special arrangements should be made for deliveries of boxed information. The Docket Facility telephone number is (703) 305-5805.Start Printed Page 37847
In the Federal Register of August 1, 2007 (72 FR 42075-42077) (FRL-8129-8), EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide tolerance petition (PP 6F7143) by Monsanto Company, 800 North Lindbergh Blvd. St. Louis, MO 63167. The petition requested that 40 CFR part 174 be amended by establishing an exemption from the requirement of a tolerance for residues of the Bacillus thuringiensis Cry2Ab2 protein in or on all food commodities when used as plant-incorporated protectant in all food commodities. This notice included a summary of the petition prepared by the petitioner Monsanto Company. One commenter objected to the petition, expressing concerns about Monsanto obtaining an exemption from tolerance and potential harmful effects. The Agency understands the commenter's concerns about potential effects of this particular plant-incorporated protectant to humans and the environment. Pursuant to its authority under the FFDCA, EPA conducted a comprehensive assessment of Cry2Ab2 protein, including a review of acute oral toxicity data on Cry2Ab2 protein, amino acid sequence comparisons to known toxins and allergens, as well as data demonstrating that Cry2Ab2 proteins are rapidly degraded by gastric fluid in vitro, are not glycosylated, and are present in low levels in the tissues expressing the plant-incorporated protectant. Based on these data, the Agency has concluded that there is a reasonable certainty that no harm will result from dietary exposure to residues of Cry1Ab2 protein in the food and feed commodities of corn; corn, field; corn, sweet; and corn, pop, when used as a plant-incorporated protectant. Thus, under the standard in FFDCA section 408(b)(2), a tolerance exemption is appropriate.
In taking this action, EPA, pursuant to its authority under section 408(d)(4)(A)(i) of the FFDCA, is issuing a final regulation that varies from the regulation sought by Monsanto in its petition. Specifically, instead of issuing a tolerance exemption that covers residues of the subject plant-incorporated protectant in all food commodities, EPA is issuing a tolerance exemption that covers residues of the subject plant-incorporated protectant in those commodities in which it will be used as a plant-incorporated protectant — in this case, the food and feed commodities of corn; corn,field; corn, sweet; and corn, pop. In this way, the tolerance exemption is coextensive with the registered uses for this particular plant-incorporated protectant. In addition, instead of amending the existing temporary tolerance exemption in 40 CFR 174.503 for the Bacillus thuringiensis Cry2Ab2 protein in corn by making it a permanent exemption, EPA instead is opting to amend the existing permanent tolerance exemption in 40 CFR 174.519 for the Bacillus thuringiensis Cry2Ab2 protein in cotton by adding to that provision the permanent tolerance exemption for Bacillus thuringiensis Cry2Ab2 protein in corn established by this final rule.
Section 408(c)(2)(A)(i) of FFDCA allows EPA to establish an exemption from the requirement for a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the exemption is “safe.” Section 408(c)(2)(A)(ii) of FFDCA defines “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. Pursuant to section 408(c)(2)(B) of FFDCA, in establishing or maintaining in effect an exemption from the requirement of a tolerance, EPA must take into account the factors set forth in section 408(b)(2)(C) of FFDCA, which require 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. . . . ” Additionally, section 408(b)(2)(D) of FFDCA requires that the Agency consider “available information concerning the cumulative effects of a particular pesticide's residues ” and “other substances that have a common mechanism of toxicity.”
Mammalian toxicity and allergenicity assessment. Monsanto has submitted acute oral toxicity data demonstrating the lack of mammalian toxicity at high levels of exposure to the pure Cry2Ab2 protein. These data demonstrate the safety of the product at a level well above maximum possible exposure levels that are reasonably anticipated in corn using Cry2Ab2 expression values found in corn. Basing this conclusion on acute oral toxicity data without requiring further toxicity testing and residue data is similar to the Agency position regarding toxicity testing and the requirement of residue data for the microbial Bacillus thuringiensis products from which this plant-incorporated protectant was derived (See 40 CFR 158.2130). For microbial products, further toxicity testing (Tiers II and III) and residue data are only triggered when significant adverse acute effects occur in toxicological studies, such as the acute oral toxicity study, to verify the observed adverse effects and clarify the source of these effects.
An acute oral toxicity study in mice (Master Record Identification Number 44966602) indicated that Cry2Ab2 is non-toxic to humans. The Cry2Ab2 protein does not appear to cause any significant adverse effects at an exposure level of up to 1,000 milligrams/kilograms (mg/kg) bodyweight.
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 acute effects were shown to be caused by Cry2Ab2, even at relatively high dose levels, the Cry2Ab2 protein is not considered toxic. Further, amino acid sequence comparisons between the Cry2Ab2 protein and known toxic proteins in protein databases showed no similarities that would raise a safety concern. In addition, the Cry2Ab2 protein was shown to be substantially degraded by heat when examined by immunoassay. This instability to heat would also lessen the potential dietary exposure to intact Cry2Ab2 protein in cooked or processed foods. These biochemical features, along with the lack of adverse results in the acute oral toxicity test support the conclusion that Start Printed Page 37848there is a reasonable certainty no harm from toxicity will result from dietary exposure to residues of Cry2Ab2 in or on the identified corn commodities.
Since Cry2Ab2 is a protein, allergenic potential was also considered. Currently, no definitive tests for determining the allergenic potential of novel proteins exist. Therefore, EPA uses a weight-of- evidence approach where the following factors are considered: Source of the trait; amino acid sequence comparison with known allergens; and biochemical properties of the protein, including in vitro digestibility in simulated gastric fluid (SGF), and glycosylation. This approach is consistent with the approach outlined in the Annex to the Codex Alimentarius, “Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Plants.” The allergenicity assessment for Cry2Ab2 follows:
2. Amino acid sequence. A comparison of the amino acid sequence of Cry2Ab2 with known allergens showed no significant overall sequence similarity (using the CODEX similarity standard of 35% amino acid similarity in any 80 amino acid window) or identity at the level of eight contiguous amino acid residues, indicting a lack of potential linear epitopes found in known food allergens.
3. Digestibility. The Cry2Ab2 protein was digested within 15 seconds in simulated gastric fluid containing pepsin. The rapid degradation of Cry2Ab2 in the gastric environment suggests little possible exposure to intact protein in the intestinal lumen, where sensitization to food allergens occurs.
4. Glycosylation. Cry2Ab2 expressed in corn was shown not to be glycosylated.
5. Conclusion. Considering all of the available information, EPA has concluded that the potential for Cry2Ab2 to be a food allergen is minimal. The information on the safety of pure Cry2Ab2 protein provides adequate justification to address possible exposures in all corn crops.
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 residues of the plant-incorporated protectant, and exposure from non-occupational sources. Although the allergenicity assessment focuses on its potential to be a food allergen, the data (comparing amino acid sequence similarity to allergens, including aeroallergens) also indicate a low potential for Cry2Ab2 to be an inhalation allergen. Exposure via residential or lawn use to infants and children is also not expected because the use sites for the Cry2Ab2 protein are agricultural. Oral exposure, at very low levels, may occur from ingestion of processed corn products and, theoretically, drinking water. However, oral toxicity testing done at dose levels several orders of magnitude above the plant expression level showed no adverse effects.
Food. The data submitted and cited regarding potential health effects for the Cry2Ab2 protein includes the characterization of the expressed Cry2Ab2 protein in corn, as well as the acute oral toxicity study, amino acid sequence comparisons to known allergens and toxins, and the in vitro digestibility of the protein. The results of these studies were used to evaluate human risk, and the validity, completeness, and reliability of the available data from the studies were also considered.
Adequate information was submitted to show that the Cry2Ab2 test material derived from microbial culture was biochemically and functionally equivalent to the protein in the plant. Microbially produced protein was used in the safety studies so that sufficient material for testing was available.
The acute oral toxicity data submitted support the prediction that the Cry2Ab2 protein would be non-toxic to humans. As mentioned in this unit, 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)). Since no treatment-related adverse effects were shown to be caused by the Cry2Ab2 protein even at high dose levels (e.g., 1,450 mg/kg bodyweight), the Cry2Ab2 protein is not considered toxic. Basing this conclusion on acute oral toxicity data without requiring further toxicity testing and residue data is similar to the Agency's position regarding toxicity and the requirement of residue data for the microbial Bacillus thuringiensis products from which this plant-incorporated protectant was derived (See 40 CFR 158.740(b)(2)(i)). For microbial products, further toxicity testing and residue data are only triggered when significant adverse effects are seen in toxicological studies, such as the acute oral toxicity study. Further studies verify the observed adverse effects and clarify the source of those effects.
Residue chemistry data were not required for a human health effects assessment of the subject plant-incorporated protectant because of the lack of mammalian toxicity. Nonetheless, data submitted demonstrated low levels of the Cry2Ab2 protein in corn tissues (1-3 ppm in grain, 20-90 ppm in forage or leaf tissue), indicating a low potential for dietary exposure.
Since Cry2Ab2 is a protein, potential allergenicity is also considered as part of the toxicity assessment. Considering all of the available information:
1. Cry2Ab2 originates from a non-allergenic source;
2. Cry2Ab2 has no sequence similarities with known allergens;
3. Cry2Ab2 is not glycosylated; and
4. Cry2Ab2 is rapidly digested in simulated gastric fluid; EPA has concluded that the potential for Cry2Ab2 to be a food allergen is minimal.
Neither available information concerning the dietary consumption patterns of consumers (and major identifiable subgroups of consumers, including infants and children) nor safety factors that are generally recognized as appropriate for the use of animal experimentation data were evaluated. The lack of mammalian toxicity at high levels of exposure to the Cry2Ab2 protein, as well as the minimal potential to be a food allergen, demonstrate the safety of the product at levels well above possible maximum exposure levels anticipated in the crop.
The genetic material necessary for the production of the plant-incorporated protectant active ingredient include the nucleic acids (DNA, RNA) that encode these proteins and regulatory regions. The genetic material (DNA, RNA) necessary for the production of the Cry2Ab2 protein has been exempted Start Printed Page 37849from the requirement of a tolerance under 40 CFR 174.507 (Nucleic acids that are part of a plant-incorporated protectant; exemption from the requirement of a tolerance).
Dermal and inhalation exposure. Exposure via the skin or inhalation is not likely since the plant-incorporated protectant is contained within plant cells, which essentially eliminates these exposure routes or reduces these exposure routes to negligible. In addition, even if exposure can occur through inhalation, the potential for Cry2Ab2 to be an allergen is minimal as discussed in Unit.III.
Pursuant to section 408(b)(2)(D)(v) of FFDCA, EPA has considered available information on the cumulative effects of such residues and other substances that have a common mechanism of 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 from the plant-incorporated protectant, we conclude that there are no cumulative effects for the Cry2Ab2 protein.
Section 408(b)(2)(C) of FFDCA provides that EPA shall assess the available information about consumption patterns among infants and children, special susceptibility of infants and children to pesticide chemical residues and the cumulative effects on infants and children of the residues and other substances with a common mechanism of toxicity. In addition, section 408(b)(2)(C) of FFDCA also provides that EPA shall apply an additional tenfold margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database unless EPA determines that a different margin of safety will be safe for infants and children.
In this instance, based on all the available information, the Agency concludes that there is a finding of no toxicity for the Cry2Ab2 protein. Thus, there are no threshold effects of concern and, as a result, the provision requiring an additional tenfold margin of safety does not apply. Further, the considerations of consumption patterns, special susceptibility, and cumulative effects do not apply.
A protocol for an enzyme-linked immunosorbent assay for the detection and quantification of Cry2Ab2 in corn tissue has been submitted, and a commercially available qualitative immunochromatographic test strip was shown to detect the Cry2Ab2 protein in corn tissues.
No Codex maximum residue level exists for the plant-incorporated protectant Bacillus thuringiensis Cry2Ab2.
There is a reasonable certainty that no harm will result from aggregate exposure to the U.S. population, including infants and children, to residues of the Cry2Ab2 protein in or on all food and feed commodities of corn; corn, field; corn, sweet; and corn, pop. 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, nor any indication of allergenicity potential for the plant-incorporated protectant.
This final rule establishes a tolerance exemption under section 408(d) of FFDCA 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). Because this final rule has been exempted from review under Executive Order 12866, this final rule is not subject to Executive Order 13211, Actions Concerning Regulations That Significantly Affect Energy Supply, Distribution, or Use (66 FR 28355, May 22, 2001) or Executive Order 13045, entitled Protection of Children from Environmental Health Risks and Safety Risks (62 FR 19885, April 23, 1997). This final rule does not contain any information collections subject to OMB approval under the Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et seq., nor does it require any special considerations under Executive Order 12898, entitled Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations (59 FR 7629, February 16, 1994).
The Congressional Review Act, 5 U.S.C. 801 et seq., generally provides that before a rule may take effect, the agency promulgating the rule must submit a rule report to each House of the Congress and to the Comptroller General of the United States. EPA will submit 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 United States prior to publication of this final rule in the Start Printed Page 37850 Federal Register. This final rule is not a “major rule” as defined by 5 U.S.C. 804(2).
2. Section 174.503 is removed.
3. Section 174.519 is revised to read as follows:
Bacillus thuringiensis Cry2Ab2 protein in corn and cotton; exemption from the requirement of a tolerance.
Residues of Bacillus thuringiensis Cry2Ab2 protein in or on corn or cotton are exempt from the requirement of a tolerance when used as a plant-incorporated protectant in the food and feed commodities of corn; corn, field; corn, sweet; corn, pop; and cotton seed, cotton oil, cotton meal, cotton hay, cotton hulls, cotton forage, and cotton gin byproducts.
[FR Doc. E8-14794 Filed 7-1-08; 8:45 am]