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Bacillus thuringiensis (Bt) Plant-Incorporated Protectants - page 6 / 30





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Bt Plant-Incorporated Protectants October 15, 2001 Biopesticides Registration Action Document

types of data are required for the Bt plant-incorporated protectants in order for the Agency to make the “reasonable certainty of no harm” finding that is required by the Federal Food, Drug, and Cosmetic Act. The data are evaluated in order to determine that (1) the protein behaves as would be expected of a dietary protein breaking down rapidly in digestive fluids; (2) the protein is not structurally related to any known food allergen or protein toxin; and (3) the protein does not display any oral toxicity when administered at high doses. In this section of the assessment, product specific data are addressed for each of the following areas: in vitro digestion assay, heat stability and amino acid sequence homology comparisons, and acute oral toxicity, including mutagenicity and developmental toxicity, subchronic toxicity and chronic exposure and oncogenicity. Product specific information is also addressed for immune system effects, endocrine effects, dose response and dietary risk characterizations. The rationale is presented for why any dietary protein, including the Bt proteins, would not be expected to raise concerns for subchronic and chronic effects such as mutagenicity, oncogenicity and developmental toxicity. A discussion of immune system effects, endocrine effects and dietary and non-dietary risk characterization is included for each product as would be found in any assessment for a pesticide chemical's food tolerance determination since implementation of the FQPA amendments to the FFDCA.

This document will also serve as EPA’s review of the associated tolerance exemptions (i.e., tolerance exemption reassessments) under 408(q) of the FFDCA. By this reassessment, EPA has completed its tolerance reassessment for Cry1Ab (180.1173) and for Cry3A (180.1147). The tolerance exemptions for Cry1Ac (180.1155) and Cry1F (180.1217) do not require reassessment at this time.

Since the September 2000 version of the risk and benefits assessments and the October 2000 SAP meeting, these sections have been updated by indicating additional data which might be needed. Product characterization data supporting currently registered products is adequate, but would be improved with more information. This information includes: analytical methods and method validation for the currently registered Cry proteins following OPPTS guidelines, heat stability and/or processing data, amino acid sequencing data comparing to known toxins, stepwise 8 amino acid fragment comparisons to known allergens, post-translational modifications (i.e. potential glycosylation sites), and as valid methods become available, more complete analysis of the amino acid sequence expressed in the plant (known as the MALDI-TOF).

a. Bt Corn

Tests have shown no toxicity to mammals from the Cry1Ab and Cry1F proteins; the proteins are readily digestible in gastric fluids and are non-glycosylated, the proteins are inactivated by typical food processing, and anticipated exposure of farm workers to the proteins is negligible. The Cry1Ab protein acute oral toxicity data submitted demonstrated no effects at the relatively high dose level of 4,000 mg/kg. The Cry1F protein acute oral toxicity data submitted demonstrated no effects at the relatively high dose level of 5,050 mg/kg. The Cry1Ab and Cry1F proteins were readily degraded in gastric fluid in vitro. Exposure via the skin or inhalation is not likely since the Cry1Ab and Cry1F


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