Pesticides; tolerances in food, animal feeds, and raw agricultural commodities: Alpha-cyclodextrin, etc.,
[Federal Register: July 6, 2005 (Volume 70, Number 128)]
[Rules and Regulations]
[Page 38780-38785]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr06jy05-10]
ENVIRONMENTAL PROTECTION AGENCY
[OPP-2002-0294; FRL-7720-9]
Alpha-cyclodextrin, Beta-cyclodextrin, and Gamma-cyclodextrin; Exemption from the Requirement of a Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
SUMMARY: This regulation establishes an exemption from the requirement of a tolerance under 40 CFR 180.950 for residues of alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin when used in or on various food commodities. Wacker Specialties submitted a petition to EPA under the Federal Food, Drug, and Cosmetic Act
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(FFDCA), as amended by the Food Quality Protection Act (FQPA) of 1996, requesting an exemption from the requirement of a tolerance. This regulation eliminates the need to establish a maximum permissible level for residues of alpha-cyclodextrin, beta- cyclodextrin, and gamma- cyclodextrin.
DATES: This regulation is effective July 6, 2005. Objections and requests for hearings must be received on or before September 6, 2005.
ADDRESSES: To submit a written objection or hearing request follow the detailed instructions as provided in Unit VIII. of the SUPPLEMENTARY INFORMATION. EPA has established a docket for this action under docket identification (ID) number OPP-2002-0294. All documents in the docket are listed in the EDOCKET index at http://www.epa.gov/edocket. Although
listed in the index, some information is not publicly available, i.e., 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 either electronically in EDOCKET or in hard copy at the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2, 1801 S. Bell St., Arlington, VA. This docket facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The docket telephone number is (703) 305-5805.
FOR FURTHER INFORMATION CONTACT: Rame Cromwell, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone number: (703) 308-9068; e-mail address: cromwell.rame@epa.gov.
SUPPLEMENTARY INFORMATION:
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General Information
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Does this Action Apply to Me?
You may be potentially affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected entities may include, but are not limited to:
Crop production (NAICS code 111)
Animal production (NAICS code 112)
Food manufacturing (NAICS code 311)
Pesticide manufacturing (NAICS code 32532)
This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in this unit could also be affected. The North American Industrial Classification System (NAICS) codes have been provided to assist you and others in determining whether this action might apply to certain entities. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.
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How Can I Access Electronic Copies of this Document and Other Related Information?
In addition to using EDOCKET (http://www.epa.gov/edocket/), you may
access this Federal Register document electronically through the EPA Internet under the ``Federal Register '' listings at http://www.epa.gov/fedrgstr/. A frequently updated electronic version of 40
CFR part 180 is available at E-CFR Beta Site Two at http://www.gpoaccess.gov/ecfr/ .
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Background and Statutory Findings
In the Federal Register of November 14, 2002 (67 FR 220) (FRL-7279- 3), EPA issued a notice pursuant to section 408(d)(3) of the FFDCA, 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide tolerance petition (2E6514) by Wacker Specialities, 3301 Sutton Road, Adrian, MI, 49221-9397. The petition requested that residues of a certain pesticide chemical in or on various food commodities be exempted from the requirement of a tolerance. This notice included a summary of the petition prepared by the petitioner Wacker Specialties. No comment was submitted.
Section 408(c)(2)(A)(i) of the 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 tolerance is ``safe.'' Section 408(c)(2)(A)(ii) 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), 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), which 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 establishes exemptions from the requirement of a tolerance only in those cases where it can be clearly demonstrated that the risk from aggregate exposure to pesticide chemical residues under reasonably foreseeable circumstances will pose no appreciable risks to human health. In order to determine the risks from aggregate exposure to pesticide inert ingredients, the Agency considers the toxicity of the inert in conjunction with possible exposure to residues of the inert ingredient through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings. If EPA is able to determine that a finite tolerance is not necessary to ensure that there is a reasonable certainty that no harm will result from aggregate exposure to the inert ingredient, an exemption from the requirement of a tolerance may be established.
EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. First, EPA determines the toxicity of the pesticide chemical. 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.
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Inert ingredient Definition
Inert ingredients are all ingredients that are not active ingredients as defined in 40 CFR 153.125 and include, but are not limited to, the following types of ingredients (except when they have a pesticidal efficacy of their own): Solvents such as alcohols and hydrocarbons; surfactants such as polyoxyethylene polymers and fatty acids; carriers such as clay and diatomaceous earth; thickeners such as carrageenan and modified cellulose; wetting, spreading, and dispersing agents; propellants in aerosol dispensers; microencapsulating agents; and emulsifiers. The term ``inert'' is not intended to imply nontoxicity; the ingredient may or may not be chemically active. Generally, EPA has exempted inert ingredients from the requirement of a tolerance based on the low toxicity of the individual inert ingredients.
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Description of Alpha-cyclodextrin, Beta-cyclodextrin, and Gamma- cyclodextrin
Alpha-cyclodextrin is a non-reducing cyclic saccharide comprised of six glucose units linked by alpha-1,4 bonds. It is produced by the action of cyclodextrin glucosyltransferase (CGTase) on hydrolyzed starch syrups at neutral pH and moderate temperatures. Beta- cyclodextrin is a cyclic heptamer composed of seven glucose units joined ``head-to-tail'' by alpha-1,4 links. Gamma-cyclodextrin is a ring-shaped molecule made up of eight glucose units linked by alpha-1,4 bonds. Alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin are naturally occurring compounds derived from the degradation of starch by the glucosyltransferase enzyme (CGTase). They are formed naturally from bacteria and synthetically. The annular (or doughnut- shaped) structure provides a hydrophobic cavity that allows formulation of inclusion complexes with a variety of non-polar organic molecules of appropriate size. The hydrophobic nature of the outer surface of the cyclic structure makes the compounds water soluble. The hydrophobic cavity and the hydrophilic outer surface form the basis for its use in the food industry.
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Toxicological Profile
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 reliability and the relationship of this information to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.
The Joint Expert Food Committee Additives (JEFCA) is an international expert scientific committee that is administered jointly by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO). In the Food Additive Series 32, 42, and 48, JEFCA reviewed alpha-, beta-, and gamma-cyclodextrins and assigned an acceptable daily intake (ADI) of ``not specified'' to alpha-cyclodextrin. As to beta-cyclodextrin, a temporary ADI of 0-6 milligrams/kilogram (mg/kg) was allocated, based on a no adverse observed effect level (NAOEL) of 2.5% in the diet (equal to 1,230 mg/ kg/bwt day) in the study of dogs using a safety factor of 200. As to gamma-cyclodextrin, there were sufficient data to allocate a temporary ADI of ``not specified.'' A ``not specified'' designation is used to refer to a food substance of very low toxicity, with, on the basis of the available data (chemical, biochemical, and other) and the total dietary intake of the substance, does not, in the opinion of the Committee, represent a hazard to health. These compounds are natural occurring cyclic non-reducing torus-shaped maltooligosaccharides. They originate from the decomposition of starch by a bacterial enzyme called cyclodextrin glycosyltransferase. Alpha-, beta-, and gamma- cyclodextrins are comprised of D-glucose molecules.
In its May 20, 2003, response to a Generally Recognized as Safe (GRAS) notification, the Food and Drug Administration (FDA) had no questions regarding a conclusion by qualified experts that alpha-, beta-, and gamma- cyclodextrins meet appropriate food grade specifications and if manufactured in accordance with good manufacturing practices are generally recognized as safe.
Alpha-cyclodextrin was examined by JEFCA for its ability to induce ocular irritation in albino rabbits in two separate studies. In the first study, a dose of 0.062 g instilled in the conjuctival cul-de-sac of the right eye of three rabbits was irritating but not corrosive. In the second study, two groups of three rabbits were given alpha- cyclodextrin as a 14.5% or a 50% dilution in demineralized water. No or minimal irritation was found in the eyes and there was no corrosion.
A sample of 0.5 of alpha-cyclodextrin moistened with tap water was applied to the shaven backs and flanks of three albino rabbits for 4 hours under a semi-occlusive dressing. No skin irritation was observed for up to 72 hours. Similarly, in guinea-pigs, a 10% or 30% solution of alpha-cyclodextrin induced no signs of sensitization in the dermally induced animals.
Short-term (28-day and 90-day) studies of toxicity indicated that alpha-cyclodextrin has little effect when given orally to rats and dogs. Alpha-cyclodextrin is not digested in the gastrointestinal tract but is fermented by the intestinal micro flora. Absorbed alpha- cyclodextrin is excreted rapidly in the urine.
Studies conducted with mice, rabbits, and rats with alpha- cyclodextrin at concentrations of up to 20% did not indicate teratogenic effects.
Beta-cyclodextrin of 0.5 g moistened with 0.5 ml saline was applied to shaved dorsal skin of 3 white rabbits under occlusion for 24 hours. The mean primary irritation score was 0.50 (minimally irritating), and there were no eschar or oedma and the treatment sites were normal by 24 hours after removal of the pad containing the chemical. A primary dermal irritation study in albino rabbits used an abraded skin protocol, and the index of primary cutaneous irritation which was obtained (0.01) classified beta- cyclodextrin as non-irritant.
In an ocular irritancy/corrosion test in albino rabbits, beta- cyclodextrin was classified as slightly irritating.
Gamma-cyclodextrin was not irritating or corrosive to the eyes of albino rabbits. In a skin sensitization assay in guinea-pigs, a 30% solution induced no signs of sensitization.
Short term (28-day and 90-day) studies of toxicity indicate that gamma-cyclodextrin has little toxicity when given orally to rats or dogs. Studies conducted in rats and rabbits with gamma-cyclodextrin at doses up to 20% of the diet did not indicate any teratogenic effects. Similarly, the results of a battery of studies of genotoxicity were negative. Long-term studies of toxicity, carcinogenicity, and reproductive toxicity have not been conducted, but, given the rapid metabolism of this substance to glucose and its lack of genotoxicity, such studies were not required for an evaluation.
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Aggregate Exposure
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Food. Alpha-cyclodextrin, beta-cyclodextrin, and gamma- cyclodextrin are naturally occurring and are used as food additives. The following was taken from the WHO INCHEM (Food Additives Series 32, 42, 48). Alpha-cyclodextrin is used as a carrier for flavors, colors, and sweeteners in foods such as dry mixes, baked goods, and instant teas and coffee, as a stabilizer for flavors, colors, vitamins, and polyunsaturated fatty acids in dry mixes and dietary supplements (
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