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was given either 30min before IOMNP injection in the 4-h SCI group or 4h after injury in the 24-h survival groups. These observations are the first to show that IOMNPs are safe for the CNS and cerebrolysin treatment prevented CNS pathology following a combination of trauma and IOMNP injection. The petition proposed to amend the color additive regulations in 73.200 Synthetic iron oxide (21 CFR 73.200) by expanding the permitted uses of synthetic iron oxides as a color additive to include use in dietary supplement tablets and capsules, including coatings and printing inks. In our review of this petition, we did not consider whether section 301(ll) of the FD&C Act or any of its exemptions apply to food containing this color additive. Such reactions may account for the distribution of trace metals (Francis and Dodge, 1990; Rose et al., 1993; Tessier et al., 1996) and radionuclides like uranium in sediments (McKee et al., 1987) and anoxic water columns (McKee and Todd, 1993). 1). There were also minimal changes in the results of blood tests, which were not of clinical importance. This final rule contains no collection of information. The dose-response assessment, which concludes with an estimate of the UL, is built upon three toxicological concepts commonly used in assessing the risk of exposures to chemical substances: No-observed-adverse-effect level, lowest-observed-effect level, and an uncertainty factor (Ref. For example, section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act (21 U.S.C. Learn more here. For these characteristics, they have been investigated for liver imaging, macrophage imaging or blood pool agents. 07/29/2022, 48 While every effort has been made to ensure that

We commonly use the EDI for the 90th percentile consumer of a color additive as a measure of high chronic exposure.Start Printed Page 54871. The reference without an asterisk is not on public display at https://www.regulations.gov because it has copyright restriction but is available at the website address. MRI iron oxide causes loss of signal intensity, especially on T1 and T2 weighted images, and the contrast between the lesions and the surrounding tissues is increased owing to loss of signal in the healthy tissues. This PDF is They are taken up by the reticuloendothelial system. regulatory information on FederalRegister.gov with the objective of oxides, hydroxides, and oxy-hydroxides are known to date. the current document as it appeared on Public Inspection on documents in the last year, 1451 Interaction of metal oxides with trace metals is considered to be of major importance in sediment and water column chemistry (Balistrieri and Murray, 1982, 1984; Tessier et al., 1996).

Accordingly, this final rule should not be construed to be a statement that a food containing this color additive, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll) of the FD&C Act. This repetition of headings to form internal navigation links 321, 341, 342, 343, 348, 351, 352, 355, 361, 362, 371, 379e. Any objections received in response to the regulation may be seen in the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday, and will be posted to the docket at https://www.regulations.gov. documents in the last year, 1038 In a phase 2 study in 104 patients with focal liver or spleen pathology who underwent MRI with ferumoxtran-10 (0.8, 1.1, and 1.7mg of iron per kg), 15% reported a total of 33 adverse events, most commonly dyspnea (3.8%), chest pain (2.9%), and rashes (2.9%) [5]. 2). establishing the XML-based Federal Register as an ACFR-sanctioned Fe(II) is oxidized into Fe(III) by photochemically produced H2O2 and the redox cycling (Fenton's reaction) is thereby complete. the Federal Register. There were no significant adverse effects during or after the scans. Open for Comment, Proposed Addition of American Single Malt Whisky to the Standards of Identity for Distilled Spirits, Economic Sanctions & Foreign Assets Control, Vessel Repair Duties for Vessels Entering U.S. for better understanding how a document is structured but FDA-2017-C-6238 for Listing of Color Additives Exempt from Certification; Synthetic Iron Oxide. Received objections, those filed in a timely manner (see ADDRESSES), will be placed in the docket and, except for those submitted as Confidential Submissions, publicly viewable at https://www.regulations.gov or with the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday. For complete information about, and access to, our official publications In the final rule approving the use of synthetic iron oxides for use in candy, mints, and chewing gum (80 FR 14839, March 20, 2015), FDA discussed that elemental iron from synthetic iron oxides is not readily bioavailable and is poorly absorbed by the human gastrointestinal tract (80 FR 14839 at 14840). This feature is not available for this document. documents in the last year, 22 Sara Nidal Abed, Rakesh K. Tekade, in Basic Fundamentals of Drug Delivery, 2019. documents in the last year, 804 This final rule is not a statement regarding compliance with other sections of the FD&C Act. *3. on FederalRegister.gov Magnetic nanoparticles are a widely studied class of nanoparticles because they offer great possibilities in a number of diagnostic applications and therapies (Laurent etal., 2009; Veiseh etal., 2009). The exposure to elemental iron from the petitioned use of synthetic iron oxides is estimated to be 10 mg/p/d at the mean and 25 mg/p/d at the 90th percentile. To support the safety of the proposed use of synthetic iron oxides, Colorcon proposed a maximum use level of the color additive in dietary supplements such that the total amount of elemental iron consumed shall not exceed 5 mg per day for labeled dosages. There are various types of iron oxides that include iron(II) oxide, wstite (FeO), magnetite (Fe3O4), iron(III) oxide (Fe2O3), alpha phase, hematite (-Fe2O3), beta phase, (-Fe2O3), gamma phase, maghemite (-Fe2O3), epsilon phase, (-Fe2O3). 07/29/2022, 250 Ultrasmall superparamagnetic particles of iron oxide (USPIOs) of median diameter no less than 50nm have been studied as blood-pool agents and are given intravenously to enhance liver imaging in patients with cirrhosis and to visualize lymph nodes. 21 U.S.C. FDA reviewed the data and information in the petition and other available relevant material and determined the petitioned use of synthetic iron oxides in dietary supplement tablets and capsules is safe. NC100150 shows promise for myocardial perfusion analysis. The President of the United States issues other types of documents, including but not limited to; memoranda, notices, determinations, letters, messages, and orders. Iron oxides, either Fe3O4 or -Fe2O3, can be prepared from aqueous Fe2+/Fe3+ salt solutions by the addition of a base under an inert atmosphere at room temperature or at elevated temperature (Bee etal., 1995). Liver tumors have few or no reticuloendothelial cells and so there is a contrast between normal liver and tumor. Listing of Color Additives Exempt From Certification; 3)-CAP 7C0308_Toxicology Review Memo_Finalized_Redacted, 2)-CAP 7C0308_Chemistry Memo_Finalized_Redacted, 1)-FDA-2017-C-6238_List of References_CAP 7C0308, IV. Cerebrolysin (2.5mL/kg, i.v.) Five patients had 10 adverse events, including rectal pain, diarrhea, edema, a phobic reaction, nausea, and a rash; all recovered without further therapy. documents in the last year, 264 The documents posted on this site are XML renditions of published Federal High quality, monodisperse, as well as biocompatible DMSA-coated SPIONs have been attained by a thermal decomposition followed by ligand exchange reaction. documents in the last year, by the Indian Affairs Bureau Within each numbered objection, you must specifically state whether you are requesting a hearing on the particular provision that you specify in that numbered objection. However, NC100150 interferes with iron metabolism, since iron is incorporated into the body after biodegradation. Our review of this petition was limited to section 721 of the FD&C Act. Submit either electronic or written objections and requests for a hearing on the final rule by December 3, 2018. documents in the last year, 889 Under section 721(b)(4) of the FD&C Act (21 U.S.C. Preeti K. Menon, Hari S. Sharma, in International Review of Neurobiology, 2017. If you request a hearing, your objection must include a detailed description and analysis of the specific factual information you intend to present in support of the objection in the event that a hearing is held. informational resource until the Administrative Committee of the Federal Federal Register provide legal notice to the public and judicial notice Iron oxide nanoparticles with a high level of monodispersity and size control were obtained by high-temperature decomposition of iron organic precursors, such as Fe(Cup)3, Fe(CO)5, or iron(III) acetylacenonate [Fe(acac)3], using organic solvents and surfactants (Hyeon etal., 2001). These tools are designed to help you understand the official document Iron oxides can be synthesized by all known wet chemical methods but tailoring the particle size to the nano range and the morphology toward a particular application remains a challenging task.

on NARA's archives.gov. Copyright 2022 Elsevier B.V. or its licensors or contributors. Iron oxide-containing contrast agents consist of suspended colloids of iron oxide nanoparticles, which reduce T2 MRI signals. High-quality diagnostic information was provided by the MRI examination. In addition, light and iron interactively promote particle formation from dissolved humic substances. The President of the United States communicates information on holidays, commemorations, special observances, trade, and policy through Proclamations. These contrast agents are well tolerated, with no serious adverse effects. documents in the last year, 53 In all groups, leakage of serum albumin in the CNS as a marker of BBB breakdown and activation of astrocytes using glial fibrillary acidic protein was evaluated by immunohistochemistry. Objections received by mail/hand delivery/courier (for written/paper submissions) will be considered timely if they are postmarked or the delivery service acceptance receipt is on or before that date. The Food and Drug Administration (FDA or we) is amending the color additive regulations to provide for the expanded safe use of synthetic iron oxides as color additives to include use in dietary supplement tablets and capsules. 2. include documents scheduled for later issues, at the request One had a diffuse erythematous rash associated with a feeling of pressure in the thorax, which lasted for 30 minutes.

Institute of Medicine, Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press (U.S.); 2001. https://www.ncbi.nlm.nih.gov/books/NBK222310/pdf/Bookshelf_NBK222310.pdf. electronic version on GPOs govinfo.gov. These changes were not considered to be of clinical importance. Several phase transfer strategies have been applied to hydrophobic magnetic nanoparticles to obtain the aqueous dispersion necessary for biomedical applications (Deng etal., 2005; Del Monte etal., 1997; Kim and Kim, 2006; Yu etal., 2006; Qin etal., 2007). The reference without an asterisk is available for viewing only at the Dockets Management Staff. However, the attained results have revealed a limited influence of SPIONs on treated skeletal myoblasts without interfering with the basic cell functions (Wierzbinski et al., 2018). Considering this, FDA has estimated exposure to elemental iron resulting from the petitioned use of synthetic iron oxides in dietary supplements as described below. documents in the last year, 678 In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016. Register, and does not replace the official print version or the official Other methods, including microemulsion, hydrothermal, and sol-gel, have also been investigated for the synthesis of magnetic nanoparticles. on We have not received any new information or comments that would affect our previous determination. In a document published in the Federal Register on November 9, 2017 (82 FR 52037), we announced that we filed a color additive petition (CAP 7C0308) submitted by Colorcon, Inc., 275 Ruth Rd., Harleysville, PA 19438. For the subject petition, synthetic iron oxides are intended for coloring dietary supplement tablets and capsules, including coatings for tablets and capsules and printing inks applied to dietary supplement tablets and capsules, such that the total amount of elemental iron in the dietary supplements does not exceed 5 mg per day for labeled dosages. 1). Sixteen pure phases of iron oxides, i.e. the official SGML-based PDF version on govinfo.gov, those relying on it for corresponding official PDF file on govinfo.gov. Manganese oxide fibers have been used to collect radium from seawater (Moore, 1975), and metal oxides have been proposed as a means for disposal of radionuclide waste (Mott et al., 1993). However, administration of IOMNPs in SCI group slightly enhanced the pathological changes in the CNS after 24h but not 4h after trauma. 07/29/2022, 841 2). Synthetic iron oxides also are approved for use as color additives in cosmetics generally, including cosmetics applied to the area of the eye, in amounts consistent with GMP (21 CFR 73.2250). We considered the UL established by IOM for iron (45 mg/d) relative to the cumulative exposure for bioavailable elemental iron of 7.2 mg/p/d (at the 90th percentile for U.S. population 2 years and older) as the primary basis for assessing the safety of exposure to elemental iron from the proposed use of synthetic iron oxides (Ref. Memorandum from T. Thurmond, Toxicology Team, Division of Petition Review, OFAS, CFSAN, FDA to M. Harry, Division of Petition Review, OFAS, CFSAN, FDA, September 17, 2018. This exposure is negligible compared to that for use of elemental iron as a color additive in tablets and capsules and in coatings applied to dietary supplements. of the issuing agency. Feruglose (NC100150, Clariscan, Nycomed, Oslo, Norway) has been given to 18 healthy men in doses of 2, 3, and 4mg/kg [3]. When the Fe(III)DOM complex is exposed to UV light, the complex is broken, resulting in colloids of DOC and Fe(II). 1). If you will be adversely affected by one or more provisions of this regulation, you may file with the Dockets Management Staff (see ADDRESSES) either electronic or written objections. We will publish notice of the objections that we have received or lack thereof in the Federal Register. For biomedical applications, it is crucial that SPIONs have a well-defined shape, are monodispersed, and exhibit a high magnetization capacity (Laurent etal., 2009; Kunzmann etal., 2011b).

1). The authors concluded that ferumoxtran-10 is safe and well tolerated. Attachment of iron oxide NPs to the surface of anticancer drugs facilitates precise imaging of the tumor in one-step by magnetic resonance and as a targeted therapy. 3). The petitioner requested that the proposed uses be permitted at a maximum use level of 5 milligrams (mg), calculated as elemental iron, per day for labeled dosages. There was a significant increase in systolic blood pressure (from 137 to 141mmHg) 5 minutes after injection; it returned to normal within 4 hours. The iron oxide particle could be located not exactly at the center of the coating material rather peripherally and is also known as York structure. Section 301(ll) of the Federal Food, Drug, and Cosmetic Act, PART 73LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION, https://www.federalregister.gov/d/2018-23863, MODS: Government Publishing Office metadata, https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf, https://www.ncbi.nlm.nih.gov/books/NBK222310/pdf/Bookshelf_NBK222310.pdf. Results revealed that NPs have perhaps caused an induction of a local inflammation and subsequent employment of the peripheral lymphocytes. The Public Inspection page may also Memorandum from D. Doell, Chemistry Review Team, Division of Petition Review, Office of Food Additive Safety (OFAS), Center for Food Safety and Applied Nutrition (CFSAN), FDA to M. Harry, Division of Petition Review, OFAS, CFSAN, FDA, September 17, 2018. and services, go to About the Federal Register 1). documents in the last year, 75 Ports, Packaging and Transportation of Radioactive Material, Rate Adjustments for Indian Irrigation Projects, Bolstering Efforts To Bring Hostages and Wrongfully Detained United States Nationals Home, Establishing an Emergency Board To Investigate Disputes Between Certain Railroads Represented by the National Carriers' Conference Committee of the National Railway Labor Conference and Their Employees Represented by Certain Labor Organizations, Colorcon, Inc.; Filing of Color Additive Petition. They consist of non-stoichiometric microcrystalline iron oxide cores, which are coated with dextrans (in ferumoxides) or siloxanes (in ferumoxsils). 1). edition of the Federal Register. 10/31/2018 at 8:45 am. Taking into account the bioavailability of iron from synthetic iron oxides, the exposure to elemental iron from the petitioned use of synthetic iron oxides for the U.S. population aged 2 years and older is estimated to be 0.10 mg/p/d at the mean and 0.25 mg/p/d at the 90th percentile (Ref 1). (iii) In dietary supplement tablets and capsules, including coatings and printing inks, such that the total amount of elemental iron per day for labeled dosages does not exceed 5 milligrams. The reported adverse effects include low back pain, vomiting and diarrhea, urticaria, flushing, dizziness, and muscle spasm [1]. The dose of iron was 6.011.7mol/kg. An iron oxide that is used as a pigment in rubber, paper, glass, ceramics, and linoleum, in paint for iron, as a polishing agent, in electrical resistors and semiconductors, as a catalyst and in magnets and magnetic tapes. Cerebrolysin treatment markedly attenuated IOMNP-induced aggravation of SCI-induced cord pathology and induced significant neuroprotection. In another study, superparamagnetic iron oxide NPs (SPIONs) have been synthesized and investigated as agents for the direct labeling of cells for stem cells imaging. Iron oxides are some of the most important transition metal oxides for technological applications. Only official editions of the Therefore, clearance by the Office of Management and Budget under the Paperwork Reduction Act of 1995 is not required. Iron oxides are compounds that are basically composed of iron and oxygen. From: Dictionary of Toxicology (Third Edition), 2015, J.K. Aronson MA, DPhil, MBChB, FRCP, HonFBPhS, HonFFPM, in Meyler's Side Effects of Drugs, 2016. Iron oxide nanocomposites have potential applications in areas such as magnetic recording, magnetic data storage devices, and toners and inks for xerography, as well as in MRI, wastewater treatment, bioseparation, and medicine (Raj and Moskovitz, 1990; Hfeli etal., 1997; Schutt etal., 1997; Denizli and Say 2001). The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on. As provided in 71.15, we will delete from the documents any materials that are not available for public disclosure.Start Printed Page 54872. We further conclude that the color additive will achieve its intended technical effect and is suitable for the petitioned use. Please note that late, untimely filed objections will not be considered. To establish with reasonable certainty that a color additive intended for use in foods is not harmful under its intended conditions of use, we consider the projected human dietary exposure to the color additive, the additive's toxicological data, and other relevant information (such as published literature) available to us. The UL is determined using a risk assessment model developed specifically for nutrients and may consider intake from such sources as food, water, nutrient supplements, and pharmacological agents (Ref. 1). that agencies use to create their documents. This is suggested to be due to products of photolysis, including reactive oxygen species, which transform DOM into less soluble forms. documents in the last year, by the Forest Service We use cookies to help provide and enhance our service and tailor content and ads. Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the Search box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 3). An indication that iron is of importance for sedimentation of organic matter in lakes is the relationship between sediment carbon stock burial and total iron concentration in the lake water. The neuronal injury was examined by Nissl staining. After intravenous injection it is sequestered by the reticuloendothelial system, mostly in the liver and spleen. The following references marked with an asterisk (*) are on display in the Dockets Management Staff (see ADDRESSES) and are available for viewing by interested persons between 9 a.m. and 4 p.m., Monday through Friday; they are also available electronically at https://www.regulations.gov. Possibly, humic colloids are stabilized by Fe(III), but are more prone to aggregation when the Fe(III)DOM complex is broken. The use of SPION-based MRI contrast agents is well established and a number of SPIONs have been approved by the U.S. Food and Drug Administration (FDA) (Hamm etal., 1994; Reimer and Balzer 2003). *1. This rule is effective December 4, 2018. Therefore, considering the exposure of 0.10 mg/p/d for elemental iron from the proposed use of synthetic iron oxides, the updated cumulative exposure to bioavailable iron from the current and proposed sources for the U.S. population aged 2 years and older is estimated to be 3.6 mg/p/d at the mean and 7.2 mg/p/d at the pseudo-90th percentile (Ref. documents in the last year, by the Maritime Administration FDA's color additive regulations in 21 CFR 70.3(i) define safe to mean that there is convincing evidence that establishes with reasonable certainty that no harm will result from the intended use of the color additive.