Handbook of Food, Drug, and Cosmetic Excipients Susan c Smolinske, B.S., R.Ph Manager POISINDEX® AND IDENTIDEX® Information Systems Micromedex, Inc Denver, Colorado Library of Congress Cataloging-in-Publication Data Smolinske, Susan C., 1953Handbook of food, drug, and cosmetic excipients / author, Susan C Smolinske p cm Includes bibliographical references and index ISBN 0-8493-3585-X Excipients-Handbooks, manuals, etc I Title [DNLM: Cosmetics-handbooks Excipients-handbooks Food Additives-handbooks QV 735 S666h] RS201.E875S66 1992 615.9-dc20 DNLMIDLC for Library of Congress 91-29427 CIP This book contains information obtained from authentic and highly regarded sources Reprinted material is quoted with permission, and sources are indicated A wide variety of references are listed Reasonable efforts have been made to publish reliable data and information, but the authors and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale Specific permission must be obtained in writing from CRC Press LLC for such copying Direct all inquiries to CRC Press LLC, 2000 N.W Corporate Blvd., Boca Raton, Florida 33431 Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe Visit the CRC Press Web site at www.crcpress.com © 1992 by CRC Press LLC No claim to original U.S Government works International Standard Book Number 0-8493-3585-X Library of Congress Card Number 91-29427 Printed in the United States of America Printed on acid-free paper DEDICATION To my husband, Mark, for adding your excitement, loving encouragement, and support to this project To the Rocky Mountain Poison and Drug Center for providing the clinical educational training background, and the opportunity to pursue and develop my interest in excipient toxicology ACKNOWLEDGMENTS I wish to acknowledge Micromedex, Inc for allowing the use of their equipment and resources, Priscilla Hall, L.P.N for her expeditous library research assistance, and the Advisory Panel for providing many constructive comments and suggestions Portions of the text were adapted from the following articles published by Adis International Limited: Golightly, L K., Smolinske, S C., Bennett, M L., Sutherland, E W., and Rumack, B H., Pharmaceutical excipients: adverse effects associated with inactive ingredients in drug products (Part I), Med Taxieol., 3, 128, 1988 Golightly, L K., Smolinske, S c., Bennett, M L., Sutherland, E W., and Rumack, B H., Pharmaceutical excipients: adverse effects associated with inactive ingredients in drug products (Part II), Med Taxieal., 3, 209, 1988 ADVISORY BOARD William Banner, Jr., M.D., Ph.D Associate Professor of Pediatrics Division of Pediatric Critical Care University of Utah Salt Lake City, Utah Barry H Rumack, M.D Professor of Pediatrics University of Colorado Health Sciences Center Denver, Colorado Ken Kulig, M.D Clinical Toxicologist Denver, Colorado John C Selner, M.D Allergy Respiratory Institute of Colorado Denver, Colorado TABLE OF CONTENTS Introduction Acacia Acesulfame 13 Aluminum 17 Annatto 23 Aspartame 25 Benzalkonium Chloride 31 Benzoic Acid 41 Benzyl Alcohol 47 Bronopol ; 55 Butylated Hydroxyanisole!Butylated Hydroxy toluene 59 Canthaxanthine 65 Castor Oil 69 Cellulose 71 Cetyl Alcohol 75 Chloroacetamide 79 Chlorobutanol 81 Chlorocresol 87 Chlorofluorocarbons 91 Cinnamon Oil 99 Com Starch 105 Cottonseed Oil 109 D&C Red No 22 111 D&C Yellow No 10 115 Diazolidinyl Urea 123 Ethanol 127 Ethylenediamine 135 FD&C Blue No 141 FD&C Blue No 151 FD&C Red No 157 FD&C Red No 40 163 FD&C Yellow No 169 FD&C Yellow No 179 Geraniol 193 Gluten 195 Glycerin 199 Imidazolidinyl Urea 205 Isopropyl Myristate 209 Kathon CG® 205 Lactose 219 Lanolin 225 Mineral Oil 231 Monosodium Glutamate 235 Musk Ambrette 243 Oleic Acid 247 Olive Oil 249 Parabens 251 Parachlorometaxylenol 259 Peru Balsam 261 Petrolatum 265 Phenol 271 Phenylmercuric Salts 275 Polyethoxylated Castor Oil 279 Polyethylene Glycol 287 Polysorbates 295 Povidone 303 Propylene Glycol 307 Propyl Gallate 325 Quaternium-15 329 Rosin 333 Saccharin 337 Sesame Oil 343 Shellac 347 Sodium Benzoate 351 Sodium Lauryl Sulfate 359 Sorbic Acid/Potassium Sorbate 363 Sorbitan Trioleate 369 Sorbitol 371 Soya Lecithin 381 Soybean Oil 383 Sucrose 387 Sulfites 393 Talc 407 Thimerosal 411 Tincture of Orange 419 Tragacanth 423 TransdermaI Systems 427 Urocanic Acid 433 Index • • ••.• • • .• •• • 435 INTRODUCTION I REGULATORY ACTIVITY IMPACTING EXCIPIENTS A Summary of Regulations The Pure Food and Drugs Act of 1906 was the first attempt to regulate the safety of additives in foods and pharmaceuticals This act prohibited the use of any color additive in foods if the color would deceive the consumer, conceal inferiority or damage, or result in misbranding or adulteration Under this statute, premarketing authority was not granted, and court proceedings had to be initiated to remove an adulterated or misbranded product As a result of this act, 80 commonly used color additives were evaluated; only of these were recommended as safe for use in foods In 1907, these recommendations were published, along with a system for voluntary food color certification The voluntary color certification process was rendered mandatory by the Federal Food, Drug, and Cosmetic Act of 1938 This act was precipitated by a dramatic epidemic of excipient-related toxicity Introduction of a new oral formulation of sulfanilamide in 1937, containing a vehicle composed of 72% diethylene glycol, resulted in 105 deaths from acidosis and renal failure by October 1938 The 1938 act required premarketing approval for the first time Scientific evidence of safety of the submitted drug was necessary to allow approval and marketing Drugs that were generally recognized as safe (GRAS) due to a long history of marketing were exempt from approval requirements The Food Additives Amendment was introduced in 1958, requiring demonstration of the safety of newly introduced food additives Some 670 food additives with a long history of use were designated as GRAS A review of scientific evidence on additives on the GRAS list began in the early 1970s, sparked by the discovery of suspected carcinogenicity of a widely used substance on the GRAS list, cyclamate The Color Additives Amendment to the Food, Drug, and Cosmetic Act in 1960 provided for color additives already in use to be "grandfathered" and allowed to be used on a provisional basis, while studies were completed to document safety and allow permanent listing Color additives requiring certification included synthetic dyes made from coal tar and petroleum derivatives Natural vegetable, animal, or mineral dyes were exempt from certification New color additives were required to undergo an approval process with a demonstration of safety of the additive for its intended use The permanent listing of the additive included a designation Tragacanth 425 Asthma and generalized urticaria were attributed to tragacanth in a tripelennamine tablet in one reported case An IgE-mediated mechanism was suggested by demonstration of intracutaneous testing and passive transfer B Allergic Contact Dermatitis A 4-year-old boy developed allergic contact dermatitis following the use of an electrode jelly used during an electrocardiogram procedure months earlier Patch testing was positive to the intact jelly and to gum tragacanth 1% aqueous solution VI CLINICAL RELEVANCE Immediate IgE-mediated hypersensitivity reactions, consisting of angioedema, asthma, rhinitis, or urticaria, have been rarely described Only one case of delayed-type hypersensitivity has been reported REFERENCES Gelfand, H H., The allergenic properties of the vegetable gums, J Allergy 14,203, 1942 World Health Organization, Twenty-Ninth Report of the Joint FAO/WHO Expert Committee on Food Additives, Tech Rep Ser No 723, WHO, Geneva, 1986 Food and Drug Administration, Inactive Ingredients Guide, FDA, Washington, D.C., March 1990 Nikitakis, J M., CTFA Cosmetic Ingredient Handbook 1st ed., The Cosmetic, Toiletry and Fragrance Association, Washington, D.C., 1988 Nilsson, D C., Sources of allergenic gums, Ann Allergy, 18,518, 1960 Danoff, D., Lincoln, L., Thomson, D M P., and Gold, P., "Big Mac attack", N Engl J Med., 298,1095 1978 Rubinger, D., Friedlander, M and Superstine, E., Hypersensitivity to tablet additives in transplant recipients on prednisone, Lancet, 2, 689, 1978 Brown, E B and Crepea, S B., Allergy (asthma) to ingested gum tragacanth J Allergy 18.214, 1947 Coskey, R J., Contact dermatitis caused by ECG electrode jelly Arch Dermatol 113.839, 1977 TRANS DERMAL SYSTEMS I REGULATORY CLASSIFICATION Transdennal drug delivery systems are currently available for five drugs (clonidine, estradiol, fentanyl, nitroglycerin, and scopolamine) These systems allow controlled continuous administration of drugs through the skin, avoiding side effects associated with oral administration, such as gastrointestinal discomfort Drugs being studied in transdennal fonnulations include antihistamines, coumarin, indomethacin, isoproterenol, isosorbide dinitrate, nicotine, pyridostigmine testosterone, and timolol II AVAILABLE FORMULATIONS Transdennal systems are multilayered fonnulations containing a variety of inactive ingredients The basic design consists of four layers -Sacking- membrane membrane membrane Rate-controlling membrane Adhesive-drug matrix Peel-off protective liner Skin FIGURE 71 Transdermal delivery system A Adhesive Layer This layer is in direct contact with the skin and contains active drug dispersed in an adhesive matrix Inactive matrix ingredients include acrylate polymers, polyisobutylene, mineral oil, lactose, resinous cross-linking agents, and colloidal silicone B Rate-Controlling Membrane This layer contains a semi porous membrane that allows gradual controlled diffusion of 427 428 Handbook of Food, Drug, and Cosmetic Excipients the active drug into the adhesive matrix Inactive membrane ingredients include ethylenevinyl acetate copolymers and polypropylene Some formulations not contain this layer as a separate layer, but incorporate rate-controlling materials into the adhesive layer C Drug Reservoir This layer contains the bulk of the active drug Inactive reservoir ingredients include alcohol USP, hydroxypropyl cellulose, mineral oil, polyisobutylene, lactose, and colloidal silicon dioxide D Backing Membrane This is the outermost layer, which generally contains an aluminized polyester film, with no active drug III TABLE OF COMMON PRODUCTS A Transdermal Drug Delivery Systems Trade name Catapres-TIS Deponit NTG Duragesic Estraderm Minitran Nitrodisc Nitro-Dur Transderm-Nitro Transderm-Scop Active ingredient Clonidine Nitroglycerin Fentanyl Estradiol Manufacturer Adhesive type Boehringer Ingelheim Polyisobuty lene Schwarz Pharma Janssen Polyisobutylene Silicon-based Ciba Polyisobutylene Nitroglycerin 3M Nitroglycerin Searle Acrylate-based polymer Acrylate-based polymer Nitroglycerin Nitroglycerin Scopolamine Key Acrylate-based polymer Summit Ciba Silicon-based Polyisobutylene IV HUMAN TOXICITY DATA A Occlusive Effects Because transdermal systems provide an occlusive barrier left on 'the skin for to d, transient adverse effects of skin occlusion are common Occlusive effects are maximized in warm or humid climates These include sweat duct occlusion, miliaria rubra, and bacterial and yeast overgrowth Alternating the site of application is recommended to minimize these reactions Modifications of the systems design have been investigated in attempts to reduce these undesirable effects of the delivery system Attachment of a hydrogel system to the adhesive layer reduced skin irritation from sweat duct occlusion, but resulted in intense bacterial growth Bacterial growth was inhibited by pretreatment of the skin with a topical chlorhexidine gluconate sQlution B Thermal Burns A second-degree bum conforming to the size and shape of a transdermal nitroglycerin patch was described in a 51-year-old man who sat next to a microwave oven which was later determined to have a leak The aluminum in the patch was presumed to have been heated by the radiation leaking from the oven Transdermal Systems 429 C Primary Irritant Reactions Nonimmunologic irritant erythema may transiently occur after removal of the adhesive from the skin Erythema is common following use of nitroglycerin transdermal systems due to the vasodilatory effects of the active drug Primary irritant effects, consisting of mild erythema at the application site, was reported in of 11 healthy volunteers following repeated application to the same site More severe primary irritant effects have been reported after a longer duration of use A sharply demarcated macular erythematous burn-like rash at the site of application of both an active nitroglycerin transdermal system and a placebo patch was reported in a 63-yearold man previously treated with nitroglycerin ointment The reaction faded, but was still visible, month after discontinuation of the patch Because of the absence of involvement of the surrounding tissue, this may have represented a primary irritant dermatitis Irritant reactions (excluding simple erythema) were reported in 15% of patients during the first 70 d of use of a transdermal nitroglycerin patch in a prospective study of 33 patients Two other cases of a burn-like primary irritant reaction were reported in patients who consistently applied the patches to the same sites or anatomic area These irritant reactions have been suggested to be related to glycerin contamination of the nitroglycerin component, which is chemically modified by the growth of bacteria at the occluded site to produce acrylic aldehyde, a strong irritant D Allergic Contact Dermatitis Clonidine A prospective open study of 29 patients treated with clonidine patches found delayed-type hypersensitivity reactions in 11 (38%) Patch testing with individual components of the transdermal system showed positive reactions to the active ingredient in six of seven patients tested; the remaining patient was allergic to polyisobutylene Consistent with the finding in this series that the majority of the allergic reactions were to the active ingredient are several case reports documenting contact sensitivity to clonidine during the first 20 weeks of transdermal product use In one series, 22 of 35 (63%) cases developed positive reactions to patch testing with clonidine 9% in petrolatum All but of 260 patients subsequently challenged with oral clonidine have been able to tolerate the drug One patient developed a localized flare-up at the site of the original dermatitis, and two patients developed a generalized maculopapular rash and prurituS 9,IO The characteristic lesion produced by the Type IV allergic reaction to this transdermal system includes severe irritation, induration, erythema, and occasionally vesiculation Lesions increase in severity for 48 h after removal of the patch Because the clonidine patch is designed to be left on the skin for a longer period of time (7 d), allergic reactions may be more frequent than with patches designed to be removed daily or every third day, such as nitroglycerin or scopolamine Estradiol During a therapeutic trial of 124 postmenopausal women treated with estradiol transdermal patches for weeks, had severe skin reactions to the placebo patch system, consisting of rash, redness, or itching I I A case report described a 35-year-old woman who developed pruritus, edema, and hyperpigmentation weeks after using an estradiol transdermal system twice weekly Extensive patch testing showed positive results only for hydroxypropyl cellulose, an ingredient of the 430 Handbook of Food, Drug, and Cosmetic Excipients drug reservoir The reaction was vehicle-dependent, with positive results in an ethanol and mineral oil vehicle and negative results in an aqueous vehicle 12 An investigation of nine patients with delayed hypersensitivity reactions to the estradiol transdermal patch found four patients sensitive to the adhesive Four other patients reacted to a component in the drug reservoir; this was shown to be hydroxypropyl cellulose in two patients, and an unknown allergen in the other two patients One patient reacted to both the active drug and to the adhesive These reactions worsened during the 48 h following removal and began to weeks after first using the patches in eight of nine cases 13 Nitroglycerin A case of severe contact dermatitis occurred months after switching from nitroglycerin ointment, used for year, to the transdermal patch and was described as a localized, painful erythematous eruption with a few ruptured vesicles The lesions disappeared when the patch was discontinued and recurred within to 12 h after application Three weeks after restarting the ointment, the rash recurred and was demonstrated to be related to the active drug after patch testing 14 Continued application of a nitroglycerin transdermal patch to the same site produced severe erythema, edema, and crusting in two patients who were also demonstrated to have delayed hypersensitivity reactions to the nitroglycerin component.1 Application to variable sites has also been reported to result in allergic contact dermatitis, subsequently shown to occur only with the active patch 15 Allergic contact dermatitis with postinflammatory hyperpigmentation was described in a 59-year-old man following use of a nitroglycerin patch for months At the time of evaluation, he presented with 45 to 50 brown-blue patches corresponding to previous sites of application Diagnostic patch testing revealed a 2+ reaction after 24 h to crushed nitroglycerin tablets in petrolatum and a 1+ reaction after 96 h to the placebo transdermal device This case was the only dermatologic reaction to nitroglycerin patches observed in 3273 patients treated in the same department 16 A similar case of allergic dermatitis with hyperpigmentation was reported 13 months after using a transdermal system correctly applied to variable sites Patch testing was positive to the intact complete system, but negative to nitroglycerin in petrolatum, a placebo transdermal system, and one component of the adhesive layer The reaction was attributed to one of the untested excipients or to a complex mixture of more than one componentP Another reaction attributed to one or more of the excipients in the adhesive bandage has been documented 18 Scopolamine The scopolamine patches are intended for short-term use, therefore allergic hypersensitivity reactions have been less frequently reported Allergic contact dermatitis has been reported after weeks of use in one case 18 A 53-year-old woman who used the patch continuously for months for the treatment of persistent vertigo developed contact dermatitis, which was attributed to the active ingredient after extensive patch testing with the individual components 19 A similar case, in a lO-year-old mentally retarded child with contact dermatitis after weeks of continuous use for control of ptyalism, was also attributed to scopolamine hypersensitivity.20 Long-term use for 1.5 to 15 months in 164 naval crew workers was associated with development of allergic contact dermatitis in 10% All patients had negative reactions to placebo patches 21 Transdermal Systems 431 E Immediate Hypersensitivity Reactions One case of angioedema and seven cases of contact urticaria have been reported following use of the clonidine transdermal system V CLINICAL RELEVANCE A Immunologic Reactions Hypersensitivity reactions occur usually to the active ingredient or to one of the inactive ingredients in the adhesive or reservoir layer Sensitization to these constituents is facilitated by the irritant and occlusive properties of the formulations The incidence and allergen involved depends on the type of active drug, the duration the patch is left on the skin uniIlterrupted, and the inactive components With some patches, such as clonidine and nitroglycerin, hypersensitivity appears to be primarily related to the active ingredient; clonidine is also the patch with the greatest skin contact duration For other patches, such as estradiol, hypersensitivity is usually related to one of the inactive ingredients Excipients involved in these delayed Type IV hypersensitivity reactions have included polyisobutylene and hydroxypropyl cellulose Patients with consistent cutaneous side effects to transdermal patches should consult their physician immediately Evidence of decreased absorption of the active drug when applied to an inflamed site has been documented by the occurrence of rebound phenomenon or a decreased therapeutic response 15 22 B Nonimmunologic Reactions Transient erythema is a fairly frequent side effect observed in all types of transdermal therapy The symptoms are generally mild and not result in discontinuation of therapy Occlusive effects, such as miliaria rubra and microbial overgrowth, are maximized in warm or humid climates and minimized by alternation of the site of application Patients using the nitroglycerin patches may be more prone to severe irritant reactions due to the tendency to place the patches over the heart with restricted site rotation Irritant reactions are characterized by erythema and induration, which is maximal at the margins A sharply demarcated lesion that does not extend beyond the dimensions of the patch is typical REFERENCES I Hurkmans, J F G M., Bodde, H E., Van Driel, L M J., Van Doorne, H., and Junginger, H E., Skin irritation caused by transdermal drug delivery systems during long·term (5 days) application, Br J Dermatol 112,461,1985 Murray, K B., Hazard of microwave ovens to transdermal delivery system N Engl J Med 310 721, 1984 Ulian, W H., Transdermal estradiol overall safety profile, Am J Obstet Gynecol 156, 1335, 1987 Letendre, P W., Barr, c., and Wilkens, K., Adverse dermatologic reaction to transdermal nitroglycerin, DIC? 18, 69, 1984 Vaillant, L., Biette, S., Machet, L., Constans, T., and Monpere, c., Skin acceptance of transcutaneous nitroglycerin patches: a prospective study of 33 patients, Contact Dermatitis 23, 142, 1990 Fischer, R G and Tyler, M., Severe contact dermatitis due to nitroglycerin patches South Med J 78, 1523 1985 Topaz, O and Abraham, D., Severe allergic contact dermatitis secondary to nitroglycerin in a transdermal therapeutic system, Ann Allergy 59 365 1987 Groth, H., Vetter, H., Knuesel, J., and Vetter, W., Allergic skin reactions to transdermal clonidine,Lancet 2,850, 1983 432 Handbook of Food, Drug, and Cosmetic Excipients Maibach, H I., Oral substitution in patients sensitized by transdermal clonidine treatment, Contact Dermatitis, 16, 1, 1987 10 Grattan, C E H and Kennedy, C T c., Allergic contact dermatitis to transdermal clonidine, Contact Dermatitis, 12, 225, 1985 11 Place, V A., Powers, M., Darley, P E., Schenkel, L., and Good, W R., A double-blind comparative study of Estraderm and Premarin in the amelioration of postmenopausal symptoms, Am Obstet Gynecol., 152, 1092, 1985 12 Schwartz, B K and Clendenning, W E., Allergic contact dermatitis from hydroxypropyl cellulose in a transdermal estradiol patch, Contact Dermatitis, 18, 106 1988 13 McBurney, E I., Noel, S B., and Collins, J H., Contact dermatitis to transdermal estradiol system, Am Acad Dermatol., 20, 508, 1989 14 Rosenfeld, A S and White, W B., Allergic contact dermatitis secondary to transdermal nitroglycerin, Am Heart 1., 108, 1061, 1984 15 Carmichael, A J and Foulds, I S., Allergic contact dermatitis from transdermal nitroglycerin, Contact Dermatitis, 21, 113, 1989 16 Harari, Z., Sommer, I., and Knobel, B., Multifocal contact dermatitis to Nitroderm ITS with extensive postinflammatory hypermelanosis, Dermatologica, 174,249, 1987 17 Di Landro, A., Valsecchi, R., and Cainelli, T., Contact dermatitis from Nitroderm, Contact Dermatitis, 21, 115, 1989 18 Fisher, A A., Dermatitis due to transdermal therapeutic systems, Cutis, 34, 526, 1984 19 Trozak, D J., Delayed hypersensitivity to scopolamine delivered by a transdermal device, Am Acad Dermatol., 13, 247, 1985 20 van der Willigen, A H., Oranje, A P., Stolz, E., and van Joost, Th., Delayed hypersensitivity to scoplamine in transdermal therapeutic systems, Am Acad Dermatol., 18, 146, 1988 21 Gordon, C R., Shupak, A., Doweck, I., and Spitzer, 0., AllergiC contact dermatitis caused by transdermal hyoscine, Br Med 1., 298, 1220, 1989 22 White, T M and Guidry, J R., Rebound hypertension associated with transdermal clonidine and contact dermatitis, West Med., 145, 104, 1986 UROCANIC ACID I REGULATORY CLASSIFICATION Urocanic acid is used as a skin conditioning agent in cosmetics ~ N ~)CH=CHCOOH FIGURE 72 Urocanic acid II SYNONYMS Deaminated histidine 4-imidazoleacrylic acid Imidazole-4-acrylic acid Imidazoleacrylic acid Urocaninic acid III AVAILABLE FORMULATIONS Urocanic acid is a naturally occuning substance found in high concentrations in human stratum corneum In 1989, there were 15 cosmetic products listed with the FDA containing urocanic acid These products included ten sunscreens, three body lotions, one makeup base, and one makeup foundation Most of these products have been reformulated IV TABLE OF COMMON PRODUCTS The following list of cosmetics includes those formerly containing urocanic acid Some of these products may remain available to consumers until existing store stocks are depleted 433 434 Handbook of Food, Drug, and Cosmetic Excipients Trade name Manufacturer Facial moisturizing lotion Facial nourishing cream rich Germaine Monteil Pre-tan conditioner Oil-free tanning formula Overnight Pre-Tan Accelerator Pre-makeup cream base Self-tanning formula Sun Face Block for Sensitive Skin Waterworld sunscreen Shiseido Shiseido Revlon Estee Lauder Estee Lauder Shiseido Clinique Estee Lauder Estee Lauder V ANIMAL TOXICITY DATA A Immunosuppression The naturally occurring trans-isomer of urocanic acid, present in about 0.7% of dry weight of the epidermis, has been shown to act as a receptor for ultraviolet light, resulting in conversion to the cis-isomer It was originally thought to act as a natural sunscreen or photoprotective agent An immunosuppressive effect was found in irradiated skin pretreated with urocanic acid, possibly due to generation of suppressor T -cells I B Carcinogenicity Topical application of a commercial water-resistant sunscreen base containing transurocanic acid 0.2% to hairless mice exposed chronically to daily minimal erythemal doses of ultraviolet light resulted in an increase in the number of overt UV-initiated tumors from 1.7 to 3.3 tumors per mouse The urocanic-acid treated mice also had a greater percentage of malignant types of tumors The proposed mechanism is evasion of ultraviolet-initiated tumor cells from the immunosurveillance mediated by T-cells in the epidermis Urocanic acid shares a 4-substituted imidazole ring structure with azathioprine, an immunosuppressant that increases susceptibility to malignant skin tumors in renal transplant patients VI CLINICAL RELEVANCE There is no evidence of skin cancer-promoting activity of urocanic acid in humans This excipient has been voluntarily withdrawn from most or all of the cosmetics involved REFERENCES I Norval, M., Simpson, T J., and Ross, J A., Urocanic acid and immunosuppression Photochem Photobiol 50, 267, 1989 Reeve, V E., Greenoak, G E., Canfield, P J.• Boehm-Wilcox, c., and Gallagher, C H., Topical urocanic acid enhances UV-induced tumour yield and malignancy in the hairless mouse Phorochem.Photobiol 49 459 1989 INDEX A Benzoesaure.41-45 Benzoic acid 41-45 Benzoic acid sodium salt 351-356 Benzoic sulphimide, 337-341 Benzyl alcohol 47-52 Benzytol 259-260 BHT.5tKi3 Bisodium sulfite, 393 Blue X, 151-155 BNPD, 55-56 Brilliant Blue FCF 141-148 Bromofluoroesceic acid, 111-112 2-Bromo-2-nitropropane-1,3-diol, 55-56 2-Bromo-2-nitro-I.3-propanediol,55-56 Bronopol 55-56 Button Lac 347-349 Butylated hydroxyanisole/butylated hydroxylOluene, 5tKi3 2-tert-Butyl-4-methoxyphenol (BHA) 5tKi3 2-tert-Butyl-5-methyl phenol 62 Butylparaben 251-257 Abitol® 333 335 Acacia 7-10, 423 Aceite de ricino 69-70 Acesulfame 13-15 Acetosulfam 13-15 Acetoxyphenylmercury, 275 Acetylated lanolin, 225-228 Acidum benzoicum, 41-45 Aciele de Algodon 109-110 Acieto de Ajonjoli, 343-344 Alcohol, denatured 127-132 Aleunic acid 347 Alkylbenzyldimethylammonium chlorides 31-37 Allergic reactions, see specific agents Allura Red AC 163-168 Alpha-cellulose, 71-74 Aluminum, 17-21 Aluminum oxide 407 Aluminum silicate 407 Aminophylline, 135, 137 Ammonium bisulfite 394 Animal toxicity see specific agents Annano 23-24 Annota 23-24 APM.25-29 Amatta, 23-24 Aromatic Cascara sagrada fluidextract 100 Aspaname 25-29 Aspirin, 173 175 Avicel® 71-74 Azeite 249-250 Azucar, 387-391 c Cane sugar 387-391 Canthaxanthin 63-68 Carbowax.287-292 Carboxybenzene.41-45 CarboxymethyJcellulose, 71-74 Carmoisine 238 Cascara sagrada fluidextract aromatic 100 Cassia oil 99-102 Castor oil 69-70 Castor oil polyethoxylated 279-284 Cellulose 71-74 CeraphylIPL® 209-2 11 Ceruleinum, 151-155 CelOmacrogolis 75-76 Cetostearyl alcohol 75-76 Cetyl alcohol 75-76 CFC Ii 91-96 CFC 12.91-96 CFC 114.91-96 B Balsam of Peru, 52, 261-263 Benne oil 343-344 Benzalkonium chloride 31-37 Benzenecarboxylic acid 41-45 Benzenemethanol,47-52 Benzoate of Soda 351-356 435 436 Handbook of Food, Drug, and Cosmetic Excipients Chinese seasoning, 235-240 Chloracetamide/chloroacetamide, 79-80 Chlorbutol/chlorobutanol, 81-84 Chloreto de Benzalconio, 31-37 Chloretone, 81-84 Chloroallyl hexaminium chloride, 329-331 Chloroallyl methenamine chloride, 329-331 n-(3-Chloroallyl)-3,5,7 -triaza-I-azonioadamatane chloride, 329-331 Chlorocresol, 260 Chlorofluorocarbons, 91-96 2-Chloro-5-hydroxytoluene, 87-89 5-Chloro-2-methyl-4-isothiazolin-3-one, 213-216 4-Chloro-3-methylphenol,87-89 Chlororesol, 87-89 Chloroxylenol, 88 p-Chloro-m-xylenol, 259-260 Chloroxylenol, 259-260 4-Chloro-3,5-xylenol, 259-260 c.l 15985, 179-190,238 c.l 16035, 163-168 c.l 19140,169-176 c.l 40850, 63-68 C.I 42090, 141-148 c.l 45380, 111-112 c.l 45430, 157-162 c.l 73015,151-155 c.l Acid Blue 9,141-148 c.l Acid Red L 157-162 CJ Acid Red 87,111-112 c.l Food Blue I, 151-155 C.I Food Blue 2, 141-148 c.l Food Orange 8, 63-68 C.L Food Red 14, 157-162 c.l Food Red 17, 163-168 C.L Food Yellow 3,179-190,238 c.l Food Yellow 4, 169-176 Cinnamaldehyde, 99, 100 Cinnamic alcohol, 100 Cinnamic aldehyde, 101 Cinnamon oil, 99-102 Cinnamyl acetate, 99 Cinnamyl alcohol, 99 Citrus fruits, 193-194 Colophane, 333-335 Colophonium, 333-335 Colophony BP, 333-335 Compound orange spirit, 419-420 Compound Vanillin Elixir, 100 Compressible sugar NF, 387-391 Confectioner'S sugar, 387-391 Com starch, 105-107 Cosmetics, 3, 4-5, see also specific agents Cotton oiL 109-1 10 Cottonseed oil, 109-110 Cremophor® formulations, 279-284 Crillet®, 295-300 Crospovidone, 303 Cryfluorane, 91-96 Crystalline cellulose, 71-74 Cyancobalamin, 402 D D&C Blue No.4, 142 D&C Red No, 21, III, 112 D&CRedNo,22,1l1-1l2 D&CYellowNo 10, 115-121 Deaminated histidine, 433-434 Denatured alcohol, 127-132 Diazolidinyl urea, 123-125 2,6-Di-tert-butyl-p-cresol, 56-63 Diethylene glycol, I Difluorodichloromethane, 91-96 (Dihydrdogen borato) phenyl mercury, 275-276 1,2-Dihydroxypropane, 307-321, see also Propylene glycol 4,4-Diketo-beta-carotene, 63-68 Dipotassium pyrosulphite, 394 Disodium pyrosulfite, 393-394 Dodecyl gallate, 327 Dodecyl sodium sulfate, 359-361 Dowicil75, 100,200*,329-331 Dracylic acid, 41-45 Drugs, 3-4, 5, see also specific agents E EI02,169-176 EIIO, 179-190,238 EI32,151-155 E160, 23-24 E21! 351-356 E221, 393 E222, 393 E223, 393-394 E224, 394 E228,394 E31O,325-327 E413, 423-425 E422, 199-203 E460, 71-74 EDA,135-138 Emulphor EL ®, 279-284 Eosin isodium, 111-112 Equal®, 25-29 Erythrolaccin, 347 Erythrosine, 157-162 1,2-Ethanediamine, 135-138 EthanoL 127-132 Ethoxylated lanolins, 226-228 Ethylenediamine, 135-138 Ethylparaben, 251-257 Eugenol,99 European Fragrance Mix 2, 193 Exsiccated sodium sulphite, 393 F FD&C Blue No 1, 141-148 Index FD&C Blue No.2, 151-155 FD&C Red No.3, 157-162 FD&C Red No 40, 163-168 FD&C Yellow No.5, 169-176 FD&C Yellow No.6 179-190,238 Flowers of benzoin, 41-45 FLuorotrichloromethane, 91-96 Food additives, 4, see also specific agents Formaldehyde, 30,55, 124,206,207.359,361 Fragrances, 243, 261 Fre;ns®,91-96 Fructose, 376 G Geraniol, 193-194 Germall 115® 205-207 Germall IJ® 123-125 Gingelly oil 343-344 Gingilli oil, 343-344 Gliadin, 195 Glicerol, 199-203 GLuten 195-197 Glycerin/glycerol, 199-203 GLycerol polyethylenglycol riciinoleate 279-284 Goma alcatira 423-425 Gomenoleo oil 249-250 Gum arabic, 7-10 Gum rosin 333-335 Gum tragacanth 423-425 H Hexadecyl alcohol, 75-76 2,4-Hexadienoic acid, 363-366 Hexylene glycol, Histamine 236 238 Hordeins 195 Huile de ricinL 69-70 Hydrated magnesium silicate, 407-409 Hydroabietic acid, 333 335 Hydrogenated lanolin 225-228 Hydrolyzed vegetable protein 196 235 Hydrophilic Ointment USp, 265, 361 Hydrophilic Petrolatum USP 265 Hydroxycitronellal 194 Hydroxypropyl cellulose 429-430 Hypersensitivity reactions see specific agents 4-Imidazoleacrylic acid, 433-434 I Imidazolidinyl urea 124.205-207 Imidurea 205-207 IMP, 209-211 India bum, 423 Indigo carmine lSI-ISS Indigotin lSI-ISS Indigotinsulfonate sodium 151-155 Iodine, 161 437 Isopropyl myristate, 209-211 K Karaya, 423 Kathon CG® 213-2166 Kollodion®.303-305 Kombu extract, 235 L LaclLacca,347-349 Lactose, 219-224,427 Lactosum.219-224 Lanolin 225-228 Lauryl sodium sulfate, 359-361 Leaf Lac, 347-349 Legislation, 1-5 Lethicin,381-382 Liquid paraffin, 231-234 Liquid petrolatum, 231-234 Lowinox®,62 M Macrogol 287-292 Maize starch 105-107 Malt 196 Mercury, (acetato) phenyl, 275 Merphenyl nitrate 276 Merthiolate®, 135,411-416 2-Methoxycinnamaldehyde, 99 2-Methoxy-3.5-dinitro-4-methyl tertiary butyl benzene, 243-245 Methyl cinnamate, 100 Methyl ethylene glycol 307-321, see also Propylene glycol Methyl glycol 307-321 see also Propylene glycol 2-Methyl-4-isothizolin-3-one, 213-216 6-Methyl-I,2.3-oxathiazine-4-(3H)-one-2,2-dioxide potassium 13-15 Methylparaben 251-257 Methyl salicylate 127 Microcrystalline cellulose, 71-74 Milk sugar 219-224 Mineral oil 231-234, 427 Monitan® 295-300 Monosodium glutamate 235-240 Moskene, 244 MSG 235-240 Musk ambrette, 243-245 Musk ketone and xylene 244 Myacide BT®, 55-56 N Natrium benzoicum 351-356 Natural flavor 235 Nitratophenylmercury.276 beta-Norbixin, 23-24 438 Handbook of Food, Drug, and Cosmetic Excipients NutraSweet®,25-29 Nystatin, 135 o Octyl gallate, 327 Oilive oil, 249-250 Oil of Chinese cinnamon 99-102 Oleic acid, 247-248 Oleum Gossypii Seminis 109-110 Oleum olivae, 249-250 Oleum ricini, 69-70 Oleum sesame 343-344 Oleum sojae 383-384 Onyx ride 500®, 55-56 Orange oil, 419-420 Orange shellac, 347-349 Orange spirit NF, 419-420 Orange Yellow S, 179-190.238 Orthoborato-( I )-O-phenylmercury, 275-276 Over-the-counter (OTC) drugs, 2-3, see also specific agents p Palmityl alcohol, 75-76 Parabens.251-257 Parachlorometacresol, 87-89 Parachlorometaxylenol, 259-260 Paraffin, liquid 231-234 Paraffin jelly, 265-268 Paraphenylenediamine 256 Patent Blue AC, 141-148 PCMC, 87-89 PCMX, 259-260 PEG, 287-292 PEG 40 and 60 hydrogenated castor oil, 279-284 Peru(vian) balsam, 261-263 Petrolatum, 265-268 Petrolatum liquid 231-234 Petrolatum Gauze USP, 265 Petroleum jelly, 265-268 Pharmaceutical glaze, 347-349 Phenol 271-273 Phenomeroborum, 275-276 Phenylcarbinol,47-52 Phenylcarboxylic acid 41-45 Phenylformic acid, 41-45 Phenylmercuriborate 275-276 Phenylmercuric acetate, 275 Phenylmercuric borate, 275-276 Phenylmercuric nitrate, 276 Phenylmercuric salts, 275-277 Phenylmethanol, 47-52 Pine resin, 333-335 Plasdone®.303-305 PMN,276 Polyethoxylated castor oil, 279-284 Polyethylene glycol, 287-292 Polyethylene oxide sorbitan esters 295-300 Polyisobutylene, 429 Polyoxyethylene lanolins, 226-228 Polyoxyethylene sorbitan esters, 295-300 Polyoxyl 35 castor oil 279-284 Polyoxyl 40 hydrogenated castor oil, 279-284 Polysorbates, 295-300 Polyvidone 303-305 Polyvinylpyrrolidone, 303-305 Potassium benzoate, 354 Potassium bisulfite, 394, see also Sulfites Potassium metabisulfite, 394, see also Sulfites Potassium sorbate, 363-366 Povidone, 303-305 Powdered talc, 407-409 Pregelatinized starch, 105-107 Prolamins, 195 Promyr®, 209-21 I Propal®, 209-211 1,2-Propanediol, see Propylene glycol 1,2.3-Propanetriol, 199-203 Propane-I,2,3-triol, 199-203 I-Propanol-I,I, l-trichloro-2-methyl 81-84 2-PropenylacryJic acid, 363-366 Propranolol,281 Propylene glycol, 307-321 animal toxicity, 312-313 clinical relevance, 320-321 formulations 307 human toxicity 313-320 products, 308-312 Propyl gallate, 325-327 Propylparaben, 251-257 Propyl-3,4,5-trihydroxybenzoate, 325-327 PVP.303-305 Q Quatemium 15.329-331 Quinophthalone, 115-121 R Refined Bleached Shellac USP, 347 Refined sugar, 387-391 Regulatory activity, 1-5 Resin, 333-335 Resina pini, 333-335 Resina terebinthinae 333-335 Ricini oleum, 69-70 Rosin 333-335 s Saccharin 337-341 Saccharose 387-391 Saccharum lactis, 219-224 Saigon cinnamon, 99-102 Secalins, 195 Sesame oil, 343-344 Shellac, 347-349 SLS, 359-361 Soapstone, 407-409 Index Sodii benzoas, 351-356 Sodium benzoate, 44 351-356 Sodium N-dodecyl sulfate, 359-361 Sodium ethylmercurithiosalicylate 135.411-416 Sodium glutamate, 235-240 Sodium hydrogen sulfite, 393 see also Sulfites Sodium lauryl sulfate 359-361 Sodium metabisulfite 393-394 Sodium sulfite, 393, see also Sulfites Sorbic acid, 363-366 Sorbitan trioleate, 369-370 Sorbitol,371-378 Sorlate®, 295-300 Soya lethicin, 381-382 Soybean oil 383-384 Soy hydrolyzed vegetable protein, 235 Stearyl alcohol, 75-76 Steatite, 407-409 Sucre, 387-391 Sucrose, 387-391 Sulfites, 393-403 clinical relevance, 403 formulations 394-395 products, 395-400 synonyms 393-394 toxicity, 400-402 Sulfonamides, 340 Sulfur dioxide, 394 Sunset Yellow FCF, 179-190, 238 Sweet orange peel tincture, 419-420 T Talc 73 407-409 Tall oil rosin 333-335 Tartrazine, 169-176, 189 190 Teel oil 343-344 Tenox®, 56-63 Tetrabromofluorescein, 111-112 Tetrafluorodichloroethane, 91-96 2',4'.5'.7'-Tetraiodofluorescein, disodium, 157-162 Theophylline, 135 Thimerosal 135.411-416 Tincture of orange, 419-420 Tolu balsam 261-263 Toxicity see specific agents Tragacanth 423-425 Transdermal systems 427-431 Transesterified lanolin, 226 228 I ,1.I-Trichloro-2-methyl-2-propanol 81-84 Trichloromonofluoromethane, 91-96 Trihydroxypropane glycerol, 199-203 Tris-Nitro®,55 Tween 80® 295-300 Tyramine 236 238 u Urea imidazolidinyl, 205-207 Urocanic acid, 433-434 v Vaseline officinale 265-268 Vinylpyrrolidone polymer, 303-305 w Wheat flour/starch 195-197 Wheat hydrolyzed vegetable protein, 235 White mineral oil 231-234 White Ointment USP 265 White petrolatum 265-268 White shellac 347 Wood rosin 333-335 Wool fat 225-228 y Yellow petrolatum, 265-268 z Zaharina, 337-341 Zeins.195 439 ... Data Smolinske, Susan C., 195 3Handbook of food, drug, and cosmetic excipients / author, Susan C Smolinske p cm Includes bibliographical references and index ISBN 0-8493-3585-X Excipients- Handbooks,.. .Handbook of Food, Drug, and Cosmetic Excipients Susan c Smolinske, B.S., R.Ph Manager POISINDEX® AND IDENTIDEX® Information Systems Micromedex, Inc Denver, Colorado Library of Congress... demonstration of safety of the additive for its intended use The permanent listing of the additive included a designation Handbook of Food, Drug, and Cosmetic Excipients of the petitioned use listed