Revised Tentative Report of the Cosmetic Ingredient Review Expert Panel Safety Assessment of Alcohol Denat. including SD Alcohol 3-A, SD Alcohol 30, SD Alcohol 39, SD Alcohol 39-B, SD Alcohol 39-C, SD Alcohol 40, SD Alcohol 40-B, and SD Alcohol 40-C and the denaturants Denatonium Benzoate, Quassin, and Brucine Sulfate/Brucine April 22, 2005 All interested persons are provided 90 days from the above date to comment on this Revised Tentative Safety Assessment and to identify additional published data that should be included or provide unpublished data which can be made public and included. Information may be submitted without identifying the source or the trade name of the cosmetic product containing the ingredient. All unpublished data submitted to CIR will be discussed in open meetings , will be available at the CIR office for review by any interested party, and may be cited in a peer-reviewed scientific journal. Please submit data, comments, or requests to the CIR Director, Dr. F. Alan Andersen. This safety assessment will again be considered at the September 12-13, 2005 meeting of the CIR Expert Panel. The 2005 Cosmetic Ingredient Review Expert Panel members are: Chairman, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Curtis D. Klaassen, Ph.D.; James G. Marks, Jr., M.D., Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. Cosmetic Ingredient Review 1101 17th Street, NW, Suite 310 " Washington, DC 20036-4702 " ph 202.331.0651 " fax 202.331.0088 " [email protected] TABLE OF CONTENTS INTRODUCTION .................................................................... 1 PART I: DENATURANTS ............................................................. 2 CHEMISTRY ....................................................................... 3 Definition and Structure ........................................................ 3 Quassin .............................................................. 3 Brucine Sulfate......................................................... 4 Denatonium Benzoate ................................................... 5 Method of Manufacture......................................................... 7 Quassin .............................................................. 7 Brucine ............................................................... 8 Denatonium Benzoate ................................................... 8 Analytical Methods ............................................................ 8 Quassin .............................................................. 8 Brucine ............................................................... 9 Denatonium Benzoate ................................................... 9 Impurities.................................................................... 9 Brucine .............................................................. 10 Quassin ............................................................. 10 Denatonium Benzoate .................................................. 10 USE ............................................................................. 10 Cosmetic ................................................................... 10 Non-Cosmetic ............................................................... 12 GENERAL BIOLOGY................................................................ 20 Absorption, Metabolism, and Distribution.......................................... 20 Quassin ............................................................. 20 Lidocaine ............................................................ 20 Anti-feedant and Insecticidal Activity ............................................. 20 Quassin ............................................................. 20 Cytotoxicity ................................................................. 21 Brucine and Quassin ................................................... 21 TOXICOLOGY ..................................................................... 22 Acute Oral Toxicity ........................................................... 22 Quassin ............................................................. 22 Brucine .............................................................. 22 Denatonium Benzoate .................................................. 22 Acute Inhalation Toxicity....................................................... 23 Denatonium Benzoate .................................................. 23 Acute Ocular Toxicity ......................................................... 23 Denatonium Benzoate .................................................. 23 Acute Parenteral Toxicity ...................................................... 23 Quassin ............................................................. 23 Brucine .............................................................. 24 Short-Term Toxicity .......................................................... 24 Quassin ............................................................. 24 Chronic Toxicity ............................................................. 24 Denatonium Benzoate .................................................. 24 Dermal Irritation ............................................................. 25 Denatonium Benzoate .................................................. 25 Genital Irritation.............................................................. 26 Denatonium Benzoate .................................................. 26 REPRODUCTIVE AND DEVELOPMENTAL TOXICITY..................................... 26 Quassin ............................................................. 26 Lidocaine ............................................................ 27 MUTAGENICITY ................................................................... 27 Brucine .............................................................. 27 CARCINOGENECITY ............................................................... 28 Denatonium Benzoate .................................................. 28 CLINICAL ASSESSMENT OF SAFETY ................................................. 28 Dermal Sensitization and Irritation ............................................... 28 Brucine .............................................................. 28 Denatonium Benzoate .................................................. 31 Taste Aversion .............................................................. 33 Denatonium Benzoate .................................................. 33 Photoallergy ................................................................ 34 Denatonium Benzoate .................................................. 34 Brucine Sulfate........................................................ 35 Phototoxicity ................................................................ 36 Denatonium Benzoate .................................................. 36 Brucine Sulfate........................................................ 36 Case Studies................................................................ 37 Denatonium Benzoate .................................................. 37 PART II: ETHANOL ................................................................. 39 CHEMISTRY ...................................................................... 39 Definition and Structure ....................................................... 39 Chemical and Physical Properties ............................................... 39 Method of Manufacture........................................................ 39 Analytical Methods ........................................................... 39 Impurities................................................................... 39 USE ............................................................................. 40 Cosmetic ................................................................... 40 GENERAL BIOLOGY................................................................ 41 Absorption .................................................................. 41 Dermal .............................................................. 41 Distribution ................................................................. 42 Parenteral............................................................ 42 Inhalation ............................................................ 43 Oral................................................................. 44 Penetration Enhancement ..................................................... 44 ANIMAL TOXICOLOGY.............................................................. 46 Acute Toxicology............................................................. 46 Inhalation ............................................................ 46 .................................................................... 46 Ocular............................................................... 46 Short-Term Toxicity .......................................................... 46 Inhalation ............................................................ 46 Subchronic Toxicity .......................................................... 47 Oral................................................................. 47 Chronic Toxicity ............................................................. 47 REPRODUCTIVE AND DEVELOPMENTAL TOXICITY..................................... 48 Drosophila ........................................................... 48 Mice ................................................................ 48 Rats ................................................................ 49 Rabbits .............................................................