Safety evaluation of certain food additives - ipcs inchem

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FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS, ALCOHOLS, ALDEHYDES, KETONES, CARBOXYLIC ACIDS AND RELATED ESTERS, SULFIDES, DISULFIDES AND ETHERS (addendum) First draft prepared by Dr G.M. Williams, 1 Dr A. Mattia 2 and Dr A. Renwick 3 1 New York Medical College, Valhalla, NY, United States of America (USA) 2 Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD, USA 3 School of Medicine, University of Southampton, Southampton, England Explanation................................................................................. Biological data............................................................................ Biochemical aspects............................................................ Hydrolysis...................................................................... Absorption, distribution and excretion............................ Metabolism.................................................................... Alkyl-substituted furan (Nos 1487–1496) and furyl ketone (Nos 1503–1512) derivatives.................. Furan-substituted aldehydes, carboxylic acids and related esters (Nos 1497–1502 and 1513–1519)......................................................... Furan-substituted ethers (Nos 1520–1522)............. Furan-substituted sulfides, disulfides and thioesters (Nos 1523–1526)................................................ Furan metabolism and mechanism of action........... Toxicological studies............................................................ Acute toxicity.................................................................. Short-term studies of toxicity......................................... 2-Pentylfuran (No. 1491) ........................................ 2,3-Dimethylbenzofuran (No. 1495) ....................... 3-(2-Furyl)acrolein (No. 1497) ................................ 3-(2-Furyl)acrolein (No. 1497), 2-furyl methyl ketone (No. 1503) and isobutyl 3-(2-furan)propionate (No. 1514) ........................................ 2-Phenyl-3-(2-furyl)prop-2-enal (No. 1502) ............ 4-(2-Furyl)-3-buten-2-one (No. 1511) ..................... 3-Acetyl-2,5-dimethylfuran (No. 1506) and furfuryl methyl ether (No. 1520) ..................................... O-Ethyl S-(2-furylmethyl)thiocarbonate (No. 1526) .......................................................... Structurally related substance 2,5-dimethyl-3-furan thioisovalerate (No. 1070) .................................. Structurally related substance furfuryl mercaptan (No. 1072) .......................................................... - 481 - 482 488 488 488 490 491 491 497 498 498 499 501 501 502 504 505 505 507 509 510 510 510 511 512
482 FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS Genotoxicity studies ...................................................... In vitro ..................................................................... In vivo ..................................................................... Conclusions ............................................................ Comments ................................................................................. Evaluation .................................................................................. References ................................................................................ 1. EXPLANATION 512 519 522 523 525 526 526 At its sixty-fifth meeting (Annex 1, reference 177), the Committee reviewed a group of 40 furan-substituted aliphatic hydrocarbons, alcohols, aldehydes, ketones, carboxylic acids and related esters, sulfides, disulfides and ethers. The Committee at that meeting took note of the extensive evidence for the genotoxicity of several members of this group of flavouring agents related to furan, including the clastogenicity of 2-furyl methyl ketone (No. 1503) in mouse bone marrow. This substance accounts for 87–96% of total exposure to this group of flavouring agents. Noting also that furan is carcinogenic and is known to undergo epoxidation and ring opening to form a reactive 2-ene-1,4-dicarbonyl intermediate, the Committee at its sixty-fifth meeting expressed concern that the observed genotoxicity might be due to formation of a reactive metabolite. Few data on genotoxicity in vivo were available, and specific assays to address potential carcinogenicity in vivo were lacking. The Committee at its sixty-fifth meeting therefore concluded that the Procedure for the Safety Evaluation of Flavouring Agents could not be applied to this group because of the above concerns. It was also concluded that studies of metabolism and in vivo assays for deoxyribonucleic acid (DNA) reactivity, mutagenicity and carcinogenic potential of members of this group with representative structures would assist in resolving the concerns (Annex 1, reference 177). Additional studies of genotoxicity in vitro and in vivo with 2-furyl methyl ketone (No. 1503) were available to the Committee at its present meeting (Durward, 2007a, 2007b; Sujita, 2007). The Committee included the new studies in its reevaluation of the group of 40 furan-substituted aliphatic hydrocarbons, alcohols, aldehydes, ketones, carboxylic acids and related esters, sulfides, disulfides and ethers. The structures of these 40 compounds are given in Table 1.
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WHO FOOD ADDITIVES SERIES: 60 Safet
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CONTENTS Preface ..................
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PREFACE The monographs contained in
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ASPARAGINASE FROM ASPERGILLUS NIGER
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16 CALCIUM LIGNOSULFONATE (40-65) 1
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18 CALCIUM LIGNOSULFONATE (40-65) ~
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20 CALCIUM LIGNOSULFONATE (40-65) A
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22 CALCIUM LIGNOSULFONATE (40-65) c
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24 CALCIUM LIGNOSULFONATE (40-65) T
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28 CALCIUM LIGNOSULFONATE (40-65) i
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ETHYL LAUROYL ARGINATE First draft
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ETHYL LAUROYL ARGINATE 41 and Devel
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ETHYL LAUROYL ARGINATE 43 lauroyl a
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ETHYL LAUROYL ARGINATE 45 arginine.
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ETHYL LAUROYL ARGINATE 47 resulting
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ETHYL LAUROYL ARGINATE 49 Table 4.
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ETHYL LAUROYL ARGINATE 51 weight ch
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ETHYL LAUROYL ARGINATE 53 stomach l
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ETHYL LAUROYL ARGINATE 55 fibrosis
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ETHYL LAUROYL ARGINATE 57 Table 5 (
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ETHYL LAUROYL ARGINATE 59 first 4 d
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ETHYL LAUROYL ARGINATE 61 The gener
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ETHYL LAUROYL ARGINATE 63 treatment
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ETHYL LAUROYL ARGINATE 65 gestation
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ETHYL LAUROYL ARGINATE 67 Body weig
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ETHYL LAUROYL ARGINATE 69 Table 6.
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ETHYL LAUROYL ARGINATE 77 About 99%
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ETHYL LAUROYL ARGINATE 79 concentra
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ETHYL LAUROYL ARGINATE 81 theoretic
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ETHYL LAUROYL ARGINATE 83 Huntingdo
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PAPRIKA EXTRACT First draft prepare
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PAPRIKA EXTRACT 87 of capsanthin ra
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PAPRIKA EXTRACT 89 biochemical para
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PAPRIKA EXTRACT 91 Table 1. Sales o
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PAPRIKA EXTRACT 93 Table 2. Estimat
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PAPRIKA EXTRACT 95 The European Sci
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PAPRIKA EXTRACT 97 The potential di
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PAPRIKA EXTRACT 99 Hornero-Mendez,
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PAPRIKA EXTRACT 101 Appendix 1. Res
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PAPRIKA EXTRACT 103 Appendix 1. (co
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PAPRIKA EXTRACT 105 Appendix 1. (co
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108 PHOSPHOLIPASE C EXPRESSED IN PI
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PHYTOSTEROLS, PHYTOSTANOLS AND THEI
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166 POLYDIMETHYLSILOXANE (addendum)
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STEVIOL GLYCOSIDES (addendum) First
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STEVIOL GLYCOSIDES (addendum) 185 r
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STEVIOL GLYCOSIDES (addendum) 187 c
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STEVIOL GLYCOSIDES (addendum) 189 a
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STEVIOL GLYCOSIDES (addendum) 191 N
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STEVIOL GLYCOSIDES (addendum) 193 2
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STEVIOL GLYCOSIDES (addendum) 195 T
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STEVIOL GLYCOSIDES (addendum) 197 a
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STEVIOL GLYCOSIDES (addendum) 199 r
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STEVIOL GLYCOSIDES (addendum) 201 l
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STEVIOL GLYCOSIDES (addendum) 203 g
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STEVIOL GLYCOSIDES (addendum) 209 t
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STEVIOL GLYCOSIDES (addendum) 211 t
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STEVIOL GLYCOSIDES (addendum) 213 s
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STEVIOL GLYCOSIDES (addendum) 215 C
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STEVIOL GLYCOSIDES (addendum) 217 L
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STEVIOL GLYCOSIDES (addendum) 219 W
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222 SULFITES: ASSESSMENT OF DIETARY
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SAFETY EVALUATIONS OF GROUPS OF REL
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264 INTRODUCTION Figure 1. Procedur
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DIETARY EXPOSURE ASSESSMENT OF FLAV
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292 ALIPHATIC BRANCHED-CHAIN SATURA
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332 ALIPHATIC LINEAR ,-UNSATURATED
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ALKOXY-SUBSTITUTED ALLYLBENZENES PR
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ALKOXY-SUBSTITUTED ALLYLBENZENES 35
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FURAN-SUBSTITUTED ALIPHATIC HYDROCA
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HYDROXY- AND ALKOXY-SUBSTITUTED BEN
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MISCELLANEOUS NITROGEN-CONTAINING S
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580 SUBSTANCES STRUCTURALLY RELATED
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ANNEXES
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598 ANNEX 1 10. Specifications for
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600 ANNEX 1 No. 54, 1974; WHO Techn
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602 ANNEX 1 70. Evaluation of certa
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604 ANNEX 1 108. Toxicological eval
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606 ANNEX 1 148. Residues of some v
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608 ANNEX 1 188. Safety evaluation
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610 ANNEX 2 ECG electrocardiogram E
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612 ANNEX 2 SI stimulation index SU
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614 ANNEX 3 Ms J. Baines, Food Stan
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ANNEX 4 ACCEPTABLE DAILY INTAKES, O
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ANNEX 4 619 Food additive Specifica
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ANNEX 4 621 3. FLAVOURING AGENTS 3.
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ANNEX 4 623 Flavouring agent No. Sp
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ANNEX 4 625 Flavouring agent JECFA
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ANNEX 4 627 Actual production volum
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ANNEX 4 629 Flavouring agent No. Sp
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ANNEX 5 SUMMARY OF THE SAFETY EVALU
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ANNEX 5 633 Secondary components Co
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