Safety evaluation of certain food additives - ipcs inchem

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ALKOXY-SUBSTITUTED ALLYLBENZENES PRESENT IN FOODS AND ESSENTIAL OILS AND USED AS FLAVOURING AGENTS First draft prepared by Dr G.M. Williams 1 and Dr A. Mattia 2 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 Explanation ................................................................................ Natural occurrence .............................................................. Estimated daily per capita exposure to alkoxy-substituted allylbenzenes .................................................................. From spices, herbs and herb and spice oils .................. Used as flavouring agents ............................................. Biological data ........................................................................... Biochemical aspects ............................................................ Absorption, distribution and elimination ........................ Rodents ................................................................... Humans ................................................................... Summary ................................................................. Biotransformation .......................................................... Related biochemistry studies ........................................ Enzyme induction and inhibition .................................... Oxidative stress and cytotoxicity ................................... Protein adducts ............................................................. DNA adducts ................................................................. Rodent DNA adducts .............................................. Human DNA adducts .............................................. Summary of enzyme induction and adduct formation data .......................................................................... Toxicological studies ........................................................... Acute toxicity ................................................................. Short-term studies of toxicity ......................................... Nutmeg oil ............................................................... Estragole (No. 1789) ............................................... Methyl eugenol (No. 1790) ...................................... Myristicin (No. 1791) ............................................... Safrole (No. 1792) ................................................... Long-term studies of toxicity and carcinogenicity .......... Estragole (No. 1789) ............................................... Methyl eugenol (No. 1790) ...................................... Safrole (No. 1792) ................................................... Elemicin-, myristicin- and apiole-related substances and their metabolites .......................................... Reproductive and developmental toxicity ...................... Genotoxicity .................................................................. - 351 - 352 353 354 354 356 356 356 357 357 359 361 361 370 372 374 375 376 376 380 381 383 383 384 384 387 389 391 391 392 392 394 398 402 402 405
352 ALKOXY-SUBSTITUTED ALLYLBENZENES In vitro ..................................................................... In vivo ...................................................................... Genotoxicity conclusions ........................................ Comments ................................................................................. Assessment of dietary exposure ......................................... Evaluation of toxicological data ........................................... Interpretation of carcinogenicity data from studies in which high doses were administered by gavage ...... Nature of the dose–response relationship for hepatocarcinogenicity .............................................. Non-relevance of neuroendocine gastric tumours to humans .................................................................... Relevance of the toxicity data to the ingestion of spices ................................................................... Epidemiological studies on spice ingestion ................... Evaluation .................................................................................. References ................................................................................ Appendix 1: Alkoxy-substituted allylbenzenes in herbs and spices ............................................................................. 1. EXPLANATION 405 434 435 437 437 438 The common structural features of this group of six substances are an allylbenzene nucleus and one or more alkoxy ring substituents. All have an alkoxy substitution at the para position. Three members of the group contain a 3,4methylenedioxy substituent and may have additional methoxy substituents: safrole (3,4-methylenedioxyallylbenzene, No. 1792), myristicin (5-methoxy-3,4methylenedioxyallylbenzene, No. 1791) and apiole (2,5-dimethoxy-3,4methylenedioxyallylbenzene, No. 1787) (Figure 1). Three other substances contain only methoxy substituents: estragole (4-methoxyallylbenzene, No. 1789), methyl eugenol (3,4-dimethoxyallylbenzene, No. 1790) and elemicin (3,4,5trimethoxyallylbenzene, No. 1788) (Figure 1). Because of the widespread occurrence of alkoxy-substituted allybenzenes in food, mainly in spices and herbs but also in certain vegetables and fruits, these substances are referred to by their common names. Estragole was reviewed by the Committee at its twenty-third and twenty-fifth meetings (Annex 1, references 50 and 56), and safrole was reviewed at the fifth and twenty-fifth meetings (Annex 1, references 5 and 56). For estragole, no acceptable daily intake (ADI) was allocated at the twenty-fifth meeting, and the Committee requested additional long-term studies for evaluation of carcinogenic potential. For safrole, the Committee concluded at its twenty-fifth meeting that flavouring agents containing safrole or isosafrole as the principal flavour-active ingredient should not be used as food additives; and that it is not practicable to advocate the discontinuance of spices containing safrole or isosafrole as minor constituents (e.g. nutmeg, mace and cinnamon). However, the Committee at that meeting concluded that when these spices were used, the amounts of safrole and isosafrole in the finished product should be kept as low as practicable. Only two of the substances, estragole and methyl eugenol, are used as flavouring agents intentionally added to compounded flavours. This use is limited 438 438 439 439 439 439 439 460
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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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Page 307 and 308: 300 ALIPHATIC BRANCHED-CHAIN SATURA
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ALKOXY-SUBSTITUTED ALLYLBENZENES 40
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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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