Safety evaluation of certain food additives - ipcs inchem

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ALKOXY-SUBSTITUTED ALLYLBENZENES 365 Figure 3. Metabolism of estragole, methyl eugenol and elemicin R Glu-S Glc-O R R' HO 1'-hydroxylation O-demethylation R R' R R' R O 3 SO OMe OMe OMe OH R' R R' glucuronidation sulfation OMe R reaction with glutathione R isomerization HO OMe OMe OMe OMe When rats were dosed orally with ground nutmeg as an aqueous suspension at 500 mg/kg bw (approximately 1–2 mg myristicin/kg bw, with lesser amounts of safrole and elemicin), the O-demethylenation or O-demethylation, epoxidation, and OH R' O R' OH R R' hydrolysis epoxidation R/R'=H (estragole) R=OCH 3 R'=H (methyl eugenol) R/R'=OCH 3 (elemicin) R HO HO OMe OH OH OH R' R' R'
366 ALKOXY-SUBSTITUTED ALLYLBENZENES epoxidation and hydrolysis metabolites were detected in the urine. As expected, 3,4-dihydroxy-5-methoxyallylbenzene, the product of O-demethylenation of myristicin, was the major metabolite. However, no 1-hydroxylation metabolites could be detected by this GC/electron impact MS method. The presence of the 1-hydroxy metabolites in rats given the pure substances at 100 mg/kg bw and their absence in rats given nutmeg at 500 mg/kg bw may be due to higher dose (100 versus 1–2 mg/kg bw) or to an effect of the rats being administered a nutmeg matrix, which alters the metabolic fate of each of these alkoxy-substituted allylbenzenes (Beyer et al., 2006). In a human who reported ingesting the powder of about five nutmegs (20–50 g of nutmeg, corresponding to 140–280 mg elemicin or 2.3–4.6 mg elemicin/ kg bw, 100–200 mg myristicin or 1.6–3.2 mg myristicin/kg bw, and approximately 20 mg safrole or 0.3 mg safrole/kg bw), analysis of the urine revealed that the major metabolites of each of the three constituents were detected. As for rats given ground nutmeg, no 1-hydroxylation metabolite was detected. For both rats and humans exposed to nutmeg, the corresponding O-demethylenation metabolite of safrole or myristicin was the predominant metabolite, exceeding other metabolites by at least a factor of 10. The side-chain demethylation products were the major metabolites of elemicin (Beyer et al., 2006). Two humans were administered an oral dose of 1.66 mg of [1- 14 C]safrole, and urine was collected for 24 h. The percentage of radioactivity extracted from urine increased from 32% to 73% after treatment with glucuronidase, indicating that a majority of urinary metabolites were glucuronic acid conjugates. Analysis of urine metabolites by GC/MS indicated that the O-demethylenation product was the major metabolite (65%). At the limits of detection (approximately 10 times less than the measured level of O-demethylenation metabolite), no 1-hydroxy metabolite could be detected (Benedetti et al., 1977). In the same study, rats were administered [1- 14 C]safrole at single oral doses of 0.90, 60 or 600 mg/kg bw, and urine was collected over 48 h. Glucuronidase hydrolysis significantly increased the percentage of radioactivity that was extracted, indicating that glucuronic acid conjugates accounted for the majority of urinary metabolites. The major metabolite was 1,2-dihydroxyallylbenzene, but its proportion decreased significantly when the dose was increased from 60 to 600 mg/kg bw. At 600 mg/kg bw, 1-hydroxysafrole was detected in the urine. The other metabolites identified were 3-hydroxyisosafrole and 3(4)-hydroxy-4(3)-methoxyallylbenzene. Other studies using relatively high dose levels of either safrole or myristicin via the oral or intraperitoneal route support the observation that 1,2-dihydroxyallylbenzene is the major metabolite. The detection of the 1-hydroxy metabolite in rats correlates with the appearance of low levels of protein and DNA adducts in rodents (see below). Safrole was largely metabolized by O-demethylenation in male Swiss- Webster mice, Sprague-Dawley rats or hamsters. When each of these species was administered [methylenedioxy- 14 C]safrole, 1,2-dihydroxyallylbenzene was produced as the major metabolite, resulting from oxidative metabolism that produces [ 14 C]formate or [ 14 C]carbon dioxide, which were both identified (Kamienski & Casida, 1970).
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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 321 and 322: 314 ALIPHATIC BRANCHED-CHAIN SATURA
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ALKOXY-SUBSTITUTED ALLYLBENZENES 41
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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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