Safety evaluation of certain food additives - ipcs inchem

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ALKOXY-SUBSTITUTED ALLYLBENZENES 369 side-chain (i.e. 4-methoxyhippuric acid, the glycine conjugate of 4-methoxycinnamic acid and 4-methoxyphenyllactic acid) accounted for the majority of the urinary metabolites. Urinary 1-hydroxyestragole as the glucuronic acid conjugate accounted for an average of only 0.3% of the total dose (Sangster et al., 1987). As in other rodent metabolism studies, higher dose levels produce measurable levels of 1-hydroxy metabolite that can be quantified in the urine. A 100 mg/kg bw dose of estragole given to rats by the oral or intraperitoneal route was excreted in the urine mainly as the O-demethylation product 4-allylphenol (39% oral or 46% intraperitoneal) within 48 h (see Figure 2). Approximately 5–10% of the dose was excreted as the 1-hydroxylation metabolite, 1-hydroxyestragole. Other metabolites accounting for 17% of the oral dose or 31% of the intraperitoneal dose included the product of epoxidation, hydration and subsequent oxidation of the terminal alcohol (3-hydroxy-3-(4-methoxyphenyl)propionic acid) of the allyl sidechain and the products of alkene isomerization, oxidation of the resulting C3 position and -oxidation, yielding 4-methoxybenzoic acid and 4-methoxyhippuric acid (Solheim & Scheline, 1973). At low doses in humans, mice and rats, significant amounts of safrole, myristicin, estragole or methyl eugenol are O-dealkylated; as dose levels increase, 1-hydroxylation and epoxidation of alkoxy-substituted allylbenzenes increase. The total daily urinary production of the 1-hydroxy metabolite increases significantly, as much as 6000 times, as the dose of estragole increases from 50 μg/kg bw to 50 mg/kg bw (a 1000-fold increase) and the metabolism shifts to the CYP-catalysed 1-hydroxylation pathway (roughly a 6-fold increase) (Zangouras et al., 1981; Anthony et al., 1987). Data on metabolite identification and quantification for rats given different doses (0.9–600 mg/kg bw) of safrole demonstrate similar effects of dose on metabolic shifting. These studies support the conclusion that the combination of increased dose and metabolic shifting results in significant increases in tissue concentrations and total body burden of the 1-hydroxy metabolite (Benedetti et al., 1977). However, it is unlikely that the human liver is exposed to significant levels of the 1-hydroxy metabolites and the 1-sulfoxy metabolites of the allylbenzenes at daily intakes of 1–2 mg/person per day (17–33 μg/kg bw per day), as would occur from daily consumption of spices and spice oils and use as a flavouring ingredient. Biochemical evidence for this conclusion is 1) the rapid and almost complete clearance of radioactivity in humans dosed with labelled safrole and estragole at levels similar to normal daily intake; 2) lack of any detectable levels of 1-hydroxy metabolites in urine in humans administered relatively large doses of nutmeg containing myristicin, safrole or elemicin; 3) urinary excretion of low levels (0.3%) of the 1-hydroxy metabolites by humans who were administered alkoxysubstituted allylbenzenes (estragole); and 4) the presence of metabolic shifting in rodents, in which the proportion (1–2%) and level of measured radioactivity are very low in the liver of rodents administered low doses (20%) and the level are higher at higher dose levels (50–1200 mg/kg bw). Dosing of rodents with high levels of alkoxy-substituted allylbenzenes in this group resulted in a marked increase in production of the urinary 1-hydroxy metabolite. Increased 1-hydroxylation of safrole, myristicin, estragole or methyl
370 ALKOXY-SUBSTITUTED ALLYLBENZENES eugenol is reflected by dose-dependent increases in urinary levels of this metabolite (e.g. for estragole, 10 mg/kg bw) provides an understanding for the observation that protein and DNA adducts were first detected in early studies at high dose levels. As DNA and protein adduct methodology has evolved and detection limits have decreased, adduct formation has been identified even at levels of exposure similar to those for humans consuming spices and spice oils containing alkoxy-substituted allylbenzene constituents. However, based on studies in humans and rodents at lower dose levels (
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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 325 and 326: 318 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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