Safety evaluation of certain food additives - ipcs inchem

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SUBSTANCES STRUCTURALLY RELATED TO MENTHOL (addendum) First draft prepared by Dr P.J. Abbott 1 and Ms E. Vavasour 2 1 Biosearch Consulting, Canberra, ACT, Australia 2 Food Directorate, Health Canada, Ottawa, Ontario, Canada Evaluation .................................................................................. Introduction ......................................................................... Assessment of dietary exposure ......................................... Absorption, distribution, metabolism and elimination .......... Application of the Procedure for the Safety Evaluation of Flavouring Agents ........................................................... Consideration of combined intakes from use as flavouring agents ............................................................................. Consideration of secondary components ............................ Conclusion .......................................................................... Relevant background information .............................................. Explanation ......................................................................... Additional considerations on intake .................................... Biological data ..................................................................... Biochemical data: absorption, distribution, metabolism and excretion ............................................................ Toxicological studies ..................................................... Acute toxicity .......................................................... Short-term studies of toxicity .................................. Genotoxicity ............................................................ References ................................................................................ 1. EVALUATION 579 579 580 582 1.1 Introduction The Committee evaluated a group of 10 flavouring agents structurally related to menthol, including 4 esters of menthol (Nos 1852, 1854, 1855 and 1858), 1 ketone (No. 1856), 3 alicyclic alcohols or ethers (Nos 1853, 1860 and 1861), 1 diketone (No. 1857) and 1 ketal (No. 1859). The evaluations were conducted according to the Procedure for the Safety Evaluation of Flavouring Agents established by the Committee at its forty-ninth meeting (Figure 1, Introduction) (Annex 1, reference 131). None of these flavouring agents has previously been evaluated by the Committee. At its fifty-first meeting, the Committee evaluated menthol and 13 other members of this group of flavouring agents (Annex 1, reference 137). All 14 agents in that group were concluded to be of no safety concern based on current estimated levels of intake. - 579 - 580 587 587 588 588 588 588 588 588 588 588 589 590 591
580 SUBSTANCES STRUCTURALLY RELATED TO MENTHOL (addendum) Five of the 10 additional flavouring agents in this group are natural components of foods (Nos 1852, 1860, 1856, 1857 and 1861). They have been detected in a variety of peppermint and cornmint oils, honeys, teas, starfruit, shrimp, lemon balm, citrus peel oils and cognac (Nijssen et al., 2007). 1.2 Assessment of dietary exposure The total annual volume of production of the 10 substances structurally related to menthol is approximately 409 kg in Europe (European Flavour and Fragrance Association, 2005), 485 kg in the USA (Gavin et al., 2007) and 162 kg in Japan (Japan Flavor & Fragrance Materials Association, 2002). The estimated daily per capita intake of each flavouring agent is reported in Table 1. Annual volumes of production of this group of flavouring agents are summarized in Table 2. 1.3 Absorption, distribution, metabolism and elimination The menthyl esters in this group (Nos 1852, 1854, 1855 and 1858) can be expected to be readily hydrolysed to menthol and their respective carboxylic acids (Heymann, 1980; Anders, 1989). Carboxylesterases are found in the endoplasmic reticulum of most mammalian tissues (Hosokawa et al., 2001), but occur predominantly in hepatocytes (Heymann, 1980; Graffner-Nordberg et al., 1998; Hosokawa et al., 2001). The metabolites of menthol are eliminated in the urine and/or faeces either unchanged or conjugated with glucuronic acid (Yamaguchi et al., 1994). The ketal (No. 1859) is expected to be hydrolysed to yield ()- or (±)menthone and simple glycols (Heymann, 1980). The ketone menthone is primarily reduced to the corresponding secondary alcohol, neomenthol, which is metabolized and eliminated by pathways similar to those of its stereoisomer, menthol (Williams, 1940). The ketones (Nos 1856 and 1857) in this group would be reduced to their corresponding secondary alcohols and conjugated mainly with glucuronic acid (Quick, 1928; Williams, 1940; Atzl et al., 1972). The alicyclic alcohols (Nos 1853, 1860 and 1861) are expected to be conjugated mainly with glucuronic acid and eliminated in the urine or faeces. 1.4 Application of the Procedure for the Safety Evaluation of Flavouring Agents Step 1. In applying the Procedure for the Safety Evaluation of Flavouring Agents to this group of flavouring agents, the Committee assigned five of the flavouring agents (Nos 1852–1855 and 1860) to structural class I (Cramer et al., 1978). The remaining five flavouring agents (Nos 1856–1859 and 1861) were assigned to structural class II (Cramer et al., 1978). Step 2. All the flavouring agents in this group are expected to be metabolized to innocuous products. The evaluation of all flavouring agents in this group therefore proceeded via the A-side of the Procedure. Step A3. The estimated daily per capita intakes of all five of the flavouring agents in structural class I are below the threshold of concern (i.e. 1800 μg/person per day for class I). The estimated daily per capita intakes of all five of the flavouring agents in structural class II are below the threshold of concern (i.e. 540 μg/ person per day for class II).
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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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FURAN-SUBSTITUTED ALIPHATIC HYDROCA
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Page 534 and 535: FURAN-SUBSTITUTED ALIPHATIC HYDROCA
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Page 589 and 590: 582 SUBSTANCES STRUCTURALLY RELATED
Page 602: ANNEXES
Page 605 and 606: 598 ANNEX 1 10. Specifications for
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Page 615 and 616: 608 ANNEX 1 188. Safety evaluation
Page 617 and 618: 610 ANNEX 2 ECG electrocardiogram E
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Page 624 and 625: ANNEX 4 ACCEPTABLE DAILY INTAKES, O
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Page 630 and 631: ANNEX 4 623 Flavouring agent No. Sp
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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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