Safety evaluation of certain food additives - ipcs inchem

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ALIPHATIC BRANCHED-CHAIN SATURATED AND UNSATURATED ALCOHOLS 311 metabolic transformation. It is not exactly clear how these inhibitors act in the citric acid cycle, but, according to the authors, this indicates that methyl 2-methyl-2-propenoate enters the citric acid cycle as pyruvate (Pantucek, 1969). In an in vivo metabolism study involving methyl 2-methyl-2-propenoate, the percentage of 14 CO2 was measured with respect to the amount of administered radiolabelled methyl [ 14 C]2-methyl-2-propenoate via intragastric and intravenous routes. Irrespective of the route of administration, the major metabolite detected was 14 CO2. Other minor metabolites were identified as [ 14 C]methylmalonate, [ 14 C]succinate and possibly [ 14 C]-hydroxyisobutyrate and [ 14 C]2-formylpropionate. In addition, formation of 14 C-labelled normal physiological metabolites may be expected owing to anabolism from 14 CO2 and from [ 14 C]acetate via the citric acid cycle (see Figure 2) (Bratt & Hathway, 1977). According to Pantucek (1969), methyl 2-methyl-2-propenoate enters the citric acid cycle via the formation of pyruvate rather than via the formation of succinyl coenzyme A (CoA). However, in both cases, eventually methyl 2-methyl-2-propenoate will be fully oxidized in the citric acid cycle. Figure 2. Proposed metabolism of methyl 2-methyl-2-propenoate C H 2 C H 3 HO O HO C H 3 O O O CH 3 O O CoA O O CoA O H 2 C H 2 C H 3 methyl 2-methyl-2-propenoate methacrylate methacryl-CoA methyl malonyl mutase succinyl CoA NADH NAD + CoA 2.3.2 Toxicological studies (a) Acute toxicity H C H 3 O O OH methyl malonyl semialdehyde O OH NADH C H 3 CoA To citric acid cycle OH NAD + β-hydroxy-isobutyric acid dehydrogenase C H 2 C H 3 H C H 3 OH O CoA O H 2 O OH β-hydroxy-isobutyric acid Oral median lethal dose (LD50) values have been reported for 11 of the 20 substances in this group, 1 of them being tested in mice, rats, guinea-pigs and
312 ALIPHATIC BRANCHED-CHAIN SATURATED AND UNSATURATED ALCOHOLS dogs, 9 of them being tested in rats only and 1 of them being tested in mice only (see Table 3). In dogs and guinea-pigs, the oral LD50 values were 4680 and 5897 mg/kg bw, respectively (Spealman et al., 1945). In mice, oral LD50 values ranged from >4550 to 5251 mg/kg bw (Lawrence et al., 1974; Ward, 1976; Moreno, 1982). In rats, oral LD50 values ranged from >2000 to >10 000 mg/kg bw (Deichmann, 1941; Deichmann & LeBlanc, 1943; Spealman et al., 1945; Shelanski, 1972; Moreno, 1976, 1977a, 1977b, 1978, 1980; Kajiura, 1977a; BASF, 1978; Moore, 2000; Klein, 2003). These LD50 values indicate that the acute toxicity of orally administered aliphatic branched-chain unsaturated and saturated alcohols, aldehydes, acids and related esters is low. Table 3. Results of studies of oral acute toxicity with aliphatic branched-chain saturated and unsaturated alcohols, aldehydes, acids and related esters No. Flavouring agent Species; sex LD50 (mg/kg bw) 1817 (±)(E,Z)-5-(2,2- Dimethylcyclopropyl)- 3-methyl-2-pentenal Reference Rats; M, F >2000 Klein (2003) 1822 (E)-Geranyl tiglate Rats; M, F >5000 Shelanski (1972) 1823 (E)-Citronellyl 2-methylbut- 2-enoate Rats; NR >5000 Moreno (1978) 1824 (E)-Ethyl tiglate Rats; M >5000 Moreno (1980) 1825 (E,Z)-Geranic acid Rats; NR 3700 Moreno (1976) 1827 Prenyl acetate Rats; NR 3000 Moreno (1977a) 1830 (±)-Dihydrofarnesol Rats; M >2000 Kajiura (1997a) 1831 (E,Z)-3,7,11- Trimethyldodeca-2,6,10-trienyl acetate Mice; M, F >4550a Ward (1976) 1831 (E,Z)-3,7,11- Trimethyldodeca-2,6,10-trienyl acetate Mice; NR >5000 Moreno (1982) 1832 (E,Z)-Phytol Rats; NR >5000 Moreno (1977b) 1832 (E,Z)-Phytol Rats; NR >10 000 BASF (1978) 1833 (E,Z)-Phytyl acetate Rats; M, F >2000 Moore (2000) 1834 Methyl 2-methyl-2-propenoate Mice; NR 5251 b Lawrence et al. (1974) 1834 Methyl 2-methyl-2-propenoate Rats; NR 7872 b Deichmann (1941) 1834 Methyl 2-methyl-2-propenoate Rats; NR 8560 Deichmann & LeBlanc (1943) 1834 Methyl 2-methyl-2-propenoate Rats; M, F 9360 b Spealman et al. (1945)
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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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Page 268: SAFETY EVALUATIONS OF GROUPS OF REL
Page 271 and 272: 264 INTRODUCTION Figure 1. Procedur
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ALKOXY-SUBSTITUTED ALLYLBENZENES 36
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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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