Safety evaluation of certain food additives - ipcs inchem

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ETHYL LAUROYL ARGINATE 55 fibrosis and inflammation of the non-glandular epithelium and reflected the depressions noted in the forestomach at necropsy. The observations were significantly different from control only in the group treated with 18 000 mg/kg diet. The authors considered that these changes represented a local response to irritation and thus were not indicative of direct systemic toxicity. No other changes were observed in the non-glandular region of the forestomach, and there were no changes in the glandular region. There were no treatment-related effects on organ weights. The authors concluded that no significant toxicological effects were observed in the animals receiving 2000 or 6000 mg/kg diet and that the NOAEL was 6000 mg ethyl lauroyl arginate/kg diet (equal to 307 mg ethyl lauroyl arginate/kg bw per day). The lowest-observed-adverse-effect level (LOAEL) was concluded to be 18 000 mg ethyl lauroyl arginate/kg diet (equal to 907 mg ethyl lauroyl arginate/kg bw per day), based on local irritant changes in the forestomach and low body weight gain (Huntingdon Life Sciences Ltd, 2005a). The Committee concluded that the changes seen in the stomach represented local irritation in the forestomach caused by storage of ingested diet and were thus not indicative of systemic toxicity. The Committee noted that the observed effects on leukocytes were inconsistent within and between studies and were not likely to be biologically significant. Furthermore, the changes were not accompanied by histopathological changes in the progenitor cell populations of the bone marrow or lymphoid tissue, which would be expected if the effect were due to systemic toxicity. Therefore, the Committee concluded that the highest dietary concentration tested, 18 000 mg/kg (equal to average doses of ethyl lauroyl arginate of approximately 900 mg/kg bw per day in male rats and 1100 mg/kg bw per day in female rats), was the NOAEL for systemic toxicity. 2.2.4 Genotoxicity Several studies, carried out in compliance with GLP and OECD guidelines, were performed to investigate the mutagenicity of ethyl lauroyl arginate, a formulation containing ethyl lauroyl arginate in propylene glycol/water and N - lauroyl-L-arginine (Table 5). Ethyl lauroyl arginate, the formulation and N -lauroyl- L-arginine were tested in a reverse mutation assay (Ames test). Ethyl lauroyl arginate and the formulation were also tested for mutagenic potential in a mammalian cell mutation assay (mouse lymphoma L5178Y cells) and for the ability to induce chromosomal aberrations in human lymphocytes. N -Lauroyl-L-arginine was assessed in an in vivo test for induction of micronuclei in mouse bone marrow cells. Ethyl lauroyl arginate, the formulation and N -lauroyl-L-arginine showed no evidence of mutagenic or clastogenic activity in any of these assays. 2.2.5 Reproductive toxicity In a preliminary study conducted to GLP and OECD guidelines, the effects of ethyl lauroyl arginate (purity, 88.2% ethyl-N -lauroyl-L-arginate HCl) on reproductive performance were assessed. Ethyl lauroyl arginate was administered to Crl:CD rats at dietary concentrations of 0, 1500, 5000 or 15 000 mg/kg (equal to 0, 113, 380 and 1151 mg/kg bw per day for males; and 0, 123, 432 and 1295 mg/ kg bw per day for females). These dietary concentrations were selected based on
56 ETHYL LAUROYL ARGINATE Table 5. Results of assays for genotoxicity with ethyl lauroyl arginate and associated material Formulation Test system Test subject Concentration Results Reference In vitro 1.5–150 μg/plate Negative Huntingdon Life Sciences Ltd (2001a) Reverse mutationc Salmonella typhimurium TA98, TA100, TA1535 and TA1537; Escherichia coli WP2 uvrA/pKM101 Ethyl lauroyl arginate (89.4% active ingredienta ) 5–5000 μg/plate Negative Huntingdon Research Centre Ltd (1995b) Formulationb Reverse mutationc S. typhimurium TA98, TA100, TA1535 and TA1537 Negative Cidasal (2003b) 156.25–5000 μg/ plate Reverse mutationc S. typhimurium TA98, TA100, TA1535 and TA1537; E. coli WP2 uvrA/pKM101 N-Lauroyl-L arginine (purity 98.6%) Cell mutationc Mouse lymphoma L5178Y cells 1–50 μg/ml Negative Huntingdon Life Sciences Ltd (2004) Ethyl lauroyl arginate (88.2% active ingredient) Formulationb Cell mutationc Mouse lymphoma L5178Y cells 100–300 μg/ml Negative Huntingdon Research Centre Ltd (1995c) Huntingdon Life Sciences Ltd (2001b) Human lymphocytes 50–200 μg/ml Negative; some evidence of polyploidy at cytotoxic doses Chromosomal aberrationc Ethyl lauroyl arginate (89.4% active ingredient) Human lymphocytes 125–1000 μg/ml Negative Huntingdon Research Centre Ltd (1995d) Formulationb Chromosomal aberrationc
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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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Page 27 and 28: 20 CALCIUM LIGNOSULFONATE (40-65) A
Page 29 and 30: 22 CALCIUM LIGNOSULFONATE (40-65) c
Page 31 and 32: 24 CALCIUM LIGNOSULFONATE (40-65) T
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Page 56 and 57: ETHYL LAUROYL ARGINATE 49 Table 4.
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Page 68 and 69: ETHYL LAUROYL ARGINATE 61 The gener
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Page 76 and 77: ETHYL LAUROYL ARGINATE 69 Table 6.
Page 84 and 85: ETHYL LAUROYL ARGINATE 77 About 99%
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Page 88 and 89: ETHYL LAUROYL ARGINATE 81 theoretic
Page 90 and 91: ETHYL LAUROYL ARGINATE 83 Huntingdo
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Page 94 and 95: PAPRIKA EXTRACT 87 of capsanthin ra
Page 96 and 97: PAPRIKA EXTRACT 89 biochemical para
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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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ALKOXY-SUBSTITUTED ALLYLBENZENES 35
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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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