Fema Gras 28 20180423 0

GRAS 28
FLAVORING
S U BSTA N C E S
About FEMA GRAS Program
FEMA EXPERT PANEL: S.M. COHEN, S. FUKUSHIMA, N.J. GOODERHAM, F.P. GUENGERICH, S.S. HECHT,
I.M.C.M. RIETJENS, R.L. SMITH
28. GRAS FLAVORING SUBSTANCES: This list of substances will appear in the 28th publication
authored by the Expert Panel of the Flavor and Extract Manufacturers Association on recent
progress in the consideration of flavoring ingredients “generally recognized as safe” (GRAS) under
conditions of their intended use in food flavorings in accordance with the 1958 Food Additives
Amendment to the Federal Food, Drug and Cosmetic Act. For more information on FEMA GRAS see
“About the FEMA GRAS Program” on the FEMA website.
DISCLAIMER: The user of this list agrees that its use of this document and the information contained
therein is at the user’s sole risk and that FEMA shall have no liability to any person for any loss or
damage arising out of the use of this document. This document and the information contained herein
is subject to change. It is the responsibility of the user to ensure the information is up to date.
STATEMENT REGARDING GENERALLY RECOGNIZED AS SAFE STATUS OF EUGENYL
METHYL ETHER (METHYL EUGENOL): The FEMA GRAS status of methyl eugenol (CAS NO. 93-
15-2; FEMA No. 2475) under its conditions of intended use as a flavor ingredient, was reviewed by
the FEMA Expert Panel. After reviewing the available information relevant to the FEMA GRAS status
of methyl eugenol, including recent studies, the Expert Panel concluded that additional data are
required to support the continuation of its GRAS status. Such data should clarify the relevance to
humans of DNA adducts formed by methyl eugenol. Until such data are available for review by the
Expert Panel, the flavor ingredient methyl eugenol has been removed from the FEMA GRAS list.
The Expert Panel also considered the FEMA GRAS status of herbs, spices, and essential oils
that contain naturally-occurring methyl eugenol, including basil, pimento, allspice, etc. and their
extractives. The Panel concluded that these flavorings continue to meet the criteria for FEMA GRAS
under their conditions of intended use as flavorings.
TABLE 1: Primary Names & Synonyms
Primary names (in boldface) & Synonyms (in lightface)
FEMA NO. SUBSTANCE PRIMARY NAMES AND SYNONYMS FEMA NO. SUBSTANCE PRIMARY NAMES AND SYNONYMS
4817 S-[(Methylthio)methyl]thioacetate 4835 2,4-Dihydroxy-N-[(4-hydroxy-3-methoxyphenyl)methyl]

3,5-Dithiahexan-2-one benzamide
Methylthiomethyl acetyl sulfide 2,4-Dihydroxybenzoic acid vanillylamide
4818 trans-1-Ethyl-2-methylpropyl 2-butenoate 4836 10% solution of 3,4-dimethyl-2,3-dihydrothiophene-2-thiol

1-Ethyl-2-methylpropyl (2E)-2-butenoic acid ester
4819 Erythritol 4837 Chrysanthemum parthenium extract

(2R,3S)-rel-1,2,3,4-Butanetetrol Feverfew extract
(2R,3S)-Butane-1,2,3,4-tetrol Common pellitory extract
meso-Erythritol Motherwort extract
Mesoerythritol Tanacetum parthenium extract
4820 Purified Damar Gum 4838 Valencene 80 extract

Purified Shorea javanica Gum
4821 gamma-Aminobutyric acid:Linoleic acid conjugates 4839 Mixture of 3- and 4-butyl-2-thiophenecarboxyaldehyde

GABA:Linoleic acid conjugates
4822 2,6-Dipropyl-5,6-dihydro-2H-thiopyran-3-carboxaldehyde 4840 (±)-Tetrahydronootkatone

3,6-Dihydro-2,6-dipropyl-2H-thiopyran-5-carboxaldehyde (±)-Octahydro-4,4a-dimethyl-6-(1-methylethyl)-2(1H)-
naphthalenone
(±)-6-Isopropyl-4,4a-dimethyl-decalin-2-one
4823 Allyl 1-propenyl disulfide
Allyl propenyl disulfide 4841 cis-5-Dodecenyl acetate
1-Propenyl 2-propenyl disulfide (Z)-5-Dodecen-1-ol acetate
cis-Dodec-5-en-1-yl acetate
4824 2-(5-Isopropyl-2-methyl-tetrahydrothiophen-2-yl)-ethyl
acetate 4842 2,4,5-Trithiaoctane
Tetrahydro-2-methyl-5-(1-methylethyl)-2-thiopheneethanol 1-(Methylthiomethyl)-2-propyldisulfane
acetate
4825 E-6-Nonenal 4843 3-(Allyldithio)butan-2-one

trans-6-Nonenal 3-(Allyldisulfanyl)butan-2-one
3-(2-Propen-1-yldithio)-2-butanone
4826 3-Phenylpropyl 2-(4-hydroxy-3-methoxyphenyl)acetate 4844 (2E,4E)-2,4-Decadien-1-ol acetate

3-Phenylpropyl homovanillate trans, trans-2,4-decadien-1-yl acetate
4827 1-(4-Methyl-3-cyclohexen-1-yl)-ethanone 4845 Glucosylated stevia extract

1-Methyl-4-acetyl-1-cyclohexene
1-(4-Methylcyclohex-3-enyl)ethanone
4-Methyl-3-cyclohexen-1-yl methyl ketone
4846 Grapefruit essence oil (Citrus paradisi Macf.)
4828 1,1-Propanedithioacetate Citrus paradisi Macf. essence oil
S,S’-propane-1,1-diyl diethanethioate
Propane-1,1-dithioacetate
Ethanethioic acid S,S’-propylidene ester 4847 Grapefruit oil, terpeneless (Citrus paradisi Macf.)
1,1-Propanedithiol, diacetate Citrus paradisi Macf. Oil, terpeneless
4829 2-Pyrrolidone
alpha-Pyrrolidone 4848 Lemon terpenes
gamma-Aminobutyrolactam Citrus limon (L.) Burm. f. , terpenes
Butyrolactam
4830 7,8-Dihydroxyflavone 4849 Lime terpenes

7,8-Dihydroxy-2-phenyl-4H-1-benzopyran-4-one Citrus aurantifolia Swingle, terpenes
7,8-Dihydroxy-2-phenyl-4-benzopyrone Citrus medica var, acida, terpenes
7,8-Dihydroxy-2-phenyl-4H-chromen-4-one Citrus latifolia, terpenes
4831 Katemfe fruit extract 4850 Orange terpenes

Thaumatococcus daniellii fruit extract Citrus sinensis (L.) Osbeck., terpenes
4832 2-(3-Benzyloxypropyl)pyridine 4851 Grapefruit terpenes

2-[3-(Phenylmethoxy)propyl]-pyridine Citrus paradisi Macf., terpenes
4833 (2S)-3´,7-Dihydroxy-8-methyl-4’-methoxyflavan 4852 Lemon essence oil (Citrus limon (L) Burm. f.)
(S)-2-(3-Hydroxy-4-methoxyphenyl)-8-methylchroman-7-ol Citrus limon (L.) Burm. f. essence oil
(2S)-7,3´-Dihydroxy-4´-methoxy-8-methylflavane
4834 (R)-5-hydroxy-4-(4´-hydroxy-3´-methoxyphenyl)-7-
methylchroman-2-one
(4R)-4-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethyl-3,4-
dihydro-2H-1-benzopyran-2-one
TABLE 1 Continued: Primary Names & Synonyms
Primary names (in boldface) & Synonyms (in lightface)
FEMA NO. SUBSTANCE PRIMARY NAMES AND SYNONYMS FEMA NO. SUBSTANCE PRIMARY NAMES AND SYNONYMS
4853 Petitgrain oil terpeneless 4869 4-(l-Menthoxy)-2-butanone

Citrus aurantium L. oil terpeneless 4-[(1R,2S,5R)- 2-Isopropyl-5-methylcyclohexyl]-oxybutan-2-
one
4854 Tangelo oil (Citrus paradisi Macf. x Citrus tangerine hort. 4870 2-Ethyl-4-methyl-1,3-dithiolane
ex Tanaka)
Citrus paradisi Macf. x Citrus tangerine hort. ex Tanaka oil
Citrus x tangelo oil
4871 2-Phenoxyethyl 2-(4-hydroxy-3-methoxyphenyl)acetate
4855 Clementine oil (Citrus clementina hort. ex Tanaka)
Citrus clementina hort. ex Tanaka oil
4872 3-(3-Hydroxy-4-methoxyphenyl)-1-(2,4,6-trihydroxyphenyl)
4856 Blood orange oil (Citrus sinensis (L.) Osbeck ‘Blood propan-1-one
orange’) Hesperetin dihydrochalcone
Citrus sinensis (L.) Osbeck ‘Blood orange’ oil
4873 Watermint, Mentha aquatica L., extract
4857 Iyokan oil (Citrus iyo) Marsh mint extract
Citrus iyo oil Hairy mint extract
Smartweed extract
Pepperwort extract
4858 Hassaku oil (Citrus hassaku hort. ex Tanaka) Wild mint extract
Citrus hassaku hort. ex Tanaka oil
4876 Enzyme modified stevia, stevioside 20%
4859 Sikuwasya oil (Citrus depressa)

Citrus depressa oil
Shiikuwasha oil 4877 (E)-3-(3,4-Dimethoxyphenyl)-N-[2-(4-methoxyphenyl)-
ethyl]-acrylamide
4860 Natsumikan oil (Citrus natsudaidai) 4-methoxyphenylethylamine 3,4-dimethoxycinnamic amide
Citrus natsudaidai oil
4878 Cordyceps sinensis fermentation product
4861 Mikan oil (Citrus unshiu)

Citrus unshiu oil
Satsuma mandarin oil
4862 Yuzu oil (Citrus junos (Sieb.) c. Tanaka)

Citrus junos Siebold ex Tanaka oil
4863 Sudachi oil (Citrus sudachi hort. ex Shirai)

Citrus sudachi hort. ex Shirai oil
4864 Kabosu oil (Citrus sphaerocarpa)

Citrus sphaerocarpa oil
4865 Ponkan oil (Citrus reticulata Blanco ‘Ponkan’)

Citrus reticulata Blanco ‘Ponkan’ oil
4866 Orange essence water phase (Citrus sinensis (L.) Osbeck)

Orange aroma water phase
4867 (3S,5R,8S)-3,8-Dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-
hexahydro-2H-azulen-1-one
(-)-Guaia-1(5),11-dien-2-one
4868 4-(4-Methyl-3-penten-1-yl)-2(5H)-furanone
TABLE 2: Average Usual Use Levels/Average Maximum Use Levels
Average Usual Use Levels (ppm)/Average Maximum Use Levels (ppm) for new FEMA GRAS Flavoring Substances on
which the FEMA Expert Panel based its judgements that the substances are generally recognized as safe (GRAS).
2-(5-Isopropyl-2meth-
gamma-Aminobutyric
S-[(Methylthio)meth-
trans-1-Ethyl-2-meth-
ylpropyl 2-butenoate
thoxyphenyl)acetate
2H-thiopyran-3- car-
Purified Damar Gum
2-(4-hydroxy-3-me-
2,6-Dipropyl-5,6-di-
yl- tetrahydrothio-
acid:Linoleic acid
phen-2- yl)-ethy
3-Phenylpropyl
Allyl 1-propenyl
yl]thio-acetate
boxaldehyde
E-6-Nonenal
conjugates
Erythritol
disulfide
acetate
hydro-
FEMA No.
FEMA No. 4818 4819 4820 4821 4822 4823 4824 4825 4826
4817
Baked Goods 0.5/1 0.4/4 0.02/0.5 1/4 0.3/1 0.001/0.01
Beverages, 0.2/2 5000/12500 100/200 0.01/0.25 0.05/5 0.1/0.5 0.1/0.5 0.00001/0.0001 3/15
Non-Alcoholic
Beverages, 0.2/2 100/200 0.0002/0.005 0.03/10 0.3/2 0.00001/0.0001 3/15

Alcoholic
Breakfast 0.4/4 0.02/0.5 1/4 0.3/1 0.001/0.01

Cereals
Cheeses 0.5/1 0.1/0.5 0.02/0.5 1/4 0.001/0.01
Chewing Gum 0.5/5 0.02/0.5 10/100 1/5 0.0001/0.001 25/100
Condiments 0.01/0.25 1/4 5/40

and Relishes
Confections 0.4/4 0.01/0.25 0.3/30 0.5/2 0.0001/0.001

and Frostings
Egg Products 0.01/0.25 0.0001/0.001
Fats and Oils 0.5/1 0.02/0.5 1/4 0.3/1 0.01/0.1
Fish Products 0.01/0.25 1/4 0.0001/0.001
Frozen Dairy 0.5/5 0.01/0.5 0.5/50 0.1/0.5 0.0001/0.001
Fruit Ices 0.2/2 5000/12500 0.01/0.25 0.05/5 0.1/0.5 0.0001/0.001
Gelatins and 0.2/2 0.01/0.25 0.2/10 0.1/0.5 0.0001/0.001

Puddings
Granulated
Sugar
Gravies 0.3/1 0.01/0.25 1/4 0.001/0.01
Hard Candy 0.4/4 0.02/0.5 0.5/50 0.5/2 0.001/0.01 5/20
Imitation Dairy 0.02/0.5 0.05/5 0.001/0.01
Instant Coffee 0.1/1 5000/12500 0.0002/0.005 0.05/5 0.01/0.1 0.2/1 0.00001/0.0001 2/15
and Tea
Jams and 1/5 0.01/0.25 0.5/20 0.3/1

Jellies
Meat Products 0.5/1 0.02/0.5 1/4 0.0001/0.001 5/40
Milk Products 0.2/2 0.01/0.25 0.05/5 1/4 0.1/0.5 0.00001/0.0001 2/10
Nut Products 0.002/0.05 1/4 0.0001/0.001
Other Grains 0.002/0.05 1/4 0.0001/0.001
Poultry 0.5/1 0.02/0.5 1/4
Processed 0.4/4 5000/12500 0.01/0.25 0.05/5 0.1/0.5

Fruits
Processed 0.5/1 0.01/0.25 0.5/4

Vegetables
Reconstituted 0.01/0.25 0.5/4

Vegetables
Seasonings 0.5/1 0.2/2 0.01/0.25 0.5/20 1/4 0.1/0.5 0.1/1.0 50/300

and Flavors
Snack Foods 0.5/2 0.2/2 0.01/0.25 1/4 0.1/0.5 0.0001/0.001 5/40
Soft Candy 0.4/4 0.01/0.25 0.2/5 0.5/2 0.0001/0.001
Soups 0.2/1 0.01/0.25 1/4 0.0001/0.001 5/20
Sugar 0.005/0.15
Substitutes
Sweet Sauces 0.2/2 0.005/0.15 0.2/10 0.5/2

TABLE 2 Continued: Average Usual Use Levels/Average Maximum Use Levels
Average Usual Use Levels (ppm)/Average Maximum Use Levels (ppm) for new FEMA GRAS Flavoring Substances on which the FEMA
Expert Panel based its judgements that the substances are generally recognized as safe (GRAS).
methylchroman-2-one
2-(3-Benzyloxypropyl)
7,8-Dihydroxyflavone
Katemfe fruit extract
(2S)-3’,7-Dihydroxy-
methyl] benzamide
parthenium extract
methoxyphenyl)-7-
dihydrothiophene-
1,1-Propanedithio-
3,4-dimethyl-2,3-
4-(4’-hydroxy-3’-
Chrysanthemum
N-[(4-hydroxy-3-
cyclohexen-1-yl)-
methoxyphenyl)
10% Solution of
(R)-5-Hydroxy-
methoxyflavan
2,4-Dihydroxy-
1-(4-Methyl-3-
2-Pyrrolidone
8-methyl-4’-
ethanone
pyridine
acetate
2-thiol
CATEGORY 4827 4828 4829 4830 4831 4832 4833 4834 4835 4836 4837
Baked Goods 0.5/1.5 0.1/0.5 5/20 4/10 1/10 0.04/0.4
Beverages, 0.05/0.25 5/20 5/15 4/10 0.1/1 30/50 15/20 10/100 0.01/0.05 30/60
Non-Alcoholic
Beverages, 0.5/2.5 5/20 5/15 4/10 30/50 15/20 0.03/0.15 30/60

Alcoholic
Breakfast 0.5/2.5 0.1/0.2 5/20 4/10 10/100

Cereals
Cheeses 0.2/2.5 0.1/0.3 5/20 4/10 1/10 0.01/1
Chewing Gum 0.5/2.5 50/200 100/1000 4/10 30/50 15/20 0.03/0.3 300/1000
Condiments 0.2/2.5 0.2/3 5/20 10/30 4/10 0.01/1 50/200

and Relishes
Confections 0.5/2.5 10/40 4/10 30/50 15/20 0.03/0.3

and Frostings
Egg Products 0.05/0.25 5/20 4/10 0.2/2
Fats and Oils 0.5/2.5 5/20 0.01/0.5
Fish Products 0.05/0.15 5/20 4/10 0.5/5 50/200
Frozen Dairy 0.5/2.5 5/20 4/10 0.1/1
Fruit Ices 0.5/2.5 5/20 5/15 4/10 0.04/0.4 50/200
Gelatins and 0.5/1.5 5/20 4/10 0.03/0.3

Puddings
Granulated 0.25/0.85 40/160

Sugar
Gravies 0.05/0.5 0.3/3 5/20 10/30 4/10 1/10 0.01/1 50/200
Hard Candy 0.5/2.5 10/40 50/200 4/10 0.04/0.4 250/500
Imitation Dairy 0.5/2.5 5/20 4/10 0.5/5
Instant Coffee 0.05/0.25 5/20 5/15 4/10

and Tea
Jams and 0.5/1.5 10/40 4/10 0.04/0.4 50/200

Jellies
Meat Products 0.05/0.15 0.5/2 5/20 10/30 4/10 0.5/5 0.01/1
Milk Products 0.25/0.85 5/20 4/10 0.2/2 10/100
Nut Products 0.05/0.25 5/20 4/10 0.1/1
Other Grains 0.5/2.5 5/20 4/10
Poultry 0.05/0.25 5/20 10/30 4/10 0.01/1
Processed 0.5/2.5 5/20 4/10 50/200

Fruits
Processed 0.2/2 0.2/1 5/20 4/10 0.1/1 0.01/1

Vegetables
Reconstituted 0.05/0.15 0.2/1 5/20 4/10 0.1/1

Vegetables
Seasonings 0.05/0.5 0.1/2 5/20 30/100 4/10 1/10 0.01/1 400/800

and Flavors
Snack Foods 0.05/0.5 0.1/2 5/20 50/200 4/10 1/10 0.01/1 400/800
Soft Candy 0.5/2.5 10/40 50/200 4/10 0.04/0.4 250/500
Soups 0.25/2 0.3/1 5/20 10/20 4/10 0.5/5 0.01/1
Sugar 0.5/1.5 10/40

Substitutes
Sweet Sauces 0.5/1.5 5/20 4/10

(Citrus paradisi Macf.)

(2E,4E)-2,4-Decadien-
Grapefruit essence oil
oil terpeneless(Citrus
Valencene 80 extract
4-butyl-2-thiophene-
3-(Allyldithio)butan-
Glucosylated Stevia
(±)-Tetrahydronoot-
Grapefruit essence
2,4,5-Trithiaoctane
carboxyaldehyde
Mixture of 3- and
Lemon terpenes
cis-5-Dodecenyl
paradisi Macf.)
1-ol acetate
acetate
Extract
katone
2-one
CATEGORY 4838 4839 4840 4841 4842 4843 4844 4845 4846 4847 4848
Baked Goods 0.9/0.9 0.1/0.5 0.1/8 30/100 363/5000 45/1000 366/5000
Beverages, 0.6/0.6 0.2/5 0.2/5 0.05/5 0.1/5 30/100 78/500 11/275 70/500
Non-Alcoholic
Beverages, 0.9/0.9 0.5/10 0.5/5 0.15/10 0.3/15 30/100 91/500 16/100 81/1000
Alcoholic
Breakfast 0.9/0.9 0.01/0.05 30/100 133/1000 28/200 102/1000

Cereals
Cheeses 0.01/2 0.03/3 30/100 200/1000 40/200 200/1000
Chewing Gum 20/1000 1/20 1/10 0.5/25 1/40 30/100 1341/20000 253/5000 1355/20000
Condiments 0.1/2 0.2/3 30/100 88/500 9/100 68/500

and Relishes
Confections 0.9/0.9 0.6/10 0.6/5 0.25/10 0.5/20 30/100 385/5000 55/1000 393/5000
and Frostings
Egg Products 0.03/0.3 0.1/0.5 1000/5000 200/1000 1000/5000
Fats and Oils 0.5/10 0.5/2 0.2/10 0.03/0.3 0.1/0.5 0.5/20 41/500 10/100 47/500
Fish Products 51/180 0.2/2 41/180
Frozen Dairy 0.9/0.9 0.2/5 0.2/1 0.05/5 0.1/10 30/100 142/1000 26/200 172/1000
Fruit Ices 0.2/5 0.2/5 0.05/5 0.1/5 30/100 110/1000 21/200 136/1000
Gelatins and 0.9/0.9 30/100 238/1000 25/200 238/2000

Puddings
Granulated 100/500 10/30 100/500

Sugar
Gravies 0.1/2 0.1/2.5 30/100 200/1000 40/200 200/1000
Hard Candy 0.6/10 0.6/5 0.25/10 0.5/25 30/100 359/5000 59/1000 392/5000
Imitation Dairy 0.1/1 30/100 153/500 38/180 253/900
Instant Coffee 0.3/5 0.3/5 0.2/5 0.2/10 30/100 75/500 20/100 113/1000
and Tea
Jams and 0.5/10 0.5/2 0.2/10 0.5/15 30/100 375/5000 75/1000 372/5000
Jellies
Meat Products 0.1/5 0.1/3 2/20 2/6 2/20
Milk Products 0.9/0.9 50/100 92/500 26/150 177/750
Nut Products 30/100 100/500 20/100 100/500
Other Grains 30/100 100/500 20/100 50/500
Poultry 0.1/5 0.05/0.5 26/100 0.2/2 30/100
Processed 0.2/5 0.2/5 0.1/5 0.1/.5 0.2/10 30/100 200/1000 44/210 327/1050
Fruits
Processed 0.1/2 30/100 100/500 20/100 100/500

Vegetables
Reconstituted 30/100
Vegetables
Seasonings 0.5/10 0.05/2 0.2/5 0.1/5 0.01/8 0.4/10 30/100 351/5000 340/5000 1735/5000
and Flavors
Snack Foods 0.1/5 0.2/2 30/100 117/1000 15/200 101/1000
Soft Candy 0.6/10 0.6/3 0.25/5 0.5/10 30/100 342/5000 50/1000 331/5000
Soups 0.1/2 0.1/1 10/50 50/250 10/50 26/250
Sugar 100/500 20/100 100/500

Substitutes
Sweet Sauces 30/100 253/2000 28/200 354/5000

paradisi Macf. x Citrus
Clementine oil (Citrus
Iyokan oil (Citrus iyo)

Grapefruit terpenes
clementina hort. ex
Hassaku oil (Citrus

(L.) Osbeck 'Blood
Lemon essence oil
Tangelo oil (Citrus
tangerine hort. ex
(Citrus limon (L.)
Orange terpenes
Blood orange oil

(Citrus sinensis
Lime terpenes
Petitgrain oil
terpeneless
hassaku)
Burm. f.)
orange')
Tanaka)
Tanaka)
CATEGORY 4849 4850 4851 4852 4853 4854 4855 4856 4857 4858
Baked Goods 440/5000 470/5000 564/5000 291/5000 60/1000 491/5000 516/5000 501/5000 125/300
Beverages, 81/750 80/1550 98/500 53/500 31/500 72/500 70/500 102/2400 34/64 14/60
Non-Alcoholic
Beverages, 93/1000 93/1000 115/1000 93/1000 36/500 92/500 114/1000 90/1000 37/74 16/36
Alcoholic
Breakfast 104/1000 101/1000 133/1000 122/1000 200/1000 133/1000 133/1000 100/1000 50/100
Cereals
Cheeses 200/1000 100/1000 200/1000 200/1000 200/1000 200/1000 200/1000 200/1000 60/275
Chewing Gum 2240/20000 1943/20000 1504/20000 1530/20000 1070/20000 1524/20000 1484/20000 1829/20000 300/1000 125/350
Condiments 90/500 71/500 93/500 108/500 48/500 88/500 92/500 49/500 100/200 20/50
and Relishes
Confections 474/5000 489/5000 600/5000 322/5000 116/1000 495/5000 528/5000 470/5000 2/20
and Frostings
Egg Products 1000/5000 1000/5000 1000/5000 1000/5000 200/1000 1000/5000 1000/5000 1000/5000
Fats and Oils 47/500 43/500 43/500 38/500 51/500 41/500 42/500 43/500 100/200 60/125
Fish Products 34/180 38/180 55/180 55/180 0.2/1 51/180 53/180 55/180 30/80
Frozen Dairy 205/1000 215/1000 215/1000 123/1000 70/1000 160/1000 198/1000 150/1000 12/35
Fruit Ices 164/1000 166/1000 200/1000 106/1000 85/1000 148/1000 170/1000 138/1000 63/123 20/43
Gelatins and 303/2000 323/2000 323/2000 220/2000 70/1000 237/1000 234/2000 228/2000 88/168 28/59
Puddings
Granulated 100/500 100/500 100/500 100/500 100/500 100/500 100/500

Sugar
Gravies 200/1000 200/1000 200/1000 121/1000 100/1000 200/1000 200/1000 73/1000
Hard Candy 542/5000 507/5000 550/5000 370/5000 99/1000 359/5000 407/5000 416/5000 192/312 70/135
Imitation Dairy 253/900 190/900 253/900 153/500 140/500 173/540 193/660 193/660 11/35
Instant Coffee 100/500 113/1000 113/1000 88/1000 45/500 80/500 93/1000 98/1000
and Tea
Jams and 463/5000 475/5000 475/5000 326/5000 93/36526 388/5000 418/5000 352/5000 88/168 34/90
Jellies
Meat Products 2/20 10/50 10/50 18/50 0.2/1 2/20 5/25 15/50 30/80
Milk Products 179/750 181/788 233/750 113/500 84/500 150/500 183/550 183/550
Nut Products 100/500 50/500 100/500 100/500 100/500 100/500 100/500 100/500
Other Grains 100/500 100/500 100/500 100/500 100/500 100/500 100/500 100/500
Poultry 26/100 30/100 30/100 30/100 0.2/1 26/100 28/100 30/100
Processed 307/1050 333/1050 333/1050 217/1000 137/1000 223/1000 257/1000 263/1000

Fruits
Processed 100/500 100/500 100/500 100/500 100/500 100/500 100/500 100/500

Vegetables
Reconstituted
Vegetables
Seasonings 1727/5000 1738/5000 2600/5000 600/5000 501/5000 2600/5000 2600/5000 2600/5000 24/45 30/80
and Flavors
Snack Foods 163/1000 100/1000 133/1000 133/1000 101/1000 117/1000 127/1000 174/1000 100/300 75/150
Soft Candy 477/5000 449/5000 476/5000 304/5000 95/1000 472/5000 562/5000 418/5000 188/368 70/169
Soups 27/250 29/250 50/250 28/250 50/250 50/250 50/250 50/250 20/50
Sugar 100/500 50/500 100/500 100/500 100/500 100/500 100/500 100/500

Substitutes
Sweet Sauces 440/5000 440/5000 440/5000 264/5000 117/1000 265/2000 328/3500 270/5000 100/200 35/125
4-(4-Methyl-3-penten-
Natsumikan oil (Citrus
hexahydro-2H-azulen-
phase (Citrus sinensis
Orange essence water
Yuzu oil (Citrus junos
Sikuwasya oil (Citrus
1-yl)-2(5H)-furanone
Dimethyl-5-prop-1-
Sudachi oil (Citrus
en-2-yl-3,4,5,6,7,8-
Kabosu oil (Citrus
Ponkan oil (Citrus

(Sieb.) c. Tanaka)
reticulata Blanco
Mikan oil (Citrus
sudachi hort. ex
(3S,5R,8S)-3,8-
sphaerocarpa)
natsudaidai)
(L.) Osbeck)
depressa)
'Ponkan')
unshiu)
Shirai)
1-one
CATEGORY 4859 4860 4861 4862 4863 4864 4865 4866 4867 4868
Baked Goods 400/860 50/200 60/184 2/2 463/746 556/10000 0.001/0.02 0.0001/0.001
Beverages, 20/40 113/276 24/55 14/45 12/31 11/24 59/110 537/5000 0.0001/0.005 0.00001/0.0001
Non-Alcoholic
Beverages, 106/160 24/44 25/71 11/24 13/23 61/140 802/10000 0.0001/0.005 0.00001/0.0001
Alcoholic
Breakfast 50/200 50/200 40/200 0.0001/0.001

Cereals
Cheeses 30/60 33/170 40/200 0.001/0.01
Chewing Gum 844/1608 100/200 384/1150 360/1100 1498/8000 0.001/0.02 0.0001/0.001
Condiments 30/60 37/100 250/5000

and Relishes
Confections 440/800 8/9 560/880 356/2000 0.0003/0.005 0.0001/0.001

and Frostings
Egg Products 200/1000 0.0003/0.005 0.0001/0.001
Fats and Oils 30/60 30/150 0.02/0.2 0.001/0.01
Fish Products 30/60 18/70 0.0003/0.005 0.0001/0.001
Frozen Dairy 175/400 30/60 18/65 219/440 334/5000 0.0002/0.003 0.0001/0.001
Fruit Ices 240/400 25/45 16/57 3/10 5/5 280/440 334/5000 0.0002/0.003 0.00001/0.0001
Gelatins and 313/883 45/75 24/64 9/30 15/15 239/440 168/1000 0.0003/0.002 0.0001/0.001
Puddings
Granulated
Sugar
Gravies 40/200 0.001/0.01 0.001/0.01
Hard Candy 342/1978 55/145 64/154 9/30 15/15 318/1965 952/8000 0.001/0.01 0.0001/0.001
Imitation Dairy 360/600 30/60 19/98 420/660 550/2000 0.001/0.01 0.0001/0.001
Instant Coffee 120/200 140/220 300/500 0.0001/0.001 0.00001/0.0001

and Tea
Jams and 300/500 45/75 28/79 3/90 15/15 250/550 256/1250

Jellies
Meat Products 30/60 18/70 0.00001/0.0001
Milk Products 180/500 15/76 350/550 360/2000 0.001/0.01 0.00001/0.0001
Nut Products 0.001/0.01 0.0001/0.001
Other Grains 0.0001/0.001
Poultry
Processed 420/700 20/50 490/770 528/5000 0.00001/0.0001

Fruits
Processed 20/50 200/2000

Vegetables
Reconstituted
Vegetables
Seasonings 20/37 25/90 3/10 5/5 1200/10000 0.1/1 0.01/0.1

and Flavors
Snack Foods 50/200 47/114 40/200 0.001/0.01 0.0001/0.001
Soft Candy 552/1084 55/145 98/284 55/165 15/15 595/1251 313/2000 0.001/0.01 0.0001/0.001
Soups 30/60 13/60 50/250 0.0001/0.002 0.0001/0.001
Sugar
Substitutes
Sweet Sauces 300/500 30/60 14/64 350/550 450/5000 0.001/0.01

[2-(4-methoxyphenyl)-
Stevia, stevioside 20%
Dimethoxyphenyl)-N -
fermentation product
2-Ethyl-4-methyl-1,3-
Cordyceps sinensis
Watermint, Mentha
aquatica L., extract
4-(l-Menthoxy)-2-
ethyl]-acrylamide
trihydroxyphenyl)
Enzyme Modified
methoxyphenyl)-
3-(3-Hydroxy-4-
methoxyphenyl)
2-(4-hydroxy-3-
2-Phenoxyethyl
propan-1-one
(E )-3-(3,4-
dithiolane
butanone
1-(2,4,6-
acetate
CATEGORY 4869 4870 4871 4872 4873 4876 4877 4878
Baked Goods 1/2 75/150 5/10 50/100 75/100 30/50
Beverages, 1/5 1/2 10/20 1.5/10 90/120 40/1000

Non-Alcoholic
Beverages, 1/5 1/2 10/30 1.5/10 75/100 100/1000

Alcoholic
Breakfast 5/15 5/10 75/100 15/30

Cereals
Cheeses 1/2 50/100 100/400 75/100 20/50
Chewing Gum 1/10 2000/5000 5/10 75/100
Condiments 1/2 15/50 4/10 200/800 80/110 25/50

and Relishes
Confections 50/200 80/110

and Frostings
Egg Products 1/2 5/10 200/800 80/110
Fats and Oils 1/2 50/100 200/800 80/110 20/50
Fish Products 1/2 20/50 50/100 75/100 15/50
Frozen Dairy 30/60 3/10 90/120
Fruit Ices 5/10 5/10 75/100
Gelatins and 10/20 3/10 80/110

Puddings
Granulated 5/10
Sugar
Gravies 1/5 1/2 15/50 2/10 200/800 75/100 20/50
Hard Candy 100/300 2/10 80/110
Imitation Dairy 20/50 100/200 90/120
Instant Coffee 1/5 10/20 1.5/10 75/100

and Tea
Jams and 5/10 80/110

Jellies
Meat Products 1/2 25/50 100/200 75/100 20/50
Milk Products 20/50 2/10 50/100 90/120 15/100
Nut Products 100/250 50/100 75/100
Other Grains 5/15 75/100 50/150
Poultry 1/2 25/50 100/200 75/100 15/50
Processed 5/10 3/10 80/110

Fruits
Processed 1/2 5/10 2/10 50/100 75/100

Vegetables
Reconstituted 5/10 2/10 50/100 75/100 20/50

Vegetables
Seasonings 1000/5000 1/2 100/200 2/10 50/100 75/100 50/80

and Flavors
Snack Foods 1/2 75/500 6/10 100/400 75/100 50/80
Soft Candy 1/5 50/100 5/10 80/110
Soups 1/5 1/2 35/100 1/10 100/200 75/100 20/50
Sugar 5/10 4/10

Substitutes
Sweet Sauces 15/50 4/10 80/110

TABLE 3: Updated Average Usual Use Levels/Average Maximum Use Levels
Average Usual Use Levels (ppm)/Average Maximum Use Levels (ppm) for flavoring substances previously recognized as FEMA GRAS.
Superscript ‘a’ represents a new use level.
pentafluorobenzamide
yl-2-hydroxycyclohex-
N-(2-Methylcyclohex-
(+/-)-(2,6,6-Trimeth-
hexanecarboxamide
phenyl]-5-methyl-2-
Polyglycerol Ester of
(propan-2-yl)cyclo-
ylidene) acetic acid
Amino-2-oxoethyl)
(2S,5R)-N-[4-(2-
dihydrochalcone
Neohesperidine
gamma-lactone
Rebaudioside A
Cinnamic Acid
Thaumatin B-
Recombinant
yl)- 2,3,4,5,6-
Geranic Acid
Fatty Acids
Thaumatin
FEMA NO. 2288 3732 3811 3814 4020 4121 4201 4601 4678 4684
GRAS
3 13 17 17 20 22 22 24 25 25
PUBLICATION
CATEGORY
Baked Goods 232/384 7a/7a 5/7a 1/1 5a/20a 10/50 6/6 20/30 1a/5a 0a/0a
Beverages, Non-
300/400 7a/7a 5/15 5/7a 5a/20a 3/15 4a/20a 20/30 1/5 10a/50a
Alcoholic
Beverages,
570/712 7a/7a 5/15 5/7a 5a/20a 4a/20a 20/30 1a/3a
Alcoholic
Breakfast
7a/7a 8/20 1/2 5a/20a 5/25 6/20 20/30 1a/5a
Cereals
Cheeses 7a/7a 3/4 7a/7a 5a/20a 3/15 0a/0a
Chewing Gum 224/300 150a/150a 200/300 150/150a 50a/200a 165a/500a 200/200 10/20 400a/800a
Condiments and
7a/7a 2/3 1/2 5a/20a 5/25 6/200 20/30 1a/25a 0a/0a
Relishes
Confections and
7a/7a 3/3 2/5 10a/40a 10/50 20/30 1/5 25a/100a
Frostings
Egg Products 7a/7a 2/3 2/5 5a/20a
Fats and Oils 746/1000 7 /7

a a
4/4 5a/20a 2/10
Fish Products 7 /7
a a
2/3 5/7 a
5a/20a 2/10 1a/2a
Frozen Dairy 192/263 7a/7a 2/8 1/2 5a/20a 3/15 20/30 1/8a
Fruit Ices 7a/7a 2/3 2/5 5a/20a 3/15 20/30 1/5
Gelatins and
459/500 7a/7a 3/8 1/2 5a/20a 5/25 20/30 1/5
Puddings
Granulated
Sugar
Gravies 746/1000 7a/7a 3/4 2/5 5a/20a 15/75 60/400 20/30 1a/25a 0a/0a
Hard Candy 0.01/0.01 7 /7

a a
5/15 2/5 10 /40
a a
100 /400
a a
20/30 1/5 25a/100a
Imitation Dairy 7 /7
a a
3/10 7 /7
a a
5 /20
a a
3/15 20/30 1 /8
a a
Instant Coffee
224/300 7 /7
a a
3/6 2/5 5 /20
a a
20/30 1/5 0a/0a
and Tea
Jams and Jellies 373/500 7a/7a 2/3 2/5 10a/40a 5/25 20/30 1a/5a 25a/100a
Meat Products 7a/7a 2/3 2/2 2/10 20/75 1a/2a
Milk Products 700a/1000a 7a/7a 3/10 3/6 5a/20a 3/15 20a/30a 1/8a
Nut Products 7a/7a 3/4 5/7a 5a/20a 1a/5a
Other Grains 7a/7a 3/4 5a/20a 5/25 1a/5a
Poultry 7 /7
a a
2/3 2/5 5 /20
a a
2/10 20/75 1a/2a
Processed Fruits 37/50 7 /7

a a
2/3 2/5 2/10 20/30 1/5
Processed
7a/7a 2/3 2/5 20/30
Vegetables
Reconstituted
7a/7a 2/3 2/5 5a/20a
Vegetables
Seasonings and
7a/7a 3/4 0.5/1 5a/20a 5/25 2.3/15 20/30 1a/25a
Flavors
Snack Foods 7a/7a 3/3 1/2 5a/20a 10/50 0.2/40 20/30 1a/25a 0a/0a
Soft Candy 249/356 7a/7a 4/10 2/5 10a/40a 20/30 1/5 25a/100a
Soups 7a/7a 5/7a 2/5 5a/20a 5/25 20/30 1a/2a
Sugar
746/1000 0a/0a 0a/0a
Substitutes
Sweet Sauces 746/1000 7a/7a 2/3 2/5 5a/20a 5/25 20/30 1/5
* Figures in parentheses represent the amount of diluted Sugar Cane Distillate in the commercial product as used in food.
TABLE 3 Continued: Updated Average Usual Use Levels/Average Maximum Use Levels
Average Usual Use Levels (ppm)/Average Maximum Use Levels (ppm) for flavoring substances previously recognized as FEMA GRAS.
Superscript ‘a’ represents a new use level.
Sugar Cane Distallate*

N-(1H-pyrazol-3-yl)-N-
methyl)piperidin-1-yl)-
rubusoside glycosides
(thiophen-2-ylmethyl)
2-(4-Methylphenoxy)-
Tea Extract Catechins

20-30% glucosylated
benzothiadiazin-5-yl)
oxy]-2,2-dimethyl-N-
3-methylbutan-1-one
suavissimus extract,
(S)-1-(3-(((4-Amino-
Palmitoylated Green
Glucosylated Rubus
propylpropanamide
thiadiazin-5-yl)oxy)
methylquinoline-3-
(isopropylamino)-
dioxido -1H-2,1,3-
3-[(4-Amino-2,2-
2,2-dimethyl-3-
Glucosyl steviol
oxopropoxy)-2-
benzo[c][1,2,6]
2,2-dioxido-1H-
carboxylic acid
4-Amino-5-(3-
acetamide
glycosides
FEMA NO. 4701 4728 4774 4800 4802 4809 4812 4816
GRAS
25 26 26 27 27 27 27 27
PUBLICATION
CATEGORY
Baked Goods 10/22 150a/500a 10a/30a 6/6 3a/15a 100/400a 0.01 (2,250)/0.01(2,250)
Beverages,
125/175a 8/30 150/350 2.5/6 1/3 0.016(3,600)a/0.016(3,600)a
Non-Alcoholic
Beverages,
5/22 125/175a 10/30 75/200 2.5/6 2/6
Alcoholic
Breakfast
15/22 200a/500a 12/30 150/400 6/6 3a/15a 50/600a
Cereals
Cheeses 100/133a
Chewing Gum 30/300 500a/1500a 30/300 400a/1000a 6/6 75/150
Condiments and
3/22 125/200a 8/30 6/6 3a/15a 100/600a
Relishes
Confections and
10/22 50/100 30/300 150a/300a 6/6 5a/30a 50/600a 0.01 (2,250)/0.01(2,250)
Frostings
Egg Products 3a/15a 150a/600a
Fats and Oils 125/189 a

8/30 3/6 3 /15
a a
200/2800a
Fish Products 10 /22a

a
250/600a
Frozen Dairy 5/22 125/133a 10a/30a 200/300 3/6 1/3 0.016(3,600)a/0.016(3,600)a
Fruit Ices 5/22 125/133a 10/30 100/300 3/6 1/3
Gelatins and
5/22 125/133a 8/30 150a/300a 3/6 1/3
Puddings
Granulated
Sugar
Gravies 125/133a 8/30 100/150 3/6 3a/15a 150a/600a
Hard Candy 15/75 100/133 a

10/30 400 /1000
a a
3/6 5/15
Imitation Dairy 5a/22a 125/250a 8/30 2.5/6 1/3 150a/600a 0.016(3,600)a/0.016(3,600)a
Instant Coffee
5a/22a 125/175a 8/30 150/350 2.5/6 1/3 150a/500a
and Tea
Jams and Jellies 10/22 125a/200a 10/30 150a/300a 6/6 1a/3a
Meat Products 10a/22a 100/150 3a/15a 250/400a
Milk Products 3/22 133a/225a 8/30 200/300 2.5/6 1/3 150a/400a 0.016(3,600)a/0.016(3,600)a
Nut Products 133a/175a 3/6 1a/3a 50/600a
Other Grains 100/133a 150/400a
Poultry 10 /22
a a
3 /15
a a
250/400a
Processed Fruits 133 /200

a a
10 /30a
a
3/6 1 /3
a a
Processed
100/133a 3a/15a
Vegetables
Reconstituted
133a/133a 3a/15a
Vegetables
Seasonings and
10a/22a 133a/175a 10a/30a 100/150 3a/6a 3a/15a 750a/1500a
Flavors
Snack Foods 133a/133a 12/30 6/6 3a/15a 100/600a 0.01 (2,250)/0.01(2,250)
Soft Candy 15/75 100/133a 10/30 400a/1000a 6/6 5/15 50/600a
Soups 133a/133a 8/30 100/150 3/6 3a/15a 100/600a
Sugar
0a/0a
Substitutes
Sweet Sauces 10/22 133a/133a 15/30 3/6 5/15 150a/600a 0.01 (2,250)/0.01(2,250)
* Figures in parentheses represent the amount of diluted Sugar Cane Distillate in the commercial product as used in food.
SUPPLEMENTARY INFORMATION 1: Identity for Natural Flavor Complexes as
Evaluated by the Expert Panel
FEMA NO. FEMA PRIMARY NAME THE IDENTITY DESCRIPTION AS REVIEWED BY THE FEMA EXPERT PANEL
Total steviol glycosides 80-90% inclusive of supraglucosylated steviol glycosides 75-80%;

4728 Glucosyl steviol glycosides Rebaudioside A 1-6%; stevioside 2-4% and other individual steviol glycosides not further
glucosylated each less than 3%. Maltodextrin 3-20%
Oxygenated triterpenes and sesquiterpenes 34-39% measured as isomers of

4820 Purified Damar Gum hydroxydammarenone, dammerene diol, oleanonic aldehyde and urosonic aldehyde and acid
and polycadenene 14-17%.
Derived from the Katemfe fruit, Katemfe fruit extract is measured as thaumatin 45-55%,
4831 Katemfe fruit extract
Carbohydrates 13-17%; Ash no more than 35% with less than 8% sodium.
Derived from the aerial parts of the Chrysanthemum parthenium plant, Chrysanthemum
Chrysanthemum parthenium parthenium extract is measured as carbohydrate up to 74%; flavanoids 5-6% (luteolin
4837
extract glycosides and apigenin glycosides); sesquiterpene lactones 3-4% (parthenolide); chlorogenic
acid derivatives 3-4% (caffeoylquinic acid); amino acids 4-5%; protein 2-3%; fat 1-2%; ash
Valenecene >80% with no less than 15% other sequiterpene hydrocarbons typically
4838 Valencene 80 extract
aristolochene, selinenes and cadinenes.
At least 80% steviol glycosides, not more than 10% Rebaudioside A, not more than 4%
4845 Glucosylated stevia extract Rebaudioside C, not more than 5% stevioside, and no individual steviol glycosides further
glucosylated ≤3%.
Prepared by extraction of the leaves of Mentha aquatica, watermint extract is measured as

Watermint, Mentha aquatica
4873 8-12% polyphenols, 1.2-1.4% rosmarinic acid, 5-7% polysaccharides, 20-30% water, 25-30%
L., extract
propylene glycol and 5-7% total protein.
90-95% steviol glycosides inclusive of supraglucosylated steviol glycosides 64-70%; rebaudio-

Enzyme modified stevia,
4876 side A 10-13%; stevioside 20-22%, maltodextrin 1-6%, and other individual steviol glycosides not
stevioside 20%
further glucosylated each less than 1%.
Cordyceps sinensis Approximately 25% alpha-glucans; approximately 60-70% maltodextrin and its degradation
4878
fermentation product products with no more than 1.5% protein.
1
FEMA 4846-4866 will be included within “GRAS Affirmation of
Citrus Natural Flavor Complexes Used as Flavor Ingredients” publication pending.
Supplementary Information 2. Key Findings of the FEMA Expert Panel Safety Evaluations for GRAS 28
Since its initial publication of GRAS determinations for flavor (1800 µg/person/day) (Munro et al., 1996). The Panel
ingredients (Hall and Oser, 1965), the FEMA Expert Panel has considered the specification of the material to be adequately
consistently made available to the public information on its characterized by the purity assay and supporting spectral data
determinations, including conditions of intended use for provided for FEMA GRAS evaluation. It is presumed that
individual flavor ingredients, and the scientific basis and trans-1-ethyl-2-methylpropyl 2-butenoate will rapidly
information supporting these determinations. Included herein hydrolyze to produce trans-2-butenoic acid and 2-methyl-3-
are the key findings for each of the new GRAS determinations pentanol (Fukami and Yokoi, 2012; Hosokawa, 2008). These
included within GRAS 28. Comprehensive monographs of the hydrolysis products are predicted to form conjugates and be
information relevant to the evaluations are also published as excreted in the urine. No increases in the number of reverse
part of the FEMA Expert Panel’s ongoing GRAS re-evaluation mutations were observed in the Ames assay for trans-1-ethyl-
program (see Hallagan and Hall (2009)). For more information 2-methylpropyl 2-butenoate in S. typhimurium strains TA98,
on the FEMA GRAS program, please see “About the FEMA TA100, TA1535 and TA1537 and E. coli stain WP2 uvrA in
GRAS™ Program” on femaflavor.org. either the absence or presence of S-9 metabolic activation
(Thompson, 2013). trans-1-Ethyl-2-methylpropyl 2-butenoate
The Panel reviewed the GRAS application and supporting did not induce chromosomal aberrations in human peripheral
information regarding S-[(methylthio)methyl]thioacetate (CAS lymphocytes treated for 4 hours with a 20-hour recovery
38634-59-2) and concluded that the substance is GRAS period in the absence and presence of S-9 metabolic
(FEMA 4817) (Smith et al., 2005a) for use as a flavor activation, or when continuously incubated in human
ingredient in the food categories and at the use levels peripheral lymphocytes treated for 24 hours in the absence of
specified in the GRAS application (see Table 2). The S-9 metabolic activation (Bowles, 2014). Based on these
substance was evaluated individually within the context of the results, the Panel did not identify specific concerns related to
chemical group of simple aliphatic and aromatic sulfides and the genotoxicity of trans-1-ethyl-2-methylpropyl 2-butenoate.
thiols (SLR B5C; JECFA, 2000a, 2004, 2008, 2011). The A 13-week CFW male and female rat study for the structurally
Panel calculated the anticipated per capita intake (“eaters related substance trans-2-hexenal (FEMA 2560) provided in
only”) of S-[(methylthio)methyl] thioacetate from use as a the diet resulted in a NOAEL of 80 mg/kg bw/day, which is
flavor ingredient to be 0.2 µg/person/day, which is below the 16,000,000 times the anticipated daily per capita intake of
threshold of toxicological concern for structural class I (1800 trans-1-ethyl-2-methylpropyl 2-butenoate from use as a flavor
µg/person/day) (Cramer et al., 1978; Munro et al., 1996). The ingredient (Gaunt et al., 1971).
Panel considered the specification of the material to be
adequately characterized by the purity assay and supporting The Panel reviewed the GRAS application and supporting
spectral data provided for FEMA GRAS evaluation. It is information regarding erythritol (CAS 149-32-6) (Smith et al.,
presumed that S-[(methylthio)methyl]thioacetate will undergo 2005a) and concluded that the substance is GRAS (FEMA
hydrolysis to acetic acid and (methylthio)methanethiol, 4819) for use as a flavor ingredient in the food categories and
followed by S-oxidation and elimination (Parkinson, 1996; at the use levels specified in the GRAS application (see Table
Williams et al., 1966). No increases in the number of reverse 2). The substance was evaluated individually within the
mutations were observed in the Ames assay for the context of the chemical group of aliphatic polyhydroxy
structurally related substance, S-methyl-2- compounds (SLR B1F; JECFA, 1999). The Panel calculated
(acetyloxy)propanethioate (FEMA 3788) in S. typhimurium the anticipated per capita intake ("eaters only") of erythritol
strains TA98, TA100, TA102, TA1535 and TA1537 in either from anticipated use as a flavor ingredient to be 290
the absence or presence of S-9 metabolic activation µg/person/day, which is below the threshold of toxicological
(Watanabe and Morimoto, 1989a, b). Based on these results, concern for structural class I (1800 µg/person/day) (Munro et
as well as the structure of the substance and the arrangement al., 1996). The substance occurs naturally in cheese, grapes,
and identify of the functional groups therein, the Panel did not melons, miso, pears, sake, sherry wine, soy sauce,
identify specific concerns related to the genotoxicity of S- watermelon, and wine (de Cock, 2012; Shindou and Ishizuka,
[(methylthio)methyl]thioacetate. A 90-day dietary study in 1996; Sreenath and Venkatesh, 2008), but only qualitative
male and female rats resulted in a No-Observed-Adverse- data is available and, thus, no consumption ratio can be
Effect Level (NOAEL) of greater than 6.48 mg/kg bw/day for calculated. The Panel considered the specification of the
the structurally related substance, ethyl thioacetate (FEMA material to be adequately characterized by the purity assay
3282) (Shellenberger, 1970). This is greater than 1,940,000 and supporting spectral data provided for FEMA GRAS
times the anticipated daily per capita intake of S- evaluation. The Panel evaluated sensory data included within
[(methylthio)methyl]thioacetate from use as a flavor the application and found it satisfactory with regard to
ingredient. intended conditions of use for the flavoring ingredient
(Harman and Hallagan, 2013). Erythritol is rapidly absorbed
The Panel reviewed the GRAS application and supporting from the proximal intestine. It is distributed and eliminated
information regarding trans-1-ethyl-2-methylpropyl 2- within 24 hours (Noda et al., 1996; Noda and Oku, 1992; van
butenoate (CAS 1370711-06-0) (Smith et al., 2005a) and Ommen et al., 1996). In humans, erythritol is not metabolized
concluded that the substance is GRAS (FEMA 4818) for use systemically but about 10% is degraded by intestinal
as a flavor ingredient in the food categories and at the use microflora. The remaining 90 % of erythritol administered to
levels specified in the GRAS application (see Table 2). The humans is excreted unchanged in urine (Bornet et al., 1996a,
substance was evaluated individually within the context of the b). No increases in the number of reverse mutations were
chemical group of aliphatic, alicyclic, linear, alpha, beta- observed in the Ames assay for erythritol in Salmonella
unsaturated aldehydes, acids, and related alcohols, acetals typhimurium strains TA98, TA100 and TA1537 and
and esters (FEMA, 1985; JECFA, 2005, 2009, 2012). The Escherichia coli WP2 uvrA in either the absence or presence
Panel calculated the anticipated per capita intake ("eaters of S-9 metabolic activation. No chromosomal aberrations
only") of trans-1-ethyl-2-methylpropyl 2-butenoate from use were observed with concentrations of erythritol up to 10 mmol
as a flavor ingredient to be 0.3 µg/person/day, which is below in Chinese hamster fibroblast cells (Kawamura et al., 1996).
the threshold of toxicological concern for structural class I In an in vitro comet assay, erythritol treatment of L5178Y tk+/−
cells resulted in slight increases in the percentage of tail DNA, the levels of intake proposed, metabolism by well-established
but the increases were not concentration dependent and were detoxication pathways to innocuous products (ERINI, 2014;
all less than 2-fold when compared to controls, and thus the He et al., 2014; Kong et al., 2013; Scheline, 1991; Ukiya et
authors concluded that the results were negative. There were al., 2010; Xie et al., 2012; Zhang et al., 2009; Zhang et al.,
no increases in the numbers of micronucleated polychromatic 2014). No evidence of genotoxic effects was observed with
erythrocytes in an in vivo mouse micronucleus assay purified damar gum in S. typhimurium strains TA98, TA100,
performed with up to 5000 mg/kg bw erythritol (Chung and TA102, TA1535 and TA1537 in either the presence or
Lee, 2013). Based on these results, the Panel did not identify absence of metabolic activation in an Ames assay, or in a
any specific concerns related to the genotoxicity of erythritol. Chinese hamster ovary cell in a chromosomal aberration
Erythritol was evaluated in a two-generation dietary assay in the presence and absence of S-9 metabolic
administration reproductive study in male and female rats. No activation (King and Harnasch, 1999a). Purified damar gum
effects on reproductive performance or fertility, offspring did not induce genotoxicity in an in vivo mouse bone marrow
developments, or incidences of abnormalities were observed micronucleus assay (King and Harnasch, 1999b). A 90-day
at doses up to 6.5 g/kg (males) and 16 g/kg (females), which male and female rat study with purified damar gum resulted in
were the highest doses tested (Waalkens-Berendsen et al., a NOAEL of 540 and 1000 mg/kg bw/day, respectively
1996). A study at a single low dose of erythritol (5 mg/kg) (Bisson et al., 2012). The NOAEL of 540 mg/kg bw/day for
reported rib malformations in pups, but fewer fetal resorptions purified damar gum is greater than 4,300 times the anticipated
than control group. However, only limited information was daily intake from use as a flavor adjuvant.
available for the study (Keehr and Hunt, 2000). Erythritol was
evaluated in a study wherein pregnant Wistar rats were given The Panel reviewed the GRAS application and supporting
up to 6.6 g/kg bw/day during gestational days 0 to 21. No information regarding gamma-aminobutyric acid:linoleic acid
adverse reproductive, embryotoxic, fetotoxic, or teratogenic enriched conjugates (CAS 1444005-46-2, 1444005-47-3,
effects occurred at doses up to 6.6 g/kg bw/day, which was 1444005-48-4, 1444005-49-5) and concluded that the
the highest dose tested (Smits-Van Prooije et al., 1996). No substance is GRAS (FEMA 4821) (Smith et al., 2005a) for use
toxicologically-related fetal effects were observed in a as a flavor ingredient in the food categories and at the use
teratogenicity study in which pregnant KBL:JW rabbits were levels specified in the GRAS application (see Table 2). The
administered erythritol at doses up to 5 g/kg bw/day during substance was reviewed individually within the context of the
gestational days 6 to 18. Maternal effects were considered to chemical group of aliphatic and aromatic amines and amides
be transient and related to osmotic loading and diuresis due (SLR A7; C21; JECFA, 2006, 2008, 2011, 2012). The Panel
to the high doses of erythritol administered (Shimizu et al., calculated the anticipated per capita intake ("eaters only") of
1996). A two-year toxicity and carcinogenicity study for gamma-aminobutyric acid:linoleic acid enriched conjugates
erythritol was conducted in Wistar rats at 2, 5 or 10% in the from anticipated use as a flavor ingredient to be 590
diet (ca. 1000, 2500 and 5000 mg/kg bw/day). No µg/person/day, which is above the threshold of toxicological
toxicologically relevant effects attributable to the test concern for structural class II (540 µg/person/day) (Munro et
substance were observed in any of the test parameters. There al., 1996). The Panel considered the specification of the
was no evidence of toxicity or carcinogenicity at levels of material to be adequately characterized by the purity assay
erythritol up to 10% (5000 mg/kg bw/day) in the diet (Lina et and supporting spectral data provided for FEMA GRAS
al., 1996). The resulting NOAEL was considered to be 5000 evaluation. It is anticipated that gamma-aminobutyric
mg/kg bw/day which is greater than 1,030,000 times the acid:linoleic acid enriched conjugates will undergo oxidative
anticipated daily per capita intake of erythritol from use as a metabolism. The pharmacokinetic parameters of gamma-
flavor ingredient. Other toxicity studies were reported, aminobutyric acid:linoleic acid enriched conjugates were
including 28-day, 13-week, and 1-year studies in rodents and determined in single-dose mice studies; elimination half-lives
beagle dogs, and where effects were observed they were ranged from 2 to approximately 4.5 hours (Boggs, 2014).
attributed to physiological, and not toxicological, responses to Based on the structure of the substance and the identity and
the high dose levels of erythritol, which is well-absorbed and arrangements of functional groups therein, the Panel did not
rapidly excreted unchanged in the urine (Noda et al., 1996; identify specific concerns related to the potential genotoxicity
Noda and Oku, 1992; van Ommen et al., 1996). of gamma-aminobutyric acid:linoleic acid enriched
conjugates. For the amino component, gamma-aminobutyric
The Panel reviewed the natural flavor complex GRAS acid, a 90-day gavage administration toxicity study in
application and supporting information regarding purified Sprague-Dawley male and female rats resulted in a NOAEL
damar gum (CAS 9000-16-2) and concluded that the material of 2500 mg/kg bw/day, which was the highest dose tested
is GRAS (FEMA 4820) (Smith et al., 2005a) for use as a flavor (Takeshima et al., 2014). This NOAEL is greater than 250,000
adjuvant, specifically as a flavor stabilizer within flavor the anticipated daily per capita intake of gamma-aminobutyric
formulations, in the food categories and at the use levels acid:linoleic acid enriched conjugates from use as a flavor
specified in the GRAS application (see Table 2). This material ingredient.
was evaluated within the context of the procedure for the
safety evaluation of natural flavor complexes (Smith et al., The Panel reviewed the GRAS application and supporting
2005b). The Panel calculated the anticipated per capita intake information regarding 2,6-dipropyl-5,6-dihydro-2H-thiopyran-
("eaters only") of purified damar gum from use as a flavor 3-carboxaldehyde (CAS 61407-00-9) and concluded that the
adjuvant to be 7400 µg/person/day, which is above the substance is GRAS (FEMA 4822) (Smith et al., 2005a) for use
threshold of toxicological concern for structural class III (90 as a flavor ingredient in the food categories and at the use
µg/person/day) (Munro et al., 1996). Purified damar gum is levels specified in the GRAS application (see Table 2). The
derived from the Shorea javanica tree trunk. The Panel substance was evaluated individually within the context of the
considered the identity description of the material to be chemical group of aliphatic alcohols, aldehydes acids and
adequate for FEMA GRAS evaluation (see Appendix 1). related esters with thiol or sulfide functions (SLR B5A; JECFA,
Metabolic data exists for representative members of each 2000a, 2004, 2008, 2011). The Panel calculated the
congeneric group of purified damar gum that would predict, at anticipated per capita intake ("eaters only") of 2,6-dipropyl-
5,6-dihydro-2H-thiopyran-3-carboxaldehyde from anticipated The Panel reviewed the GRAS application and supporting
use as a flavor ingredient to be 0.3 µg/person/day, which is information regarding 2-(5-isopropyl-2-methyl-
below the threshold of toxicological concern for structural tetrahydrothiophen-2-yl)-ethyl acetate (CAS 1658479-63-0)
class II (540 µg/person/day) (Munro et al., 1996). The Panel and concluded that the substance is GRAS (FEMA 4824)
considered the specification of the material to be adequately (Smith et al., 2005a) for use as a flavor ingredient in the food
characterized by the purity assay and supporting spectral data categories and at the use levels specified in the GRAS
provided for FEMA GRAS evaluation. Based on analogy, 2,6- application (see Table 2). The substance was evaluated
dipropyl-5,6-dihydro-2H-thiopyran-3-carboxaldehyde would individually within the context of the chemical group of sulfur-
be expected to undergo oxidation at the aldehyde function to containing heterocyclic compounds (Cohen et al., 2017; SLR
the corresponding carboxylic acid followed by conjugation D15; JECFA, 2004, 2008, 2012, 2015). The Panel calculated
with glycine and excreted as such. Furthermore, the sulfur the anticipated per capita intake ("eaters only") of 2-(5-
center might be expected to oxidize to the sulfoxide and isopropyl-2-methyl-tetrahydrothiophen-2-yl)-ethyl acetate
perhaps further to the sulfone. In addition, the propyl side- from use as a flavor ingredient to be 0.03 µg/person/day,
chains might be predicted to undergo oxidative metabolism which is below the threshold of toxicological concern for
(Parkinson, 1996; Rance, 1989). No increases in the number structural class III (90 µg/person/day) (Munro et al., 1996).
of reverse mutations were observed in the Ames assay for The substance occurs naturally in lemon peel, but only
2,6-dipropyl-5,6-dihydro-2H-thiopyran-3-carboxaldehyde in qualitative data is available and, thus, no consumption ratio
S. typhimurium strains TA98, TA100 TA1535 and TA1537 in can be calculated (Cannon et al., 2015). The Panel
either the absence or presence of S-9 metabolic activation considered the specification of the material to be adequately
using both the plate incorporation and pre-incubation methods characterized by the purity assay and supporting spectral data
(Merrill, 2015b). Based on these results, as well as the provided for FEMA GRAS evaluation. 2-(5-isopropyl-2-
structure of the substance and the arrangement and identity methyltetrahydrothiophen-2-yl)-ethyl acetate is predicted to
of the functional groups therein, the Panel did not identify undergo hydrolysis at the ester moiety, subsequent
specific concerns related to the genotoxicity of 2,6-dipropyl- conjugation of the resulting alcohol with glucuronic acid, and
5,6-dihydro-2H-thiopyran-3-carboxaldehyde. then elimination in the urine (Rance, 1989). Additionally,
oxidation of the sulfur to the sulfoxide and sulfone and
The Panel reviewed the GRAS application and supporting subsequent excretion in the urine is anticipated (Mozier and
information regarding allyl 1-propenyl disulfide (CAS 33368- Hoffman, 1990). Based on the structure of the substance and
82-0) and concluded that the substance is GRAS (FEMA the arrangement and identity of the functional groups therein,
4823) (Smith et al., 2005a) for use as a flavor ingredient in the the Panel did not identify specific concerns related to the
food categories and at the use levels specified in the GRAS genotoxicity of 2-(5-isopropyl-2-methyltetrahydrothiophen-2-
application (see Table 2). The substance was evaluated yl)-ethyl acetate. A 90-day dietary study for a structurally
individually within the context of the chemical group of simple related substance, alpha-methyl-beta-hydroxypropyl alpha-
aliphatic and aromatic sulfides and thiols (SLR B4; JECFA, methyl-beta-mercaptopropyl sulfide (FEMA 3509), was
2000a, 2004, 2008, 2011). The Panel calculated the conducted in male and female rats at a single dose of 2.82
anticipated per capita intake ("eaters only") of allyl 1-propenyl mg/kg bw/day. There were no adverse test substance-related
disulfide from use as a flavor ingredient to be 0.02 effects observed (Morgareidge et al., 1974). The resulting
µg/person/day, which is below the threshold of toxicological NOAEL was considered by the authors to be greater than 2.82
concern for structural class II (540 µg/person/day) (Munro et mg/kg bw/day, which is greater than 5,640,000 times the
al., 1996). The Panel considered the specification of the anticipated daily per capita intake of 2-(5-isopropyl-2-
material to be adequately characterized by the purity assay methyltetrahydrothiophen-2-yl)-ethyl acetate from use as a
and supporting spectral data provided for FEMA GRAS flavor ingredient.
evaluation. Allyl 1-propenyl disulfide would be predicted to be
reduced to its two sulfhydryl metabolites. These in turn would The Panel reviewed the GRAS application and supporting
be expected to undergo methylation of the sulfhydryl groups information regarding (E)-6-nonenal (CAS 2277-20-5) and
and possibly further oxidation. The allyl groups may undergo concluded that the substance is GRAS (FEMA 4825) (Smith
epoxidation followed by interaction with glutathione or et al., 2005a) for use as a flavor ingredient in the food
hydration followed by oxidation (Germain et al., 2008; categories and at the use levels specified in the GRAS
Teyssier and Siess, 2000). In an in vivo mouse micronucleus application (see Table 2). The substance was evaluated
induction assay with structurally related substances allyl individually within the context of the chemical group of
sulfide (FEMA 2042), allyl disulfide (FEMA 2028) and diallyl aliphatic primary alcohols, aldehydes, esters and acids (SLR
trisulfide (FEMA 3265), no induction of micronuclei was M1; JECFA, 1999, 2012). The Panel calculated the
reported (Reddy et al., 1993). Based on these results, the anticipated per capita intake ("eaters only") of (E)-6-nonenal
structure of the substance and the arrangement and identity from use as a flavor ingredient to be 0.003 µg/person/day,
of the functional groups therein, the Panel did not identify which is below the threshold of toxicological concern for
specific concerns related to the genotoxicity of allyl 1-propenyl structural class I (1800 µg/person/day) (Munro et al., 1996).
disulfide. A 90-day dietary study for a structurally related The substance occurs naturally in Rooibos tea (Aspalathus
substance, propyl disulfide (FEMA 3228), was conducted in linearis), but only qualitative data is available and, thus, no
male and female rats at single doses of 7.29 or 8.17 mg/kg consumption ratio can be calculated (Nijissen, 2017). The
bw/day, respectively. No adverse effects were noted as a Panel considered the specification of the material to be
result of propyl disulfide in the diet (Posternak et al., 1969). adequately characterized by the purity and assay and
The resulting NOAEL was considered to be greater than 7.29 supporting spectral data provided for FEMA GRAS
mg/kg bw/day, which is greater than 21,800,000 times the evaluation. Based on the metabolism of linear and branched-
anticipated daily per capita intake of allyl 1-propenyl disulfide chain aliphatic, unsaturated, unconjugated alcohols,
from use as a flavor ingredient. aldehydes, acids and related esters, it is predicted that (E)-6-
nonenal will be oxidized to (E)-6-nonenoic acid which will
enter into beta-oxidation and ultimately be metabolized to CO2
that will be expired (Nelson and Cox, 2008). No increases in The Panel reviewed the GRAS application and supporting
the number of reverse mutations were observed in the Ames information regarding 1-(4-methyl-3-cyclohexen-1-yl)-
assay for a structurally related substance, trans-4-decenal ethanone (CAS 6090-09-1) and concluded that the substance
(FEMA 3264) in S. typhimurium strains TA102, TA98, TA100 is GRAS (FEMA 4827) (Smith et al., 2005a) for use as a flavor
TA1535 and TA1537 in either the absence or presence of S- ingredient in the food categories and at the use levels
9 metabolic activation using both the plate incorporation specified in the GRAS application (see Table 2). The
method (Sokolowski, 2007). An in vivo mouse micronucleus substance was evaluated individually within the context of the
assay at doses of 500, 1000 and 2000 mg/kg bw administered chemical group of aliphatic secondary alcohols, ketones and
via gavage showed no increases in micronuclei induction related substances (SLR C4; JECFA, 1999). The Panel
(Honarvar, 2008). A 98-day drinking water study for a calculated the anticipated per capita intake ("eaters only") of
structurally related substance, cis-3-hexenol (FEMA 2563), 1-(4-methyl-3-cyclohexen-1-yl)-ethanone from use as a flavor
was conducted in male and female rats at doses of 310, 1250 ingredient to be 0.4 µg/person/day, which is below the
and 5000 ppm. There were no adverse test substance-related threshold of toxicological concern for structural class I (1800
effects observed (Gaunt et al., 1969). The resulting NOAEL µg/person/day) (Munro et al., 1996). The substance naturally
was considered to be 1250 ppm (ca., 120-150 mg/kg bw/day), occurs in orange juice (1000 ppm) and the consumption ratio
which is greater than 2,400,000,000 times the anticipated was calculated as 1,424,000 (Nijissen, 2017). The Panel
daily per capita intake of (E)-6-nonenal from use as a flavor considered the specification of the material to be adequately
ingredient. characterized by the purity and assay and supporting spectral
data provided for FEMA GRAS evaluation. It is predicted that
The Panel reviewed the GRAS application and supporting 1-(4-methyl-3-cyclohexen-1-yl)-ethanone will undergo
information regarding 3-phenylpropyl 2-(4-hydroxy-3- reduction of the ketone moiety followed by conjugation and
methoxyphenyl)acetate (CAS 105025-99-8) and concluded elimination (Ferdinandi, 1993). Alternatively, oxidation of the
that the substance is GRAS (FEMA 4826) (Smith et al., cyclohexene ring followed by hydrolysis of the epoxide and
2005a) for use as a flavor ingredient in the food categories conjugation and elimination in the urine could occur. Based
and at the use levels specified in the GRAS application (see on data for related substances as well as the structure of the
Table 2). The substance was evaluated individually within the substance and the identity and the position of the functional
context of the chemical group of hydroxy- and alkoxy- groups therein, the Panel did not identify any specific
substituted benzyl derivatives (SLR C18; JECFA, 2002, concerns for the genotoxic potential of the substance. A
2009). The Panel calculated the anticipated per capita intake NOAEL of 200 mg/kg bw/day in a 28-day study in male and
("eaters only") of 3-phenylpropyl 2-(4-hydroxy-3- female rats for the structurally related substance p-menthane-
methoxyphenyl)acetate from use as a flavor ingredient to be 3,8-diol (FEMA 4053) is greater than 28,570,000 times the
16 µg/person/day, which is below the threshold of anticipated daily per capita intake of from use of 1-(4-methyl-
toxicological concern for structural class I (1800 3-cyclohexen-1-yl)-ethanone from use as a flavor ingredient
µg/person/day) (Munro et al., 1996). The Panel considered (Braun et al., 2000).
the specification of the material to be adequately
characterized by the purity and assay and supporting spectral
data provided for FEMA GRAS evaluation. It is predicted that The Panel reviewed the GRAS application and supporting
the substance will readily undergo hydrolysis to homovanillic information regarding 1,1-propanedithioacetate (CAS
acid and 3-phenylpropanol. Homovanillic acid could be 729602-98-6) and concluded that the substance is GRAS
excreted in the urine unchanged or undergo conjugation at the (FEMA 4828) (Smith et al., 2005a) for use as a flavor
phenolic moiety or the acid moiety and be excreted. 3- ingredient in the food categories and at the use levels
Phenylpropanol could be conjugated with sulfate or glucuronic specified in the GRAS application (see Table 2). The
acid and excreted, or undergo further oxidative steps and be substance was evaluated individually within the context of the
excreted in the urine (Strand and Scheline, 1975). No chemical group of dithiols and related substances (SLR D1;
increases in the number of reverse mutations were observed JECFA, 2000a, 2004, 2008, 2011). The Panel calculated the
in the Ames assay for the structurally related substance, ethyl anticipated per capita intake ("eaters only") of 1,1-
2-(4-hydroxy-3-methoxyphenyl)acetate (FEMA 4810) in S. propanedithioacetate from use as a flavor ingredient to be
typhimurium strains TA98, TA100 TA1535, TA1537 and E. 0.04 µg/person/day, which is below the threshold of
coli WP2 uvrA in either the absence or presence of S-9 toxicological concern for structural class III (90 µg/person/day)
metabolic activation using both the plate incorporation method (Munro et al., 1996). The Panel considered the specification
(Sokolowski, 2014). The structurally related substance of the material to be adequately characterized by the purity
Vanillin (FEMA 3107) was reported negative in the Ames and assay and supporting spectral data provided for FEMA
assay at doses up to 10,000 µg/plate in the absence and GRAS evaluation. It is predicted that 1,1-
presence of S-9 metabolic activation (Heck et al., 1989; propanedithioacetate will undergo hydrolysis to the
Ishidate et al., 1984; Kasamaki et al., 1982; Mortelmans et al., corresponding acid, acetic acid, which will be metabolized to
1986; Pool and Lin, 1982; Rapson et al., 1980). No induction CO2 and expired. The other hydrolysis product, 1,1-
of micronuclei was observed when mice were dosed with up propanedithiol, will likely undergo S-alkylation and oxidation
to 500 mg/kg bw of vanillin. The allowable daily intake (ADI) to produce a polar sulfonate. The other sulfur is anticipated to
of 10 mg/kg bw/day of vanillin was established by the Joint undergo conjugation with cysteine to form a mixed disulfide
Food and Agriculture Organization/World Health Organization that could subsequently be excreted (Maiorino et al., 1996).
Expert Committee on Food Additives (JECFA) based on a Based on the structure of the substance and the arrangement
NOAEL of 1000 mg/kg bw per day from a 2-year study in rats and identity of the functional groups therein, the Panel did not
(Hagan et al., 1967). The resulting ADI set by JECFA is identify specific concerns related to the genotoxicity of 1,1-
37,500 times the anticipated daily per capita intake of 3- propanedithioacetate. A 90-day dietary study for a structurally
phenylpropyl 2-(4-hydroxy-3-methoxyphenyl)acetate from related substance, ethyl thioacetate (FEMA 3282), was
use as a flavor ingredient. conducted in male and female rats at a single dose of 6.48
mg/kg bw/day. There were no adverse test substance-related
effects observed (Shellenberger, 1970). The resulting NOAEL structure of the substance and the identity and arrangements
was considered to be greater than 6.48 mg/kg bw/day, which of the functional groups therein, the Panel did not identify
is 9,720,000 times the anticipated daily per capita intake of specific concerns related to the genotoxicity of 7,8-
1,1-propanedithioacetate from use as a flavor ingredient. dihydroxyflavone. A conservative NOAEL from the 2-year
study for quercetin in F344/N rats (NTP, 1992) assigned by
The Panel reviewed the GRAS application and supporting the Panel at 40 mg/kg bw/day is greater than 3,400,000 times
information regarding 2-pyrrolidone (CAS 616-45-5) and the anticipated daily per capita intake of 7,8-dihydroxyflavone
concluded that the substance is GRAS (FEMA 4829) (Smith from use as a flavor ingredient.
et al., 2005a) for use as a flavor ingredient in the food
categories and at the use levels specified in the GRAS The Panel reviewed the natural flavor complex GRAS
application (see Table 2). The substance was evaluated application and supporting information regarding Katemfe
individually within the context of the chemical group of extract (CAS 90131-57-0) and concluded that the material is
pyridine, pyrrole and quinoline derivatives (SLR D3; JECFA, GRAS (FEMA 4831) (Smith et al., 2005a) for use as a flavor
2006, 2012). The Panel calculated the anticipated per capita ingredient in the food categories and at the use levels
intake ("eaters only") of 2-pyrrolidone from use as a flavor specified in the GRAS application (see Table 2). This material
ingredient to be 0.2 µg/person/day, which is below the was evaluated within the context of the procedure for the
threshold of toxicological concern for structural class I (1800 safety evaluation of natural flavor complexes (Smith et al.,
µg/person/day) (Munro et al., 1996). The substance naturally 2005b). The Panel calculated the anticipated per capita intake
occurs in beer, cocoa, rice, wheaten bread, whisky, wine, malt ("eaters only") of Katemfe extract from anticipated use as a
and taro (Colocasia esculenta), but only qualitative data are flavor ingredient is 220 µg/person/day, which is above the
available and thus no consumption ratio can be calculated threshold of toxicological concern for structural class III (90
(Nijissen, 2017). The Panel considered the specification of the µg/person/day) (Munro et al., 1996). The material is derived
material to be adequately characterized by the purity and from the fruit arils of the Katemfe plant (Thaumatococcus
assay and supporting spectral data provided for FEMA GRAS daniellii). Katemfe extract is primarily composed of protein,
evaluation. 2-Pyrrolidone is endogenous to the human body. ash, and carbohydrate. The Panel evaluated sensory data
No increases in the number of reverse mutations were included within the application and found it satisfactory with
observed in the Ames assay for 2-pyrrolidone in S. regard to intended conditions of use for the flavoring
typhimurium strains TA1538, TA98, TA100, TA1535 and ingredient (Harman and Hallagan, 2013). Thaumatin, the
TA1537 in either the absence or presence of S-9 metabolic principal constituent, would likely be hydrolyzed to its
activation (ECHA, 2015). No mutations were observed in vitro component amino acids that would then be utilized in protein
when 2-pyrrolidone was incubated with CHO cells in the synthesis. Partial reduction of the disulfide bonds resulted in
absence and presence of metabolic activation. An in vitro auto-digestion of the protein. One study indicated that the
human peripheral lymphocyte micronucleus assay with digestibility of thaumatin is comparable to that of egg albumin
pyrrolidone showed no increases in micronuclei induction (Stanworth, 1977). The carbohydrates would enter into
(ECHA, 2015). In addition, in vivo chromosomal aberration standard metabolic pathways and be utilized for energy. The
assays in mice showed no indication of genetic damage ash is expected to be excreted via the feces (Stanworth,
(ECHA, 2015). A NOAEL of 207 mg/kg bw/day for 2- 1977). The principal constituent of Katemfe extract,
pyrrolidone administered to male and female Wistar rats is thaumatin, was not mutagenic in an Ames test in S.
62,100,000 times the anticipated daily per capita intake of 2- typhimurium strains TA98, TA100, TA1535, TA1537, and E.
pyrrolidone from use as a flavor ingredient (ECHA, 2015). coli strain WP2, in either the presence or absence of S-9
metabolic activation (Higginbotham et al., 1983). Thaumatin
The Panel reviewed the GRAS application and supporting was also negative for the induction of dominant-lethal
information regarding 7,8-dihydroxyflavone (CAS 38183-03- mutations in the gametes of male mice (Tesh et al., 1977).
8) and concluded that the substance is GRAS (FEMA 4830) Based on these results the Panel did not identify a specific
(Smith et al., 2005a) for use as a flavor ingredient in the food concern for the genotoxic potential of katemfe extract. In a 13-
categories and at the use levels specified in the GRAS week study in male and female rats, the principal constituent
application (see Table 2). The substance was evaluated of Katemfe extract, thaumatin, was administered via the diet
individually within the context of the chemical group of phenol and produced NOAELs of 2502 mg/kg bw/day (males) and
and phenol derivatives (SLR C12, JECFA, 2001, 2011, 2015). 2889 mg/kg bw/day (females), which were the highest doses
The Panel calculated the anticipated per capita intake ("eaters administered (Hawigara et al., 2005). The NOAEL of 2502
only") of 7,8-dihydroflavone from use as a flavor ingredient to mg/kg bw/day is greater than 682,300 times the anticipated
be 0.7 µg/person/day, which is below the threshold of daily per capita intake of Katemfe extract used as a flavor
toxicological concern for structural class III (90 µg/person/day) ingredient.
(Munro et al., 1996). It is predicted that 7,8-
dihydroxyflavanone would be metabolized along various The Panel reviewed the GRAS application and supporting
routes: conjugation of the hydroxyl functions with glucuronic information regarding 2-(3-benzyloxypropyl)pyridine (CAS
acid and sulfate and excretion of these conjugates; 108715-62-4) and concluded that the substance is GRAS
demethylation and ring-opening of the heterocyclic ring (FEMA 4832) (Smith et al., 2005a) for use as a flavor
function to form the corresponding hydroxyphenylpropionic ingredient in the food categories and at the use levels
acid (Day et al., 2000; Donovan et al., 2006; Gee et al., 2000; specified in the GRAS application (see Table 2). The
Manach et al., 2005). No increases in the number of reverse substance was evaluated individually within the context of the
mutations were observed in the Ames assay for 7,8- chemical group of pyridine pyrrole, and quinoline derivatives
dihydroxyflavone in S. typhimurium strains TA98, TA100 (SLR D2; JECFA, 2009, 2012). The Panel calculated the
TA1535 and TA1537 and E. coli WP2uvrA (pKM101) in either anticipated per capita intake ("eaters only") of 2-(3-
the absence or presence of S-9 metabolic activation using benzyloxypropyl)pyridine from anticipated use as a flavor
both the plate incorporation and pre-incubation methods ingredient to be 0.2 µg/person/day, which is below the
(Merrill, 2015a). Based on these results, as well as the threshold of toxicological concern for structural class III (90
µg/person/day) (Munro et al., 1996). The Panel considered The Panel reviewed the GRAS application and supporting
the specification of the material to be adequately information regarding (R)-5-hydroxy-4-(4´-hydroxy-3´-
characterized by the purity and assay and supporting spectral methoxyphenyl)-7-methylchroman-2-one (CAS 1793064-68-
data provided for FEMA GRAS evaluation. 2-(3- 2) and concluded that the substance is GRAS (FEMA 4834)
Benzyloxypropyl)pyridine is predicted to undergo side chain (Smith et al., 2005a) for use as a flavor ingredient in the food
oxidation as well as N-oxidation or methylation to yield polar categories and at the use levels specified in the GRAS
metabolites that are conjugated and eliminated in the urine application (see Table 2). The substance was evaluated
(Cowan et al., 1978; Damani et al., 1980; Damani et al., 1982; individually within the context of the chemical group of phenol
Hawksworth and Scheline, 1975; Nguyen et al., 1988). No and phenol derivatives (SLR C12; JECFA, 2001, 2011, 2015).
increases in the number of reverse mutations were observed The Panel calculated the anticipated per capita intake from
in the Ames assay for 2-(3-benzyloxypropyl)pyridine in S. use as a flavor ingredient to be 3 µg/person/day, which is
typhimurium strains TA98 and TA100 in the absence and below the threshold of toxicological concern for structural
presence of S-9 metabolic activation (Kawaguchi and Komai, class III (90 µg/person/day) (Munro et al., 1996). The Panel
2015). Based on the results from this initial screening assay, considered the specification of the material to be adequately
as well as the structure of the substance and the identity and characterized by the purity and assay and supporting spectral
arrangement of functional groups therein, the Panel did not data provided for FEMA GRAS evaluation. The Panel
identify a specific concern for the genotoxic potential of 2-(3- evaluated sensory data included within the application and
benzyloxypropyl)pyridine. A NOAEL of 196 mg/kg bw/day for found it satisfactory with regard to intended conditions of use
astructurally related substance, dibenzyl ether (Burdock and for the flavoring ingredient (Harman and Hallagan, 2013). In
Ford, 1992) administered to male and female rats is vitro rat and human hepatocyte studies provided evidence
58,800,000 times the anticipated daily per capita intake of 2- that (R)-5-hydroxy-4-(4´-hydroxy-3´-methoxyphenyl)-7-
(3-benzyloxypropyl)pyridine from use as a flavor ingredient. methylchroman-2-one is likely to be rapidly metabolized in
vivo, primarily by conversion to the glucuronic acid conjugate
The Panel reviewed the GRAS application and supporting (Kandel, 2015). It is anticipated that this would be followed by
information regarding 2-(3-(2S)-3',7-dihydroxy-8-methyl-4'- excretion in the urine. No increases in the number of reverse
methoxyflavan (CAS 87733-81-1) and concluded that the mutations in the Ames assay were observed for (R)-5-
substance is GRAS (FEMA 4833) (Smith et al., 2005a) for use hydroxy-4-(4´-hydroxy-3´-methoxyphenyl)-7-methylchroman-
as a flavor ingredient in the food categories and at the use 2-one in S. typhimurium strains TA98, TA100, TA1535, and
levels specified in the GRAS application (see Table 2). The TA1537 and E. coli WP2uvrA (pKM101) in either the absence
substance was evaluated individually within the context of the or presence of S-9 metabolic activation using both the plate
chemical group of phenol and phenol derivatives (SLR C12; incorporation and pre-incubation methods (Soltesova, 2015).
JECFA, 2001, 2011, 2015). The Panel calculated the No increases in micronucleus production were observed in
anticipated per capita intake ("eaters only") of 2-(3-(2S)-3',7- Chinese hamster ovary (CHO) cells incubated with (R)-5-
dihydroxy-8-methyl-4'-methoxyflavan from anticipated use as hydroxy-4-(4´-hydroxy-3´-methoxyphenyl)-7-methylchroman-
a flavor ingredient to be 7 µg/person/day, which is below the 2-one in the absence or presence of S-9 metabolic activation
threshold of toxicological concern for structural class III (90 (Zhao, 2015). Based on the results from these data, as well
µg/person/day) (Munro et al., 1996). The Panel considered as the structure of the substance and the identity and
the specification of the material to be adequately arrangement of functional groups therein, the Panel did not
characterized by the purity and assay and supporting spectral identify a specific concern for the genotoxic potential of (R)-5-
data provided for FEMA GRAS evaluation. The Panel hydroxy-4-(4´-hydroxy-3´-methoxyphenyl)-7-methylchroman-
evaluated sensory data included within the application and 2-one.
found it satisfactory with regard to intended conditions of use
for the flavoring ingredient (Harman and Hallagan, 2013). In The Panel reviewed the GRAS application and supporting
vitro rat and human hepatocyte studies provided evidence information regarding 2,4-dihydroxy-N-[(4-hydroxy-3-
that (2S)-3',7-dihydroxy-8-methyl-4'-methoxyflavan is likely to methoxyphenyl)methyl]benzamide (CAS 877207-36-8) and
be rapidly metabolized in vivo, primarily by conversion to the concluded that the substance is GRAS (FEMA 4835) (Smith
glucuronic acid conjugate (Kandel, 2015). It is anticipated that et al., 2005a) for use as a flavor ingredient in the food
this would be followed by excretion in the urine. No increases categories and at the use levels specified in the GRAS
in the number of reverse mutations in the Ames assay were application (see Table 2). The substance was reviewed
observed for (2S)-3',7-dihydroxy-8-methyl-4'-methoxyflavan individually within the context of the chemical group of
in S. typhimurium strains TA98, TA100, TA1535, and TA1537 aliphatic and aromatic amines and amides (SLR A7; C21;
and E. coli WP2uvrA (pKM101) in either the absence or JECFA, 2006, 2008, 2011, 2012). The Panel calculated the
presence of S-9 metabolic activation using both the plate anticipated per capita intake ("eaters only") of 2,4-dihydroxy-
incorporation and pre-incubation methods (Soltesova, 2015). N-[(4-hydroxy-3-methoxyphenyl)methyl]benzamide from
Marginal increases in micronucleus production were observed anticipated use as a flavor ingredient to be 7 µg/person/day,
in Chinese hamster ovary (CHO) cells incubated with (2S)- which is below the threshold of toxicological concern for
3',7-dihydroxy-8-methyl-4'-methoxyflavan in the absence of structural class III (90 µg/person/day) (Munro et al., 1996).
S-9 metabolic activation (Zhao, 2015). No increase in The Panel considered the specification of the material to be
micronucleated polychromatic erythrocytes were observed in adequately characterized by the purity and assay and
femoral bone marrow of CD-1 mice of both sexes (Pant, supporting spectral data provided for FEMA GRAS
2015). Based on the results from these data, as well as the evaluation. The Panel evaluated sensory data included within
structure of the substance and the identity and arrangement the application and found it satisfactory with regard to
of functional groups therein, the Panel did not identify a intended conditions of use for the flavoring ingredient
specific concern for the genotoxic potential of 2-(3-(2S)-3',7- (Harman and Hallagan, 2013). 2,4-Dihydroxy-N-[(4-hydroxy-
dihydroxy-8-methyl-4'-methoxyflavan. 3-methoxyphenyl)methyl]benzamide is predicted to undergo
conjugation with sulfate or glucuronic acid, and the
conjugation products will be eliminated in the urine (Nelson
and Cox, 2008). No increases in the number of reverse in the food categories and at the use levels specified in the
mutations were observed in the Ames assay for 2,4- GRAS application (see Table 2). This material was evaluated
dihydroxy-N-[(4-hydroxy-3- within the context of the procedure for the safety evaluation of
methoxyphenyl)methyl]benzamide in S. typhimurium strains natural flavor complexes (Smith et al., 2005b). The Panel
TA97a, TA98, TA100 and TA1535 and E. coli strain WP2uvrA calculated the anticipated per capita intake ("eaters only") of
in the absence and presence of S-9 metabolic activation Chrysanthemum parthenium extract from use as a flavor
(Sokolowski, 2015). Based on the results from this assay, as ingredient to be 4 µg/person/day, which is below the threshold
well as the structure of the substance and the identity and of toxicological concern for structural class III (90
arrangement of functional groups therein, the Panel did not µg/person/day) (Munro et al., 1996). The Panel considered
identify a specific concern for the genotoxic potential of 2,4- the identity description to be adequate for FEMA GRAS
dihydroxy-N-[(4-hydroxy-3- evaluation (see Appendix 1). Metabolic data exist for
methoxyphenyl)methyl]benzamide. A NOAEL of 8 mg/kg representative members of each congeneric group of C.
bw/day for a structurally related substance, N-(4-hydroxy-3- parthenium extract that would predict metabolism by well-
methoxylbenzyl)nonanamide (CAS 244-46-4; FEMA 2787) established detoxication pathways to innocuous products. No
administered to male and female rats (Posternak, 1963) is increases in the occurrence of reverse mutations were
80,000 times the anticipated daily per capita intake of 2,4- observed in an Ames test in S. typhimurium strains TA98,
dihydroxy-N-[(4-hydroxy-3- TA100, TA1535, TA1537, and E. coli strain WP2, in either the
methoxyphenyl)methyl]benzamide from use as a flavor presence or absence of S-9 metabolic activation (Merrill,
ingredient. 2016). A conservative NOAEL from the 2-year study for
quercetin in F344/N rats (NTP, 1992) assigned by the Panel
The Panel reviewed the GRAS application and supporting at 40 mg/kg bw/day is greater than 666,000 times the
information regarding 10% solution of 3,4-dimethyl-2,3- anticipated daily per capita intake of Chrysanthemum
dihydrothiophene-2-thiol (CAS 137363-86-1) and concluded parthenium extract used as a flavor ingredient.
that the substance is GRAS (FEMA 4836) (Smith et al.,
2005a) for use as a flavor ingredient in the food categories The Panel reviewed the flavor complex GRAS application and
and at the use levels specified in the GRAS application (see supporting information regarding valencene 80 extract and
Table 2). The substance was reviewed individually within the concluded that the material is GRAS (FEMA 4838) for use as
context of the chemical group of sulfur containing heterocyclic a flavor ingredient in the food categories and at the use levels
compounds (SLR D15; JECFA, 2003, 2008, 2012, 2015). The specified in the GRAS application (see Table 2). This material
Panel calculated the anticipated per capita intake ("eaters was evaluated within the context of the procedure for the
only") of 10% solution of 3,4-dimethyl-2,3-dihydrothiophene- FEMA GRAS evaluation of flavor ingredients produced
2-thiol from use as a flavor ingredient to be 0.2 µg/person/day, through biotechnology processes (Cohen et al., 2015; Smith
which is below the threshold of toxicological concern for et al., 2005b). The Panel calculated the anticipated per capita
structural class III (90 µg/person/day) (Munro et al., 1996). intake ("eaters only") of valencene 80 extract from use as a
The Panel considered the specification of the material to be flavor ingredient to be 47 µg/person/day, which is below the
adequately characterized by the purity assay and supporting threshold of toxicological concern for structural class I (1800
spectral data provided for FEMA GRAS evaluation. The Panel µg/person/day) (Munro et al., 1996). The material is produced
noted that due to the instability of the neat material, the by bacterial fermentation. The Panel considered the identity
substance is used as a flavor ingredient as a 10% solution in description to be adequate for FEMA GRAS evaluation (see
a food grade solvent. 10% Solution of 3,4-dimethyl-2,3- Appendix 1). Metabolic data exist for representative members
dihydrothiophene-2-thiol is predicted to undergo S-oxidation of each congeneric group of valencene 80 extract that would
on the ring sulfur, as well as conjugation with glutathione on predict metabolism by well-established detoxication pathways
the thiol moiety. Hydroxylation of a methyl group followed by to innocuous products (Adams et al., 2011). No increases in
conjugation could also occur. In all cases, formation of polar the occurrence of reverse mutations for a structurally related
metabolites would result in excretion in the urine (Dansette et substance d-limonene (FEMA 2633) were observed in an
al., 1992). No increases in the number of reverse mutations Ames test in S. typhimurium strains TA98, TA100, TA1535,
were observed in the Ames assay for 10% Solution of 3,4- TA1537, and/or TA102, UTH8413 or UTH8414, in either the
dimethyl-2,3-dihydrothiophene-2-thiol in S. typhimurium presence or absence of S-9 metabolic activation (Connor et
strains TA97a, TA98, TA100 and TA1535 and E. coli strain al., 1985; Florin et al., 1980; Haworth et al., 1983; Heck et al.,
WP2uvrA in the absence and presence of S-9 metabolic 1989; Müller et al., 1993). d-Limonene was also negative in a
activation (Swartz, 2016). Based on the results from this chromosomal aberration study in CHO cells, a sister
assay, as well as the structure of the substance and the chromatid exchange assay in CHO cells, and a mouse
identity and arrangement of functional groups therein, the lymphoma forward mutation assay in L5178Y cells, either in
Panel did not identify a specific concern for the genotoxic the presence or absence of S-9 metabolic activation
potential of 10% solution of 3,4-dimethyl-2,3- (Anderson et al., 1990; Heck et al., 1989; Kauderer et al.,
dihydrothiophene-2-thiol. A NOAEL of greater than 0.29 1991; Myhr et al., 1990; Sasaki et al., 1989). Based on the
mg/kg bw/day for a structurally related substance, 2- results for the structurally related substance, as well as the
thienyldisulfide (FEMA 3323), administered to male and structures of the components within valencene 80 extract, the
female rats (Morgareidge and Oser, 1970) is greater than Panel did not identify specific concerns related to the
96,000 times the anticipated daily per capita intake of 10% genotoxic potential of valencene 80 extract. The structurally
solution of 3,4-dimethyl-2,3-dihydrothiophene-2-thiol from use related substance d-limonene (FEMA 2633) was administered
as a flavor ingredient. via gavage to F344/N rats for 13 weeks. Findings included
significantly increased relative kidney and relative liver
The Panel reviewed the natural flavor complex GRAS weights in high dose rats; hyaline droplet formation in the
application and supporting information regarding kidneys, granular casts and multiple cortical changes,
Chrysanthemum parthenium extract and concluded that the classified as chronic nephrosis. There were no
material is GRAS (FEMA 4837) for use as a flavor ingredient histopathological changes noted in the livers of treated rats.
The NOAEL for nephrotoxicity was reported to be 5 mg/kg Tetrahydronootkatone is predicted to undergo ring and side-
bw/day (NTP, 1990; Webb et al., 1989). This NOAEL is chain oxidation by cytochrome P450s, and these metabolites
greater than 6,000 times the anticipated daily per capita intake would either be excreted or undergo conjugation and
of valencene 80 extract from use as a flavor ingredient. excretion (Dansette et al., 1992). No increases in the number
of reverse mutations were observed in the Ames assay for the
The Panel reviewed the GRAS application and supporting structurally related substance nootkatone (FEMA 3166) in S.
information regarding mixture of 3- and 4-butyl-2- typhimurium strains TA98, TA100, TA1535, TA1537 and
thiophenecarbaldehyde (CAS 163460-99-9 & 163461-01-6) TA102 in the absence and presence of S-9 metabolic
and concluded that the mixture is GRAS (FEMA 4839) (Smith activation. Nootkatone was not reported to induce increases
et al., 2005a) for use as a flavor ingredient in the food of micronuclei in an human peripheral blood lymphocytes in
categories and at the use levels specified in the GRAS the presence of S-9, but did in the absence S-9 (Lloyd, 2011).
application (see Table 2). The substance was evaluated In a combined in vivo rat micronucleus induction and comet
individually within the context of the chemical group of sulfur- assay, no evidence of either micronuclei induction or DNA
containing heterocyclic compounds (SLR D15; Cohen et al., damage in the liver was found (Beevers, 2012). Based on the
2017; JECFA, 2002, 2008, 2012, 2014). The Panel calculated results from these of in vitro assays on a structurally related
the anticipated per capita intake ("eaters only") of the mixture substance, as well as the structure of the substance and the
of 3- and 4-butyl-2-thiophenecarbaldehyde from use as a identity and arrangement of functional groups therein, the
flavor ingredient to be 0.4 µg/person/day, which is below the Panel did not identify a specific concern for the genotoxic
threshold of toxicological concern for structural class II (540 potential of (±)-tetrahydronootkatone. In a 28-day gavage
µg/person/day) (Munro et al., 1996). The Panel considered study, 10 mg/kg bw/day of the structurally related substance
the specification of the material to be adequately nootkatone was administered to male and female rats (Jones
characterized by the purity and assay and supporting spectral et al., 2004). The resulting NOAEL was considered by the
data provided for FEMA GRAS evaluation. The mixture of 3- authors to be greater than 10 mg/kg bw/day, which is greater
and 4-butyl-2-thiophenecarbaldehyde is predicted to undergo than 2,000,000 times the anticipated daily per capita intake of
S-oxidation and side-chain C-oxidation, and these (±)-tetrahydronootkatone from use as a flavor ingredient.
metabolites would either be excreted or undergo conjugation
and excretion (Dansette et al., 1992). No increases in the The Panel reviewed the GRAS application and supporting
number of reverse mutations were observed in the Ames information regarding cis-5-dodecenyl acetate (CAS 16676-
assay for 5-methyl-2-thiophene carboxaldehyde (FEMA 96-3) and concluded that the substance is GRAS (FEMA
3209), a structurally related substance, in S. typhimurium 4841) (Smith et al., 2005a) for use as a flavor ingredient in the
strains TA98, TA100, TA1535, TA1537 and TA102 in the food categories and at the use levels specified in the GRAS
absence and presence of S-9 metabolic activation (Beevers, application (see Table 2). The substance was evaluated
2009). 5-methyl-2-thiophene carboxaldehyde was reported to individually within the context of the chemical group of linear
induce weak induction of micronuclei in an human peripheral and branched-chain aliphatic, unsaturated, unconjugated
blood lymphocytes in the presence of S-9 but not in the alcohols, aldehydes, acids and related esters (SLR M1;
absence (Lloyd, 2011). In a combined in vivo rat micronucleus JECFA, 2000b, 2007, 2012, 2014). The Panel calculated the
induction and comet assay, no evidence of either micronuclei anticipated per capita intake ("eaters only") of cis-5-dodecenyl
induction or DNA damage in the liver (Beevers, 2012). Based acetate from use as a flavor ingredient to be 0.4
on the results from this series of in vitro and in vivo assays on µg/person/day, which is below the threshold of toxicological
a structurally related substance, as well as the structure of the concern for structural class I (1800 µg/person/day) (Munro et
substance and the identity and arrangement of functional al., 1996). The Panel considered the specification of the
groups therein, the Panel did not identify a specific concern material to be adequately characterized by the purity and
for the genotoxic potential of mixture of 3- and 4-butyl-2- assay and supporting spectral data provided for FEMA GRAS
thiophenecarbaldehyde. A NOAEL of 7.5 mg/kg bw/day for a evaluation. cis-5-Dodecenyl acetate is predicted to undergo
structurally related substance, 5-ethyl-2- hydrolysis by carboxylesterases or other esterases to acetate
thiophenecarbaldehyde, administered to male and female rats and the corresponding unsaturated alcohol, cis-5-dodecenol.
(Bauter, 2013) is 1,125,000 times the anticipated daily per The alcohol is expected to enter the fatty acid beta-oxidation
capita intake of mixture of 3- and 4-butyl-2- pathway (Nelson and Cox, 2008). No increases in the number
thiophenecarbaldehyde from use as a flavor ingredient. of reverse mutations were observed in the Ames assay for the
structurally related substance cis-3-hexen-1-ol (FEMA 2563)
The Panel reviewed the GRAS application and supporting in S. typhimurium strains TA98, TA100, TA1535 and TA1537
information regarding (±)-tetrahydronootkatone (CAS 38427- and E. coli WPuvrA in the absence and presence of S-9
80-4) and concluded that the substance is GRAS (FEMA metabolic activation (Bhalli and Phil, 2014a). cis-3-Hexen-1-
4840) (Smith et al., 2005a) for use as a flavor ingredient in the ol was reported to induce no increases of micronuclei in an
food categories and at the use levels specified in the GRAS human peripheral blood lymphocytes in the presence of S-9
application (see Table 2). The substance was evaluated but not in the absence (Bhalli and Phil, 2014b). Based on the
individually within the context of the chemical group of results from these of in vitro assays on a structurally related
monocyclic and bicyclic secondary alcohols, ketones and substance, as well as the structure of the substance and the
related esters (SLR A5; Adams et al., 1996; JECFA, 2006, identity and arrangement of functional groups therein, the
2009, 2015). The Panel calculated the anticipated per capita Panel did not identify a specific concern for the genotoxic
intake ("eaters only") of (±)-tetrahydronootkatone from use as potential of cis-5-dodecenyl acetate. A NOAEL of 125 mg/kg
a flavor ingredient to be 0.3 µg/person/day, which is below the bw/day for a structurally related substance, cis-3-hexen-1-ol
threshold of toxicological concern for structural class II (540 administered to male and female rats (Gaunt et al., 1969) is
µg/person/day) (Munro et al., 1996). The Panel considered greater than 18,750,000 times the anticipated daily per capita
the specification of the material to be adequately intake of cis-5-dodecenyl acetate from use as a flavor
characterized by the purity and assay and supporting spectral ingredient.
data provided for FEMA GRAS evaluation. (±)-
The Panel reviewed the GRAS application and supporting from these in vitro assays on structurally related substances
information regarding 2,4,5-trithiaoctane (CAS 911212-28-7) and on the structure of the substance and the identity and
and concluded that the substance is GRAS (FEMA 4842) arrangement of functional groups therein, the Panel did not
(Smith et al., 2005a) for use as a flavor ingredient in the food identify a specific concern for the genotoxic potential of 3-
categories and at the use levels specified in the GRAS (allyldithio)-butan-2-one. A NOAEL of greater than 1.89 mg/kg
application (see Table 2). The substance was evaluated bw/day for a structurally related substance, 3-mercapto-2-
individually within the context of the chemical group of simple pentanone (FEMA 3300) administered to male and female
aliphatic and aromatic sulfides and thiols (SLR B4; JECFA, rats is greater than 1,620,000 times the anticipated daily per
2000a, 2004, 2008, 2011). The Panel calculated the capita intake of 3-(allyldithio)-butan-2-one from use as a flavor
anticipated per capita intake ("eaters only") of 2,4,5- ingredient.
trithiaoctane from use as a flavor ingredient to be 0.07
µg/person/day, which is below the threshold of toxicological The Panel reviewed the GRAS application and supporting
concern for structural class III (90 µg/person/day) (Munro et information regarding (2E,4E)-2,4-decadiena-1-ol, acetate
al., 1996). The Panel considered the specification of the (CAS 118026-67-8) and concluded that the substance is
material to be adequately characterized by the purity and GRAS (FEMA 4844) (Smith et al., 2005a) for use as a flavor
assay and supporting spectral data provided for FEMA GRAS ingredient in the food categories and at the use levels
evaluation. 2,4,5-Trithiaoctane is predicted to undergo specified in the GRAS application (see Table 2). The
reductive cleavage of the disulfide bond followed by oxidative substance was evaluated individually within the context of the
metabolism by cytochrome P450 and flavin-containing chemical group of aliphatic, linear, alpha, beta-unsaturated
monooxygenases to sulfoxides and sulfones (Waring, 1996; aldehydes, acids and related alcohols, acids and esters (SLR
Cotgreave et al., 1989; Wells et al., 1993; Williams et al., M1; JECFA, 2004, 2007). The Panel calculated the
1966). Based on the structure of the substance and the anticipated per capita intake ("eaters only") of (2E,4E)-2,4-
identity and arrangement of functional groups therein, the decadiena-1-ol, acetate from use as a flavor ingredient to be
Panel did not identify a specific concern for the genotoxic 0.3 µg/person/day, which is below the threshold of
potential of 2,4,5-trithiaoctane. A NOAEL of greater than 1.9 toxicological concern for structural class I (1800
mg/kg bw/day for a structurally related substance, 3,5- µg/person/day) (Munro et al., 1996). The Panel considered
dimethyl-1,2,4-trithiolane (FEMA 3541) administered to male the specification of the material to be adequately
and female rats (BIBRA, 1976) is greater than 1,628,000 characterized by the purity and assay and supporting spectral
times the anticipated daily per capita intake of 2,4,5- data provided for FEMA GRAS evaluation. (2E,4E)-2,4-
trithiaoctane from use as a flavor ingredient. Decadiena-1-ol, acetate is predicted to undergo hydrolysis by
carboxylesterases or other esterases to acetate and the
The Panel reviewed the GRAS application and supporting corresponding unsaturated alcohol, (2E,4E)-2,4-decadiena-1-
information regarding 3-(allyldithio)-butan-2-one (CAS ol. The alcohol is expected to enter the fatty acid beta-
1838169-65-5) and concluded that the substance is GRAS oxidation pathway (Nelson and Cox, 2008). No increases in
(FEMA 4843) (Smith et al., 2005a) for use as a flavor the number of reverse mutations were observed in the Ames
ingredient in the food categories and at the use levels assay for a structurally related substance 2,4-decadienal
specified in the GRAS application (see Table 2). The (FEMA 3135) in S. typhimurium strains TA97, TA98, TA100,
substance was evaluated individually within the context of the TA102, TA104 and TA1535 in the absence and presence of
chemical group of simple aliphatic and aromatic sulfides and S-9 metabolic activation (Chan, 2011). Equivocal results were
thiols (SLR B4; JECFA, 2000a, 2004, 2008, 2011). The Panel reported for the in vivo rat micronucleus assay (Chan, 2011).
calculated the anticipated per capita intake ("eaters only") of 2,4-Decadienal was reported to induce no increases of
3-(allyldithio)-butan-2-one from use as a flavor ingredient to micronuclei in the bone marrow of rats (Lloyd, 2011). Based
be 0.07 µg/person/day, which is below the threshold of on the results from these in vitro and in vivo assays, the Panel
toxicological concern for structural class III (90 µg/person/day) did not identify a specific concern for the genotoxic potential
(Munro et al., 1996). The Panel considered the specification of (2E,4E)-2,4-decadien-1-ol, acetate. In a 14-week study in
of the material to be adequately characterized by the purity male and female B6C3F1 mice, a structurally related
and assay and supporting spectral data provided for FEMA substance, trans,trans-2,4-decadien-1-al (FEMA 3135) was
GRAS evaluation. 3-(Allyldithio)-butan-2-one (CAS 1838169- administered at doses of 50, 100, 200, 400, or 800 mg/kg
65-5) is predicted to undergo reductive cleavage of the bw/day (Chan, 2011) with effects of epithelial erosion or
disulfide bond followed by oxidative metabolism by ulceration of the forestomach in males of the mid- and highest
cytochrome P450 and flavin-containing monooxygenases to dose groups. In a 14-week study, a structurally related
sulfoxides and sulfones (Cotgreave et al., 1989; Waring, substance trans,trans-2,4-decadien-1-al (FEMA 3135)
1996; Wells et al., 1993; Williams et al., 1966). No increases administered to male and female rats at doses of of 45, 133,
in the number of reverse mutations were observed in the 400, 1,200, and 3,600 mg/kg bw/day (Chan, 2011) resulted in
Ames assay for a structurally related substance allyl disulfide a NOAEL of 100 mg/kg bw/day, which is 20,400,000 times the
(FEMA 2028) in S. typhimurium strain TA100 in the absence anticipated daily per capita intake of (2E,4E)-2,4-decadiena-
and presence of S-9 metabolic activation (Beevers, 2009; 1-ol, acetate from use as a flavor ingredient.
Eder et al., 1980). Equivocal results were obtained in an in
vitro cytogenetic assay in CHO cells where sister chromatid The Panel reviewed the natural flavor complex GRAS
exchanges and chromosomal aberrations were observed but application and supporting information regarding glucosylated
showed no concentration dependence (Musk et al., 1996) and stevia extract (CAS 1225018-62-1) and concluded that the
negative results were obtained from an in vivo mouse material is GRAS (FEMA 4845) for use as a flavor ingredient
micronucleus assay (Marks et al., 1992). Using a second in the food categories and at the use levels specified in the
structurally related substance, diallyl trisulfide (FEMA 3265) in GRAS application (see Table 2). This material was evaluated
an in vivo mouse micronucleus assay showed no increases in within the context of the procedure for the safety evaluation of
the frequency of micronucleated polychromatic erythrocyctes natural flavor complexes (Smith et al., 2005b). The Panel
in bone marrow cells (Marks et al., 1992). Based on the results calculated the anticipated per capita intake ("eaters only") of
glucosylated stevia extract from use as a flavor ingredient to

be 370 µg/person/day. Glucosylated stevia extract is derived The Panel reviewed the GRAS application and supporting
from the leaves of Stevia rebaudiana. The Panel evaluated information regarding (3S,5R,8S)-3,8-dimethyl-5-prop-1-en-
sensory data included within the application and found it 2-yl-3,4,5,6,7,8-hexahydro-2H-azulen-1-one (CAS 18374-76-
satisfactory with regard to intended conditions of use for the 0) and concluded that the substance is GRAS (FEMA 4867)
flavoring ingredient.(Harman and Hallagan, 2013). Metabolic (Smith et al., 2005a) for use as a flavor ingredient in the food
data exist for representative members of each congeneric categories and at the use levels specified in the GRAS
group that would predict, at the intake levels proposed, application (see Table 2). The substance was evaluated
metabolism by well-established detoxication pathways to individually within the context of the chemical group of
innocuous products (Gardana et al., 2003; Geuns et al., 2003; monocyclic and bicyclic secondary alcohols, ketones and
Geuns et al., 2007; Geuns and Pietta, 2004; Hutapea et al., related esters (SLR A5; Adams et al., 1996; JECFA, 2006,
1997; Koyama et al., 2003a; Koyama et al., 2003b; Nakayama 2009, 2015). The Panel calculated the anticipated per capita
et al., 1986; Renwick and Tarka, 2008; Roberts and Renwick, intake ("eaters only") of (3S,5R,8S)-3,8-dimethyl-5-prop-1-en-
2008; Simonetti et al., 2004; Wheeler et al., 2008; Wingard et 2-yl-3,4,5,6,7,8-hexahydro-2H-azulen-1-one from use as a
al., 1980). The genotoxicity of the major marker constituents flavor ingredient to be 0.001 µg/person/day, which is below
(steviol glycosides) has been thoroughly examined in a wide the threshold of toxicological concern for structural class II
range of studies. While some positive results are reported in (540 µg/person/day) (Munro et al., 1996). The Panel
in vitro mutagenicity assays, in vivo studies do not provide considered the specification of the material to be adequately
evidence of genotoxic effects (Nakajima, 2000; Pezzuto et al., characterized by the purity assay and supporting spectral data
1985, 1986; Rummelhard et al., 2016; Suttajit et al., 1993; provided for FEMA GRAS evaluation. (3S,5R,8S)-3,8-
Terai et al, 2002; Toyoda et al., 1997; Williams and Burdock, Dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-2H-azulen-
2009). Based on the results for the various steviol glycosides, 1-one is predicted to follow a similar metabolic pathway as
the Panel did not identify specific concerns related to the other lipophilic ketones or those with sterically hindered
potential genotoxicity of glucosylated stevia extract. In a 108- functional groups. Specifically, this is anticipated to occur via
week carcinogenicity study for stevioside, no carcinogenic oxidation at a ring position by nonspecific cytochrome P-450
effects were observed (Toyoda et al., 1997). In a 2-year mixed function oxidases, followed by conjugation and
feeding study, male and female rats were administered the excretion in the urine. In an alternative pathway, reduction of
equivalent of 0, 50, 150, or 550 mg/kg bw/day of a stevia the ketone functional group followed by conjugation and
extract comprised of 74% stevioside and 16% rebaudioside excretion in the urine would possibly occur (Asakawa et al.,
A. The authors considered the NOAEL from this 2-year rat 1986; Nelson et al., 1992). No increase in reverse mutations
feeding study of a stevia extract to be equal to 550 mg/kg was observed in the Ames assay regarding (3S,5R,8S)-3,8-
bw/day, or approximately 89.5 mg/kg bw/day of rebaudioside dimethyl-5-prop-1-en-2-yl-3,4,5,6,7,8-hexahydro-2H-azulen-
A (Yamada et al., 1985), which is greater than14,500 times 1-one on S. typhimurium strains TA98 and TA100 in the
the anticipated daily per capita intake of the stevia extract absence or presence of S-9 metabolic (Kawaguchi, 2015b).
enzymatically modified from use as a flavor ingredient. No increases in the number of reverse mutations were
observed in the Ames assay for the structurally related
The Panel reviewed the natural flavor complex GRAS substance nootkatone (FEMA 3166) in S. typhimurium strains
applications and supporting information regarding Grapefruit TA98, TA100, TA1535, TA1537 and TA102 in the absence
essence oil (Citrus paradisi Macf.), Grapefruit oil, terpeneless and presence of S-9 metabolic activation (Marzin, 1998).
(Citrus paradisi Macf.), Lemon terpenes, Lime terpenes, Nootkatone was reported to induce no increases of
Orange terpenes, Grapefruit terpenes, Lemon essence oil micronuclei in human peripheral blood lymphocytes in the
(Citrus limon (L) Burm. f.), Petitgrain oil terpeneless, Tangelo presence of S-9 but not in its absence (Stone, 2011). Based
oil (Citrus paradisi Macf. x Citrus tangerine hort. ex Tanaka), on the results from these assays on the substance itself and
Clementine oil (Citrus clementina Hort. ex Tan), Blood orange a structurally related substance, as well as the structure of the
oil (Citrus sinensis (L.) Osbeck 'Blood orange'), Iyokan oil substance and the identity and arrangement of functional
(Citrus iyo), Hassaku oil (Citrus hassaku hort. ex Tanaka), groups therein, the Panel did not identify a specific concern
Sikuwasya oil (Citrus depressa), Natsumikan oil (Citrus for the genotoxic potential of (3S,5R,8S)-3,8-dimethyl-5-prop-
natsudaidai), Mikan oil (Citrus unshiu), Yuzu oil (Citrus junos 1-en-2-yl-3,4,5,6,7,8-hexahydro-2H-azulen-1-one. In a 28-
(Sieb.) c. Tanaka), Sudachi oil (Citrus sudachi hort. ex Shirai), day gavage study, 10 mg/kg bw/day of the structurally related
Kabosu oil (Citrus sphaerocarpa), Ponkan oil (Citrus reticulata substance nootkatone was administered to male and female
Blanco 'Ponkan'), and Orange essence water phase (Citrus rats (Jones et al., 2004). The resulting NOAEL was
sinensis (L.) Osbeck) and concluded that the substances are considered by the authors to be greater than 10 mg/kg bw/day
GRAS for use as flavor ingredients in the food categories and is greater than 600,000,000 times the anticipated daily per
at the use levels specified in the GRAS applications (FEMA capita intake of regarding (3S,5R,8S)-3,8-dimethyl-5-prop-1-
4846-4866, respectively) (see Table 2). These materials were en-2-yl-3,4,5,6,7,8-hexahydro-2H-azulen-1-one from use as a
evaluated within the context of the revised procedure for the flavor ingredient.
safety evaluation of natural flavor complexes (Smith et al.,
2005b; Cohen et al., 2017, submitted for publication; Cohen The Panel reviewed the GRAS application and supporting
et al, 2017, manuscript in preparation). These citrus information regarding 4-(4-methyl-3-penten-1-yl)-2(5H)-
ingredients are derived from commonly consumed fruits. The furanone (CAS 61315-75-1) and concluded that the
Panel considered the identity descriptions of each material to substance is GRAS (FEMA 4868) (Smith et al., 2005a) for use
be adequate for FEMA GRAS evaluation. These citrus flavor as a flavor ingredient in the food categories and at the use
ingredients were evaluated using a rigorous procedure that levels specified in the GRAS application (see Table 2). The
considers the chemical composition, anticipated per capita substance was evaluated individually within the context of the
intake, metabolic fate and toxicity of the identified constituents chemical group of tetrahydrofuran and furanone derivatives
and potential toxicity and genotoxicity of unidentified (SLR D9; JECFA, 2006). The Panel calculated the anticipated
constituents. per capita intake ("eaters only") of 4-(4-methyl-3-penten-1-yl)-
2(5H)-furanone from use as a flavor ingredient to be 0.001 data provided for FEMA GRAS evaluation. 4-(l-Menthoxy)-2-
µg/person/day, which is below the threshold of toxicological butanone is predicted to undergo oxidation at a ring position
concern for structural class III (90 µg/person/day) (Munro et by nonspecific cytochrome P-450 mixed function oxidases,
al., 1996). The Panel considered the specification of the followed by conjugation and excretion in the urine based on
material to be adequately characterized by the purity and data available for the structural relative, menthol (FEMA 2665)
assay and supporting spectral data provided for FEMA GRAS (Heck, 2010). 4-(l-Menthoxy)-2-butanone gave no increases
evaluation. 4-(4-Methyl-3-penten-1-yl)-2(5H)-furanone is in mutant frequencies relative to vehicle control when tested
predicted to follow a similar metabolic pathway as other in an Ames assay in S. typhimurium strains TA98 and TA100
alpha,beta-unsaturated lactones. Specifically, this is in the presence and absence of S-9 metabolic activation
anticipated to hydrolyze to the corresponding ring-opened (Tomi and Kawaguchi, 2014). Based on the results from these
alpha,beta-unsaturated hydroxycarboxylic acid and undergo assays, as well as the structure of the substance and the
condensation with acetyl-CoA and biotransformation in the identity and arrangement of functional groups therein, the
beta-oxidation pathway. Minor amounts of the lactone are Panel did not identify a specific concern for the genotoxic
expected to form conjugates with glutathione followed by potential of 4-(l-menthoxy)-2-butanone. In a 91-day study, CD
excretion in the urine as the mercapturic acid conjugate rats were administered diets containing the structurally related
(Boyland and Chasseaud, 1970; Chasseaud, 1979; Fry et al., substance 3-(l-menthoxy)propane-1,2-diol (FEMA 3784) at
1993; Köppel and Tenczer, 1991; Nelson and Cox, 2008). No 30, 200 and 1000 mg/kg bw/day. A NOAEL of 30 mg/kg
increase in reverse mutations was observed in the Ames bw/day in males and 200 mg/kg bw/day in females was
assay for 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone on S. reported by the authors based on effects identified during
typhimurium strains TA 98 and TA100 in the absence or histopathological examination at higher doses (Wolfe, 1992).
presence of S-9 metabolic activation (Kawaguchi, 2015a). No The NOAEL of 30 mg/kg bw/day is greater than 450,000 times
increases in the number of reverse mutations were observed greater than the anticipated daily per capita intake of 4-(l-
in the Ames assay for the structurally related substances menthoxy)-2-butanone from use as a flavoring ingredient.
gamma-heptalactone, gamma-nonalactone, and gamma-
undecalactone (FEMA 2539, 2781 and 3091, respectively) in The Panel reviewed the GRAS application and supporting
S. typhimurium strains TA98, TA100, TA1535, TA1537 and information regarding 2-ethyl-4-methyl-1,3-dithiolane (CAS
TA102 in the absence and presence of S-9 metabolic 17564-27-1) and concluded that it is GRAS (FEMA 4870)
activation (Fujita and Sasaki, 1987; Heck et al., 1989; Ishidate (Smith et al., 2005a) for use as a flavor ingredient in the food
et al., 1984). In a standard mouse lymphoma assay, gamma- categories and at the use levels specified in the GRAS
nonalactone showed a weak mutagenic response at high application (see Table 2). The substance was evaluated
concentrations when in the presence of S-9, but the authors individually within the context of the chemical group of simple
noted that effects on the osmolality or pH may have aliphatic and aromatic sulfides and thiols (SLR A8; JECFA,
contributed to the result. gamma-Heptalactone did not induce 2000a, 2004, 2008, 2011). The Panel calculated the
an increase in unscheduled DNA synthesis (Heck et al., anticipated per capita intake ("eaters only") of 2-ethyl-4-
1989). No increases in the incidence of micronucleated methyl-1,3-dithiolane from use as a flavor ingredient to be 0.1
polychromatic erythrocytes were observed in ddY mice µg/person/day, which is below the threshold of toxicological
treated with gamma-undecalactone by intraperitoneal concern for structural class II (540 µg/person/day) (Munro et
injection (Hayashi et al., 1988). Based on the results from al., 1996). The substance occurs naturally in onions, garlic,
these in vitro and in vivo assays on structurally related chives, and beef, but only qualitative data is available and,
substances and the substance itself, as well as the structure thus, no consumption ratio can be calculated (Takahashi and
of the substance and the identity and arrangement of Shibamoto, 2008). The Panel considered the specification of
functional groups therein, the Panel did not identify a specific the material to be adequately characterized by the purity
concern for the genotoxic potential of 4-(4-methyl-3-penten-1- assay and supporting spectral data provided for FEMA GRAS
yl)-2(5H)-furanone. In a 90-day dietary study, male and evaluation. 2-ethyl-4-methyl-1,3-dithiolane is predicted to
female rats were given 14.6 mg/kg bw/day of the structurally undergo S-oxidation to yield the corresponding monocyclic
related substance gamma-undecalactone. Necropsy and sulfoxide, which is considered a major metabolic pathway
histopathological examinations revealed no evidence of (Grosa et al., 1991). Further oxidation to the corresponding
toxicity (Oser et al., 1965). The resulting NOAEL of greater monocyclic cyclic sulfone (S,S’-dioxide) is predicted to occur
than 14.6 mg/kg bw/day is greater than 876,000,000 times the at a slower rate (Cashman et al., 1990). The monosulfoxides
anticipated daily per capita intake of 4-(4-methyl-3-penten-1- are predicted to be the main urinary metabolite produced.
yl)-2(5H)-furanone from use as a flavor ingredient. Based on the structure of the substance as well as the
arrangement and identity of the functional groups therein, the
The Panel reviewed the GRAS application and supporting Panel did not identify specific concerns related to the
information regarding 4-(l-menthoxy)-2-butanone (CAS genotoxicity of 2-ethyl-4-methyl-1,3-dithiolane. A 91-day
886449-15-6) and concluded that the substance is GRAS gavage study for a structurally related substance, 2-methyl-
(FEMA 4869) (Smith et al., 2005a) for use as a flavor 1,3-dithiolane (FEMA 3705), was conducted in male and
ingredient in the food categories and at the use levels female rats at a single dose calculated to be 7 mg/kg bw/day.
specified in the GRAS application (see Table 2). The There were no adverse test substance-related effects
substance was evaluated individually within the context of the observed (Griffiths et al., 1979). The resulting NOAEL is
chemical group of aliphatic and aromatic ethers (SLR D12; greater than 7 mg/kg bw/day, which is greater than 4,200,000
JECFA, 2004, 2012). The Panel calculated the anticipated per times the anticipated daily per capita intake of 2-ethyl-4-
capita intake ("eaters only") of 4-(l-menthoxy)-2-butanone methyl-1,3-dithiolane from use as a flavor ingredient.
from use as a flavor ingredient to be 4 µg/person/day, which
is below the threshold of toxicological concern for structural The Panel reviewed the GRAS application and supporting
class II (540 µg/person/day) (Munro et al., 1996). The Panel information regarding 2-phenoxyethyl 2-(4-hydroxy-3-
considered the specification of the material to be adequately methoxyphenyl)acetate (CAS 1962956-83-7) and concluded
characterized by the purity and assay and supporting spectral that the substance is GRAS (FEMA 4871) (Smith et al.,
2005a) for use as a flavor ingredient in the food categories intestine undergo further metabolism by micro flora in the
and at the use levels specified in the GRAS application (see large intestine and colon (Borges et al., 2013). The microflora
Table 2). The substance was evaluated individually within the cleave conjugate moieties with the resultant aglycones
context of the chemical group of hydroxy- and alkoxy- undergoing ring fission leading to phenolic acid and cinnamic
substituted benzyl derivatives (SLR C9; JECFA, 2001). The acid derivatives. These metabolites are absorbed and
Panel calculated the anticipated per capita intake ("eaters ultimately excreted in the urine in excess of those flavonoid
only") of 2-phenoxyethyl 2-(4-hydroxy-3- metabolites in the circulatory system via the small intestine
methoxyphenyl)acetate from use as a flavor ingredient to be (Donovan et al., 2006). Any unabsorbed metabolites are
236 µg/person/day, which is below the threshold of ultimately excreted in feces (Marin et al., 2015). An Ames
toxicological concern for structural class I (1800 assay of 3-(3-hydroxy-4-methoxyphenyl)-1-(2,4,6-
µg/person/day) (Munro et al., 1996). The Panel considered trihydroxyphenyl)propan-1-one using S. typhimurium strains
the specification of the material to be adequately TA98, TA100, TA1535, TA1537 and E. coli WP2 showed no
characterized by the purity assay and supporting spectral data increase in revertant colony numbers as compared with
provided for FEMA GRAS evaluation. 2-phenoxyethyl 2-(4- control counts with and without metabolic activation
hydroxy-3-methoxyphenyl)acetate is predicted to undergo (Leuschner, 2016). Based on this assay, the structure of the
hydrolysis to form the corresponding 4-hydroxy-3- substance and the arrangement and identity of the functional
methoxyphenyl acetic acid, which would form a glycine groups therein, the Panel did not identify specific concerns
conjugate and be excreted in the urine. The 2-phenoxyethanol related to the genotoxicity of 3-(3-hydroxy-4-methoxyphenyl)-
(FEMA 4620) would likely undergo glucuronic acid 1-(2,4,6-trihydroxyphenyl)propan-1-one. A 13-week dietary
conjugation of sulfation and be excreted primarily in the urine study for turmeric oleoresin (containing approximately 79-
(Strand and Scheline, 1975; Wong and Sourkes, 1966). 85% curcumin) was conducted in male and female rats at
Based on the structure of the substance and the arrangement dose levels of 2.5% and 5% (Lilja et al., 1983). The resulting
and identity of the functional groups therein, the Panel did not NOAEL was considered to be 1300 mg/kg bw/day, which
identify specific concerns related to the genotoxicity of 2- corresponds to 1027 mg/kg bw/day of curcumin. The dose of
phenoxyethyl 2-(4-hydroxy-3-methoxyphenyl)acetate. A two- 1027 mg/kg bw/day is greater than 8,800,000 times the
year dietary study for a structurally related substance, vanillin anticipated daily per capita intake of 3-(3-hydroxy-4-
(FEMA 3107), was conducted in male and female rats at methoxyphenyl)-1-(2,4,6-trihydroxyphenyl)propan-1-one from
doses of 250, 500, or 1000 mg/kg bw/day. There were no use as a flavor ingredient.
adverse test substance-related effects observed (Hagan et
al., 1967). In a 13-week study, vanillin was administered to The Panel reviewed the natural flavor complex GRAS
Sprague Dawley rats by oral gavage at doses of 80, 240, and application and supporting information regarding watermint,
400 mg/kg bw/day (Mancebo et al., 2003). The NOAEL for Mentha aquatica L., extract (CAS 90063-96-0) and concluded
vanillin concluded upon by the authors to be 400 mg/kg that the material is GRAS (FEMA 4873) for use as a flavor
bw/day, which is greater than 101,000 times the anticipated ingredient in the food categories and at the use levels
daily per capita intake of 2-phenoxyethyl 2-(4-hydroxy-3- specified in the GRAS application (see Table 2). This material
methoxyphenyl)acetate from use as a flavoring ingredient. was evaluated within the context of the procedure for the
safety evaluation of natural flavor complexes (Smith et al.,
The Panel reviewed the GRAS application and supporting 2005b). The Panel calculated the anticipated per capita intake
information regarding 3-(3-hydroxy-4-methoxyphenyl)-1- ("eaters only") of watermint, Mentha aquatica L., extract from
(2,4,6-trihydroxyphenyl)propan-1-one (CAS 35400-60-3) and use as a flavor ingredient to be 140 µg/person/day. The Panel
concluded that the substance is GRAS (FEMA 4872) (Smith considered the identity description of the material to be
et al., 2005a) for use as a flavor ingredient in the food adequate for FEMA GRAS evaluation (see Appendix 1). The
categories and at the use levels specified in the GRAS Panel evaluated sensory data included within the application
application (see Table 2). The substance was evaluated and found it satisfactory with regard to intended conditions of
individually within the context of the chemical group of phenol use for the flavoring ingredient (Harman and Hallagan, 2013).
and phenol derivatives (SLR C12; JECFA, 2001, 2011, In a metabolic study of rats orally administered 50 mg/kg bw
2015). The Panel calculated the anticipated per capita intake of rosmarinic acid, a principal constituent of watermint extract,
("eaters only") of 3-(3-hydroxy-4-methoxyphenyl)-1-(2,4,6- orally, the metabolites identified in the plasma were
trihydroxyphenyl)propan-1-one from anticipated use as a rosmarinic acid, monomethylated rosmarinic acid and m-
flavor ingredient to be 7 µg/person/day, which is below the coumaric acid and those identified in the urine were
threshold of toxicological concern for structural class III (90 rosmarinic acid, monomethylated RA, caffeic acid, ferulic acid
µg/person/day) (Munro et al., 1996). The Panel considered and m-coumaric acid. In the urine 34 and 37 % of rosmarinic
the specification of the material to be adequately acid and monomethylated rosmarinic acid were excreted as
characterized by the purity assay and supporting spectral data such without conjugation but the remainder were either
provided for FEMA GRAS evaluation. The Panel evaluated sulfated or formed glucuronic acid conjugates (Baba et al.,
sensory data included within the application and found it 2004). In a Comet assay, male rats were administered 2 or 8
satisfactory with regard to intended conditions of use for the mg/kg bw of rosmarinic acid via intraperitoneal injection. No
flavoring ingredient (Harman and Hallagan, 2013). 3-(3- genotoxicity was observed compared to the controls (Pereira
hydroxy-4-methoxyphenyl)-1-(2,4,6-trihydroxyphenyl)propan- et al., 2005). In an Ames assay, an extract derived from
1-one is predicted to undergo metabolism forming sulfate and spearmint containing 15.4% rosmarinic acid showed no
glucuronide conjugates and/or methylated through the mutagenic activity in S. typhimurium strains TA98, TA100,
respective action of sulfotransferases (SULT), uridine-50- TA1535, and TA1537 at concentrations up to 5000 mg/plate
diphosphate glucuronosyltransferases (UGTs) and catechol- with and without metabolic activation (Lasrado et al., 2015).
O-methyltransferases (COMT) (Borges et al., 2013; Donovan The same extract, when tested at concentrations up to 5000
et al., 2006). Upon entry into the blood stream, the metabolites µg extract/mL culture did not induce chromosomal aberrations
are further transformed in phase II metabolic processes in the when tested with human peripheral blood lymphocytes, both
liver (Marin et al., 2015). Metabolites not absorbed in the small with and without metabolic activation, in an OECD compliant
study (Lasrado et al., 2015). Based on these assays and the JECFA, 2006, 2008, 2011, 2012). The Panel calculated the
composition of the material therein, the Panel did not identify anticipated per capita intake ("eaters only") of (E)-3-(3,4-
specific concerns related to the genotoxicity of watermint, dimethoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]acrylamide
Mentha aquatica L., extract. In a 90-day gavage study in male from use as a flavor ingredient to be 240 µg/person/day, which
and female rats, a spearmint extract containing 15.4% is above the threshold of toxicological concern for structural
rosmarinic acid was administered at dose levels class III (90 µg/person/day) (Munro et al., 1996). The Panel
corresponding to 422, 844, or 1948 mg/kg bw/day of dry considered the specification of the material to be adequately
spearmint extract, producing a NOAEL of 422 mg/kg bw/day characterized by the purity assay and supporting spectral data
of dry spearmint extract (Lasrado et al., 2015). This NOAEL is provided for FEMA GRAS evaluation. The Panel evaluated
greater than 170,000 times the anticipated per capita daily sensory data included within the application and found it
intake of watermint, Mentha aquatica L., extract from use as satisfactory with regard to intended conditions of use for the
a flavor ingredient. flavoring ingredient. (Harman and Hallagan, 2013). (E)-3-(3,4-
dimethoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-acrylamide
is predicted to be metabolized primarily by O-demethylation
The Panel reviewed the natural flavor complex GRAS and O-demethylation to yield phenolic derivatives that form
application and supporting information regarding enzyme glucuronic acid and sulfate conjugates, which are then
modified stevia, stevioside 20% (CAS 57817-89-7; 58543-16- excreted primarily in the urine (Nelson and Cox, 2008). No
1) and concluded that the material is GRAS (FEMA 4876) for genotoxic potential was observed when the structurally
use as a flavor ingredient in the food categories and at the use related substance N-2[2-(3,4-dimethoxyphenyl)ethyl]-3,4-
levels specified in the GRAS application (see Table 2). This dimethoxycinnamic acid amide (FEMA 4310) was incubated
substance was evaluated within the context of the procedure with S. typhimurium strains TA98, TA100, TA102, TA1535
for the safety evaluation of natural flavor complexes (Smith et and TA1537 with or without metabolic activation in two
al., 2005b). The Panel calculated the anticipated per capita separate experiments using the plate incorporation method
intake ("eaters only") of enzyme modified stevia, stevioside and the pre-incubation method (Uhde, 2004). In a standard
20% from use as a flavor ingredient to be 4400 µg/person/day. mouse micronucleus bone marrow assay, groups of 63 male
The Panel considered the identity description of the material mice were injected intraperitoneally with 175, 350, or 700 mg
to be adequate for FEMA GRAS evaluation (see Appendix 1). per kg bw of the structurally related substance, N-(heptan-4-
The Panel evaluated sensory data included within the yl)benzo[d][1,3]dioxole-5-carboxamide (FEMA 4232). No
application and found it satisfactory with regard to intended statistically significant differences were observed in the
conditions of use for the flavoring ingredient (Harman and number of polychromatic erythrocytes with micronuclei
Hallagan, 2013). The Panel concluded that metabolic data between each of the test groups and the negative control
exist for a representative members of the principal congeneric (Pucaj, 2004). Based on these assays, the structure of the
group that indicate, in the context of anticipated levels of substance and the arrangement and identity of the functional
intake, that the group would be expected to be metabolized groups therein, the Panel did not identify specific concerns
primarily by well-established detoxication pathways to related to the genotoxicity of (E)-3-(3,4-dimethoxyphenyl)-N-
innocuous products (Gardana et al., 2003; Geuns, 2003; [2-(4-methoxyphenyl)ethyl]-acrylamide. Toxicity studies for
Geuns et al., 2003; Koyama et al., 2003a; Koyama et al., structurally related substances have resulted in NOAEL
2003b; Nikiforov et al., 2013; Purkayastha et al., 2015; values that are, at minimum, greater than 2000 times the
Purkayastha et al., 2016; Purkayastha et al., 2014; Roberts anticipated daily per capita intake of (E)-3-(3,4-
and Renwick, 2008). Negative results were obtained in Ames dimethoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-acrylamide
assays for rebaudioside A at levels of up to 10 to 50 mg/plate from use as a flavor ingredient.
with and without metabolic activation (Rumelhard et al.,
2016). Rebaudioside A did not induce chromosome The Panel reviewed the GRAS application and supporting
aberrations in vitro in Chinese hamster lung fibroblasts with or information regarding Cordyceps sinensis fermentation
without metabolic activation at levels of up to 5 mg/mL product (CAS 1883732-47-5) and concluded that the material
(Williams and Burdock, 2009). An in vivo mouse micronucleus is GRAS (FEMA 4878) for use as a flavor ingredient in the
study with rebaudioside A at dose levels up to 2,000 mg/kg food categories and at the use levels specified in the GRAS
bw, administered once daily for 2 days by gavage, was application (see Table 2). This material was evaluated within
negative (Nakajima, 2000). Based on these assays and the the context of the procedure for the safety evaluation of
composition of the material therein, the Panel did not identify natural flavor complexes (Smith et al., 2005b). The Panel
specific concerns related to the genotoxicity of glucosylated calculated the anticipated per capita intake ("eaters only") of
rebaudioside A. A 90-day study of rebaudioside A Cordyceps sinensis fermentation product from use as a flavor
administered to Sprague-Dawley rats via the diet resulted in a ingredient to be 100 µg/person/day, which is below the
NOAEL of 2,000 mg/kg bw/day (Rumelhard et al., 2016). The threshold of toxicological concern for structural class III (90
resulting NOAEL of 2000 mg/kg bw/day is 27,200 times the µg/person/day) (Munro et al., 1996). The Panel considered
anticipated daily per capita intake of enzyme modified stevia, the identity description of the material to be adequate for
stevioside 20% from use as a flavor ingredient. FEMA GRAS evaluation (see Appendix 1). The Panel
evaluated sensory data included within the application and
The Panel reviewed the GRAS application and supporting found it satisfactory with regard to intended conditions of use
information regarding (E)-3-(3,4-dimethoxyphenyl)-N-[2-(4- for the flavoring ingredient (Harman and Hallagan, 2013).
methoxyphenyl)ethyl]-acrylamide (CAS 76733-95-4) and Metabolic data exists for representative members of each
concluded that the substance is GRAS (FEMA 4877) (Smith congeneric group of Cordyceps sinensis fermentation product
et al., 2005a) for use as a flavor ingredient in the food that would predict, at the levels of intake proposed,
categories and at the use levels specified in the GRAS metabolism by well-established detoxication pathways to
application (see Table 2). The substance was evaluated innocuous products (Miao et al., 2014). Cordyceps sinensis
individually within the context of the chemical group of fermentation product did not produce any evidence of
aliphatic and aromatic amines and amides (SLR A7; C21; mutagenicity in an Ames assay in S. typhimurium strains
TA98, TA100, TA1535 and TA1537 and E. coli strain WP2 Bhalli, J., Phil, M., 2014a. cis-3-hexenol (CAS # 928-96-1):
uvrA in the absence and presence of S-9 metabolic activation Bacterial reverse mutation assay: plate incorporation method
(Soni and Langan, 2018). Cordyceps sinensis did not with a confirmatory assay. Study no. 8289058. Covance
increase the number of micronucleated cells relative to Laboratories Inc., Greenfield, IN, USA. Unpublished report
vehicle controls in an in vitro micronucleus study in human provided by the Research Institute for Fragrance Materials to
peripheral blood lymphocytes in the absence and presence of the FEMA Expert Panel.
S-9 metabolic activation (Soni and Langan, 2018). Based on
these assays, and the composition of the material therein, the Bhalli, J., Phil, M., 2014b. cis-3-hexenol (CAS # 928-96-1): In
Panel did not identify specific concerns related to the vitro micronucleus assay in human peripheral blood
genotoxicity of Cordyceps sinensis fermentation product. lymphocytes. Study no. 8289135 Covance Laboratories Inc.,
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GRAS 28

4817 S-[(Methylthio)methyl]thioacetate 4835 2,4-Dihydroxy-N-[(4-hydroxy-3-methoxyphenyl)methyl]

4818 trans-1-Ethyl-2-methylpropyl 2-butenoate 4836 10% solution of 3,4-dimethyl-2,3-dihydrothiophene-2-thiol

4819 Erythritol 4837 Chrysanthemum parthenium extract

4820 Purified Damar Gum 4838 Valencene 80 extract

4821 gamma-Aminobutyric acid:Linoleic acid conjugates 4839 Mixture of 3- and 4-butyl-2-thiophenecarboxyaldehyde

4822 2,6-Dipropyl-5,6-dihydro-2H-thiopyran-3-carboxaldehyde 4840 (±)-Tetrahydronootkatone

4825 E-6-Nonenal 4843 3-(Allyldithio)butan-2-one

4826 3-Phenylpropyl 2-(4-hydroxy-3-methoxyphenyl)acetate 4844 (2E,4E)-2,4-Decadien-1-ol acetate

4827 1-(4-Methyl-3-cyclohexen-1-yl)-ethanone 4845 Glucosylated stevia extract

4830 7,8-Dihydroxyflavone 4849 Lime terpenes

4831 Katemfe fruit extract 4850 Orange terpenes

4832 2-(3-Benzyloxypropyl)pyridine 4851 Grapefruit terpenes

4853 Petitgrain oil terpeneless 4869 4-(l-Menthoxy)-2-butanone

4859 Sikuwasya oil (Citrus depressa)

4861 Mikan oil (Citrus unshiu)

4862 Yuzu oil (Citrus junos (Sieb.) c. Tanaka)

4863 Sudachi oil (Citrus sudachi hort. ex Shirai)

4864 Kabosu oil (Citrus sphaerocarpa)

4865 Ponkan oil (Citrus reticulata Blanco ‘Ponkan’)

4866 Orange essence water phase (Citrus sinensis (L.) Osbeck)

Baked Goods 0.5/1 0.4/4 0.02/0.5 1/4 0.3/1 0.001/0.01

Beverages, 0.2/2 100/200 0.0002/0.005 0.03/10 0.3/2 0.00001/0.0001 3/15

Breakfast 0.4/4 0.02/0.5 1/4 0.3/1 0.001/0.01

Cheeses 0.5/1 0.1/0.5 0.02/0.5 1/4 0.001/0.01

Chewing Gum 0.5/5 0.02/0.5 10/100 1/5 0.0001/0.001 25/100

Condiments 0.01/0.25 1/4 5/40

Confections 0.4/4 0.01/0.25 0.3/30 0.5/2 0.0001/0.001

Egg Products 0.01/0.25 0.0001/0.001

Fats and Oils 0.5/1 0.02/0.5 1/4 0.3/1 0.01/0.1

Fish Products 0.01/0.25 1/4 0.0001/0.001

Frozen Dairy 0.5/5 0.01/0.5 0.5/50 0.1/0.5 0.0001/0.001

Fruit Ices 0.2/2 5000/12500 0.01/0.25 0.05/5 0.1/0.5 0.0001/0.001

Gelatins and 0.2/2 0.01/0.25 0.2/10 0.1/0.5 0.0001/0.001

Gravies 0.3/1 0.01/0.25 1/4 0.001/0.01

Hard Candy 0.4/4 0.02/0.5 0.5/50 0.5/2 0.001/0.01 5/20

Imitation Dairy 0.02/0.5 0.05/5 0.001/0.01

Jams and 1/5 0.01/0.25 0.5/20 0.3/1

Meat Products 0.5/1 0.02/0.5 1/4 0.0001/0.001 5/40

Milk Products 0.2/2 0.01/0.25 0.05/5 1/4 0.1/0.5 0.00001/0.0001 2/10

Nut Products 0.002/0.05 1/4 0.0001/0.001

Other Grains 0.002/0.05 1/4 0.0001/0.001

Poultry 0.5/1 0.02/0.5 1/4

Processed 0.4/4 5000/12500 0.01/0.25 0.05/5 0.1/0.5

Processed 0.5/1 0.01/0.25 0.5/4

Reconstituted 0.01/0.25 0.5/4

Seasonings 0.5/1 0.2/2 0.01/0.25 0.5/20 1/4 0.1/0.5 0.1/1.0 50/300

Snack Foods 0.5/2 0.2/2 0.01/0.25 1/4 0.1/0.5 0.0001/0.001 5/40

Soft Candy 0.4/4 0.01/0.25 0.2/5 0.5/2 0.0001/0.001

Soups 0.2/1 0.01/0.25 1/4 0.0001/0.001 5/20

Sweet Sauces 0.2/2 0.005/0.15 0.2/10 0.5/2

Katemfe fruit extract

Baked Goods 0.5/1.5 0.1/0.5 5/20 4/10 1/10 0.04/0.4

Beverages, 0.5/2.5 5/20 5/15 4/10 30/50 15/20 0.03/0.15 30/60

Breakfast 0.5/2.5 0.1/0.2 5/20 4/10 10/100

Cheeses 0.2/2.5 0.1/0.3 5/20 4/10 1/10 0.01/1

Condiments 0.2/2.5 0.2/3 5/20 10/30 4/10 0.01/1 50/200

Confections 0.5/2.5 10/40 4/10 30/50 15/20 0.03/0.3

Egg Products 0.05/0.25 5/20 4/10 0.2/2