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GRASFLAVORINGSUBSTANCES27FEMA EXPERT PANEL: S.M. COHEN, S. FUKUSHIMA, N.J. GOODERHAM, S.S. HECHT, L.J. MARNETT,I.M.C.M. RIETJENS and R.L. SMITH

27. GRAS FLAVORING SUBSTANCES: This list of substances will appear in the 27th publicationauthored by the Expert Panel of the Flavor and Extract Manufacturers Association on recent progress inthe consideration of flavoring ingredients generally recognized as safe (GRAS) under conditions of theirintended 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 onthe FEMA website.

DISCLAIMER: The user of this list agrees that its use of this document and the information contained therein

is at the users sole risk and that FEMA shall have no liability to any person for any loss or damage arising outof the use of this document.

CHANGE IN GRAS STATUS OF QUINOLINE, ETHYLENE OXIDE, AND STYRENE: The FEMA GRASstatuses of quinoline (FEMA No. 3470), ethylene oxide (FEMA No. 2433), and styrene (FEMA No. 3233)under their conditions of intended use as flavor ingredients were reviewed. For quinoline, the Expert Panelconcluded that additional data, including in vivo genotoxicity and chronic toxicity testing, were required to

support the continuation of its GRAS status. Until such data are available for review, the flavor ingredientquinoline has been removed from the FEMA GRAS list. There is little evidence that ethylene oxide or styreneare used for the technical effect of flavoring; based on this lack of evidence, the Panel concluded that both

ethylene oxide and styrene should be removed from the FEMA GRAS list.

http://www.femaflavor.org/grashttp://www.femaflavor.org/gras

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FEMA NO. S UBST ANCE PRIMAR Y NAME AND S YNO NY MS FEMA NO . S UBS TANCE PRIMAR Y NAMES AND S YNONY MS

4779 () -2 -Me rca pto -5 -me th yl he pt a n-4-o ne

()-5-Methyl-2-sulfanylheptan-4-one

4780 Ca ry ophy ll a-3(4) ,8-d ie n -5 -ol

Mixtureof 10,10-Dimethyl-2,6-dimethylenebicyclo[7.2.0]-undecan-5-ol and4,11 ,11-Trimethyl-8-methylenebicyclo[7.2.0]undec-3-en-5-ol

4781 L-Cy st ei ne m et hy l es te r hy droch lo ride

Methyl(R)-2-amino-3-mercaptopropanoatehydrochloride

4 78 2 2 (3 )- He xa ne th io l

4783 Mixture of 1-Vinyl-3-cyclohexenecarbaldehydeand 4-Vinyl-1-cyclohexenecarbaldehyde

Mixtureof 1-Ethenyl-3-cyclohexene-1-carboxaldehydeand4-Ethenyl-1-cyclohexene-1-carboxaldehyde

4784 () -4-Hydroxy-6 -m e th yl -2 -h e pt a no ne

4 78 5 2- Oc ty l- 2- do de ce na l

4 78 6 2- He xy l-2 -d ec en al

4787 trans-6-Octenal

(E)-6-Octenal(6E)-Octenal

4788 (E)-3-Ben zo [1 ,3] d io xo l-5 -y l-N,N-diphenyl-2-propenamide

(2E)-3-(1,3-benzodioxol-5-yl)-N,N-diphenylprop-2-enamide

4 78 9 2 ,6 -D im et hy l- 5- he pt en ol

4790 () -Bi cyclo [ 2.2 .1] he pt-5 -e ne -2-carboxylic acid, ethyl ester

()-Ethylbicyclo[2.2.1]hept-5-ene-2-carboxylate()-5-Norbornene-2-carboxylicacid, ethylester

4 79 1 3 -( Ac et yl th io )h ex an al

4 79 2 ( ) -3 -M er ca pt o- 1- pe nt an ol

4793 (3R,3S)-3-[[(4-Amino-2,2-dioxido-1 H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]- N-cyclopentyl-2-oxo-3-piperidinecarboxamide

(3R,3S)-3-[[(4-Amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]-N-cyclopentyl-2-oxopiperidine-3-carboxamide

4 79 4 ( ) -1 -C yc lo he xy le th an ol

()-Methylcyclohexylcarbinol()-Cyclohexanemethanol

4 79 5 () -8 -M et hy ld ec an al

4 79 6 S te vi ol g l yc os id e e xt ra ct ,Steviarebaudiana, Rebaudioside C 30%

47 97 () -N ar ingenin

()-5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-chroman-4-one

4798 2 -( ((3 -(2,3 -D im et ho xyphe ny l) - 1H-1,2,4-triazol-5-yl)thio)methyl)pyridine

2-((5-(2,3-Dimethoxyphenyl)-2H-1,2,4-triazol-3-ylthio)methyl)pyridine2-(((3-(2,3-dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine

4799 (2R)-3,5-Dihydroxy-4-methoxyflavanone

4 800 Gluc osylated Rubus suavissimusextract20-30% glucosylated rubusoside glycosides

GlucosylatedSweet Blackberry leaves extract20-30%glucosylated rubusosideglycosides

4 80 1 O li ve f ru it ex tr ac t

Olea europaea fruitextract

4802 (S)-1-(3-(((4-Amino-2,2-dioxido-1 H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one

1-[(3S)-3-[[(4-Amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]-1-piperidinyl]-3-methyl-1-butanone

4 80 3 8 -M et hyl non an al

Isodecanal

4804 Mixture of Ricinoleic acid, Linoleic acid, and Oleic acid

4805 S te v io l g ly co s ide e xtra ct ,Steviarebaudiana,RebaudiosideA22%

4806 S te v io l g ly co s ide e xtra ct ,Steviarebaudiana,RebaudiosideC22%

4 80 7 P in oc ar vy l a ce ta te

6,6-Dimethyl-2-methylenebicyclo[3.1.1]hept-3-ylacetate

4808 N-Ethyl-5-methyl-2-(1-methylethenyl)cyclohexanecarboxamide

N-Ethyl-5-methyl-2-(prop-1-en-2-yl)cyclohexanecarboxamide

4 80 9 2 -( 4- Me th yl ph en ox y) -N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide

N-(1H-Pyrazol-5-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide

4810 Ethyl-2-(4-hydroxy-3-methoxyphenyl)acetate

Ethylho movanillateEthyl4-hydroxy-3-methoxyphenylacetate

4 81 1 G inger M int Oil (Mentha x gracilis)

RedstemmedmintoilVietnamesemintoil

4812 Pa lm it oy la te d Gre e n Te a Ext ract Cat ech in s

PalmitoylatedCamilla sinensisExtract CatechinsLipidSoluble Green Tea Extract(Catechin PalmitateEsters)

4813 2 - (5 - Is opropyl -2 -m et hy l- te tra hy dro -thiophen-2-yl)-ethanol

4 81 4 G luc os ylate dRubus suavissimusextract,60% glucosylated rubusoside glycosides

GlucosylatedSweet Blackberry Leaves Extract60%gluco sylatedrubusoside glycosides

4815 S an dal woo d a u st roca le don icu m o il

Santalum austrocaledonicumoil

4 81 6 S ug ar C an e d is ti ll at e

TABLE 1:Primary Names & SynonymsPrimary names (in boldface) & Synonyms (in lightface)

TABLE 2:Average Usual Use Levels/Average Maximum Use LevelsAverage Usual Use Levels (ppm)/Average Maximum Use Levels (ppm) for new FEMA GRAS Flavoring Substances on which theFEMA Expert Panel based its judgments that the substances are generally recognized as safe (GRAS).

()-2-Mercapto-5-

methylheptan-4-one

Caryophylla-

3(4),8-dien-5-ol

L-Cysteinemethyl

esterhydrochloride

2(3)-Hexanethiol

Mixtureof1-Vinyl-

3-cyclohexenecarb-

aldehydeand4-Vinyl-

1-cyclohexenecarb-

aldehyde

()-4-Hydroxy-

6-methyl-2-

heptanone

2-Octyl-2-

dodecenal

2-Hexyl-2-decenal

trans-6-Octenal

CATEGORYFEMA N.

47794780 4781 4782 4783 4784 4785 4786 4787

B G 0.03/0.1 0.1/1 10/100 0.02/0.06 50/100 0.1/1 0.1/1 0.1/1

B,N-A

0.01/0.1 1/5 0.005/0.03 5/10 30/80 1/5 1/5 0.03/0.3

B,A

0.02/0.1 1/5 0.005/0.03 30/80 1/5 1/5 0.03/0.3

BC

0.03/0.1 0.1/1 0.01/0.04 40/100 0.1/1 0.1/1

C 0.1/1 10/100 0.1/1 0.1/1 0.1/1

C G 0.1/0.2 1/5 0.02/0.06 100/1000 60/100 1/5 1/5 0.1/1

C R

0.01/0.1 0.1/1 10/100 0.02/0.06 0.1/1 0.1/1

C F

0.05/0.1 1/5 0.02/0.06 5/50 1/5 1/5 0.1/1

E P 0.1/1 10/100 0.015/0.05 0.1/1 0.1/1 0.05/1

F O 0.1/1 0.1/1 0.1/1 0.03/0.5

F P 0.1/1 10/100 0.1/1 0.1/1

F D 0.05/0.1 0.1/1 0.02/0.06 50/100 0.1/1 0.1/1 0.1/1

F I 0.005/0.05 1/5 0.01/0.04 1/5 1/5

G P

0.03/0.1 1/5 10/100 0.015/0.04 40/100 1/5 1/5 0.1/1

GS

0.1/5 0.1/1 0.1/1

G 0.01/0.1 0.1/1 10/100 0.02/0.06 0.1/1 0.1/1 0.02/0.5

H C 0.1/0.2 1/5 0.02/0.05 5/50 50/100 1/5 1/5 0.05/1

I D 0.1/1 0.1/1 0.1/1 0.1/1

I C T

0.1/1 10/100 0.02/0.06 50/100 0.1/1 0.1/1 0.03/0.5

J J 1/5 0.02/0.06 1/5 1/5

M P 0.1/1 10/100 0.02/0.08 0.1/1 0.1/1

M P 0.1/1 0.005/0.04 40/80 0.1/1 0.1/1 0.2/2

N P 0.1/1 0.01/0.04 0.1/1 0.1/1 0.05/0.2

O G 0.1/1 0.01/0.06 0.1/1 0.1/1

P 0.1/1 10/100 0.1/1 0.1/1

P F 0.02/0.1 0.1/1 0.01/0.05 0.1/1 0.1/1

PV

0.1/1 10/100 0.1/1 0.1/1

RV

0.1/1 10/100 0.1/1 0.1/1

S F

0.005/0.2 1/5 10/100 0.01/0.1 10/100 50/100 1/5 1/5 0.05/0.5

S F 0.02/0.1 0.1/1 0.01/0.06 0.1/1 0.1/1

S C 0.05/0.1 1/5 0.01/0.04 10/100 50/100 1/5 1/5 0.1/1

S 0.03/0.1 0.1/1 10/100 0.02/0.06 0.1/1 0.1/1 0.02/0.5

SS

0.1/1 0.1/1 0.1/1

S S 0.03/0.1 0.1/1 10/100 0.02/0.06 50/100 0.1/1 0.1/1 0.1/1

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2,6-Dimethyl-

5-heptenol

()-Bicyclo[2.2.1]

hept-5-ene-2-

carboxylicacid,

ethylester

3-(Acetylthio)

hexanal

()-3-Mercapto-

1-pentanol

(3R,3S)-3-[[(4-amino-

2,2-dioxido-1H-2,1,3-

benzothiadiazin-5-yl)

oxy]methyl]-N-

cyclopentyl-2-oxo-3-

piperidinecarboxamide

()-1-Cyclohexylethanol

()-8-Methyldecanal

Steviolglycoside

extract,Stevia

rebaudiana,

Rebaudioside

C30%

()-Naringenin

2-(((3-(2,3-Dimethoxyphenyl)-

1H-1,2,4-triazol-5-yl)

thio)methyl)pyridine

ATEGORY 4789 4790 4791 4792 4793 4794 4795 4796 4797 4798

G 1/10 0.5/1 0.5/3 2/10 3/8 2/20 30/90 200/600 2/6

,-A

1/5 0.2/1 0.1/1 1/6 5/8 0.5/5 20/75 100/300 1/2

,

1/5 0.2/1 2/8 0.5/5 20/75 100/300

1/5 0.5/1 0.5/2 1/8 3/8 1/5 30/90 200/600 5/10

1000/1000 2/6

G 2/20 0.5/2 1/5 3/10 10/27 1000/3000 2/10 100/125 200/400

R

200/400 5/10

F

2/10 0.4/2 3/8 50/100 2/10 20/75 200/400

P 0.2/2 0.2/2 2/6

O 1/10 0.02/0.5 1/10 100/200 4/8

P 4/10

D 1/2 0.3/1 0.5/1 1/8 2/8 1/2 20/75 100/500

I 1/2 0.3/1 2/8 30/60 0.5/5 20/75 100/200

1/10 0.2/1 2/8 1/10 20/75 100/400

0.05/2 1/8 2/8 20/50 100/500 4/10

C 1/10 0.4/2 5/8 100/300 1/10 100/400

D 1/10 1/10 20/75 100/500

C T

1/10 0.02/1 1/8 2/8 1/10 100/200

J 1/10 0.4/2 0.02/1 1/8 1/10 20/75 100/400

P 0.05/0.5 2/8 10/20 100/200 4/10

P 1/5 0.02/1 1/8 3/8 1/5 30/90 100/500

P 50/100 2/6

G 2/6

100/200 2/6

F 0.1/1 50/400

50/100 2/6

50/100 2/6

F

1/10 0.2/1 2/8 1/10 20/50 500/1000 10/20

F 1/10 0.02/1 1/6 2/8 1/10 200/400 10/20

C 1/10 0.3/2 5/8 50/200 1/10 100/400

1/10 0.05/0.8 2/8 1/10 100/300 4/8

100/200

S 3/8 100/400

TABLE 2 Continued:Average Usual Use Levels/Average Maximum Use LevelsAverage Usual Use Levels (ppm)/Average Maximum Use Levels (ppm) for new FEMA GRAS Flavoring Substances on which theFEMA Expert Panel based its judgments that the substances are generally recognized as safe (GRAS).

TABLE 2 Continued:Average Usual Use Levels/Average Maximum Use LevelsAverage Usual Use Levels (ppm)/Average Maximum Use Levels (ppm) for new FEMA GRAS Flavoring Substances on which theFEMA Expert Panel based its judgments that the substances are generally recognized as safe (GRAS).

(2R)-3,5-Dihydroxy-

4-methoxyflavanone

GlucosylatedRubus

suavissimusextract

20-30%g

lucosylated

rubusosideglycosides

Olivefruitextract

(S)-1-(3-(((4-Amino-

2,2-dioxido-1H-

benzo-[c][1,2,6]

thiadiazin-5-yl)-oxy)

methyl)-piperidin-1-yl)-

3-methylbutan-1-one

8-Methylnonanal

MixtureofRicinoleic

acid,Linoleicacid,

andOleicacid

Steviolglycoside

extract,Stevia

rebaudiana,

RebaudiosideA22%

Steviolglycoside

extract,Stevia

rebaudiana,

RebaudiosideC22%

Pinocarvylacetate

CATEGORY 4799 4800 4801 4802 4803 4804 4805 4806 4807

B G 120/720 6/6 2/20 5/20 70/70 100/100

B,N-A

20/25 150/350 120/720 2.5/6 0.5/10 1/5 70/70 110/110 0.1/5.0

B,A

20/25 75/200 120/720 2.5/6 0.5/10 1/5 70/70 100/100 0.5/7.5

BC

20/25 150/400 120/720 6/6 1/10 1/5 70/70 100/100

C 120/720 5/20

C G 6/6 2/20 1/5 70/70 100/100 0.5/7.5

C R

120/720 6/6 5/10 70/70 100/100

C F

20/25 6/6 2/20 1/5 70/70 100/100 0.5/7.5

E P 120/720 0.2/2 1/10 70/70

F O 120/720 3/6 1/20 10/50 70/70 100/100

F P 120/720 1/5

F D 200/300 120/720 3/6 1/5 1/5 70/70 100/100 0.1/5.0

F I 100/300 3/6 0.5/5 1/5 70/70 100/100

G P

3/6 1/10 1/5 70/70 100/100

GS

G 100/150 120/720 3/6 5/20 70/70 100/100

H C 20/25 3/6 1/20 1/5 70/70 100/100 0.5/7.5

I D 2.5/6 1/10 5/20 70/70 100/100 0.1/5.0

I C T

20/25 150/350 2.5/6 1/10 1/5 70/70 100/100

J J 20/25 6/6 1/10 1/5 70/70 100/100

M P 100/150 120/720 5/20

M P 20/25 200/300 120/720 2.5/6 1/10 5/20 70/70 100/100 0.1/5.0

N P 120/720 3/6 1/5 70/70 100/100

O G

P 120/720 5/25

P F 3/6 1/5 70/70 100/100

PV

1/5 70/70 100/100

RV

1/5

S F

100/150 120/720 1/10 5/50 70/70 100/100

S F 20/25 120/720 6/6 1/10 5/50 70/70 100/100

S C 20/25 6/6 1/10 1/5 70/70 100/100 0.5/7.5

S 100/150 120/720 3/6 1/10 5/25 70/70 100/100

SS

20/25 1/5 70/70 100/100

S S 20/25 120/720 3/6 1/5 70/70 100/100

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TABLE 2 Continued:Average Usual Use Levels/Average Maximum Use LevelsAverage Usual Use Levels (ppm)/Average Maximum Use Levels (ppm) for new FEMA GRAS Flavoring Substances on which theFEMA Expert Panel based its judgments that the substances are generally recognized as safe (GRAS).

TABLE 3:Updated Average Usual Use Levels/Average Maximum Use LevelsAverage usual use levels (ppm)/average maximum use levels (ppm) for flavoring substances p reviously recognized as FEMA GRAS.Superscript arepresents a new use level.

2-(4-Methylphenoxy)-

N-(1H-pyrazol-3-yl)-N-

(thiophen-2-ylmethyl)

acetamide

Ethyl-2-(4-hydroxy-3-

methoxyphenyl)acetate

GingerMintOil

(Menthaxgracilis)

PalmitoylatedGreen

TeaExtractCatechins

2-(5-Isopropyl-2-

methyltetrahydro-

thiophen-2-yl)ethanol

Glucosylated

Rubusextract,

60%g

lucosylated

rubusosideglycosides

Sandalwood

Austrocaledonicumoil

SugarCaneDistillate*

ATEGORY 4809 4810 4811 4812 4813 4814 4815 4816

G 25/200 100/200 0.2/2 30/150 5/10 0.01(2250)/0.01(2250)*

,-A

1/3 10/75 0.05/2 30/150 1/2

,

2/6 10/75 0.1/2 30/150 0.5/1

50/75 0.2/2 30/150

G 75/150 100/500 4000/8000 0.5/5 30/150 3/3

R

25/200 100/200

F

5/15 250/1000 50/100 0.5/5 30/150 0.01(2250)/0.01(2250)*

P 0.1/2

O 1/3 200/500 0.2/5

P 250/300

D 1/3 25/100 250/1000 0.1/2 50/150 3/4

I 1/3 25/100 0.05/2 50/150

1/3 0.2/5 30/150 0.3/1

0.2/5

C 5/15 25/100 2500/5000 0.5/5 90/90

D 1/3 0.2/5

C T

1/3 10/75 0.2/5 30/150

J 0.2/5

P 25/100 250/300

P 1/3 10/100 0.1/5 50/150

P 50/100

G 150/300

250/300

F 30/150

F

50/300 0.1/2

F 25/200 100/200 0.1/2 30/150 0.01(2250)/0.01(2250)*

C 5/15 2500/5000 50/100 0.2/5 30/150 5/10

1/3 25/100 100/200 0.2/5 30/150

30/150

S 5/15 30/150 0.01(2250)/0.01(2250)*

*Figures in parentheses represent the amount of diluted aqueous Sugar Cane Distillate in the commercial product as used in food.

Potassiumcinnamate

Quillaiaextract

Glycine

N-(Heptan-4-yl)

benzo[d][1,3]dioxole-

5-carboxamide

3-[(4-Amino-2,2-

dioxido-1H-2,1,3-

benzothiadiazin-5-yl)

oxy]-2,2-dimethyl-N-

propylpropanamide

Glutamyl-valyl-glycine

LuoHanFruit

Concentrate

FEMA NO. 2288 2973 3287 4232 4701 4709 4711

GRAS PUBLICATION 3 3 4 22 25 25 25

CATEGORY

B G 233/384 24/30 50/150 1/2 10/22 15/30 40/60

B, N-A

300/400 91.5/103 250/1000 2/5 0/0 20/50 40/60

B,A

570/712 90/100 2a/5a 5a/22a 40/60

B C 15a/75a 15/22 80/160 40/80

C 15a/75a 1/3 20/50

C G 224a/300 7.5a/30a 30/300 10a/30a 200a/400a

C R

15a/75a 150/3000a 2/4 3/22 30/60 5/40

C F

7.5a/30a 10/22 40/80

E P 7.5a/30a 2a/5a 15/45

F O 746a/1000a 2/4 30/60

F P 7.5a/30a 1/3 15/45

F D 192/263 15a/75a 5/22 20/50 5/80

F I 7.5a/30a 5/22 20/50 5/40

G P

459a/500a 7.5a/30a 5/22 40/80

G S

G 746a/1000a 7.5a/30a 150/4000a 2/4 30/60 5/40

H C 0.01/0.01 18/30a 25/150 15/75 40/80

I D 7.5a/30a 50/150 20/50 5/40

I C T

224a/300a 1.5a/30a 150/150 10/30

J J 373a/500a 7.5a/30a 10/22 10/40

M P 7.5a/75a 1/3 15/45

M P 1.5a/30a 3/22 15/45 40/80

N P 30a/120a 2a/5a 5/40

O G 7.5a/30a

P15

a

/75

a

1/3 15/45P F 37a/50a 1.5a/30a 5/40

PV

7.5a/30a 1/3 15/45

RV

7.5a/30a 2a/5a 15/45

S F

15a/75a 5/10 80/160 5/40

S F 15a/75a 5/10 80/160 5/40

S C 249/356 16a/30a 25/150 15/75 40/80

S 15a/75a 150/6000a 2/4 20/50

S S 746a/1000a 7.5a/30a 80/160

S S 746a/1000a 15a/75a 10/22 30/60 5/40

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FEMANO.

FEMA PRIMARY NAME THE IDENTIT Y DESCRIPTION AS REVIE WED BY THE FEMA EXPERT PANEL

4796 Steviol glycoside extract, Steviarebaudiana, Rebaudioside C 30%

Total steviol glycosides >95%, including 28-33% rebaudioside C, 17-23%rebaudioside A, 10-15% stevioside, 25-36% other steviol glycosides (includingrebaudiosides B, D, E and F, steviolbioside, rubusoside and dulcoside A).

4800 Glucosylated Rubus suavissimusextract20-30% glucosylated rubusoside glycosides

20-30% Multiply-glucosylated rubusoside glycosides; 25% glycerol;up to 10% other carbohydrates; no more than 25% water.

4801 Olive fruit extract 65-67% Phenolic derivatives (primarily measured as hydroxytyrosoland tyrosol); 9-10% saturated alicyclic primary alcohols, aldehydes,acids and related esters; the intended condition of use is as amixture of 12% olive fruit extract and 88% maltodextrin.

4805 Steviol glycoside extract, Steviarebaudiana, Rebaudioside A 22%

Total principal steviol glycosides 60-63%, including 18-22% rebaudiosideA, 5-8% stevioside, 8-14% rebaudioside D; rebaudiosides B, C, E, F, N,O, M, steviolbioside, rubusoside, and dulcoside A individually present atconcentrations up to 6%. Additional steviol glycosides, 36-42%.

4806 Steviol glycoside extract, Steviarebaudiana, Rebaudioside C 22%

Total principal steviol glycosides 56-59%, including 13-22% rebaudiosideC, 13-18% rebaudioside A, 5-8% stevioside; rebaudiosides B, D, E, F, N,O, and M, steviolbioside, rubusoside and dulcoside A individually presentat concentrations up to 4%. Additional steviol glycosides, 38-45%.

4811 Ginger Mint Oil (Mentha x gracilis) 4 3-6 5% Aliphatic ter tiar y a lcohols, typically measured as linalool; 23-4 8%aliphatic and aromatic hydrocarbons; 1-4% alicyclic monoterpene secondaryalcohols and ketones, typically measured as l-menthone or l-menthol.

4812 Palmitoylated Green Tea Extract Catechins 74-86% Catechin mono-, di- and tri-palmitate esters derived from green tea; 14-15%palmitic acid; no individual free catechin present at concentrations above 1%.

4814 Glucosylated Rubus suavissimusextract60% glucosylated rubusoside glycosides

60-70% Multiply-glucosylated rubusoside glycosides;7-8% rubusoside; 20-30% dextrins.

4815 Sandalwoo d aus tr oc al ed onic um oi l 80-85% Ali cyc li c p ri mary al co ho ls , a ld ehyd es and aci ds , typ ic al ly meas ur ed assantalol derivatives; 4-5% aliphatic and aromatic hydrocarbons; 2-4% aliphaticand aromatic tertiary alcohols; 0.5-1.5% aliphatic and aromatic ethers.

4816 Sugar Cane Distillate Aqueous solution of 0.0005% sugar cane distillate of which the major markerconstituents are phenyl-substituted secondary ketones alcohols and relatedesters, primarily measured as beta-damascenone and acetophenone.

Supplementary Information 1:Identity for Natural Flavor Complexes as Evaluated by theExpert Panel

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Supplementary Information 2. Key Findings of the FEMA Expert Panel Safety Evaluations for GRAS 27

Since its initial publication of GRAS determinations forflavor ingredients (Hall and Oser, 1965), the FEMA ExpertPanel has consistently made available to the publicinformation on its determinations, including the conditionsof intended use for individual flavor ingredients, and thescientific basis and information supporting thesedeterminations. Included herein are the key findings foreach of the GRAS determinations included within GRAS

27.1 Comprehensive monographs of the informationrelevant to the evaluations are also published as part of theFEMA Expert Panels ongoing GRAS re-evaluation program(see Hallagan and Hall, 2009). For more information on theFEMA GRAS program, please see About the FEMA GRASProgramon femaflavor.org.

The Panel reviewed the GRAS application and supportinginformation regarding ()-2-mercapto-5-methylheptan-4-one (CAS 1416051-88-1) and concluded that it is GRAS(FEMA 4779) for use as a flavor in the food categories andat the use levels specified in the GRAS application (seeTable 2; Smith et al., 2005a). This substance was evaluatedindividually within the context of the chemical group ofsimple aliphatic and aromatic thiols and sulfides (SLR B5,JECFA 2000, 2004, 2008, 2011, 2012). The Panel noted

that based on an anticipated annual volume of use of 0.5 kg,the per capita intake ("eaters only") of ()-2-mercapto-5-methylheptan-4-one from use as a flavor ingredient iscalculated to be 0.07 g/person/day (0.001 g/kgbw/day), which is significantly below the threshold oftoxicological concern for structural class I (1800g/person/day) (Munro et al., 1996). The substancenaturally occurs in hazelnut, but only qualitative data areavailable and, thus, no consumption ratio can be calculated.The Panel considered the specification of the material to beadequately characterized by the purity assay andsupporting spectral data provided for FEMA GRASevaluation. Based on the functional groups present, thesubstance is anticipated to be metabolized primarily byreductive metabolism of the ketone moiety and/oroxidation of a terminal methyl group to an alcohol, followed

by glucuronic acid conjugate formation and excretion in theurine (Parkinson, 1996). Based on the lack of structuralalerts of the substance and the identity and arrangement offunctional groups therein, the Panel identified no specificconcerns related to the potential genotoxicity of thesubstance. A No-Observed-Adverse-Effect Level (NOAEL)of 1.89 mg/kg bw/day in a 12-week toxicity study of maleand female rats for the structural analog 3-mercapto-2-pentanone is more than 1,500,000 times greater than theanticipated daily per capita intake of ()-2-mercapto-5-methylheptan-4-one from its intended use as a flavoringredient in food (Morgareidge, 1971).

The Panel reviewed the GRAS application and supportinginformation regarding caryophylla-3(4),8-dien-5-ol (CAS34298-31-2; 38284-26-3) and concluded that it is GRAS

(FEMA 4780) for use as a flavor in the food categories andat the use levels specified in the GRAS application (seeTable 2; Smith et al., 2005a). This substance was evaluatedindividually within the context of the chemical group ofalicyclic ketones, secondary alcohols and related esters(SLR A5; JECFA 2004) The Panel noted that based on theanticipated annual volume of use (50 kg) the per capitaintake ("eaters only") of caryophylla-3(4),8-dien-5-ol from

1These key findings are subject to change pendingadditional information

use as a flavor ingredient is calculated to be 7g/person/day (0.1 g/kg bw/day), which is below thethreshold of toxicological concern for structural class I(1800 g/person/day) (Munro et al., 1996). The substancenaturally occurs in clary sage, clove bud, pepper and scotchspearmint oil, but only qualitative data is available and, thus,no consumption ratio can be calculated (Nijssen et al.2015). The Panel considered the specification of the

material to be adequately characterized by the purity assayand supporting spectral data provided for FEMA GRASevaluation. The substance is anticipated to be metabolizedin a manner analogous to that of other terpene alcohols: thisis expected to involve either conjugation of the secondaryalcohol with glucuronic acid or sulfate followed by excretionin the urine, or epoxidation of the exo-alkene moietiesfollowed by ring opening to yield polyols that are excreted inthe urine unchanged or after glucuronic acid or glutathioneconjugation. Evidence of genotoxicity was not observed inan Ames assay with Salmonella typhimuriumstrains TA98,TA100, TA1535, TA1537 and TA1538 in the presence andabsence of metabolic activation for the structural analogbeta-caryophyllene epoxide (Richold et al., 1979). Based onthe data, and also the structure of the substance and theidentity and arrangement of functional groups therein, the

Panel did not identify specific concerns related to thepotential genotoxicity of caryophylla-3(4),8-dien-5-ol. ANOAEL of 109 mg/kg bw/day for male rats and 137 mg/kgbw/day for female rats in a 90-day oral feeding study of thestructural analog beta-caryophyllene oxide (FEMA 4085) ismore than 900,000 times the anticipated daily per capitaintake of caryophylla-3(4),8-dien-5-ol from use as a flavoringredient (Bauter, 2012; Capen et al., 1999).

The Panel reviewed the GRAS application and supportinginformation regarding L-cysteine methyl esterhydrochloride (CAS 18598-63-5) and concluded that it isGRAS (FEMA 4781) for use as a flavor in the food categoriesand at the use levels specified in the GRAS application (seeTable 2; Smith et al., 2005a). This substance was evaluatedwithin the context of the chemical group of amino acids and

related substances (SLR B3; JECFA 2006, 2012). The Panelnoted that based on the anticipated annual volume of use(100 kg) the per capitaintake ("eaters only") of L-cysteinemethyl ester hydrochloride from use as a flavor ingredientis calculated to be 15 g/person/day (0.3 g/kg bw/day),which is significantly below the threshold of toxicologicalconcern for structural class I (1800 g/person/day)(Munro et al., 1996). The substance has not been reportedto occur naturally. The Panel considered the specification ofthe material to be adequately characterized by the purityassay and supporting spectral data provided for FEMAGRAS evaluation. By analogy to other amino acid esters, thesubstance is anticipated to be metabolized primarily byhydrolysis to the corresponding acid, L-cysteine, and enterthe amino acid pool. Oxidation to methanol and resultingformaldehyde formation was not concluded to be

significant. Excretion would occur mainly in the urine(Hosokawa 2008; Fukami and Yokoi 2012; Nelson and Cox,2008). L-Cysteine showed some increase in humanlymphocyte sister chromatid exchange, but the results notdependent upon dose and were considered by the Panel tobe due to metabolic impact of administration of high dosesof an amino acid rather than genotoxic potential. The Panelnoted that this result may also be due to peroxide formation

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from trace metals, which is a common occurrence for aminoacids and is not considered to be biologically relevant tohumans. L-Cysteine did not induce chromosomalaberrations in V79 Chinese hamster fibroblasts atconcentrations up to 121 g/ml. Based on the negative CHOcell chromosomal aberration assays and the understandingof the role of metabolic impact on genotoxicity assays for L-cysteine, the Panel did not identify specific concerns related

to the potential genotoxicity of L-cysteine methyl esterhydrochloride (Xing and Na, 1996; Speit et al., 1980;Natarajan and van Kesteren-van Leeuwen, 1981; Stich et al.,1981; Tavares et al., 1998). In a 6-month male and female ratoral gavage study, the Panel concluded that the appropriateNOAEL was 100 mg/kg bw/day based on adaptive effectsat higher doses. This NOAEL is more than 400,000 timesthe anticipated daily per capitaintake of L-cysteine methylester hydrochloride from use as a flavor ingredient(Takasaki et al., 1973).

The Panel reviewed the GRAS application and supportinginformation regarding 2(3)-hexanethiol (CAS 1679-06-7/1633-90-5) and concluded that it is GRAS (FEMA 4782)for use as a flavor in the food categories at the new uselevels specified in the GRAS application (See Table 2; Smith

et al., 2005a). This substance was evaluated within thecontext of the chemical group of simple aliphatic andaromatic sulfides and thiols (SLR A8; JECFA 2000, 2004,2008, 2011, 2012). The Panel noted that based on theanticipated annual volume of 0.5 kg, the per capita intake("eaters only") of 2(3)-hexanethiol from use as a flavoringredient is calculated to be 0.07 g/person/day (0.001g/kg bw/day), which is below the threshold oftoxicological concern for structural class I (1800g/person/day) (Munro et al., 1996). The substancenaturally occurs in white truffles, but no quantitative data isavailable to calculate a consumption ratio (Nijssen et al.,2015). The Panel considered the specification of thematerial to be adequately characterized by the purity assayand supporting spectral data provided for FEMA GRASevaluation. Based on analogy to other aliphatic thiols, the

substance is anticipated to undergo S-methylation to yieldthe corresponding methyl sulfide that is then oxidized to thesulfoxide and subsequently the sulfone that is excretedunchanged in the urine. Additionally, omega-oxidation ofthe terminal methyl groups could occur leading to beta-oxidation. Based on the structure of the substance thePanel did not identify specific concerns related to thepotential genotoxicity of 2(3)-hexanethiol. A NOAEL of 0.56mg/kg bw/day in a 90-day male and female rat dietarystudy for the structural analog cyclopentanethiol (FEMA3262) is conservatively 450,000 times higher than theanticipated daily per capitaintake of 2(3)-hexanethiol fromuse as a flavor ingredient (Oser, 1970; Moran et al., 1980;Morgareidge, 1970; Collinson, 1989; Fairchild andAtokinger, 1958).

The Panel reviewed the GRAS application and supportinginformation regarding the mixture of 1-vinyl-3-cyclohexenecarbaldehyde and 4-vinyl-1-cyclohexenecarbaldehyde (CAS 1049017-63-1 and1049017-68-6, respectively) and concluded that it is GRAS(FEMA 4783) for use as a flavor in the food categories at theuse levels specified in the GRAS application (See Table 2;Smith et al., 2005a). This mixture was evaluatedindividually in the context of the chemical group of alicyclicprimary alcohols, aldehydes, acids and related esters (SLRA5; JECFA, 2002, 2011). The Panel noted that based on the

anticipated volume of 100 kg, the per capitaintake ("eatersonly") of the mixture of 1-vinyl-3-cyclohexenecarbaldehydeand 4-vinyl-1-cyclohexenecarbaldehyde from use as a flavoringredient is calculated to be 15 g/person/day (0.3 g/kgbw/day), which is significantly below the threshold oftoxicological concern for structural class I (1800g/person/day) (Munro et al., 1996). The mixture has notbeen reported to occur naturally. The Panel considered the

specification of the material to be adequately characterizedby the purity assay and supporting spectral data providedfor FEMA GRAS evaluation. By analogy to other alicyclicaldehydes, the substance is expected to be metabolized byoxidation to the corresponding acid and excreted in theurine either unchanged or after conjugation with glucuronicacid or glycine (Ishida et al., 1989). Evidence of mutagenicitywas not observed in an Ames assay with S. typhimuriumstrains TA98, TA100, TA1535 and TA1537 or Escherichiacoli WP2uvrA following treatment with the mixture of 1-vinyl-3-cyclohexenecarbaldehyde and 4-vinyl-1-cyclohexenecarbaldehyde in the presence or absence ofmetabolic activation. Statistically significant increases inchromosomal aberrations of Chinese Hamster V79 cellsresulted from administration of the mixture of 1-vinyl-3-cyclohexenecarbaldehyde and 4-vinyl-1-

cyclohexenecarbaldehyde in the absence or presence ofmetabolic activation, but in a mouse bone marrowmicronucleus assay the number of polychromaticerythrocytes was not increased relative to the vehiclecontrol. The extensive genotoxicity data for the structuralanalog, p-mentha-1,8-dien-7-al (FEMA 3557), was alsoreviewed and the Panel considered that the weight ofevidence for this substance indicated no genotoxicpotential. Based on weight of evidence for the substanceand the structural analog, including an overall negativegenotoxicity profile in vivo,the Panel did not identify specificconcerns related to the potential genotoxicity of the mixtureof 1-vinyl-3-cyclohexenecarbaldehyde and 4-vinyl-1-cyclohexenecarbaldehyde (Sokolowski, 2011; Hall, 2011a;Hall, 2011b; Bowen, 2011; Lloyd, 2009; Lloyd, 2012; Fujita etal. 1994; Ishidate et al. 1984; Yoo, 1986; Kuroda et al., 1984;

Eder et al., 1993). A NOAEL of 120 mg/kg bw/day in a 90-day male and female rat oral gavage study for the structuralanalog, perillyl alcohol (FEMA 2664), is 480,000 timeshigher than the anticipated daily per capita intake of themixture of 1-vinyl-3-cyclohexenecarbaldehyde and 4-vinyl-1-cyclohexenecarbaldehyde from use as a flavor ingredient(Crowell, 1997; Belanger, 1998; NCI, 1996; Stark et al., 1995;Burke et al., 1997; FDA, 1993; Mills et al., 1995; Reddy et al.,1997; Maltzman et al., 1991; Broitman et al., 1996; Belanger,1998; Haag & Gould, 1994).

The Panel reviewed the GRAS application and supportinginformation regarding ()-4-hydroxy-6-methyl-2-heptanone (CAS 57548-36-4) and concluded that it is GRAS(FEMA 4784) for use as a flavor ingredient in the foodcategories at the use levels specified in the GRAS

application (See Table 2; Smith et al., 2005a). Thissubstance was evaluated individually within the context ofthe chemical group of diketones, hydroxyketones andsimple derivatives (SLR B1E; JECFA 1999, 2011) The Panelnoted that based on the anticipated annual volume of use (1kg), the per capitaintake ("eaters only"") of ()-4-hydroxy-6-methyl-2-heptanone from use as a flavor ingredient iscalculated to be 0.2 g/person/day (0.003 g/kg bw/day),which is significantly below the threshold of toxicologicalconcern for structural class I (1800 g/person/day)(Munro et al., 1996). The material was not reported to occur

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naturally in food. The Panel considered the specification ofthe material to be adequately characterized by the purityassay and supporting spectral data provided for FEMAGRAS evaluation. Based on analogy with relatedcompounds, it is anticipated that ()-4-hydroxy-6-methyl-2-heptanone would be metabolized along several pathways,namely (a) conjugation with glucuronic acid and/or sulfatefollowed by excretion; (b) reduction of the keto function

followed by conjugation and excretion; and (c) omega-oxidation of carbon centers to the corresponding alcoholand carboxylic acid. No increases in the number of reversemutations were observed in an Ames assay for thestructural analog acetoin in S. typhimuriumstrains TA98,TA100 and TA102 in either the absence or presence ofmetabolic activation, and a separate Ames assay for acetoinin S. typhimuriumstrains TA97, TA98, TA100 and TA1535also produced negative results in either the absence orpresence of metabolic activation. The structurally relatedsubstance acetoin was weakly mutagenic, with effects lessthan two-fold of the control values, at a single dose in S.typhimuriumstrain TA100 without metabolic activation. Noincreased incidences in micronuclei were observed inperipheral blood erythrocytes when acetoin wasadministered to male and female Han Wistar rats and male

and female B6C3F1 mice in a 13-week inhalation exposurestudy at concentrations up to 800 ppm. Based on a weightof evidence consideration for the structural analog, acetoin,and also based on the structure of the substance and theidentity and arrangement of functional groups therein, thePanel did not identify specific concerns related to thepotential genotoxicity of ()-4-hydroxy-6-methyl-2-heptanone (Aeschbacher et al., 1989; NTP, 2013a,b,c). A13-week male and female CFE rat drinking water studyresulted in a NOAEL of 330 mg/kg bw/day for theconservative structural analog acetoin (FEMA 2008). This is>100,000,000 times higher the anticipated daily per capitaintake of ()-4-hydroxy-6-methyl-2-heptanone from use asa flavor ingredient. (Gaunt et al., 1972, FDA, 1993).

The Panel reviewed the GRAS application and supporting

information regarding 2-octyl-2-dodecenal (CAS 25234-33-7) and concluded that it is GRAS (FEMA 4785) for use as aflavor ingredient in the food categories at the use levelsspecified in the GRAS application (See Table 2; Smith et al.,2005a). This substance was evaluated individually withinthe context of the chemical group of aliphatic branched-chain saturated and unsaturated alcohols, aldehydes, acidsand related esters (SLR M1; JECFA 2004, 2009). The Panelnoted that based on the anticipated annual volume of use (3kg), the per capita intake ("eaters only") of 2-octyl-2-dodecenal from use as a flavor ingredient is calculated to be0.4 g/person/day (0.007 g/kg bw/day), which is belowthe threshold of toxicological concern for structural class II(540 g/person/day) (Munro et al., 1996). The materialwas not reported to occur naturally in food. The Panelconsidered the specification of the material to be

adequately characterized by the purity assay andsupporting spectral data provided for FEMA GRASevaluation. Based on the metabolic behavior of alpha,beta-unsaturated aldehydes, it is anticipated that 2-octyl-2-dodecenal would be metabolized along several pathways,namely (a) oxidation of the aldehyde function to thecarboxylic acid and (b) a series of beta-oxidations to thecorresponding carboxylic acid and (c) omega-oxidation tothe corresponding alcohol and carboxylic acid. Thecarboxylic acid metabolite might be expected to beconjugated with glucuronic acid and glycine (Deuel, 1957;

Weiner, 1980; Blair and Bodley, 1969; Kassahun et al., 1991).A number of studies for the structural analog trans-2-hexenal were reviewed, including in vitro and in vivogenotoxicity studies. Based on the overall weight ofevidence for trans-2-hexenal, and also based on thestructure of the substance and the identity andarrangement of the functional groups therein, the Panel didnot identify specific concerns related to the potential

genotoxicity of 2-octyl-2-dodecenal (Kirby et al., 1983;Zeiger et al., 1985; Agarwal et al., 1985; Seed, 1982;Divincenzo et al., 1985; Tomita et al., 1982; Phillips et al.,1982; Hodgson et al., 1982; Putman et al., 1983; Eder et al.,1992, 1993; Marnett et al., 1985; Dittberner et al., 1995;Canonero et al., 1990; Griffin and Segall, 1986; NTP,1997,2001, 2003; Banerjee and Giri, 1986; Mukherjee et al., 1988;Oda, 1979; Kuroda et al., 1984; Yoo, 1986; Ishidate etal.,1984). Other structural analogs, 2-ethyl-1-hexanol(FEMA 3151) and citral (FEMA 2303) were also reviewed(Astill, 1996a,b; Astill, 1993; Rhodes et al., 1984; Lake et al.,1975; Narotsky et al., 1994; Dieter et al., 1993; Hagan et al.,1967; NTP, 2001; Geldof et al., 1992; Hoberman et al., 1989;Vollmuth et al., 1990; Nogueira et al., 1994; Gaworski et al.,1992; Gray and Beamand, 1984; Sjoberg et al., 1986; NTP,1991; Hardin et al ., 1987; EPA, 1991; Ritter et al., 1987; Tyl et

al., 1992). A 13-week dietary study for the structural analogtrans-2-hexenal (FEMA 2560) in male and female CFW ratsresulted in a NOAEL of 80 mg/kg bw/day. This NOAEL is atleast 10,000,000 times the anticipated daily per capitaintake of 2-octyl-2-dodecanal from use as a flavoringredient (Gaunt et al., 1971).

The Panel reviewed the GRAS application and supportinginformation regarding 2-hexyl-2-decenal (CAS 13893-39-5)and concluded that it is GRAS (FEMA 4786) for use as aflavor ingredient in the food categories at the use levelsspecified in the GRAS application (See Table 2; Smith et al.,2005a). This substance was evaluated individually withinthe context of the chemical group of aliphatic branched-chain saturated and unsaturated alcohols, aldehydes, acidsand related esters (SLR M1; JECFA 2004, 2009). The Panel

noted that based on the anticipated annual volume of use (5kg), the per capita intake ("eaters only") of 2-hexyl-2-decenal from use as a flavor ingredient is calculated to be0.7 g/person/day (0.01 g/kg bw/day), which is below thethreshold of toxicological concern for structural class II(540 g/person/day) (Munro et al., 1996). The materialwas not reported to occur naturally in food. The Panelconsidered the specification of the material to beadequately characterized by the purity assay andsupporting spectral data provided for FEMA GRASevaluation. Based on the metabolic behavior of alpha,beta-unsaturated aldehydes, it is anticipated that 2-hexyl-2-decenal would be metabolized along several pathways,namely (a) oxidation of the aldehyde function to thecarboxylic acid and (b) a series of beta-oxidations to thecorresponding carboxylic acid and (c) omega-oxidation to

the corresponding alcohol and carboxylic acid. Thecarboxylic acid metabolite might be expected to beconjugated with glucuronic acid and glycine (Deuel, 1957;Weiner, 1980; Blair and Bodley, 1969; Kassahun et al., 1991).A number of studies for the structural analog trans-2-hexenal were reviewed, including in vitro and in vivogenotoxicity studies. Based on the overall weight ofevidence for trans-2-hexenal, and also based on thestructure of the substance and the identity andarrangement of the functional groups therein, the Panel didnot identify specific concerns related to the potential

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genotoxicity of 2-hexyl-2-decenal. (Kirby et al., 1983; Zeigeret al., 1985; Agarwal et al., 1985; Seed, 1982; Divincenzo etal., 1985; Tomita et al., 1982; Phillips et al., 1982; Hodgson etal., 1982; Putman et al., 1983; Eder et al., 1992, 1993;Marnett et al., 1985; Dittberner et al., 1995; Canonero et al.,1990; Griffin and Segall, 1986; NTP,1997, 2001, 2003;Banerjee and Giri, 1986; Mukherjee et al., 1988; Oda, 1979;Kuroda et al., 1984; Yoo, 1986; Ishidate et al.,1984). Other

structural analogs, 2-ethyl-1-hexanol (FEMA 3151) and citral(FEMA 2303) were also reviewed (Astill, 1996a,b; Astill,1993; Rhodes et al., 1984; Lake et al., 1975; Narotsky et al.,1994; Dieter et al., 1993; Hagan et al., 1967; NTP, 2001;Geldof et al., 1992; Hoberman et al., 1989; Vollmuth et al.,1990; Nogueira et al., 1994; Gaworski et al., 1992; Gray andBeamand, 1984; Sjoberg et al., 1986; NTP, 1991; Hardin etal., 1987; EPA, 1991; Ritter et al., 1987; Tyl et al., 1992). A 13-week dietary study for the structural analog trans-2-hexenal(FEMA 2560) in male and female CFW rats resulted in aNOAEL of 80 mg/kg bw/day. This NOAEL is at least10,000,000 times the anticipated daily per capitaintake of2-hexyl-2-decanal from use as a flavor ingredient (Gaunt etal., 1971).

The Panel reviewed the GRAS application and supporting

information regarding trans-6-octenal (CAS 63196-63-4)and concluded that it is GRAS (FEMA 4787) for use as aflavor ingredient in the food categories at the use levelsspecified in the GRAS application (See Table 2; Smith et al.,2005a). The substance was evaluated individually withinthe context of the chemical group of linear and branched-chain aliphatic, unsaturated, unconjugated alcohols,aldehydes, acids, and related esters (SLR M1, JECFA 1999,2004, 2012). The Panel noted that based on the anticipatedannual volume of use (0.1 kg), the per capitaintake ("eatersonly") of trans-6-octenal from use as a flavor ingredient iscalculated to be 0.02 g/person/day (0.0003 g/kgbw/day), which is below the threshold of toxicologicalconcern for structural class I (1800 g/person/day)(Munro et al., 1996). The material was not reported to occurnaturally in food. The Panel considered the specification of

the material to be adequately characterized by the purityassay and supporting spectral data provided for FEMAGRAS evaluation. Based on the metabolism of unsaturatedacyclic fatty acids, it is anticipated that trans-6-octenal willbe oxidized and the resulting linear unsaturated mediumchain carboxylic acid will participate in the fatty acidmetabolism pathway to produce carbon dioxide and water(Nelson and Cox, 2008; Kawaguchi, 2012). No increases inthe number of reverse mutations were observed in Amesassays for trans-6-octenal in S. typhimuriumstrains TA98or TA100 in either the presence or absence of metabolicactivation. Based on the available data, and also based onthe structure of the substance and the identity andarrangement of functional groups therein, the Panel did notidentify specific concerns related to the potentialgenotoxicity of trans-6-octenal. A 98-day male and female

SPF CFE weanling rat drinking water study for the structuralanalog cis-3-hexenol (FEMA 2563) resulted in NOAELs ofapproximately 120-150 mg/kg bw/day. The lowest reportedNOAEL for the structural analog is at least 480,000,000times the anticipated daily per capita intake of trans-6-octenal from use as a flavor ingredient (Moreno, 1973;Gaunt et al., 1969; Newell et al., 1949).

The Panel reviewed the GRAS application and supportinginformation regarding (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide (CAS 69444-90-2) and concluded

that it is GRAS (FEMA 4788) for use as a flavor ingredient inthe food categories at the use levels specified in the GRASapplication (See Table 2; Smith et al., 2005a). Thesubstance was evaluated individually within the context ofthe chemical group of aliphatic and aromatic amines andamides (SLR A7, C21, JECFA 2006, 2008, 2011, 2012) ThePanel noted that based on the anticipated annual volume ofuse (100 kg), the per capitaintake ("eaters only") of (E)-3-

benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide fromuse as a flavor ingredient is calculated to be 15g/person/day (0.3 g/kg bw/day), which is below thethreshold of toxicological concern for structural class III (90g/person/day) (Munro et al., 1996). The Panel consideredthe specification of the material to be adequatelycharacterized by the purity assay and supporting spectraldata provided for FEMA GRAS evaluation. Based on themetabolism of similar diphenyl amide compounds, it isanticipated that (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide will undergo cytochrome P450-inducedpara-oxidation. Given the large number of carbon centers anumber of possible polar acid and alcohol metabolites mayresult. These are expected to conjugate with glucuronide orsulfate and be excreted in the urine, or to a minor extentunchanged in the feces. Amide hydrolysis is not expected to

be a favorable process in vivo given other metabolic options;therefore amide hydrolysis products are not expected to bemajor metabolites (Foster, 2009; Yuan, 2008; Bhat andChandrasekhara, 1986a; Schwen, 1982). No increases in thenumber of reverse mutations were observed for (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide in S.typhimuriumstrains TA98, TA100, TA1535 and TA1537 andE. coliWP2uvrA strain in either the presence or absence ofmetabolic activation. Based on the available data for thesubstance, and also based on the structure of the substanceand the identity and arrangement of functional groupstherein, the Panel did not identify specific concerns relatedto the potential genotoxicity of (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide (Uhde, 2004). A male andfemale reproductive mouse study resulted in a NOAEL of 20mg/kg bw/day for piperine. A 14-day male and female rat

dietary study resulted in NOAELs of 1443 and 1381mg/kgbw/day, respectively for (E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamide. An 8-week male and female ratdietary study for black pepper oleoresin, containing thestructural analog piperine, FEMA 2909, resulted in NOAELsequivalent to 20 mg/kg bw/day piperine. This is 80,000times higher than the anticipated daily per capitaintake of(E)-3-benzo[1,3]dioxol-5-yl-N,N-diphenyl-2-propenamidefrom use as a flavor ingredient (Piyachaturawat et al., 1983;Bhat and Chandrasekhara, 1986b; Platel and Srinivasan,2000, 2001; Daware et al., 2000; Posternak et al., 1969).

The Panel reviewed the GRAS application and supportinginformation regarding 2,6-dimethyl-5-heptenol (CAS 4234-93-9) and concluded that it is GRAS (FEMA 4789) for use asa flavor ingredient in the food categories at the use levels

specified in the GRAS application (See Table 2; Smith et al.,2005a). The substance was evaluated within the context ofthe chemical group of linear and branched-chain aliphatic,unsaturated, unconjugated alcohols, aldehydes, acids, andrelated esters (SLR M1, JECFA 1999, 2004, 2012). ThePanel noted that based on the anticipated annual volume ofuse (5 kg), the per capita intake ("eaters only") of 2,6-dimethyl-5-heptenol from use as a flavor ingredient iscalculated to be 0.7 g/person/day (0.01 g/kg bw/day),which is below the threshold of toxicological concern forstructural class I (1800 g/person/day) (Munro et al.,

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1996). The material was reported to occur naturally in Litseacubebaand Passiflora quadrangularis, also known as Badeaor giant passion fruit, but only qualitative data are availableand thus no consumption ratio can be calculated (Nijssen etal., 2015). The Panel considered the specification of thematerial to be adequately characterized by the purity assayand supporting spectral data provided for FEMA GRASevaluation. The main impurity is 2,6-dimethyl-5-heptenal

(FEMA 2389) (Oser and Hall, 1965). Based on alpha-methyl-branched fatty acid alcohol derivatives, it is anticipated that2,6-dimethyl-5-heptenol will undergo metabolism byoxidation to the corresponding aldehyde, 2,6-dimethyl-5-heptenal (FEMA 2389) and subsequent acid followed byexcretion in the urine, or will undergo conjugation withglucuronic acid and excretion in the urine. No increases inthe number of reverse mutations were observed in Amesassays for the structural analog and primary metabolite 2,6-dimethyl-5-heptenal in S. typhimurium strains TA98,TA100, TA1535, TA1537 and TA1538 in the presence andabsence of metabolic activation. 2,6-Dimethyl-5-heptenalalso gave negative results in a rat hepatocyte unscheduledDNA synthesis assay and in a mouse bone marrowmicronucleus assay. Based on the lack of genotoxicitydisplayed for the structural analog, 2,6-dimethyl-5-

heptenal, and also based on the structure of the substanceand the identity and arrangement of the functional groupstherein, the Panel did not identify specific concerns relatedto the potential genotoxicity of 2,6-dimethyl-5-heptenol(Heck et al., 1989; Wild et al., 1983; Oser, 1958; Oda, 1979;Sasaki et al., 1989; Kasamaki et al., 1982; Kono, et al., 1995;Yoo, 1986; Kuroda et al., 1984; Ishidate et al., 1984). A 90-day male and female rat dietary study for the primarymetabolite, 2,6-dimethyl-5-heptenal (FEMA 2389), resultedin a NOAEL of 37 mg/kg bw/day which is 3,000,000 timesthe anticipated daily per capita intake of 2,6-dimethyl-5-heptenol from use as a flavor ingredient (Gaunt et al., 1983,NTP 2001; Dieter et al., 1993; Oser, 1958a; Hagan et al.,1967; NTP, 2000; Hoberman et al., 1989; Vollmuth et al.,1990; Nogueira et al., 1994; Gaworski et al., 1992).

The Panel reviewed the GRAS application and supportinginformation regarding ()-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, ethyl ester (CAS 10138-32-6) andconcluded that it is GRAS (FEMA 4790) for use as a flavoringredient in the food categories at the use levels specifiedin the GRAS application (See Table 2; Smith et al., 2005a).The substance was evaluated individually within the contextof the chemical group of alicyclic primary alcohols,aldehydes, acids and related esters (SLR A5, JECFA, 2002,2011). The Panel noted that based on the anticipated annualvolume of use (2 kg), the per capitaintake ("eaters only") of()-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, ethyl esterfrom use as a flavor ingredient is calculated to be 0.3g/person/day (0.005 g/kg bw/day), which is below thethreshold of toxicological concern for structural class III (90g/person/day) (Munro et al., 1996). The material was not

reported to occur naturally in food. The Panel consideredthe specification of the material to be adequatelycharacterized by the purity assay and supporting spectraldata provided for FEMA GRAS evaluation. ()-Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, ethyl ester isexpected to be hydrolyzed in humans (viacarboxylesterases, which occur in most human tissues andpredominately in hepatocytes) to the correspondingbicycloheptene carboxylic acid and ethanol. The resultingbicycloheptene carboxylic acid is expected to be conjugatedand excreted in the urine as the corresponding glucuronic

acid and glycine conjugates or as the correspondinghippuric acids. Some of the carboxylic acid may also beexcreted unchanged. No increases in the number of reversemutations were observed in an Ames assay for ()-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, ethyl ester in S.typhimuriumstrains TA98, TA100, TA1535, TA1537 and E.coli strain WP2uvrA in either the presence or absence ofmetabolic activation. ()-Bicyclo[2.2.1]hept-5-ene-2-

carboxylic acid, ethyl ester did induce chromosomalaberrations in human lymphocytes treated for 21 hours inthe absence of metabolic activation, but it did not inducechromosomal aberrations in human lymphocytes treatedfor 3 hours with an 18 hour recovery period in either thepresence or absence of metabolic activation. ()-Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, ethyl ester didnot increase mutant frequencies in mouse lymphomaL5178Y cells under any treatment conditions in either thepresence or absence of metabolic activation. ()-Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, ethyl ester didnot produce biologically relevant increases in the frequencyof micronucleated binucleate cells in either the presence orabsence of metabolic activation in human lymphocytesunder any treatment conditions. In an in vivochromosomalaberration study in male ICR mice, no significant increases

in the frequency of bone marrow cells with structural ornumerical aberrations were observed. Based on weight ofevidence from the available studies supplied, the Panel didnot identify specific concerns related to the potentialgenotoxicity of ()-bicyclo[2.2.1]hept-5-ene-2-carboxylicacid, ethyl ester (May, 2010; May 2012; Thompson, 2007;Akhurst, 1995; Pritchard, 2011). A 90-day oral gavage studyin CFE male and female rats resulted in a NOAEL of 15mg/kg bw/day (males) for the structural analog isobornylacetate (FEMA 2160). This is >3,000,000 times theanticipated daily per capitaintake of ()-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, ethyl ester from use as a flavoringredient (Gaunt et al., 1971; Lea, 1996).

The Panel reviewed the GRAS application and supportinginformation regarding 3-(acetylthio)hexanal (CAS 22236-

44-8) and concluded that it is GRAS (FEMA 4791) for use asa flavor ingredient in the food categories at the use levelsspecified in the GRAS application (See Table 2; Smith et al.,2005a). This substance was evaluated individually withinthe context of the chemical group of simple aliphatic andaromatic thiols and sulfides (SLR B5C, JECFA 2000, 2004,2008, 2011, 2012). The Panel noted that based on theanticipated annual volume of use (1 kg), the per capitaintake ("eaters only") of 3-(acetylthio)hexanal from use as aflavor ingredient is calculated to be 0.2 g/person/day(0.002 g/kg bw/day), which is below the threshold oftoxicological concern for structural class III (90g/person/day). The material was reported to occur inciflorette (Fragaria x ananassa) strawberry, but onlyqualitative data are available and thus no consumption ratiocan be calculated (Nijssen et al., 2015). The Panel

considered the specification of the material to beadequately characterized by the purity assay andsupporting spectral data provided for FEMA GRASevaluation. 3-(Acetylthio)hexanal is anticipated to bemetabolized along a number of pathways: oxidation of thealdehyde function to the carboxylic acid followed byexcretion further unchanged or by conjugation with glycineand glucuronic acid and subsequent excretion; hydrolysis ofthe acetyl function to 3-thiohexanal which can be furthermetabolized by oxidation of the aldehyde group and thethiol function (by S-oxidation to the sulfoxide) and finally

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omega-oxidation of the terminal hexane function to theprimary alcohol and carboxylic acid and their conjugates.Thus, the metabolism of 3-(acetylthio)hexanal isanticipated to produce a array of metabolites that areexpected to be cleared primarily in the urine (Diechmannand Gerarde, 1969). Based on the structure of thesubstance and the identity and arrangements of functionalgroups therein, the Panel did not identify specific concerns

related to the potential genotoxicity of 3-(acetylthio)hexanal. A 90-day dietary toxicity study in maleand female rats conducted at a single dose resulted in aNOEL of 6.48 mg/kg bw/day for the structural analog ethylthioacetate (FEMA 3282). This is >2,500,000 times higherthan the anticipated daily per capita intake of 3-(acetylthio)hexanal from use as a flavor ingredient(Shellenberger, 1970).

The Panel reviewed the GRAS application and supportinginformation regarding ()-3-mercapto-1-pentanol (CAS548740-99-4) and concluded that it is GRAS (FEMA 4792)for use as a flavor ingredient in the food categories at theuse levels specified in the GRAS application (See Table 2;Smith et al., 2005a). This substance was evaluatedindividually within the context of the chemical group of

simple aliphatic and aromatic thiols and sulfides (SLR B5A,JECFA 2000, 2004, 2008, 2011, 2012). The Panel notedthat based on the anticipated annual volume of use (2 kg),the per capita intake ("eaters only") of ()-3-mercapto-1-pentanol from use as a flavor ingredient is calculated to be0.3 g/person/day (0.005 g/kg bw/day), which is belowthe threshold of toxicological concern for structural class I(1800 g/person/day) (Munro et al., 1996). The materialwas reported to occur in beer, black tea, and wine, but onlyqualitative data are available and thus no consumption ratiocan be calculated (Nijssen et al., 21015). The Panelconsidered the specification of the material to beadequately characterized by the purity assay andsupporting spectral data provided for FEMA GRASevaluation. The metabolism of ()-3-mercapto-1-pentanolis anticipated to involve oxidation of the thiol to the unstable

sulfenic acid (RSOH) with further oxidation to thecorresponding sulfinic (RSO2H) and sulfonic acids(RSO3H). Additionally, methylation of the thiol to yield thecorresponding sulfide, which is then oxidized to thesulfoxide and sulfone will occur. Other metabolic optionsinclude reaction with endogenous thiols to form mixeddisulfides, and conjugation of the alcohol with glucuronicacid or sulfate. All oxidation and conjugation products wouldbe anticipated to lead to excretion. No increases in thenumber of reverse mutations were observed in Amesassays for the structural analogs 3-mercapto-3-methylbutanol (FEMA 3854) and 3-mercapto-2-methyl-1-butanol (FEMA 3993) in S. typhimurium strains TA98,TA100, TA1535, TA1537, and TA1535, TA97, TA98, TA100,and TA102, respectively (Jones, 1990; Gocke, 1997). Basedon the data for structural analogs, the structure of the

substance and the identity and arrangements of functionalgroups therein, the Panel did not identify specific concernsrelated to the potential genotoxicity of ()-3-mercapto-1-pentanol. A 90-day dietary study in male and female albinoweanling rats resulted in a NOAEL of 0.705 mg/kg bw/dayfor the structural analog 2-mercapto-3-butanol (FEMA3502) (Morgareidge, 1974). This is >140,000 times higherthan the anticipated daily per capita intake of ()-3-mercapto-1-pentanol from use as a flavor ingredient.

The Panel reviewed the GRAS application and supportinginformation regarding (3R,3S)-3-[[(4-amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]-N-cyclopentyl-2-oxo-3-piperidinecarboxamide (CAS 1446687-20-2) andconcluded that it is GRAS (FEMA 4793) for use as a flavoringredient in the food categories at the use levels specifiedin the GRAS application (See Table 2; Smith et al., 2005a).This substance was evaluated individually within the

context of the chemical group of miscellaneous nitrogen-containing substances (SLR D19, JECFA 2006, 2009, 2012,2015). The Panel noted that based on the anticipated annualvolume of use (100 kg), the per capitaintake ("eaters only")of (3R,3S)-3-[[(4-amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]-N-cyclopentyl-2-oxo-3-piperidinecarboxamide from use as a flavor ingredient iscalculated to be 15 g/person/day (0.2 g/kg bw/day),which is below the threshold of toxicological concern forstructural class III (90 g/person/day) (Munro et al., 1996).The Panel considered the specification of the material to beadequately characterized by the purity assay andsupporting spectral data provided for FEMA GRASevaluation. The Panel evaluated sensory data includedwithin the application and found it satisfactory with regardto intended conditions of use for the flavoring ingredient

(Harman and Hallagan, 2013). Studies on (3R,3S)-3-[[(4-amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]-N-cyclopentyl-2-oxo-3-piperidinecarboxamide indicate a bioavailability of 0.46%.The metabolism of the structural analog, 3-[(4-amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]-2,2-dimethyl-N-propylpropanamide (FEMA 4701) was investigated inSprague-Dawley rat and human liver microsomes, and theprincipal metabolites included hydroxylated. On this basis,(3R,3S)-3-[[(4-amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]-N-cyclopentyl-2-oxo-3-piperidinecarboxamide is anticipated to primarily beexcreted in the feces unchanged, or after hydroxylation(Arthur et al., 2015) No increases in reverse mutations wereobserved in an Ames assay when S. typhimurium strainsTA98, TA100, TA1535 and TA1537 and E. coliWP2uvrA were

incubated with (3R,3S)-3-[[(4-amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]-N-cyclopentyl-2-oxo-3-piperidinecarboxamide at concentrations up to 5000g/plate in the presence and absence of metabolicactivation. No evidence of mutagenic potential wasidentified for the structural analog 3-[(4-amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]-2,2-dimethyl-N-propylpropanamide (FEMA 4701) in an Ames assay in S.typhimurium strains TA98, TA100, TA1535, TA1537, andTA102 either in the presence or absence of metabolicactivation, in a chromosomal aberration assay in Chinesehamster ovary WBL cells, and in a bone marrowmicronucleus assay in male Swiss albino CD-1 mice. Basedon the data for the substance and for structural analogs, thePanel did not identify specific concerns related to thepotential genotoxicity of (3R,3S)-3-[[(4-amino-2,2-dioxido-

1H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]-N-cyclopentyl-2-oxo-3-piperidinecarboxamide (Arthur et al., 2015). A 90-day dietary study in Crl:CD (SD) male and female ratsresulted in a NOAEL of 20 mg/kg bw/day for the structuralanalog 3-[(4-amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]-2,2-dimethyl-N-propylpropanamide (FEMA 4701)(Arthur et al., 2015). This is >80,000 times higher than theanticipated daily per capitaintake of (3R,3S)-3-[[(4-amino-2,2-dioxido-1H-2,1,3-benzothiadiazin-5-yl)oxy]methyl]-N-cyclopentyl-2-oxo-3-piperidinecarboxamide from use as aflavor ingredient.

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The Panel reviewed the GRAS application and supportinginformation regarding ()-1-cyclohexylethanol (CAS 1193-81-3) and concluded that it is GRAS (FEMA 4794) for use asa flavor ingredient in the food categories at the use levelsspecified in the GRAS application (See Table 2; Smith et al.,2005a). This substance was evaluated individually withinthe context of the chemical group of saturated aliphaticacyclic secondary alcohols, ketones, and related saturated

and unsaturated esters (SLR A1, JECFA 1999). The Panelnoted that based on the anticipated annual volume of use(50 kg), the per capita intake ("eaters only") of ()-1-cyclohexylethanol from use as a flavor ingredient iscalculated to be 7 g/person/day (0.1 g/kg bw/day),which is below the threshold of toxicological concern forstructural class II (540 g/person/day) (Munro et al.,1996). The Panel considered the specification of thematerial to be adequately characterized by the purity assayand supporting spectral data provided for FEMA GRASevaluation. ()-1-Cyclohexylethanol is an alicylic secondaryalcohol and is expected to be rapidly absorbed, metabolizedand the metabolites cleared in the urine. The main pathwaysof metabolism are anticipated to be conjugation withglucuronic acid through the hydroxyl function andhydroxylation of the cyclohexyl group followed by

conjugation with glucuronic acid (Williams, 1959). In bothcases it would be anticipated that the conjugates would beexcreted in the urine. No increases in reverse mutationswere observed in an Ames assay for 1-cyclohexylethylbutyrate in S. typhimuriumstrains TA98, TA100, TA1535,TA1537, or TA1538 in either the presence or absence ofmetabolic activation. Based on the data for the structuralanalog, as well as on the structure of the substance and theidentity and arrangements of functional groups therein, thePanel did not identify specific concerns related to thepotential genotoxicity of ()-1-cyclohexylethanol (Stevens,1978b). A 28-day oral gavage study in Charles River CD ratsresulted in a NOAEL of 3000 mg/kg bw/day for thestructural analog 1-cyclohexylethyl butyrate (CAS 63449-88-7). This is >24,000,000 times higher than theanticipated daily per capita intake of ()-1-

cyclohexylethanol from use as a flavor ingredient (Stevens,1978a).

The Panel reviewed the GRAS application and supportinginformation regarding ()-8-methyldecanal (CAS 127793-88-8) and concluded that it is GRAS (FEMA 4795) for use asa flavor ingredient in the food categories at the use levelsspecified in the GRAS application (See Table 2; Smith et al.,2005a). This substance was evaluated individually withinthe context of the chemical group of saturated aliphaticacyclic branched-chain primary alcohols, aldehydes andacids (SLR M1; JECFA 1998). The Panel noted that based onthe anticipated annual volume of use (5 kg), the per capitaintake ("eaters only") of ()-8-methyldecanal from use as aflavor ingredient is calculated to be 0.7 g/person/day(0.01 g/kg bw/day), which is below the threshold of

toxicological concern for structural class I (1800g/person/day) (Munro et al., 1996). The material wasreported to occur in lemongrass, citronella, orange, andmany other oils, including rose oil, but only qualitative dataare available and thus no consumption ratio can becalculated (Nijssen et al., 2015). The Panel considered thespecification of the material to be adequately characterizedby the purity assay and supporting spectral data providedfor FEMA GRAS evaluation. ()-8-Methyldecanal isanticipated to be metabolized in a manner consistent withdetoxification of linear aliphatic acyclic aldehydes, which

involves absorption through the gastrointestinal tract,oxidation to the corresponding acid by NAD +-dependentaldehyde dehydrogenase, and complete metabolism toendogenous products via fatty acid oxidation,tricarboxycylic acid pathways, or via reaction withglutathione and ultimate excretion in the urine (Walkensteinand Weinhouse, 1953; Dunster and Watson, 2012). Noevidence of mutagenic potential was observed in multiple

Ames assays for the structural analog 2-methylundecanalin S. typhimurium strains TA98, TA100, TA1535, TA1537,and TA102 in either the presence or absence of metabolicactivation. Based on the data for the structural analog, aswell as on the structure of the substance and the identityand arrangements of functional groups therein, the Paneldid not identify specific concerns related to the potentialgenotoxicity of ()-8-methyldecanal (Harnasch, 1999;Verspeek-Rip, 2002). A 12-week dietary study in male andfemale rats resulted in a NOAEL of 112 mg/kg bw/day for amixture of six aldehydes, including the structural analog 2-methylundecanal (FEMA 2749) at 19.1 mg/kg bw/day. Thisis >1,500,000 times higher than the anticipated daily percapita intake of ()-8-methyldecanal from use as a flavoringredient (Trubek, 1958).

The Panel reviewed the GRAS application and supportinginformation regarding rebaudioside C 30% (CAS 63550-99-2) and concluded that it is GRAS (FEMA 4796) for use asa flavor ingredient in the food categories at the use levelsspecified in the GRAS application. This material wasevaluated within the context of the procedure for the safetyevaluation of natural flavor complexes (Smith et al., 2005b).The Panel noted that based on the anticipated annualvolume of use (1000 kg), the per capita intake ("eatersonly") of rebaudioside C 30% from use as a flavor ingredientis calculated to be 147 g/person/day (2 g/kg bw/day),which is above the threshold of toxicological concern forstructural class III (90 g/person/day) (Munro et al., 1996).The material occurs in the Stevia plant which is used as atea, but a consumption ratio cannot be calculated. ThePanel considered the identity description of the material to

be adequate for FEMA GRAS evaluation . The Panelevaluated sensory data included within the application andfound it satisfactory with regard to intended conditions ofuse for the flavoring ingredient (Harman and Hallagan,2013). Metabolic studies with steviol glycosides in multiplespecies, including humans, have demonstrated that intactsteviol glycosides are poorly absorbed after oral exposurebut that they are hydrolyzed by the microflora in the gut tosteviol. A large portion of this steviol is absorbed and isconjugated to steviol glucuronide, which undergoesenterohepatic circulation. The remaining steviol is excretedin the feces. No steviol epoxide, which may have genotoxicpotential, was detected in human plasma (Carakostas et al.,2008; Nakayama et al., 1986; Koyama et al., 2003; Geuns,2003; Kraemer and Maurer, 1994; Simonetti et al., 2004;Geuns et al., 2006, 2007; Hutapea et al., 1997). The

genotoxicity of steviol glycosides has been thoroughlyexamined in a wide range of studies. While some positiveresults are reported in in vitromutagenicity assays, in vivostudies do not provide evidence of genotoxic effects. Basedon the results for various steviol glycosides, the Panel didnot identify specific concerns related to the potentialgenotoxicity of rebaudioside C 30% (Brusick, 2008). Noeffects on testicular morphology or spermatogenesis wereidentified in a multi-generation reproductive study fordietary administration of rebaudioside A. No treatment-related effects of rebaudioside A were observed in either the

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F0 or F1 generations on reproductive performanceparameters including mating performance, fertility, andgestation lengths in a two-generation reproductive study.(Curry et al., 2008; Yodyingyuad and Bunyawong, 1991;Carakostas et al., 2008). Multiple toxicity studies for varioussteviol glycosides have been conducted. The Panel notedthat a 13-week dietary study in Fischer 344 rats for thestructural analog stevioside (FEMA 4763) resulted in a

NOAEL of 2500 mg/kg bw/day. In the 108-weekcarcinogenicity study for stevioside, no carcinogenic effectswere observed, and a NOAEL of 970 mg/kg bw/day was setby the United Nations Joint FAO/WHO Expert Committeeon Food Additives (JECFA). This NOAEL identified by JECFAis >390,000 times higher than the anticipated daily percapita intake of rebaudioside C 30% from use as a flavoringredient (Carakostas et al., 2008; Aze et al., 1991; Toyodaet al., 1997; JECFA, 1999, 2006; Curry and Roberts, 2008;Maki et al, 2008).

The Panel reviewed the GRAS application and supportinginformation regarding ()-naringenin (CAS 480-41-1) andconcluded that it is GRAS (FEMA 4797) for use as a flavoringredient in the food categories at the use levels specifiedin the GRAS application (See Table 2; Smith et al., 2005a).

This substance was evaluated individually within thecontext of the chemical group of phenol and phenolderivatives (SLR C12; JECFA 2001, 2011, 2015). The Panelnoted that based on the anticipated annual volume of use(5200 kg), the per capita intake ("eaters only") of ()-naringenin from use as a flavor ingredient is calculated to be766 g/person/day (13 g/kg bw/day), which is above thethreshold of toxicological concern for structural class III (90g/person/day) (Munro et al., 1996). The material asreviewed by the Panel was reported to occur in grapefruitand the calculated consumption ratio is 33 annual percapita. The Panel considered the specification of thematerial to be adequately characterized by the purity assayand supporting spectral data provided for FEMA GRASevaluation. The Panel evaluated sensory data includedwithin the application and found it satisfactory with regard

to intended conditions of use for the flavoring ingredient(Harman and Hallagan, 2013). The disposition of ()-naringenin was examined in male Sprague-Dawley rats andthe authors concluded that glucuronide conjugates wereformed and excreted (El Mohsen et al., 2004; Hsiu et al.,2002; Yanez et al., 2008; Choudhury et al. 1999; Kanaze etal., 2007; Felgines et al., 2000). No increases in reversemutations were observed in Ames assays in S. typhimuriumstrains TA100, TA98, TA1535, TA1537, TA1538 either in thepresence or absence of metabolic activation for ()-naringenin. Based on these results, as well as on thestructure of the substance and the identity andarrangement of the functional groups therein, the Panel didnot identify specific concerns related to the potentialgenotoxicity of ()-naringenin (Batzinger, 1977; Bjeldanes &Chang, 1977; Brown & Dietrich, 1979; MacGregor and Jurd,

1978; Zeiger et al., 1987; Sahu et al., 1981). Multiplecarcinogenicity studies have been conducted in rats for thevery conservative, with respect to safety, structural analogquercetin. The Panel reviewed the results of these studies,and agreed with the International Agency for Research onCancer (IARC) conclusion that quercetin is not classifiableas a carcinogen to humans. A conservative NOAEL based onthe lowest dose tested from the 2-year dietary study inF344/N rats was assigned at 40 mg/kg bw/day. This is>3,000 times higher than the anticipated daily per capitaintake of ()-naringenin from use as a flavor ingredient

(Ortiz-Andrade et al., 2008; Brown et al., 1977; Brown andDietrich, 1979; Jurado et al., 1991; Lina et al., 1990; Booth etal., 1965; Booth, 1974; Gumbmann et al., 1978).

The Panel reviewed the GRAS application and supportinginformation regarding 2-(((3-(2,3-dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine (CAS 902136-79-2)and concluded that it is GRAS (FEMA 4798) for use as a

flavor ingredient in the food categories at the use levelsspecified in the GRAS application (See Table 2; Smith et al.,2005a). This substance was evaluated individually withinthe context of the chemical group of miscellaneousnitrogen-containing substances (SLR D19, JECFA 2006,2009, 2012, 2015). The Panel noted that based on theanticipated annual volume of use (2000 kg), the per capitaintake ("eaters only") of 2-(((3-(2,3-dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine from use as a flavoringredient is calculated to be 295 g/person/day (5 g/kgbw/day), which is above the threshold of toxicologicalconcern for structural class III (90 g/person/day) (Munroet al., 1996). The material was not reported to occurnaturally in food. The Panel considered the specification ofthe material to be adequately characterized by the purityassay and supporting spectral data provided for FEMA

GRAS evaluation. The Panel evaluated sensory dataincluded within the application and found it satisfactory withregard to intended conditions of use for the flavoringingredient (Harman and Hallagan, 2013). In vitroand in vivometabolic profiling was conducted to explore thedisposition of the substance. In the in vivo metabolismstudies in rats multiple metabolic pathways were identified,including formation of a sulfoxide metabolite, a thioetheroxidation product, a demethylation metabolite, and aphenyl hydroxylation product. Formation of a desmethyl, O-sulfate, and glucuronic acid conjugate were also observed(Bailey, 2012; Chi, 2012, 2013). 2-(((3-(2,3-Dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine did not increase reverse mutationsin an Ames assay in S. typhimuriumstrains TA98, TA100,TA1535, TA1537, and E. coli strain WP2uvrA either in the

presence or absence of metabolic activation. 2-(((3-(2,3-Dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine did not induce structural ornumerical chromosomal aberrations in human peripheralblood lymphocytes in either the presence or absence ofmetabolic activation. The substance did not induceincreases in the numbers of micronucleated binucleateChinese hamster ovary cells in either the presence orabsence of metabolic activation under any treatmentcondition. Based on the uniformly negative data from thesegenotoxicity studies, the Panel did not identify specificconcerns related to the potential genotoxicity of 2-(((3-(2,3-dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine (Yokoi, 2008; Cardoso, 2013a, b, c).A 28-day study in male and female CD [Crl:CD (SD)] ratsresulted in a NOAEL of 100 mg/kg bw/day for 2-(((3-(2,3-

dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine. A 90-day dietary study in male andfemale CD [Crl:CD (SD)] rats resulted in a NOAEL of 100mg/kg bw/day for 2-(((3-(2,3-dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine (Rose, 2012, 2013). This is>20,000 times higher than the anticipated daily per capitaintake of 2-(((3-(2,3-dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine from use as a flavor ingredient.

The Panel reviewed the GRAS application and supportinginformation regarding (2R)-3',5-dihydroxy-4'-

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methoxyflavanone (CAS 1449417-52-0) and concluded thatit is GRAS (FEMA 4799) for use as a flavor ingredient in thefood categories at the use levels specified in the GRASapplication (See Table 2; Smith et al., 2005a). Thissubstance was evaluated within the context of the chemicalgroup of phenol and phenol derivatives (SLR C12; JECFA2001, 2011, 2015). The Panel noted that based on theanticipated annual volume of use (600 kg), the per capita

intake ("eaters only") of (2R)-3',5-dihydroxy-4'-methoxyflavanone from use as a flavor ingredient iscalculated to be 88 g/person/day (2 g/kg bw/day),which is below the threshold of toxicological concern forstructural class III (90 g/person/day) (Munro et al., 1996).The material was not reported to occur naturally in food.The Panel considered the specification of the material to beadequately characterized by the purity assay andsupporting spectral data provided for FEMA GRASevaluation. The Panel evaluated sensory data includedwithin the application and found it satisfactory with regardto intended conditions of use for the flavoring ingredient(Harman and Hallagan, 2013). It is anticipated that (2R)-3',5-dihydroxy-4'-methoxyflavanone would be metabolizedalong various routes: conjugation of the hydroxyl functionswith glucuronic acid and sulfate and excretion of these

conjugates; demethylation and ring-opening of theheterocyclic ring function to form the correspondinghydroxyphenylpropionic acid (Gee et al., 2000; Day et al.,2000; Donovan et al., 2006; Manach et al., 2005). (2R)-3',5-Dihydroxy-4'-methoxyflavanone did not increase reversemutations in an Ames assay in S. typhimurium strainsTA98, TA100, TA1535, TA1537, and TA1538 either in thepresence or absence of metabolic activation. The structuralanalog naringenin (FEMA 4797) gave no increases inreverse mutations were observed in Ames assays in S.typhimurium strains TA100, TA98, TA1535, TA1537,TA1538 either in the presence or absence of metabolicactivation. Based on these results, as well as on thestructure of the substance and the identity andarrangement of the functional groups therein, the Panel didnot identify specific concerns related to the potential

genotoxicity of (2R)-3',5-dihydroxy-4'-methoxyflavanone(NTP, 1992; FDA 2010a,b; Brown and Dietrich, 1979; Nagaoet al., 1981). Multiple carcinogenicity studies have beenconducted in rats for the very conservative structuralanalog quercetin (Hirono et al., 1981, 1993; Ito et al., 1989;NTP, 1992; Dunnick and Hailey, 1992; Willhite, 1982). ThePanel reviewed these studies, which provided evidence ofcarcinogenic activity in some cases, and also reviewedavailable information on the probable mode of action for anycarcinogenic activity reported. The Panel agreed with theInternational Agency for Research on Cancer conclusionthat quercetin is not classifiable as a carcinogen to humansIARC 1999). A conservative NOAEL from the 2-year dietarystudy in F344/N rats was assigned at 40 mg/kg bw/day.This is >27,000 times the anticipated daily per capitaintakeof (2R)-3',5-dihydroxy-4'-methoxyflavanone from use as a

flavor ingredient.

The Panel reviewed the natural flavor complex GRASapplication and supporting information regardingglucosylated Rubus suavissimus extract, 20-30%glucosylated rubusoside glycosides (CAS 1268518-76-8)and concluded that it is GRAS (FEMA 4800) for use as aflavor ingredient in the food categories at the use levelsspecified in the GRAS application. This material wasevaluated within the context of the procedure for the safetyevaluation of natural flavor complexes (Smith et al., 2005b).

The Panel noted that based on the anticipated annualvolume of use (1000 kg), the per capita intake ("eatersonly") of glucosylated Rubus suavissimusextract, 20-30%glucosylated rubusoside from use as a flavor ingredient iscalculated to be 147 g/person/day (3 g/kg bw/day). Theextract has a long history of use in Chinese herbal sweet teaand as an allergy remedy in Japan without known toxicity,but only qualitative data are available and thus no

consumption ratio can be calculated. The Panel consideredthe identity description of the material to be sufficient forFEMA GRAS evaluation (see Appendix 1). The Panelevaluated sensory data included within the application andfound it satisfactory with regard to intended conditions ofuse for the flavoring ingredient (Harman and Hallagan,2013). Metabolic data exist for representative members ofeach congeneric group that would predict, at the intakelevels proposed, metabolism by well-establisheddetoxication pathways to innocuous products. The Paneldid not identify specific concerns related to the potentialgenotoxicity of glucosylated Rubus suavissimus extract,20-30% glucosylated rubusoside. In a 9-week study usingmale and female obese-prone rats that were administered220 mg/kg bw/day Chinese sweet leaf tea (Rubussuavissimus) extract, which corresponds to an average

daily intake of 50 mg/kg bw of rubusoside, reduced bodyweight and reduced abdominal fat were reported. Liver andkidney weights in a low-fat diet group were slightly higherthan those that were provided a fat supplement, but therewere no effects on hematology or blood chemistryparameters (Koh et al., 2011). This dose is >20,000 timesthe anticipated daily per capitaintake of glucosylated Rubussuavissimusextract, 20-30% glucosylated rubusoside fromuse as a flavor ingredient.

The Panel reviewed the natural flavor complex GRASapplication and supporting information regarding olive fruitextract, Olea europaea (CAS 8001-25-0) and concludedthat it is GRAS (FEMA 4801) for use as a flavor ingredient inthe food categories at the use levels specified in the GRASapplication. This material was evaluated within the context

of the procedure for the safety evaluation of natural flavorcomplexes (Smith et al., 2005b). The Panel noted thatbased on the anticipated annual volume of use (200 kg), theper capita intake ("eaters only") of olive fruit extract, Oleaeuropaeafrom use as a flavor ingredient is calculated to be30 g/person/day (0.5 g/kg bw/day). The extract isderived from commonly consumed olives (Nijssen et al.,2015). The Panel considered the identity description of thematerial to be adequate for FEMA GRAS evaluation (seeAppendix 1). Metabolic data exist for representativemembers of each congeneric group that would predict, atthe intake levels proposed, metabolism by well-establisheddetoxication pathways to innocuous products (Chen et al.,1998; Bonanome et al., 2000; De la Torre et al., 2008; Tucket al., 2001; Visioli et al., 2001; de Bock et al., 2013; Carusoet al., 2001; DAngelo et al., 2001; Manna et al., 2000;

Mateos et al., 2005; Tuck et al., 2002). A related extract,olive pulp extract, increased reverse mutations in S.typhimurium strains TA98 and TA100 in the presence ofmetabolic activation, but not in TA97a, TA1535, and E. colistrain WP2uvrA either in the presence or absence ofmetabolic activation or in TA98 and TA100 in the absenceof metabolic activation. It also induced chromosomalaberrations in Chinese hamster ovary cells but only at atoxic concentration. It was negative in a rat bone marrowmicronucleus assay. The major marker constituent,hydroxytyrosol, did not increase reverse mutations in S.

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typhimuriumstrains TA98, TA100, TA1535, TA1537, and E.colistrain WP2(pKM101) either in the presence or absenceof metabolic activation, and did not increase the number ofstructural or numerical chromosomal aberrations either inthe presence or absence of metabolic activation. Based onthese data, the Panel concluded that based on weight ofevidence it did not have specific concerns related to thepotential genotoxicity of olive fruit extract, Olea europaea. A

90-day oral toxicity study in male and female rats for arelated extract, olive pulp extract, resulted in a NOAEL of2000 mg/kg bw/day. A 90-day study for hydroxytyrosol inWistar Hannover RccHan male and female rats resulted in aNOAEL of 500 mg/kg bw/day (de Bock et al., 2013; Aunon-Calles et al., 2013; D'Angelo et al., 2001). This is >1,000,000times the anticipated daily per capitaintake of olive extract,Olea europaea, from use as a flavor ingredient.

The Panel reviewed the GRAS application and supportinginformation regarding (S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one (CAS 1469426-64-9) and concludedthat it is GRAS (FEMA 4802) for use as a flavor ingredient inthe food categories at the use levels specified in the GRASapplication (See Table 2; Smith et al., 2005a). This

substance was evaluated individually within the context ofthe chemical group of miscellaneous nitrogen-containingsubstances (SLR D19, JECFA 2006, 2009, 2012, 2015). ThePanel noted that based on the anticipated annual volume ofuse (5000 kg), the per capitaintake ("eaters only") of (S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one fromuse as a flavor ingredient is calculated to be 740g/person/day (12 g/kg bw/day), which is above thethreshold of toxicological concern for structural class III (90g/person/day) (Munro et al., 1996). The material is notknown to occur in nature and thus no consumption ratio canbe calculated. The Panel considered the specification of thematerial to be adequately characterized by the purity assayand supporting spectral data provided for FEMA GRASevaluation. The Panel evaluated sensory data included

within the application and found it satisfactory with regardto intended conditions of use for the flavoring ingredient(Harman and Hallagan, 2013). (S)-1-(3-(((4-Amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one wasshown to be poorly bioavailable (%F = 0.2-1.73%). Thesubstance is oxidized to several metabolites by microsomesin vitro. Metabolism in vivo is limited but includes theformation of two main hydroxylation products. All oxidationand conjugation reactions would be anticipated to lead toreadily excretable metabolites (Arthur et al., 2015). Noincreases in the number of reverse mutations wereobserved in Ames assays for the (S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one in S.typhimuriumstrains TA98, TA100, TA1535 and TA1537 and

E. colistrain WP2uvrA. (S)-1-(3-(((4-Amino-2,2-dioxido-1H-be