Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set
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0023 Isoflavonoids are a subclass of flavonoids which
are of interest for their estrogenic activity. The main
isoflavones are daidzain and genistein, which occur in
soya beans, chickpeas, and lentils. The normal west-
ern diet contains much smaller amounts of isofla-
vones than the Chinese or Japanese diet, due to the
low level of consumption of soy products in the west.
Epidemiological studies suggest that foods containing
phytoestrogens may have a beneficial effect in pro-
tecting against several chronic and degenerative dis-
eases, including cancer. Although antioxidant effects
may be important, the estrogenic and antiestrogenic
effects, induction of cancer cell differentiation, inhib-
ition of tyrosine kinase and DNA topoisomerase
activity, and suppression of angiogenesis may be
more important.
0024 The unsaponifiable fraction of sesame oil shows
good antioxidant activity, and this is mainly attrib-
uted to sesamolin which can be hydrolyzed on heating
to sesamol which is an active antioxidant (Figure 9).
0025 Olive oil contains a mixture of antioxidants de-
rived from hydroxytyrosol and other polyphenols.
From comparisons with a limited number of phenolic
constituents, it has been claimed that hydroxytyrosol
is the most active antioxidant compound in virgin
olive oil, although the concentration of free hydroxy-
tyrosol is low. In the last few years, the antioxidant
activity of this compound and its derivatives has been
investigated in vitro. Oleuropein is an important de-
rivative of hydroxytyrosol, which occurs in large
amounts in olive leaves and olive fruits (up to 14%
of the dry weight in unripe olives), but it appears to
have a weaker antioxidant activity than free hydroxy-
tyrosol in olive oil.
0026 Phospholipids (e.g., commercial lecithin) can also
exhibit antioxidant activity in heated oils, where they
may act as hydroperoxide decomposers and/or metal
chelators. However, they appear to be less active in
oils stored at ambient temperature. Phospholipids are
present in crude vegetable oils but are removed during
oil refining. (See Phospholipids: Properties and
Occurrence.)
0027 Phenolic acids may also play important roles as
natural antioxidants.
0028 Hydroxyderivatives of cinnamic and benzoic acids
can be found in many plant foods. In oats, esters of
caffeic acid (Figure 10, e.g., chlorogenic acid) and
ferulic acid seem to be the most important anti-
oxidants. (See Phenolic Compounds.)
0029Many spices contain antioxidants, especially ore-
gano, sage, thyme, clove, ginger, and rosemary. The
main active compound of rosemary is carnesol
(Figure 11).
0030Organic acids, such as citric and ascorbic acid and
its esters, are often used as stabilizers for fats and oils.
Citric acid (Figure 12) is a very important antioxidant
because it is very effective at chelating traces of metals
such as iron and copper that have a strongly detri-
mental effect on the shelf-life of edible oils. Citric acid
is commonly added to oils at the end of the refining
process. Ascorbic acid (Figure 13) has a weaker
metal-chelating action, but it also removes oxygen
and can contribute to the oxidative stability of foods
when a limited amount of oxygen is available, e.g., in
canned foods.
O
O
HO
fig0009 Figure 9 Sesamol.
HO
O
HO
HO
fig0010Figure 10 Caffeic acid.
OH
HO
O
O
fig0011Figure 11 Carnosol.
CH
2
OH
CHOH
O
O
HO
HO
fig0013Figure 13 Vitamin C (ascorbic acid).
HOOC
HOOC OH
COOHCH
2
CH
2
C
fig0012Figure 12 Citric acid.
264 ANTIOXIDANTS/Natural Antioxidants
0031 Amino acids are powerful synergists in combin-
ation with phenolic antioxidants, acting as scavengers
of heavy metals and promoters of hydroperoxide
decomposition. Protein hydrolysates have similar
activity. Maillard reaction products (formed by the
nonenzymic reaction of amino acids and reducing
sugars) have been shown to have some activity, par-
ticularly by chelation of heavy metals. Because of
their low solubility and color, they can only be added
to certain foods. Low-molecular-weight products of
carbonyls and amino acids produced by the Maillard
reaction, such as dihydropyridines, have strong anti-
oxidant activity. (See Browning: Toxicology of Non-
enzymatic Browning.)
0032 A wide range of other natural plant components
have also been shown to have antioxidant activity,
e.g., tannins and leaf waxes.
See also: Amino Acids: Properties and Occurrence;
Antioxidants: Role of Antioxidant Nutrients in Defense
Systems; Carcinogens: Carcinogenicity Tests;
Carotenoids: Occurrence, Properties, and
Determination; Coronary Heart Disease: Antioxidant
Status; Flavor (Flavour) Compounds: Structures and
Characteristics; Oxidation of Food Components; Olive
Oil; Phenolic Compounds; Spices and Flavoring
(Flavouring) Crops: Properties and Analysis;
Tocopherols: Properties and Determination; Physiology
Further Reading
Adlercreutz H and Mazur W (1997) Phyto-oestrogens and
western diseases. The Finnish Medical Society. Annals of
Medicine 29: 95–120.
Adlercreutz H, Goldin BR, Gorbach SL et al. (1995) Soy-
bean phytoestrogen intake and cancer risk. Journal of
Nutrition 125: 757S–770S.
Albanes D (1999) Beta carotene and lung cancer: a case
study. American Journal of Clinical Nutrition 69:
1345–1350.
Baldioli M, Servili M, Peretti G and Montedoro GF (1996)
Antioxidant activity of tocopherols and phenolic com-
pounds of virgin olive oil. Journal of the American
Chemists’ Society 73: 1589–1593.
Burton GW and Ingold KU (1984) Beta-carotene – an
unusual type of lipid antioxidant. Science 224: 569–
573.
Frankel EN (1998) Lipid Oxidation. Dundee: Oily Press.
Frankel EN, Kanner J, German JB, Park E and Kiensella JE
(1993) Inhibition of oxidation of human low-density
lipoprotein by phenolic substances in red wine. Lancet
341: 454–457.
Gordon MH (1996) Dietary antioxidants in disease preven-
tion. Natural Product Reports 13: 265–274.
Herrmann K (1976) Flavonols and flavones in food plants:
a review. Journal of Food Technology 11: 433–448.
Hertog MGL, Fresken EJM, Hollman PCH, Katan MB and
Kromhout D (1993) Dietary antioxidative flavonoids
and risk of coronary heart disease: the Zutphen Elderly
Study. Lancet 342: 1007–1011.
Hsieh RJ and Kinsella JE (1989) Antioxidant: flavonoids.
Advances in Food and Nutrition Research 33: 233–341.
Hughes DA (1999) Effects of dietary antioxidants on the
immune function of middle aged adults. Proceedings of
the Nutrition Society 58: 79–84.
Khachik F, Beecher GR and Smith JC (1995) Lutein, lyco-
pene, and their oxidative metabolites in chemopreven-
tion of cancer. Journal of Cellular Biochemistry 22:
236–246.
Kritchevsky SB (1999) Beta-carotene, carotenoids and the
prevention of coronary heart diseases. Journal of Nutri-
tion 129: 5–8.
Loelinger J (1994) Natural antioxidants. In: Allen JC and
Hamilton RJ (eds) Rancidity in Foods, 3rd edn, pp. 105–
124. London: Blackie Academic and Professional.
Lunder TL (1992) Catechins of green tea. In: Huang M-T,
Ho C-T and Lee CY (eds) Phenolic Compounds in Food
and their Effects on Health II, ACS Symposium Series
no. 507. Washington, DC: American Chemical Society.
Mayne ST (1996) Beta-carotene, carotenoids and disease
prevention in humans. FASEB Journal 10: 690–701.
Rao AV and Agarwal S (2000) Role of antioxidant lycopene
in cancer and heart disease. Journal of the American
College of Nutrition 19: 563–569.
Rice-Evans CA, Miller NJ and Paganga G (1996) Structure–
antioxidant activity relationships of flavonoids and
phenolic acids. Free Radical Biology and Medicine 20:
933–956.
Rowe PM (1996) Beta-carotene takes a collective beating.
Lancet 347: 249.
Synthetic Antioxidants
G Ramis-Ramos, Universidad de Valencia, Burjassot,
Spain
Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Background
Lipid Oxidation
0001Lipid oxidation is a process that results in rancidity
and deterioration of fats and progresses via free-
radical propagated chain reactions. Free radicals are
produced by the reaction of unsaturated fatty acids
with molecular oxygen and traces of other oxidants,
as metal ions (Fe
3þ
and Cu
2þ
are particularly effect-
ive) and H
2
O
2
, and by UV light. Primary lipid oxida-
tion yields hydroperoxides that cause a variety of
secondary reactions with evolution of aldehydes,
ketones, acids, and other low-molecular-weight vola-
tile substances. The ensuing decrease in the flavor and
color quality, which renders a food unappetizing in
ANTIOXIDANTS/Synthetic Antioxidants 265
appearance, and the accumulation of toxic reaction
products pose a major problem to the food industry.
Natural and synthetic antioxidants and antioxidant
synergists are substances of low toxicity that slow
down lipid oxidation, and therefore, they are used
to increase the stability of fat components of food
under a variety of storage and cooking conditions.
0002 Further, there is ample evidence showing that
free radical oxidation plays an important role in
many pathological situations, including many types
of cancer, atherosclerosis, coronary heart disease,
rheumatoid arthritis, and other degenerative diseases.
Antioxidants are also employed in order to prevent
and treat these pathologies. Prevention arises as a
consequence of the inhibition of the formation of
toxic and mutagenic substances during storing,
cooking and in the stomach, and the modification of
the basal levels of some enzymes, which results in
increased detoxification and reduced rates of carcino-
genic activation. Other benefits derived from the
intake of antioxidants include the increased resistance
to radiation effects, assistance in the treatment of
gastroduodenal ulcer and craniocerebral injury
(including meningitis effects), and help in slowing
down the aging process.
Mode of Action and Functions of Antioxidants and
Antioxidant Synergists
0003 Some antioxidants are reducing substances that
remove oxygen and other oxidants, thus hindering
the initiation of free-radical reactions. Examples are
sulfur dioxide, sulfites, and sodium nitrite. The anti-
oxidant activity of tocopherols, alkyl gallates, and
other phenol derivatives is mainly due to resonance
stabilization of their free radicals. Stabilized radicals
are not sufficiently reactive, and the chain reaction is
terminated. The antioxidant activity of thiodipro-
pionic acid and its esters relies on a rather different
mechanism: these decompose hydroperoxides.
0004 Antioxidant synergists are substances that prevent
free-radical initiation and catalysis by complexing
metal ions. When bound to a ligand with oxygen as
the donor atom, the redox potential of metal ions as
Fe
3þ
and Cu
2þ
is largely reduced, and their catalytic
activity is seriously limited. Typical examples are
the polycarboxylic substances, including citric and
tartaric acids, and ethylenediaminetetraacetate salts.
Some antioxidants, e.g., ascorbic acid and sodium
thiosulfate, exhibit both reducing and metal ion
complexing capabilities. Phenol derivatives are free-
radical scavengers, but they are also effective in com-
plexing iron, copper, and other metal ions.
0005 When two antioxidants of a different type are
jointly used, synergistic antioxidant activity is fre-
quently achieved, although sometimes, antagonistic
inhibition can also occur. For instance, polycarboxylic
acids are often used in combination with oxygen-
reactive antioxidants, such as ascorbates and erythor-
bates, and with free radical scavengers, as butylated
hydroxyanisole (BHA) and butylated hydroxytoluene
(BHT), to achieve synergistic food protection.
0006The substances classified by the Codex Alimentar-
ius Commission (CAC) within the class ‘antioxidant’
or the subclass ‘antioxidant synergist’ are listed in
Table 1. The order of the INS code (international
numbering system for food additives) has been
followed. As shown in the table, many antioxidants
and antioxidant synergists also belong to other CAC
classes and subclasses, whose meaning is indicated in
Table 2. The subclasses are not subclassifications but
descriptions of technological functions of the addi-
tive. The equivalent or similar definitions stated by
the FDA regulation 170.3 (reg. of title 21, as all other
FDA references within the text) are also given in this
table.
0007It should be remembered that the use of antioxi-
dants is not the only way to protect food against lipid
oxidation. For instance, protection from light and
packaging under an inert atmosphere, e.g., nitrogen
gas (INS 941), using a gas-impermeable packing
material, also constitutes a nontoxic and excellent
solution.
Natural Versus Synthetic Antioxidants
0008It is customarily understood that a ‘natural’ food
additive is extracted from a vegetal source (e.g., tar-
taric acid, which is a byproduct of the wine industry)
or produced by microorganisms using substrates of
vegetal origin (e.g., this is the case for more than 99%
of the citric acid used in food), whereas a ‘synthetic’
food additive derives from the mineral oil industry or
from other mineral resources.
0009However, this division is at least excessively simple,
as can be shown with several examples. Thus, lactic
acid is a natural product that is also produced in large
amounts by a strongly competitive chemical process.
Ascorbic acid, another natural substance, is almost
exclusively produced by a process comprising several
chemical steps assisted by a single microbiological
transformation. The microbiological production of
citric acid uses glucose as the substrate, but hydrocar-
bons can also be used. Finally, bleaching, neutraliza-
tion, or esterification of the additives using reagents
that may be of natural or synthetic origin is frequently
performed to improve their technological properties.
0010The properties of food antioxidants obtained
largely or exclusively from mineral resources, or with
important concurrence of chemical procedures, are
discussed here. Where applicable, emphasis is placed
on the similarities and differences between the natural
266 ANTIOXIDANTS/Synthetic Antioxidants
tbl0001 Table 1 Substances classified by the CAC as food antioxidants or antioxidant synergists, with the exclusion of those of exclusive
‘natural’ origin
INS substance name (common acronym) (formula); selected synonyms CAC functional classes and subclasses
220 Sulfur dioxide (SO
2
); sulfurous oxide; sulfurous anhydride Preservative, antioxidant
221 Sodium sulfite (Na
2
SO
3
) Preservative, antioxidant
222 Sodium hydrogen sulfite (NaHSO
3
); sodium bisulfite Preservative, antioxidant
223 Sodium metabisulfite (Na
2
S
2
O
5
); sodium disulfite; sodium pyrosulfite Preservative, bleaching agent,
antioxidant
224 Potassium metabisulfite (K
2
S
2
O
5
); potassium disulfite; potassium pyrosulfite Preservative, antioxidant
225 Potassium sulfite (K
2
SO
3
) Preservative, antioxidant
226 Calcium sulfite (CaSO
3
) Preservative, antioxidant
227 Calcium hydrogen sulfite [Ca(HSO
3
)
2
]; calcium bisulfite Preservative, antioxidant
228 Potassium hydrogen sulfite (KHSO
3
); potassium bisulfite Preservative, antioxidant
250 Sodium nitrite (NaNO
2
) Preservative, antioxidant
300 Ascorbic acid (C
6
H
8
O
6
); L-(þ)-ascorbic acid; vitamin C; antiscorbutic factor Antioxidant
301 Sodium ascorbate (NaC
6
H
7
O
6
); L-(þ)-ascorbic acid sodium salt; vitamin C sodium salt Antioxidant
302 Calcium ascorbate (Ca C
12
H
14
O
12
.2H
2
O); L-(þ)-ascorbic acid calcium salt dihydrate Antioxidant
303 Potassium ascorbate (KC
6
H
7
O
6
); L-(þ)-ascorbic acid potassium salt Antioxidant
304 Ascorbyl palmitate (C
22
H
38
O
7
); L-(þ)-ascorbic acid 6-palmitate Antioxidant
305 Ascorbyl stearate (C
24
H
42
O
7
); L-(þ)-ascorbic acid 6-stearate Antioxidant
306 Tocopherol-rich extract (mixed tocopherol concentrate); vitamin E Antioxidant
307 Synthetic a-tocopherol (C
29
H
50
O
2
); 5,7,8-trimethyltocol Antioxidant
308 Synthetic g-tocopherol (C
28
H
48
O
2
); 7,8-dimethyltocol Antioxidant
309 Synthetic d-tocopherol (C
27
H
46
O
2
); 8-methyltocol Antioxidant
310 Propyl gallate (PG) (C
10
H
12
O
5
); n-propyl 3,4,5-trihydroxybenzoate; gallic acid propyl
ester
Antioxidant
311 Octyl gallate (C
15
H
22
O
5
); n-octyl 3,4,5-trihydroxybenzoate; gallic acid octyl ester Antioxidant
312 Dodecyl gallate (C
19
H
30
O
5
); n-dodecyl 3,4,5-trihydroxybenzoate; gallic acid dodecyl
ester
Antioxidant
313 Ethyl gallate (C
9
H
10
O
5
); ethyl 3,4,5-trihydroxybenzoate; gallic acid ethyl ester Antioxidant
314 Guaiac resin; guaiacum; guaiac gum; gum guaiac Antioxidant
315 Erythorbic acid (C
6
H
8
O
6
); isoascorbic acid; D-araboascorbic acid Antioxidant
316 Sodium erythorbate (NaC
6
H
7
O
6
); sodium isoascorbate Antioxidant
317 Potassium erythorbate (KC
6
H
7
O
6
); potassium isoascorbate Antioxidant
318 Calcium erythorbate (CaC
12
H
14
O
12
); calcium isoascorbate Antioxidant
319 tert-Butylhydroquinone (TBHQ) (C
10
H
14
O
2
); 2-(1,1-dimethylethyl)-1,4-benzenediol Antioxidant
320 Butylated hydroxyanisole (BHA) (C
11
H
16
O
2
); 3- and 2-tert-butyl-4-methoxyphenol Antioxidant
321 Butylated hydroxytoluene (BHT) (C
15
H
24
O); butylated hydroxytoluol; 2,6-di-tert-butyl-
1-hydroxy-4-methylbenzene; 2,[6]-di-tert-butyl-p-cresol; 2,6-di-tert-butyl-4-
methylphenol; 3,5-di-tert-butyl-4-hydroxytoluene; dibunol
Antioxidant
322 Lecithins; phosphatides; phospholipids Emulsifier, antioxidant synergist
323 Anoxomer (polymerized mixture of phenolic antioxidants) Antioxidant
324 Ethoxyquin (EQ, EMQ) (C
14
H
19
NO); 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline Antioxidant
325 Sodium lactate (Na[CH
3
CH(OH)COO]); sodium 2-hydroxy-propanoate Antioxidant synergist, humectant,
bulking agent
326 Potassium lactate (K[CH
3
CH(OH)COO]); potassium 2-hydroxy-propanoate Antioxidant synergist, acidity regulator
334 Tartaric acid [HOOC-CH(OH)CH(OH)-COOH];
L(þ)-2,3-dihydroxybutanedioic acid Acidity regulator, sequestrant,
antioxidant synergist
338 Orthophosphoric acid (H
3
PO
4
) Acidity regulator, antioxidant synergist
339 Sodium orthophosphates (NaH
2
PO
4
,Na
2
HPO
4
,Na
3
PO
4
) Acidity regulator, antioxidant synergist
340 Potassium orthophosphates (KH
2
PO
4
,K
2
HPO
4
,K
3
PO
4
) Acidity regulator, antioxidant synergist
341 Calcium orthophosphates [Ca(H
2
PO
4
)
2
, CaHPO
4
,Ca
3
(PO
4
)
2
] Acidity regulator, antioxidant synergist
384 Isopropyl citrates; mixture of the citric acid esters of 2-propanol Antioxidant, preservative, sequestrant
385 Calcium disodium ethylenediaminetetraacetate
(CaNa
2
[(OOCCH
2
)
2
NCH
2
CH
2
N(CH
2
COO)
2
])
Antioxidant, preservative, sequestrant
386 Disodium ethylenediaminetetraacetate (Na
2
H
2
[(OOCCH
2
)
2
NCH
2
CH
2
N(CH
2
COO)
2
]) Antioxidant, preservative synergist,
sequestrant
387 Oxystearin; mixture of glycerides of partially oxidized stearic and other fatty acids Antioxidant, sequestrant
388 Thiodipropionic acid (S[(CH
2
)
2
COOH]
2
) Antioxidant
389 Dilauryl thiodipropionate (S[(CH
2
)
2
COO(CH
2
)
11
CH
3
]
2
); didodecyl 3,3
0
-
thiodipropionate; 3,3
0
-thiodipropionic acid di-n-dodecyl ester
Antioxidant
390 Distearyl thiodipropionate (S[(CH
2
)
2
COO(CH
2
)
17
CH
3
]
2
); dioctadecyl 3,3
0
-
thiodipropionate; 3,3
0
-thiodipropionic acid di-n-octadecyl ester
Antioxidant
Continued
ANTIOXIDANTS/Synthetic Antioxidants 267
and synthetic products. The reader should resort to
section (a) ‘Natural Antioxidants’ to become familiar
with antioxidants of exclusive vegetal or micro-
biological origin, or with complementary aspects of
some of the substances discussed here.
Properties of Synthetic Antioxidants and
Antioxidant Synergists
Sulfur Dioxide, Sulfites, Bisulfites and
Metabisulfites
0011 Sulfur dioxide is a colorless gas (a liquid below
10
C or under pressure) with a characteristic,
pungent odor, more soluble in cold than in hot
water. In moist environments, sulfurous acid, which
reacts slowly with oxygen, is formed. This reaction is
accelerated at increasing pH values. Sulfur dioxide
gas is a corrosive and severe irritant. Some individuals
are extremely sensitive to the effects of sulfur dioxide,
whereas experienced workers may become adapted to
its irritating properties, e.g., cases of acclimatization
at 20–30 mgg
1
have been observed. Exposure to high
concentrations (e.g., 1000 mgg
1
) for several minutes
produces respiratory paralysis and pulmonary edema
with a risk of death. Liquid sulfur dioxide pro-
duces skin burns from the freezing effect of rapid
evaporation.
tbl0002 Table 2 Meaningoftheclassesof Table 1accordingtotheCACandequivalentdefinitionsofFDA(170.3)
AdditiveclassCACFDA
Acidityregulators(CAC)andpHcontrol
agents(FDA)
Alterorcontroltheacidityoralkalinity
ofafood
Changeormaintainactiveacidityor
basicity,includingbuffers,acids,alkalies,
andneutralizingagents
AntioxidantsProlongtheshelf-lifeoffoodsby
protectingagainstdeterioration
causedbyoxidants,suchasfat
rancidityandcolorchanges
Preservefoodbyretardingdeterioration,
rancidity,ordiscolorationduetooxidation
Color-retentionagents(CAC)andcolors
andcoloringadjuncts(FDA)
Stabilize,retainorintensifythecolor
ofafood
Impart,preserve,orenhancethecoloror
shadingofafood,includingcolor
stabilizers,colorfixatives,color-retention
agents,etc.
HumectantsPreventfoodfromdryingoutby
counteractingtheeffectofawetting
agentatmospherehavingalow
degreeofhumidity
Promoteretentionofmoisture.Include
moisture-retentionagentsandantidusting
agents
Preservatives(CAC)andantimicrobial
agents(FDA)
Prolongtheshelf-lifeoffoodsby
protectingagainstdeterioration
causedbymicroorganisms
Preservefoodbypreventinggrowthof
microorganismsandsubsequent
spoilage,includingfungistats,moldand
ropeinhibitors,andtheeffectslistedby
theNationalAcademyofSciences/
NationalResearchCouncilunder
‘preservatives’
SequestrantsCombinewithpolyvalentmetalionstoform
asolublemetalcomplex,toimprovethe
qualityandstabilityofproducts
SynergistsActorreactwithanotherfoodingredientto
produceatotaleffectdifferentorgreater
thanthesumoftheeffectsproducedby
theindividualingredients
INSsubstancename(commonacronym)(formula);selectedsynonymsCACfunctionalclassesandsubclasses
391Phyticacid[(H
2
PO
4
)
6
C
6
H
6
];myo-inositolhexakis(dihydrogenphosphate)Antioxidant
512Stannouschloride(SnCl
2
);tin(II)chlorideAntioxidant,colour-retentionagent
539Sodiumthiosulfate(Na
2
S
2
O
3
);sodiumhyposulfiteAntioxidant,sequestrant
5864-Hexylresorcinol(C
6
H
3
(OH)
2
(CH
2
)
5
CH
3
);4-hexyl-1,3-benzenediol;4-hexyl-1,3-
dihydroxybenzene; 4-hexylresorcine; 4-n-hexylresorcinol; ascaryl
Antioxidant, colour-retention agent
1102 Glucose oxidase Antioxidant
Table 1 Continued
268 ANTIOXIDANTS/Synthetic Antioxidants
0012 Sodium, potassium and calcium sulfites, hydrogen
sulfites (bisulfites), and metabisulfites exhibit almost
identical preserving and antioxidant properties to
sulfur dioxide. Thus, anhydrous sodium sulfite is
relatively stable but reacts rapidly with oxygen in
the presence of moisture; all dissolved oxygen is re-
moved in a few seconds. Commercial sodium bisulfite
consists mainly of sodium metabisulfite. Sodium and
potassium metabisulfites are irritants and possible
sensitizers.
0013 At the levels used in food, sulfur dioxide, sulfites,
bisulfites, and metabisulfites are generally recognized
as safe (GRAS); however, a small segment of the
population has been found to develop hives, nausea,
diarrhea, shortness of breath, or even fatal shock after
consuming these substances. For this reason, its use
on fresh fruits and vegetables to be sold or served raw
to consumers, or to be presented to consumers as
fresh, was banned by the Food and Drug Adminis-
tration (FDA) (182.3862, 3766, 3637, 3616). Fur-
ther, these substances decompose vitamin B
1
,andso
they cannot be used in food recognized as a source of
vitamin B
1
.
0014 Sulfur dioxide has been used in the manufacture of
wine for thousands of years to destroy bacteria,
molds, and wild yeasts without harming the yeasts
used in fermentation. Sulfur dioxide, sulfites, bisul-
fites, and metabisulfites are used as antiseptics and
bleaching agents in breweries and other fermentation
industries, and are used to retard spoilage of meat,
egg yolks, grains, dried and fresh fruits, and other
products. Sodium sulfite is allowed as a bleaching
agent for gelatin, beet sugars, and food starch (FDA
73.85), and sodium and potassium sulfites can be
used to assist caramelization (FDA 73.85).
Sodium Nitrite
0015 Sodium nitrite is an odorless, white or slightly yellow,
hygroscopic and air-sensitive solid (it slowly oxidizes
to nitrate), having both reducing and oxidizing prop-
erties. It presents a fire risk when in contact with
reducing materials; for example, it is liable to render
any organic matter (wood, paper and textiles)
dangerously combustible when dry. It is decomposed
by acids (even weak acids) with evolution of a brown
mixture of nitrogen oxides (NO
x
). It is very toxic and
dangerous to the environment, and it is an irritant
and harmful substance that may damage the cardio-
vascular and central nervous systems. (See Nitrates
and Nitrites.)
0016 Nitrates and nitrites are used in cured meat prod-
ucts, to control the growth of microorganisms, par-
ticularly to avoid the development of Clostridium
botulinum, and also to serve as color and flavor fixa-
tives. When added to meat, nitrate and nitrite react
with the myoglobin and hemoglobin present in the
trapped red blood cells, eventually producing nitric
oxide myoglobin. After curing, almost all the nitrate
and nitrite have reacted with the meat components,
and only a very small residual amount of nitrite
remains. The FDA allows the use of sodium nitrite in
smoked cured fish products (from 10 to 200 mgg
1
)
and in meat-curing preparations (< 200 mgg
1
, mixed
with sodium nitrate, FDA 172.175).
0017In the stomach, nitrite can produce dangerous
carcinogenic nitrosamines; however, these reactions
are inhibited in the presence of phenolic antioxidants,
ascorbic acid, or other substances that are also added
to food or are present in fruit and fresh vegetable
juices that may be consumed with the cured meat.
Furthermore, nitrite is naturally present in saliva, in
concentrations higher than those found in cured meat
products, and lettuce, spinach, beets, and many other
vegetables contain nitrate, which is reduced in the
mouth to nitrite by the action of bacteria. Therefore,
the risks associated with the use of nitrate and nitrite
in cured fish and meat products seem to be very small,
whereas the benefits are large.
Ascorbic and Erythorbic Acids, and their Salts and
Esters
0018Ascorbic acid is a colorless or white crystalline
powder with a pleasant, sharp, acidic taste. When
pure and dry, it is very stable, but in solution or when
moisture is present, the acid and their salts react
readily with oxygen. Oxidation is accelerated at
both low and high pH values, and is catalyzed by
metal ions, particularly for traces of copper ions.
The optimum pH for stability in aqueous solution
is 5.4.
0019Ascorbic acid occurs widely in animals and plants,
where it constitutes the primary defensive barrier
against oxidative stress. It is also required in many
metabolic functions. Today, almost all the commer-
cially available ascorbic acid is produced by synthesis.
A process in common use (Reichstein–Gru
¨
ssner second
synthesis, 1934) starts with d-glucose and combines
chemical and microbiological steps. Natural and
synthetic ascorbic acid are exactly the same product,
with identical biological activity; however, synthetic
ascorbic acid is more economical, and frequently
purer (and, therefore, more stable) than the product
that can be extracted from lemons and other vege-
tables.
0020Ascorbic acid and its salts are added to food as
preservatives and antioxidants, to prevent the oxida-
tion of dyes, thus preserving color during storage and
cooking. They are used in the preparation of beer,
fruit juices, and canned and frozen vegetables and
fruits, to prevent browning of cut apples and other
ANTIOXIDANTS/Synthetic Antioxidants 269
fruits, and in the flour industry to enhance baking
quality and appearance of bread. Ascorbic acid is
also added together with nitrite to bacon and other
cured meat products to avoid the formation of
carcinogenic nitrosamines. Ascorbic acid does not
protect oils and fats as it is not fat-soluble. For this
purpose, the fat-soluble hydrophobic esters ascorbyl
6-palmitate and ascorbyl 6-stearate are used.
0021 Ascorbic acid is also used in nutrition as a dietary
supplement in the treatment of vitamin C deficiency.
It cures scurvy and acts as an oxidation–reduction
catalyst in the cell, thus increasing resistance to infec-
tion. It also helps in the prevention of prostate cancer.
It may aid in lowering the blood cholesterol level and
slows down the aging process. When serum levels of
ascorbic acid are high, synovial fluid becomes thinner,
allowing freer movements and reducing arthritic
pain.
0022 Pure ascorbic acid is moderately toxic and irritat-
ing; there have been cases of allergic reaction with
eczema, urticaria, and asthma. Ingestion of large
amounts (10 g or more) may cause gastrointestinal
distress and diarrhea, and increases the excretion of
oxalic acid. Urinary and blood uric acid also rise as a
result of a high intake of ascorbic acid, and these
factors may increase the risk of kidney or bladder
calculi. Finally, the mucolytic effect of ascorbic acid
might render the cervical mucus less permeable to
spermatozoa.
0023 Erythorbic or isoascorbic acid, the epimer of
l-ascorbic acid, has the same redox potential but only
one-twentieth of the vitamin C activity of l-ascorbic
acid. It is prepared by treating methyl 2-keto-
d-gluconate with sodium methoxide, although it
can also be produced by microorganisms. Sodium
erythorbate has the same antioxidant, preservative,
and color stabilizer properties as sodium ascorbate. It
is used in soft drinks, and poultry and meat curing.
When sodium nitrite is added to cure meat, erythorbic
acid is also used to inhibit undesirable nitrite reac-
tions. A brief dip in a bath containing 0.25% citric
and 0.25% erythorbic acid improves quality reten-
tion in frozen fish. This treatment is also applicable
to shellfish to sequester iron and copper ions that
catalyze bluing and darkening reactions. (See Ascor-
bic Acid: Properties and Determination.)
Tocopherols
0024Vacuum steam distillation of cereal grain, soybean,
and other vegetal oils yields a red, almost odorless,
viscous oil, unstable on exposure to heat, light, and
oxygen, that is a mixture of the four more abundant
forms of vitamin E, i.e., the a-, b-, g-andd-toco-
pherols. The proportion of the four forms varies
widely from one vegetal source to another. The most
biologically active of the four is a-tocopherol, which
plays several important roles in metabolism, includ-
ing cellular respiration, effective use and storage of
vitamin A, protection of B-complex and vitamin C
from oxidation reactions, and protection of cellular
membranes and body tissues from damaging reac-
tions caused by free radicals. The other members of
the vitamin E family also have important functions,
some of them similar to those of a-tocopherol,
whereas others are different and unique. (See Toco-
pherols: Properties and Determination.)
0025As shown in Figure 1, the differences between the
natural tocopherols are due to the number and
position of the methyl groups on the aromatic ring.
Tocopherols other than a-tocopherol can be con-
verted to this form of vitamin E by methylation of
the aromatic ring. Tocopherols also have three asym-
metric carbon atoms (one on the chromane hetero-
cyclic ring and the other two on the alkyl chain),
whose configuration is of prime importance for their
biological activity. The three carbon atoms of natural
tocopherols have the R configuration, e.g., natural
a-tocopherol is the 2R,4
0
R,8
0
R-a-tocopherol or
(RRR)-a-tocopherol isomer.
0026Synthetic a-, b-, g-, and d-tocopherols can be pro-
duced by condensation of the appropriate tri-, di-, or
monomethylhydroquinone with synthetic isophytol
(see Figure 2). In each case, a racemic mixture of the
2
3
¼ 8 possible diastereoisomers or all-rac- mixture is
obtained; for instance, 2,3,5-trimethylhydroquinone
yields all-rac-a-tocopherol. All the isomers have
HO
6
R
2
8
O
1
2
3
4
5
4⬘ 8⬘
CH
3
CH
3
CH
3
CH
3
CH
3
R
3
R
1
7
fig0001 Figure 1 Molecular structure of tocopherols, where R
1
—
—
R
2
—
—
R
3
—
—
CH
3
is a-tocopherol; R
1
—
—
R
3
—
—
CH
3
and R
2
—
—
Hisb-tocopherol;
R
2
—
—
R
3
—
—
CH
3
and R
1
—
—
Hisg-tocopherol; R
1
—
—
R
2
—
—
H and R
3
—
—
CH
3
is d-tocopherol.
270 ANTIOXIDANTS/Synthetic Antioxidants
similar antioxidant activities, but their biological
values differ widely, e.g., (SRR)-a-tocopherol (the 2S
epimer) has only 21% of the biological activity of the
natural (RRR)-a-tocopherol. In the body, the ‘incor-
rect’ configurations are rapidly excreted, thus, on a
weight basis, the synthetic all-rac-a-tocopherol is a
much less potent vitamin E than the corresponding
(RRR)-a-tocopherol.
0027 The use of 2,3,5-trimethylhydroquinone and nat-
ural phytol (which is a pure RR isomer) results in a
racemic mixture of only the two (SRR)-a- and (RRR)-
a-tocopherol isomers (this latter identical to the nat-
ural product) which is called 2-ambo-a-tocopherol;
2-ambo-mixtures of the b-, g - and d-tocopherols
can be synthesized in a similar way. Procedures to
synthesize the pure (RRR)-isomers have also been
described.
0028 Both natural and synthetic a-tocopherols are con-
sidered as GRAS and can be used as food additives
(FDA 184.1890). The recommended dietary intake
(RDI) of vitamin E is 30 IU (FDA 101.9) and should
be present in infant formulas (FDA 107.100). Toco-
pherols are used as a dietary supplement, as inhibitors
of nitrosamine formation in bacon and other cured
meat products, and to prevent rancidity in both
chicken and turkey meats during refrigeration or
frozen storage. Tocopherols are largely destroyed by
cooking and canning. Large amounts of tocopherols
are consumed to protect animal feeds, primarily in
the poultry industry, and also as supplements and
concentrates for cattle and other meat production
industries. Finally, vitamin E is used to protect other
substances, e.g., vitamin A and unsaturated lipids,
during the shelf-life and in the gastrointestinal tract,
and to improve the in vivo biostability and bio-
compatibility of medical devices made of polyether-
urethane elastomers.
0029Tocopheryl acetates and succinates are used in
pharmaceutical preparations. The esters are less re-
active than the corresponding free tocopherols, and
thus the shelf-life is much longer. The tocopherols are
liberated in the stomach where the ester bonds are
readily cleaved off. The international units of vitamin
E were standardized on the basis of the all-rac-a-
tocopheryl acetate (1 IU ¼1 mg), because this mix-
ture is the principal commercial form of vitamin E;
1mgof(RRR)-a-tocopheryl acetate equals 1.36 IU.
Alkyl Gallates, BHA, BHT, and Related Compounds
0030The molecular structures of these phenolic antioxi-
dants are shown in Figure 3. As occurs with other
phenols, the antioxidant action of alkyl gallates, tert-
butylhydroquinone (TBHQ), BHA, and BHT mainly
relies on their ability as free radical scavengers. In
contrast to tocopherols, ascorbic acid, and other anti-
oxidants, the antioxidant properties of these phenol
derivatives are not lost during cooking. According to
the FDA, these antioxidants can be added to food
products whether singly or in combination of two or
more, up to 0.02%, based on the weight of the fat or
oil content in the food product.
0031Propyl gallate (PG) is a white to nearly white odor-
less crystalline powder that has slightly bitter taste
and darkens in the presence of iron salts. It is an
OH
HO
HO
CH
3
CH
3
CH
3
CH
3
CH
3
R
1
R
2
R
3
+
H
2
C
fig0002 Figure 2 Condensation of 2,3,5-trimethylhydroquinone with synthetic isophytol yields all-rac-a-tocopherol, a racemic mixture of
eight diastereoisomers.
COOR
HO
OH
OH
OR
OH
C(CH
3
)
3
(CH
3
)
3
C
OH
CH
3
C(CH
3
)
3
I II III
fig0003 Figure 3 Molecular structures of alkyl gallates (I), tert-butylhydroquinone (II with R ¼ H), butylated hydroxyanisol (II with R ¼ CH
3
is
the 2-tert-butyl isomer) and butylated hydroxytoluene (III).
ANTIOXIDANTS/Synthetic Antioxidants 271
irritant that can cause skin dryness, dermatitis, and
sensitization. Inhalation may cause chemical pneu-
monia. PG is used to stabilize cosmetics, food pack-
aging materials, and foods including edible fats, oils,
mayonnaise and other emulsions, shortening, baked
goods, candy, dried meat, fresh pork, sausage, and
dried milk. The antioxidant activity of PG is synergic
with acids, BHA and BHT. It also shows antimicro-
bial activity, has been reported to be an effective
antioxidant-based hepatoprotector, and has been
shown to prevent neuronal apoptosis.
0032 PG is markedly hydrophillic, and so its solubility in
fats is limited. Substitution of the propyl chain by a
shorter (ethyl) or longer (octyl or dodecyl) chain,
respectively, decreases or increases fat solubility.
Propyl, octyl, and dodecyl gallates (< 0.02%) indi-
vidually or in combination with BHT, BHA, and
ascorbyl palmitate and stearate can be added to mar-
garine (FDA 166.110). Alkyl gallates, although quite
effective, can cause discoloration of food substrates,
and may also impart off-flavors. Propyl gallate is also
used for other industrial purposes, e.g., added to
ethers and aldehydes to prevent peroxidation.
0033 TBHQ is sometimes added to food as an anti-
oxidant, and it is also produced in the body as the
common metabolite of the two BHA isomers. It is a
tan-colored powder with acute irritating properties. It
is most effective against oxidation in polyunsaturated
vegetal oils, and is often added to soybean oil.
0034 Commercially available food-grade BHA is gener-
ally a mixture containing two positional isomers,
3-tert-butyl-4-methoxyphenol (> 85%) and 2-tert-
butyl-4-methoxyphenol (< 15%). It is a white or
slightly yellow waxy solid, has an aromatic odor
and a slightly bitter burning taste, and degrades
following prolonged exposure to sunlight. It is toxic
by ingestion, and there is sufficient evidence that it is
carcinogenic in animals. It dissolves readily in molten
fats, and its antioxidant properties are synergic with
acids, BHT, alkyl gallates, hydroquinone, methio-
nine, lecithin, and thiodipropionic acid. At low
concentrations, it is used as an antioxidant in fat-
containing foods, in edible fats and oils, and as a
preservative and antioxidant in cosmetic formula-
tions.
0035 BHT is a white crystalline powder. Contact causes
irritation, and inhalation produces lung injury.
Depending on the intensity and duration of exposure,
effects may vary from mild irritation to severe de-
struction of tissue. It is more hydrophobic and there-
fore more soluble in oils and fats than BHA and
TBHQ. It is normally used in combination with citric
acid in fats and oils, and with phosphate for meat
systems. It is also used to protect rubber, plastics, and
other industrial products.
0036BHT combines low costs with heat stability, good
antioxidant activity, and high fat solubility, and
thus not surprisingly has been the most widely used
antioxidant in food in the last quarter of the twentieth
century; however, continuing concern over its safety
has resulted in decreased usage. Both carcinogenic
and anticarcinogenic properties have been reported
for BHA and BHT. Thus, metabolites of BHT can
promote tumors and produce DNA damage in mice.
However, BHT has been found to inhibit the initi-
ation of hepatocarcinogenesis by aflatoxin B1. A
study performed in The Netherlands among 120 852
men and women over 6.3 years showed no significant
association with stomach cancer risk for an intake of
low levels of BHA and BHT. However, when exces-
sively concentrated, phenolic compounds can pro-
mote undesired oxidative or degenerative reactions,
e.g., natural flavonoids show a marked prooxidant
effect that is due to the chain-initiating activity of the
radicals formed during inhibition; however, BHA and
BHT have no prooxidant activity.
0037Anoxomer is a complex polymeric substance with a
molecular weight of 4500–5000. For its use in food,
no more than 5% of the polymer should be greater
than 50 000 Da, and no more than 1% of the polymer
should be less than 500 Da. It is prepared by conden-
sation polymerization of m- and p-divinylbenzene
with TBHQ, tert-butylphenol, hydroxyanisole,
p-cresol, and 4,4
0
-isopropylidenediphenol. Anoxo-
mer should be used as an antioxidant at a level no
greater than 0.5% of the fat and oil content of foods
(FDA 172.105). Gallic acid esters, BHT, BHA, and
TBHQ have high vapor pressures at temperatures
above 150
C, and so they are readily lost from ther-
mal processes generating steam. This does not occur
with anoxomer. In addition, in contrast to the mono-
meric phenolic antioxidants, pure anoxomer is not an
irritant, thus possibly indicating a greater biological
tolerance.
0038Although not collected in the INS list, there are
other phenols with antioxidant properties similar
to those exhibited by BHA and BHT, and which
have also been used as food additives. Thus, 2,4,5-
trihydroxybutyrophenone (THBP) (C
10
H
12
O
4
)or
2,4,5-trihydroxy phenyl propyl ketone has been
used as antioxidant for polyolefins, paraffin waxes
and food. Nordihydroguaiaretic acid (NDGA) or
4,4
0
-(2,3-dimethyl-tetramethylene)dipyrocatechol is
a natural antioxidant. It can be extracted from an
evergreen desert shrub, the creosote bush, Larrea
divaricata, and can also be prepared by hydrogen-
ation and subsequent demethylation of the guaiaretic
acid dimethyl ether, a constituent of gum guaiac. It is
added to fats and oils. The molecular structures of
THBP and NDGA are shown in Figure 4.
272 ANTIOXIDANTS/Synthetic Antioxidants
Ethoxyquin
0039 Ethoxyquin (EQ) (see Figure 5) is a clear, viscous,
light yellow to dark brown liquid, with an unpleas-
ant, mercaptan-like smell, that causes irritation of the
skin and eyes. It is absorbed through the skin, and is
moderately toxic by ingestion. It darkens on exposure
to light and air and tends to polymerize, particularly
at temperatures above 160
C (hazardous exothermic
reaction). EQ is considered a highly effective anti-
oxidant, is cheap and has a very long shelf-life. It
has been the antioxidant of choice in pet food for
many years, although it has also been added to other
animal feeds and human food. Concern about its
toxicity (not yet sufficiently investigated) has pro-
moted the alternative use of tocopherols in pet food,
in spite of the higher prices and increasing demand of
tocopherols for human consumption. EQ is also used
as an insecticide, herbicide, fungicide, postharvest dip
to prevent scald on apples and pears, plant growth
regulator, and antidegradation agent for rubber.
Sodium and Potassium Lactates
0040 Lactic acid is present in many foods both naturally
and as a product of in situ fermentation, as in sauer-
kraut, yogurt, and many other fermented foods.
Lactic acid is also a principal metabolic intermediate
in most living organisms. Sodium and potassium lac-
tates are produced commercially by neutralization of
natural or synthetic lactic acid (FDA 184.1768,
1639). Lactic acid to be used as a food additive can
be obtained either by fermentation of carbohydrates
or by a chemical procedure involving formation of
lactonitrile from acetaldehyde and hydrogen cyanide
and subsequent hydrolysis (FDA 184.1061).
0041The microbiological and chemical procedures to
obtain lactic acid are very competitive, with similar
production costs. One method of biosynthesis in
common use starts with glucose and produces pyru-
vate, which can be converted to both the l(þ)and
d() isomers using a stereospecific lactate dehydro-
genase; however, only the l(þ) form is produced
commercially. The racemic mixture is always
obtained by chemical synthesis. Synthetic lactic acid
is free of the contaminants normally found in the
product obtained by fermentation, and so it is com-
pletely colorless and probably more stable. Lactic
acid and its salts are highly hygroscopic, and there-
fore are usually handled in concentrated solutions
(60–80% by weight) rather than in solid form.
These solutions are colorless and odorless, and have
a mild saline taste.
0042Lactates complex metal ions, thus improving the
stability of food against oxidation. Sodium lactate is
used as a pH regulator and antimicrobial, humectant,
curing, pickling, and flavor enhancing agent in meat,
poultry, seafood, and many other products; potassium
lactate is used to replace sodium lactate in low-sodium
products. The calcium salt of lactic acid is a good
dough conditioner, and the sodium salt is both a con-
ditioner and an emulsifier for yeast-leavened bakery
products. The addition of aqueous solutions of lactic
acid and its salts during processing of carcasses, par-
ticularly those of poultry and fish, increases shelf-life
and reduces the growth of anaerobic spoilage organ-
isms such as Clostridium botulinum. Sodium lactate is
also used as a moisturizer in skin-care products, to
supplement the skin’s own naturally occurring sodium
lactate, as well as in a wide variety of industrial appli-
cations. (See Clostridium: Botulism.)
Orthophosphoric Acid and Orthophosphates
0043The antioxidant synergism of orthophosphoric acid
and its salts is a result of their ability to complex
metal ions. The redox potential of the Fe
3þ
/Fe
2þ
pair
is particularly lowered in the presence of phosphates,
OH
OH
OH
OH
HO
HO
HO
O
CH
3
CH
3
CH
3
THBP NDGA
fig0004 Figure 4 Molecular structures of 2,4,5-trihydroxybutyrophenone and nordihydroguaiaretic acid.
CH
3
CH
2
O
CH
3
CH
3
CH
3
N
H
fig0005 Figure 5 Molecular structure of ethoxyquin.
ANTIOXIDANTS/Synthetic Antioxidants 273