Inactive Ingredients / Excipients in Supplements
Review Article
Inactive Ingredients in
Vitamins and Supplements. Find Out Why Coloring Agents, Sweeteners, Fillers
& Other Inactive Ingredients Are In Your
Supplements and If They're Safe.
Medically reviewed and
edited by Tod Cooperman, M.D. 
Last Updated
: 12/06/2021 | Initially Posted:
05/11/2007Latest Update: Can a Natural Colorant Cause Adverse Effects?
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Summary
·
What are Inactive Ingredients?Inactive ingredients are inert substances
added to dietary supplements to help form and/or enhance the consistency of
formulations — for example, to add color or bulk, to improve resistance to
moisture, or to increase shelf life. These can include coating and coloring
agents, binders, fillers, and thickeners, disintegrants, emulsifiers, flavor
and flow agents, preservatives, and humectants (see Types and Examples of Acceptable Inactive Ingredients).
·
How do I know if my supplement contains preservatives,
artificial colors, flavorings, or other inactive ingredients? Inactive ingredients are
listed in the Supplement Facts Panel on dietary supplement labels as
"Other Ingredients" (also referred to as "excipients")
following the list of Active Ingredients (see Where to Look on the Label). ConsumerLab also provides the full list of ingredients,
including Inactive Ingredients, for each supplement it tests in the Results
tables in its Product Reviews.
·
Are Inactive Ingredients regulated by the FDA? All inactive
substances used to make dietary supplements are regulated as food additives.
Every inactive supplement ingredient must be (1) an approved food additive
(this includes color additives) or (2) a generally recognized as safe (GRAS)
substance based either on (a) the FDA GRAS list or (b) being a
"self-affirmed GRAS substance," i.e., having been safely used in
foods after 1997 (see How the FDA Regulates Inactive Ingredients in Supplements).
·
What are common Inactive Ingredients in supplements? Are they
safe? Learn
about different types of Inactive Ingredients, why they are used, and safety
information:
·
Binding agents (such as cellulose and
magnesium stearate)
·
Coloring agents (such as FD&C Yellow
No. 5, Yellow No. 5 and titanium dioxide)
·
Fillers
·
Flow agents (silicone dioxide, talc,
polyethylene glycol (PEG) and others)
·
Preservatives (citric acid, potassium
benzoate and others)
·
Sweetening agents (Spenda,
NutraSweet, xylitol and others)
Also see Cautions and Concerns.
Consumers often wonder
about ingredients they see listed as "Other Ingredients" on
supplement labels. This article is designed to help you understand what these
ingredients do and how they are regulated.
Where to Look on the
Label:
When you look at a
properly labeled dietary supplement, you will notice that ingredients are
listed in two areas. The most prominent is a box known as the Supplements Facts
panel. Listed there are the active ingredients, i.e., the compounds in a
product intended to supplement the human diet (herbs, vitamins, minerals,
bacteria, plant and animal extracts, etc.). Typically
right after this box is a list of "Other Ingredients." Here you will
find the "inactive ingredients" (also referred to as excipients),
which are more or less inert substances used to help form and enhance the
consistency of the dietary supplement product, (e.g., add flavor, color, bulk,
help with stabilization, shelf-life, resistance to moisture, etc.).
On ConsumerLab.com, you can view the labeled ingredients for every product that
appears in a report.
How the FDA Regulates
Inactive Ingredients in Supplements:
Dietary supplements are
regulated as foods and all inactive substances used to make dietary supplements
are regulated as food additives. Every inactive supplement ingredient must be
(1) an approved food additive (this includes color additives) or (2) a
generally recognized as safe (GRAS) substance based either on (a) the FDA GRAS
list or (b) being a "self-affirmed GRAS substance," i.e., having been
safely used in foods after 1997. A dietary supplement manufacturer wishing to
use an ingredient (active or inactive) that was not used as a food ingredient
before 1994 must notify the Food and Drug Administration (FDA) along with
evidence of the safety of the ingredient at least 75 days before marketing a
product containing the ingredient. FDA will acknowledge the notification and
within 75 days of receiving it inform the manufacturer if it considers the
evidence provided inadequate to establish the safety of the substance. If FDA
does not respond within 75 days of notification the ingredient may be used as
described by the manufacturer in the notification. Because this is a
notification, rather than an approval process, FDA may at a later date prohibit
the use of the ingredient if new information indicating lack of safety becomes
available.
Types and Examples of
Acceptable Inactive Ingredients:
Inactive ingredients are classified as binders, coatings,
colors, disintegrants, emulsifiers, fillers, flavorings, flow agents,
humectants, preservatives, solubilizing and dispersing agents, sweeteners and
thickeners. Below you will find a description of these terms and examples of
each type of excipient.
Binding agents help the ingredients used to make a
tablet hold together. Commonly used binders include: cellulose, ethyl
cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate,
methylcellulose, microcrystalline cellulose, polyethylene glycol (PEG),
povidone, sorbitol, starch, and xylitol. Rarely, anaphylactic shock has been
reported in people taking large doses of polyethylene glycol (PEG 3350,
236 g) as part of an electrolyte solution given prior to a colonoscopy
procedure (Lee, Intest
Res 2015).
Coating agents are used to protect a tablet
from breaking in the bottle, prevent it from absorbing moisture while in
storage, or to allow it to pass through the acid environment of the stomach
without disintegrating (enteric coating) so that it can release its contents in
the intestines. Gelatin, which is derived from animal cartilage, is used to
form hard-shelled capsules and soft gels. Vegetarian capsules are formed from
cellulose.
Ingredients commonly used in normal coatings include: beeswax, carob extract,
glyceryl triacetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, microcrystalline cellulose and triethyl citrate. Those often
used as enteric coatings are methacrylic acid co-polymers, cellulose acetate
(and its phthalate, succinate or tetrahydrophtalate
versions), styrol maleic acid co-polymers, poly
methacrylic acid/acrylic acid co-polymers, polyvinyl alcohol, hydroxypropyl
methylcellulose phthalate, acrylic resin and shellac.
Coloring agents are used to provide consistent
color and/or enhance appearance. Certified color additives are listed by their
specific or abbreviated name, e.g., "FD&C Yellow No. 5" or
"Yellow No. 5". Uncertified or "exempt" color additives are
listed as "Artificial Color" or "Color Added" or by the
common or usual name of the color. Commonly used coloring agents include:
annatto, caramel color (including Caramel IV), beet juice
color, turmeric, Blue 1 Lake, FD&C Blue No. 1, FD&C Red No. 3, FD&C
Red No. 40, FD&C Yellow No. 5, Red 40 Lake, Yellow 5 Lake and Yellow 6
Lake.
Some research suggests artificial colors may worsen symptoms in some children
with hyperactivity or attention deficit disorder with hyperactivity (ADHD) (McCann, Lancet 2007; Nigg, J Am Acad Child Adolesc
Psychiatry 2012). However, the FDA has stated that "a
causal relationship between exposure to color additives and hyperactivity in
children in the general population has not been established," and that
"findings from relevant clinical trials indicate that the effects on their
behavior appear to be due to a unique intolerance to these substances and not
to any inherent neurotoxic properties." (FDA 2011; FDA 2014). The FDA
Committee on Hypersensitivity to Food Constituents also noted that FD&C
Yellow No. 5 might cause hives in sensitive people (estimated to be less than
one out of 10,000 people), and therefore this color must be identified on the
label as an ingredient (FDA 2010).
Purple carrot root
powder is a coloring agent, and there is some evidence that it may help protect
other ingredients in supplements from oxidation (Assous, Ann Agric Sci 2014). Be aware that
ingestion of carrots can cause a condition called oral allergy syndrome or
pollen-food allergy syndrome in some people, particularly those who are
allergic to birch pollen. In most cases, symptoms of this condition include
itchy mouth, lips or through, mild swelling inside the mouth, watery eyes, and
runny nose. In very rare cases, this condition might lead to severe symptoms
such as chest tightness, and at least one case of anaphylaxis was reported in
an individual with a carrot-induced allergic reaction following ingestion of
ice cream containing carrot juice as a dye (Schiappoli, Allergol Immunopathol (Madr) 2002).
Whitening agents
Another common coloring agent is titanium dioxide, which
is often used to make pills white. It is an approved food coloring agent in the
U.S., appearing in chewing gum and sugar-coated candies, and is also common
ingredient in sunscreen, cosmetics and medications. It can represent up to 1%
of the formulation of a food or supplement (i.e., a 500 mg tablet may contain
up to 5 mg).
There is concern with titanium dioxide as a possible carcinogen. In-vitro and
animal studies suggest it could cause cellular damage or be carcinogenic when
directly inhaled or taken orally in large doses (Yu, Cell Biosci 2011),
but there is little research on its effect on humans when ingested. For this
reason, the International Agency for Research on Cancer (IARC) division of the
World Health Organization, has classified it as " possibly
carcinogenic to humans " (WHO IARC Titanium Dioxide Monograph). In addition, a study in mice suggests that titanium dioxide may
increase inflammation and permeability in the gut, which could potentially
increase susceptibility to inflammatory diseases and colorectal cancer --
although this has not been studied in people. In the mice, daily doses of
titanium dioxide of 2, 10 or 50 mg per kilogram of bodyweight for one month
significantly altered the release of substances produced by bacteria in the
digestive tract, resulting in higher levels of certain inflammatory markers and
decreased amounts of fatty acids that help to protect the gut. The changes were
more pronounced at the highest dose (50 mg/kg) but still significant at lower
doses — which are similar to the estimated daily intake of titanium dioxide by
adults of 0.7 to 5.9 mg per kg of body weight from foods, supplements, and
confectionery products (Pinget, Front Nutr 2019).
In 2021, the European Food Safety Agency (EFSA) re-examined
the available safety data for titanium dioxide, which, as noted above, is
primarily based on animal studies. The agency noted that although absorption of
ingested titanium dioxide particles is low, the particles may accumulate in the
body and may be immunotoxic and have the potential to
induce DNA strand breaks and chromosomal damage. The EFSA concluded that,
"on the basis of all currently available evidence along with all the
uncertainties..." titanium dioxide "can no longer be considered as
safe when used as a food additive." (Younes, EFSA J 2021).
This is a scientific decision does not represent a ban on titanium dioxide at
the present time, but it will be used by the European Commission and member
countries to determine possible regulatory actions (EFSA Newsroom).
Given the lack of evidence based on effects on people, it is not clear whether
titanium dioxide is harmful to people when taken in the small quantities found
in supplements. However, if you prefer to avoid this ingredient, ConsumerLab provides the full list of ingredients, as well
as label statements about ingredients of concern, for each of the products it
tests its Results tables its Product Reviews. For example, some products
list "free of titanium dioxide" on the label.
Disintegrants expand when exposed to
liquid, allowing tablets and capsules to dissolve and disperse their active
ingredients in the GI tract. Commonly used disintegrants include: cellulose,
croscarmellose sodium, crospovidone, microcrystalline
cellulose, sodium carboxymethyl cellulose, sodium starch glycolate and starch.
Emulsifiers help fat-soluble ingredients
and water-soluble ingredients mix together in a way that they won't separate.
Commonly used emulsifiers include: stearic acid, xanthan gum, lecithin and
other vegetable oils.
Fillers (also called diluents) are
used to increase the bulk or volume of a product when only small amounts of the
active ingredient are needed for each dose. The addition of fillers allows for
the manufacture of products that are easy and convenient to handle or measure.
Commonly used fillers include: calcium carbonate, calcium sulfate, cellulose,
dibasic calcium phosphate, lactose, lecithin, mannitol, sorbitol, sucrose, and
starch, such as pregelatinized corn starch or modified corn starch. (Note that
the word "modified" refers to starch that has been altered during
processing, with the use of heat, enzymes, or chemicals; it does not refer to
genetically modified (GMO) corn starch — however, it's possible, if not likely,
that modified corn starch in some supplements is derived from a GMO corn crop,
as corn is one of the most common GMO crops in the U.S. and is permitted in
foods (FDA 2015). Oils and
fats, such as olive oil, are often used as fillers in soft capsules (softgels).
Flavor agents are used to create a desired
taste or mask an unpleasant taste. Commonly used flavorings include: beeswax,
carob extract, glyceryl triacetate and natural orange flavor.
Flow agents prevent powder mixtures from clumping
and sticking to machinery used to form capsules and tablets. Commonly used flow
agents include: calcium stearate, glyceryl triacetate, magnesium stearate,
maltodextrin, polyethylene glycol (PEG), silica, silicone dioxide, sodium
benzoate, stearic acid and talc. Another flow agent, silicon dioxide (or
silica), is recognized as safe by the FDA (so long as it does not exceed 2% of
the weight of a food) as it is believed to be poorly absorbed; however, the
European Food Safety Authority has expressed concern about nano-sized particles
of silicon dioxide and their potential to be absorbed into the body and it has
urged the European Union to impose stricter guidelines on silicon dioxide until
further research is conducted (EFSA, January 2018).
Humectants help hold moisture in a finished
product. Commonly used humectants include: glycerin (glycerol), glyceryl
triacetate (triacetin), and sorbitol. Propylene glycol is another humectant
which is also used as a solvent. Propylene glycol is generally recognized as
safe by the FDA in the amounts used in supplements although it can be toxic if
ingested in large quantities.
Preservatives are used prevent
degradation and extend the shelf life of products. Preservatives are listed by
their usual or common name followed by a description of their function e.g.,
"preservative", "to help protect flavor", etc. Commonly
used preservatives include: citric acid, glycerin (glycerol), potassium
benzoate, potassium sorbate, sodium benzoate, sodium citrate, and antioxidants
such as vitamin C and vitamin E. BHT (butylated hydroxytoluene), a synthetic
antioxidant compound, is also used to help preserve ingredients in some
supplements; while generally recognized as safe (GRAS) when used in amounts
commonly found in food and supplements, the FDA has stated there are
"uncertainties" that require additional research (namely, potential
effects on liver enzymes and interactions with oral contraceptives found in
some animal studies when taken in much larger amounts (over 50 mg/kg of bodyweight
per day, i.e., for 3.5 grams per day for an adult) than would be found in a
tablet (FDA 2015).
Potassium sorbate, made from sorbic acid and potassium
hydroxide, prevents the growth of yeasts and molds. It may be added as a
preservative to a wide variety of products, from cosmetics and pet food, to
wine, yogurt, jellies, dried fruits, sausage and dried meats, and other foods,
as well as supplements, typically in very small amounts. Even at relatively
high doses used in laboratory and animal studies, potassium sorbate and/or
sorbic acid, have generally not been found to have genotoxic or carcinogenic
effects. The EFSA (the European equivalent of the FDA) has established an
acceptable daily intake of 11 mg/kg of bodyweight (about 748 mg per day for a
150 lb. adult) for sorbic acid and potassium sorbate; this preservative has the
potential for contamination with toxic heavy metals such as lead, mercury and
arsenic, and the EFDA panel recommended limits for contamination be established
(Younes, J EFSA 2019).
The body may absorb potassium from potassium sorbate, while the sorbic acid is
excreted as carbon dioxide when breathing (during exhalation); potassium
sorbate as a compound does not accumulate the body. Applied topically, high
concentrations of potassium sorbate may cause skin irritation, but formulations
containing up to 0.5% sorbic acid and or potassium sorbate have not been found
to have this effect (J Med Tox 1988).
Solubilizing and dispersing agents are
similar to emulsifiers, allowing certain ingredients to mix. A commonly used
agent is polysorbate 80 (polyoxyethylene (20) sorbitan
monooleate) (FDA Food Additive Status List).
Sweetening agents are used to improve the
taste or appeal of a product. Commonly used sweeteners include: aspartame
(NutraSweet®) (phenylalanine), fructose (corn syrup), glycerin, maltodextrin,
sorbitol (and other sugar alcohols), sucralose (Splenda®), sucrose, and
xylitol.
Thickening agents increase the viscosity
(thickness) of liquids. Commonly used thickeners include: carrageenan and
other alginates, methylcellulose, povidone, and sorbitol.
ConsumerTips™:
Some people may wish to avoid specific excipients based on dietary, religious,
or other personal preferences. As an example, gelatin is used to make capsules
and is derived from animal cartilage. As an alternative, people who adhere to a
vegetarian diet can select vegetarian capsules made with cellulose.
Read product labels carefully to avoid excipients that you wish to avoid. On
ConsumerLab.com, you can view the labeled ingredients for every product that
appears in a Review.
Concerns and Cautions:
Excipients
are generally considered to have little or no effect on the body. However, some
people are unable to tolerate specific excipients. People with phenylketonuria
are cautioned to avoid products containing the artificial sweetener, aspartame
(NutraSweet®). In the United States, all products containing aspartame must be
labeled: "PHENYLKETONURICS: CONTAINS PHENYLALANINE (_) mg per (dosage
unit)." In May, 2007 the FDA warned that
diethylene glycol (DEG), a toxic compound, had been substituted for glycerin
(listed above as a humectant, preservative, and sweetening agent) in
pharmaceutical products made outside the U.S. Contaminated medicines have
caused kidney failure and paralysis, resulting in several hundred deaths. The
FDA has no reason to believe that the U.S. supply of glycerin is contaminated
with DEG, but it warned companies involved in making medications to be especially
vigilant. Supplement manufacturers were not addressed by the FDA, but
ConsumerLab.com feels that they, too, should be vigilant about the potential
substitution of DEG for glycerin.
Information on this site
is provided for informational purposes only. It is not an endorsement of any
product nor is it meant to substitute for the advice provided by physicians or
other healthcare professionals. The information contained herein should not be
used for diagnosing or treating a health problem or disease. Consumers should
inform their healthcare providers of the dietary supplements they take.
Latest Clinical Research Updates for Inactive Ingredients
Can a Natural Colorant Cause Adverse Effects?
12/07/2021
A CL member recently
asked if purple carrot powder in his supplement might have caused symptoms such
as chest tightness and headache. Find out in our updated article about Inactive Ingredients/Excipients.
Whitener In Many Pills May Not Be Safe
5/11/2021
Titanium dioxide, which
is commonly used to whiten pills, is not safe according to the European
equivalent of the FDA. Find out why in our Review Article about Inactive
Ingredients.
5/25/2019
Titanium dioxide is a
common white colorant in foods and supplements. A recent study in mice,
however, suggests that it may affect the gut. For details, see the
updated Titanium Dioxide section
of the Inactive Ingredients/Excipients article.
Related CL Answers (6)