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1-Introduction

A pharmaceutical coloring agent (colorant) is “any material that is

a dye, pigment or other substance made by a process of synthesis, or

extracted. Isolated or otherwise derived from a vegetable, animal mineral

or other source that employed solely in a pharmaceutical product to

impart a color” (Wade and Weller, 1994).

1.1- Historical back ground

Color additives have long been a part of human civilization.

Archaeologists date cosmetic colors as far back as 5000 B.C. Ancient

Egyptian, writings tell of drug colorants, and historians say food colors

likely emerged around 1500 B.C.

Through the years, color additives typically came from substances

found in nature, such as turmeric, paprika and saffron. But as the 20th

century approached, new kinds of colors appeared that offered marketers

wide varieties of color. These colors, many whipped up in the chemist's

lab, also created a range of safety problems.

In the late 1800s, some manufacturers developed colored products

with potentially poisonous mineral- and metal-based compounds. Toxic

chemicals tinted certain candies and pickles, while other color additives

contained arsenic or similar poisons. Historical records show that injuries,

even deaths, resulted from tainted colorants. Food producers also

deceived customers by employing color additives to mask poor product

quality or spoiled or degraded product.

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Thus ,at the end of the century, unmonitored color additives had

spread through the marketplace in all sorts of popular foods, including

ketchup, mustard, jellies, and wine. Sellers at the time offered more than

80 artificial coloring agents, some intended for dyeing textiles, not foods.

Many color additives had never been tested for toxicity or other adverse

effects.

As the 1900s began, the bulk of chemically synthesized colors

were derived from aniline, a petroleum product that in pure form is toxic.

Originally, these were dubbed "coal-tar" colors because the starting

materials were obtained from bituminous coal (These formulations still

are used today--albeit safely--for most certifiable color additives.)

Initially, coloring agents obtained form plant, animal and mineral

sources remained in use early in this century. The manufacturers had

strong economic incentives to phase them out. Chemically synthesized

colors simply were easier to produce, less expensive, and superior in

coloring properties. Only tiny amounts were needed. They blended nicely

and didn't impart unwanted flavors to foods. But as their use grew,

question mark on safety concerns develops.

In 1906, Congress passed the Pure Food and Drugs Act regarding

the use of colorants , meant for use in food products. This marked the first

of several laws allowing the federal government to scrutinize and control

additives use. The act covered only food coloring. It was not until passage

of the Federal Food, Drug, and Cosmetic Act of 1938 that FDA's mandate

included the full range of color designations consumers still can read on

product packages: "FD&C" (permitted in food, drugs and cosmetic);

"D&C" (for use in drugs and cosmetics) and "Ext. D&C" (colors for

external-used drug and cosmetics).

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Public hearings and regulations following the 1938 law gave colors

the numbers that separate their hues. These letter and number

combinations--FD&C Blue No. 1 or D&C Red No. 17, for example--

make it easy to distinguish colors used in food, drugs or cosmetics from

dyes made for textiles and other uses. Only FDA certified color additives

can carry these special designations.

The law also created a listing of color "lakes." These water-

insoluble forms of certain approved colors are used in coated tablets,

cookie fillings, candies, and other products in which color bleeding could

make a mess or otherwise cause problems.

Though the 1938 law did much to bring color use under strict

control, nagging questions lingered about tolerance levels for color

additives. One incident in the 1950s, in which scores of children

contracted diarrhea from Halloween candy and popcorn colored with

large amounts of FD&C Orange No. 1, led FDA to retest food colors. As

a result, in 1960, the 1938 law was amended to broaden FDA's scope and

allow the agency to set limits on how much color could be safely added to

products.

FDA also instituted a pre-marketing approval process, which

requires color producers to ensure, before marketing, that products are

safe and properly labeled. Should safety questions arise later, colors can

be reexamined. The 1960 measures put color additives already on the

market into a "provisional" listing. This allowed continued use of the

colors pending FDA's conclusions on safety.

From the original 1960 catalog of about 200 provisionally listed

colors, which included straight colors and lakes, only of some colors

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remain on the provisional list. Industry withdrew or FDA banned many,

while the rest became permanently listed and are still used. Some of these

colors, derived from coal or petroleum sources, are subject to certification

and carry the F, D, or C prefix. Others, exempt from certification, are

pigments and colors derived from plant, animal and mineral sources.

They are found in a myriad of products--from the caramel that tints cola

drinks to the orange annatto that gives color to cheese.

FDA certified over 11.5 million pounds of color additives last

fiscal year. Of all those colors straight dye FD&C Red No. 40 is by far

the most popular. Manufacturers use this orange-red color in all sorts of

gelatins, beverages, dairy products and condiments. FDA certified more

than 3 million pounds of the dye in fiscal year 1992--almost a million

pounds more than the runner-up, FD&C Yellow No. 5

FDA separates color additives into two categories. These are colors

that the agency certifies (derived primarily from petroleum and known as

coal-tar dyes) and colors that are exempted from certification (obtained

largely from mineral, plant, or animal sources). Only approved substances

may be used to color foods, drugs, cosmetics, and medical devices.

FDA requires domestic and foreign manufacturers of certain colors

to submit samples from each batch of color produced. FDA scientists test

each sample of these colors to confirm that each batch of the color is

within established specifications. These certified colors are listed on

labels as FD&C, D&C or external D&C. Using the uncertified versions of

color additives that require certification is illegal in foods, drugs,

cosmetics, and medical devices.

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The color certification program is self-supporting because the law

requires manufacturers to pay FDA a user fee for each pound of color the

agency certifies. In Fiscal Year 2000 FDA certified more than 13 million

pounds of color additives.

The 1993 FDA Consumer magazine article reprinted below

provides additional information on the regulation of color additives (

Henkel , 1993).

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FACT SHEET OF COLORING AGENTS

2-Literature review .

Colors are incorporated into pharmaceutical products for several reasons

like :

i) Colors give aesthetic appearance and impart pleasing

appearance to the product, to provide more acceptability by the

patient.

ii) Colors may be used to identify product of similar appearance or to

mask the discolored degraded excipient, or drug there by maintaining

the appearance of formulation, for its entire shelf life.

iii)Colors help to minimize the possibility of mix-up drug

manufacture. The coloring agent may be classified in various ways

either inorganic or organic for purpose of the discussion (Remington,

1995).

Coloration of liquid preparations

Coloring agents may be added to oral liquid preparations to

mask an unpleasant appearance or to increase the acceptability of the

preparation to the patient. Acceptability may be enhanced by inclusion of

a color that is closely associated with the flavour of the preparation.

Colors are also added in order to produce a consistent appearance from

raw materials of variable color. Occasionally, oral liquid preparations are

colored distinctively as an aid to identification; for example, a green color

(green S and tartrazine) is used in methadone mixture (previously DTF).

Dyes should be non-toxic, non-irritant, and compatible with the active

and other ingredients of the preparation. The selection of a coloring agent

requires an in-depth knowledge of the physicochemical properties of both

the dye and all other excipients. The solubility, stability, compatibility,

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and required concentration of the dye in the particular preparation must

be considered. The color stability of dyes is often pH-dependent; for

example, sunset yellow FCF is stable at acidic pH but may be precipitated

or change color at alkaline pH.

The dyes selected must be permitted for use in orally administered

medicines in the country or countries concerned. In the European

Community (EC) colors used in human and animal medicinal products

must be selected from those permitted in foodstuffs, designated by E

numbers 100 to 180. Colors certified by the United States Food and Drug

Administration are described by FD&C numbers. Most of the colors

commonly used in pharmaceutical preparations have both an E number

and an FD&C number; for example, tartrazine is E102 and FD&C yellow

number 5. Some coloring agents, including tartrazine, amaranth, and

lissamine green are subject to further restrictions or bans in some

european countries.

Coloring agents can be classified into three categories: mineral

pigments, natural colorants, and synthetic organic dyes. Mineral pigments

such as iron oxides are used mainly in solid pharmaceutical dosage forms

and in preparations for external use; their use, in oral liquids is restricted

by the very low solubility of these minerals in water. Natural colorants

comprise a wide variety of materials isolated, extracted, or derived from

plants or animals; they include anthocyanins, carotenoids, chlorophylls,

xanthophylls, riboflavin, saffron, red beetroot extract, cochineal, and

caramel (from sucrose and other edible sugars). Disadvantages of natural

colorants may include variation in composition and color between

batches. Some solutions of natural colorants have limited stability to light

and pH and to oxidizing and reducing agents; certain natural colorants are

used mainly for coloring oily or fatty products.

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Synthetic organic dyes are commonly known as ‘coal-tar’ dyes and

are often preferred to natural colorants for oral liquids because they

provide a wider range of bright and stable colors of more uniform

intensity; however they are seldom pure compounds. There are two main

types of synthetic dyes: acid dyes and basic dyes. Acid dyes form salts

with bases, the colored ion being negatively charged; basic dyes form salt

with acids, the colored ion being positively charged. Most synthetic

coloring agents used in oral liquids are acid dyes; nearly all are sodium

salts of sulphonic acids and many are no compounds. Because of their

chemical structure, such acid dyes may interact in solution with large

cations to form insoluble compounds; thus they may be incompatible with

many alkaloids, phenothiazine derivatives, and antihistamines.

Recent concern about adverse reactions to coloring agents,

particularly tartrazine and other azo dyes, in preparations intended for

pediatric use has led to a demand for formulations free from colors. For

example, tartrazine is a permitted color in the UK but reports of rare

allergic reactions have-caused its removal from many commercial

preparations. Official formulations that in the past contained tartrazine

have been amended to open formulae. A further problem is that the

presence of dyes in liquid medicines has confused the diagnosis of

disease; for example, green or red dyes in vomit have been wrongly

assumed to be bile or blood( Lund,1994).

Coloration of pediatric preparation

Coloring agents although the correlation of the inclusion of azo

dyes in preparations with the onset of hyperactivity in children is

unproven, these substances should be avoided if at all possible. There are

several natural coloring agents available and the suitability of these

should be assessed before considering the use of an azo dye. Oral liquid

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preparations in the British Pharmacopoeia have been amended to ‘open

formulae’, thus allowing the omission of tartrazine if required.

Coloration of solid dosage forms:

The coloring of tablets or capsules allows ease of recognition. It

also gives marketing groups the opportunity to develop distinctive trade

marks. Research has indicated some colors may be more psychologically

beneficial for certain conditions than others, for example, red for

cardiovascular compounds.There is a confusion regarding the

acceptability of colors. Many dyes are acceptable in some countries but

not others, with only titanium dioxide, indigo carmine, and some iron

oxides being widely accepted. Thus the same colored tablets or capsules

may contain different dyes in different countries (Lund,1994).

2.1- Description of some coloring agents

2.1.1-Coloring agents from Plants:-

2.1 .1.1 - Annatto:-

This yellow food colorant comes from the seeds of a tropical

evergreen tree, Bixa orellana L, Used to dye cheese, butter, margarine

and soaps. Annatto extract may be safely used for coloring drugs

generally, including those intended for use in the area of the eye, in

amounts consistent with good manufacturing practice.

(http://www.ccbol.bravehost.com)

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Fig.1. Bixa orellana L

http://www .agro-condor.com

2.1.1.2-Grape-color extract:-

It is consists of an aqueous solution of anthocyanin grape

pigments made from the precipitated Concord grapes or a dehydrated

water-soluble powder prepared from the aqueous solution. It contains the

common components of grape juice: anthocyanins, tartrates, malates,

sugars, minerals, etc. The powder is prepared by spray drying the

extracted liquid with maltodextrin. (http://www.cfsan.fda.gov)

2.1.1.3-Grape-skin extract

It is also known as enocianina. This purplish-red liquid is

prepared by the aqueous extraction of fresh, deseeded marc (after grapes

have been pressed for grape juice or wine). It also contains the common

components of grape juice -- anthocyanins, tartaric acid, tannins, sugars,

minerals -- but not in the same proportion as found in grape juice. During

the steeping process, sulfur dioxide is added and most of the extracted

sugars are fermented to alcohol. The extract is concentrated by vacuum

evaporation, during which time practically all alcohol is removed. A

small amount of sulfur dioxide may be present.

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Fruit juice/vegetable juice. Fruit juice used as a colorant, can

be obtained either by expressing the juice from mature varieties of fresh,

edible fruits or vegetables, or by water infusion of dried varieties. It may

be used single-strength, concentrated or dried.

This category includes numerous products, but they must meet

this definition. Being neither fruit nor vegetable, spirulina would fall

outside of this definition.

High color with low flavor is preferable. Under the definition,

spinach juice would be considered a vegetable-juice colorant, but the

coloring strength is so low compared to the flavor level.

Most of the fruit products are high in anthocyanins. Grape,

cranberry, chokeberry, elderberry and other berries have been used in this

regard. The most commonly used vegetable dye -- red cabbage juice --

produces a bright pink-to-red color in a pH under 4. Higher pHs cause the

anthocyanin-based pigments to turn an unstable purplish-blue color.

These products dissolve in water, but not in oil.

(http://www.cfsan.fda.gov)

2.1.1.4-Carotene

This precursor for vitamin A contributes an orange-yellow color to food. Its

antioxidant properties have been widely touted. Most of the carotenes are

synthesized. It also is, according to Isager, "nature-identical." The substance also can

be derived from algae. Carotene is oil-soluble, but can be made into a water-

dispersible emulsion. (http://www.cfsan.fda.gov)

2.1.1.5- Caramel color

On controlled-heating, food-grade carbohydrates -- generally a

high dextrose-containing starch hydrolysate or corn syrup -- results in a

brown coloring agents known as caramel color. Basically, the end result

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is caramelized sugar when the sugar molecule is broken down to furans

and polymers with conjugated double bonds that absorb light and produce

colors. Use of catalysts can increase the reaction rate and create specific

types of caramel colors with different properties.

Caramel color is water-soluble. Its color ranges from golden

brown to nearly black. The color strength is defined as its tinctorial power

-- the absorbency at 560 nm on a spectrophotometer, according to

Sethness Products Company, Chicago.

The color tone, defined by the hue index, measures the red

characteristics of the color, and is a function of the absorbency at 510 and

610 nm. Generally, the higher the tinctorial power, or strength, the lower

the hue index, or red tones. The term "double strength," as applied to

caramel color, is a relative term that varies with the color range. The

specific gravity indicates the solids content and, therefore, the color

strength.

Most caramel color carries either a positive or a negative ionic

charge. Negatively charged product uses sulfite in its manufacture and,

though molecularly bound, it can be detected chemically. Because FDA

requires sulfite labeling at levels greater than 10 ppm, the level in a

specific type of caramel color may become important.

"Caramel color is stable under most conditions," says Owen

Parker, vice president of research and development, D. D. Williamson &

Co., Inc., Louisville, KY. "Certain caramel colors will darken slightly

with a rise in pH. The lighter brewing caramels are more susceptible;

with a darker caramel color the glucose or sugar is mostly used up so

there is little to polymerize further and change. And if you dilute caramel

color and expose it to direct sunlight or UV light it will eventually fade."

http://www.caramel.com

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2.1.1.6- Carrot oil:-

This is the liquid or the solid portion of the mixture or the

mixture itself obtained by the hexane extraction of edible carrots. The

hexane is removed by vacuum distillation. It consists mainly of naturally

occurring oils, fats, waxes and the carotenoid pigments µ- and carotene.

(http://www.naturesflavors.com)

2.1.1.7- Paprika oleoresin The oleoresin extracted from the pod of Capsicum annum, or

paprika, primarily contains three carotenoid pigments: capsanthin (the

main coloring agents), capsorubin and carotene. However, as many as 20

or more pigments can be present, including zeaxanthin, which, with

carotene, produces a more yellow hue. "Most of the time, these different

ratios won't have a visual impact," Locey says. "But, in some cases, they

can make a difference. Hue control is maintained by raw material

selection and blending."

Typically, paprika imparts a bright orange to red-orange color in

food products. The oleoresin is oil-soluble, but when emulsified becomes

water-dispersible.

"Color differences in paprika can be quite pronounced if you are

looking at paprika from different sources," Isager says. "Paprika grows in

Spain, Iraq, Zimbabwe, China and South America. This can give a wide

variety of shades from yellow to a yellowish-red. Because we need to

deliver a standard shade to our customers each time, that causes

difficulties. Typically, we would select based on the color, and blend, if

necessary, to a specific standard. Also, products using our special

stabilization technique will not show the differences seen in the raw

material -- another advantage of this product line."

http://www.naturesflavors.com

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Fig.2. Capsicum annum

http://www.kalash.com

2.1.1.8-Saffron

Saffron consists of the dried stigma of Crocus sativus L. It

produces a bright yellow color, due to the natural pigment crosin, a water-

soluble carotenoid. Because of its expense, it is rarely used in this

country. (http://www.safinter.com)

Fig.3. Crocus sativus L

http://www.en.wikipedia.org/wiki/Saffron

Fig.4. Saffron threads

http://www.en.wikipedia.org/wiki/Saffron

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2.1.1.9- Turmeric

Turmeric is a member of the Curcuma botanical group, which is

part of the ginger family of herbs, the Zingiberaceae. The root and

rhizome (underground stem) of the Curcuma longa L. plant is crushed

and powdered into ground Turmeric. Ground Turmeric is used worldwide

as a seasoning, the main ingredient in curry, and as a source for Curcumin

(Turmeric contains approximately 4% Curcumin). (http://www turmeric-

curcumin.com.)

Fig.5. Curcuma longa L

http://www alternativedr.com

Fig.6. Turmeric-powder

http://www turmericpowder.net

2.1.1.10-Canthaxanthine

It is a reddish-orange colouring that can be prepared

synthetically or extracted from a variety of natural sources, including

algae, Daphnia spp, one species of edible mushroom (Cantharellus

cinnabasinus) (Cot, 1987; Hallagan et al., 1995).

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2. 1.2 - Coloring agents from insects

2.1.2.1-Carmine/cochineal extract

Carminic acid, derived from the shells of dried female insects

(Dactylopius coccus costa) is the main pigment in carmine or cochineal.

Cochineal extract contains approximately 2% to 3% carminic acid.

Depending on the product and the pH, it produces colors in the orange to

purple range. Carmine is the salt of the pigment, which produces a

magentsa-red shade. The water-insoluble lake forms of carmine range

from pink to purple, and will have carminic acid contents of not less than

50%. In order to stabilize carmine at low pHs, an acid-proof version is

manufactured. (http://www.cspinet.org)

2.1.3-Coloring agents from mineral sources

2.1.3.1- Ferrous Gluconate and ferrous lactate

They are inorganic compounds, used for coloring ripe olives.

(http://sci-toys.com)

2.1.3.2-Titanium dioxide

This synthetic compound provides white color and an opaque

appearance. It is insoluble, but water- and oil-dispersible versions are

manufactured. "Titanium dioxide tends to agglomerate and require high

shear to fully and evenly disperse."Because of this, food companies

typically utilize a dispersion of titanium dioxide in a food-grade vehicle

such as oil, propylene glycol, sugar syrup or water with selective

thickeners. (http://www.titanum.dupont.com)

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2.1.4-Coloring agents from micro organism

2.1.4.1-Riboflavin

(Also, know as vitamin B2). This is a group of compounds that

produces a yellow to orange-yellow color, in addition to their vitamin

activity. (http://www.cfsan.fda.gov)

2.1.4.2-Phaffia yeast

The color additive phaffia yeast consists of the killed, dried cells of

a nonpathogenic and nontoxicogenic strain of the yeast Phaffia

rhodozyma.Phaffia yeast may be added to the fish feed only as a

component of a stabilized Color additive mixture.

(http://www.cfsan.fda.gov)

2.1.5-Coloring agents from synthetic sources

2.1.5.1-Indigotine, indigo carmine (FD&C Blue NO. 2)

The color additive FD&C Blue No. 2 is principally the disodium

salt of 2-(1,3-dihydro-3-oxo-5- sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-

oxo-1H-indole-5- sulfonic acid (CAS Reg.No. 860–22–0) with smaller

amounts of the disodium salt of 2-(1,3-dihydro-3-oxo-7-sulfo-2H-indol-

2-ylidene)-2,3- dihydro-3-oxo-1H-indole-5-sulfonic acid(CAS Reg. No.

54947–75–0) and the sodium salt of 2-(1,3-dihydro-3-oxo-2Hindol-2-

ylidene)-2, 3-dihydro-3-oxo-1Hindole- 5-sulfonic acid (CAS Reg.

No.605–18–5). Additionally, FD&C Blue No. 2 is obtained by heating

indigo (or indigo paste) in the presence of sulfuric acid. The color

additive is isolated and Subjected to purification procedures. FD&C Blue

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NO. 2 Commonly added to tablets and capsulec,also used in ice cream,

sweats and biscuits. (http://www.cfsan.fda.gov)

2.1.5.2-FD&C Green No. 3

The color additive FD&C Green No. 3 is principally the inner salt

disodium salt of N-ethyl-N- [4-[[4-[ethyl [(3-sulfophenyl) methyl] amino]

phenyl](4-hydroxy-2-sulfophenyl)methylene]-2,5-cyclohexadien-1-

ylidene]-3- Sulfobenzeneme than ammonium hydroxide (CAS Reg. No.

2353–45–9). (http://www.cfsan.fda.gov)

2.1.5.3-Citrus Red No. 2

Citrus Red No. 2 is principally 1–(2, 5–dimethoxyphenylazo)-2-

naphthol. (http://www.cfsan.fda.gov)

2.1.5.4-Erythrosine ( FD&C Red No. 3)

FD&C Red No. 3 is principally the monohydrate of 9 (o-

carboxyphenyl)-6- hydroxy tetraIodo-3H-xanthen-3-one, disodium salt,

with smaller amounts of lower imdinated fluoresceins. FD&C Red No.

3used in canned fruits, sweets and snack foods.

(http://www.cfsan.fda.gov)

2.1.5.5-Amaranth Red

It is derived from the small herbaceous plant of the same name,

used in cake mixes,fruit-flavoured fillings &jelly crystals.

(http://www.cfsan.fda.gov)

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2.2-Toxicity or safety profile of some coloring agents

2.1 Studies of coloring agents for toxicity

2.1.1- Allura Red ( FD&C Red No. 40)

Same studies found that red no 40 cause cancer in laboratory rats,

so its use is limited and may be banned. ( Anderson, 2001)

2.1.2-Amaranth ( FD&C Red No. 2)

Food and drug coloring agent can provoke asthma, eczema and

hyperactivity, caused birth defect and foetal deaths in some animal tests,

possible also cancer. (http://www.srch-results.com)

2.1.3-Brilliant Bule ( FD&C Bule No. 1)

It is used in Beverages, candy, baked foods, etc. Inadequately testing

suggested a small cancer risk. (http://www.cspinet.org)

2.1.4- Indigo Carmine (FD&C Bule No.2):-

The largest study suggested, but did not prove, that this dye

caused brain tumors in male mice. The FDA concluded that there is

"reasonable certainty of no harm." (http://www.cspinet.org)

2.1.5 - CITRUS RED 2

This artificial coloring found in Skin of some Florida oranges

only. Studies indicated that this additive causes cancer. No risk except

when eating peel. (http://www.cspinet.org)

2.1.6-GREEN 3 (FD&C Green No. 3)

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It is a artificial colorings used in Candy, beverages. In 1981,

industry-sponsored study gave hints of bladder cancer, but FDA re-

analyzed the data using other statistical tests and concluded that the dye

was safe. Fortunately, this possibly carcinogenic dye is rarely used.

(http://www.cspinet.org)

2.1.7-Erythrosine (FD&C Red No. 3)

It can cause sensitivity to light, can increase thyroid hormone

levels and lead to hyper thyroidism, and even shown to cause thyroid

cancer. (http://www.srch-results.com)

2.1.8-PANCEOU 4R (FD&C Red No. 4)

It is reported to cause high levels damaged in adrenal cortex of

dog; after 1965 it was used only in maraschino cherries and certain pills;

it is still allowed in externally applied drugs and cosmetics.

(www.tradingstandards.gov.uk )

2.1.9- Sudan 1

It is toxic, later found to be carcinogenic. (http://www.cfsan.fda.gov)

2.2.2- safety aspect of coloring agents

The following safety factor will be applied in determining whether

the proposed use of a color additive will be safe: Except where evidence

is submitted which justifies use of a different safety factor, a safety factor

of 100 to 1 will be applied in animal experimentation data to man; that is,

a color additive for use by man will not be granted a tolerance that will

exceed 1/100th of the maximum no-effect level for the most susceptible

experimental animals tested. The various species of experimental animals

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used in the tests shall conform to good pharmacological practice.

(http://www.cspinet.org)

2.2.3- Safety of Synthetic Colorants

Coal tar dye use began in the mid-nineteenth century, when the

dyes were actually derived from coal tar itself. Today, the colorants are

not extracted from actual coal tar, which is known to be a carcinogen.

Instead, synthetic dyes and pigments are created from purified raw

materials. This process dramatically reduces the risk of unwanted and

dangerous residual compounds in the final colorant product. Modern-day

pigments and dyes are now referred to in terms of their certification

(FD&C, D&C), as the term “coal tar dyes” is no longer an accurate

description. The term “laked” refers to a dye that has been rendered

insoluble through a process in which a metal salt, such as aluminum or

calcium, is attached to the dye molecule. Once insoluble, these laked

pigments show a very low tendency for harmful biological activity.

They are used when a non-FD&C color is not available, or natural colors

are not stable enough to maintain the desired color. Some desired colors,

such as the brilliant reds and pinks may not be achieved naturally.For

consistent, stable coloring in a red or pink, a certified, laked pigment is

used as a coloring agent.

The FDA closely scrutinizes dye and pigment production, and all

colorants are subject to strict regulations. Carcinogenicity, oral toxicity,

skin toxicity, sensitization, and skin irritation safety must be

demonstrated for colors intended for use in food, drug or cosmetic

products. If a colorant does not fulfill these requirements, it cannot be

used for these purposes.Out of the hundreds of dyes and pigments that

exist, only a handful are distinguished by the strict FD&C or D&C

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certification. The FD&C and D&C colors must be approved for initial

inclusion in the Code of Federal Regulations as certified coloring agents.

(http://www.cfsan.fda.gov)

2.2.4- Criteria for evaluating the safety of color additives.

The safety for external color additives will normally be determined

by tests for acute oral toxicity, primary irritation, sensitization, sub acute

dermal toxicity on intact and abraded skin, and carcinogenicity by skin

application.The Commissioner may waive any of such tests if data before

him otherwise establish that such test is not required to determine safety

for the use proposed.

Upon written request describing the proposed use of a color

additive and the proposed experiments to determine its safety, the

Commissioner will advise a person who wishes to establish the safety of a

color additive whether he believes the experiments planned will yield

data adequate for an evaluation of the safety of the additive.

(http://agnews.tamu.edu/dailynews/stories/cfam/nov2901a.htm)

2.2.5 -Allocation of color additives.

Whenever, in the consideration of a petition or a proposal to list a

color additive or to alter an existing listing, the data before the

Commissioner fail to show that it would be safe to list the color additive

for all the uses proposed or at the levels proposed, the Commissioner will

notify the petitioner and other interested persons by publication in the

FEDERAL REGISTER that it is necessary to allocate the safe tolerance

for the straight color in the color additive among the competing needs.

(http://www.cfsan.fda.gov)

23

Objective:

The objective of the project will consist of the following steps:-

- Reasons of adding coloring agents.

- Description of some coloring agents.

- Toxicity or safety profile of some coloring agents.

- Currently used coloring agent's world wide.

- Currently used food-coloring agents in the Sudan.

- Conclusion.

24

Methodology:

Information from the internet, journals, textbooks, encyclopedia and

National health laboratories will be collected regarding.

(i) Various coloring agents added in drug and food products.

(ii) Safety profile of these coloring agents.

25

Conclusion:

Every dye and pigment used as additives for a food, drug or

cosmetic goes through an intense screening process. Each approved

coloring agent must be certified for its prescribed application. Beyond

that, each batch produced must pass specified tests, which include

carcinogenicity testing. Now a days all have demonstrated a safe history

of use. Now a days is always looking for alternative natural colors for use

in their cosmetics that will provide the same level of safety and

consistency. (http://www.cfsan.fda.gov)

26

References:

Web sites:

1. Kuroiwa Y, Nishikawa A, Imazawa T, Kitamura Y, Kanki K, Ishii

Y, et al 2006 ,A subchronic toxicity study of dunaliella carotene in

F344 rats, Food chem. Toxicol , 44 (1) : 138-45.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrive&db=p

umbed&dop=abst...

2. Kodjikian L., Richter T, Halberstad M, Beby F, Flueekiger F,

Boehnke M, et al 2005,Toxic effects of indocyanine green

,infracyanine green,and trypan blue on the human retinal

pigmented epithelium , Graefes Arch Clin Exp Ophthalmol, 243 (9)

: 917-25.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrive&db=p

umbed&dop=abst...

3. http://www.ccbol.bravehost.com

4. Nabae K,Ichihara T, Hagiwara A,Hirota T, Toda Y ,Tamano S, et

al 2006 ,A90-day oral toxicity study of beta-carotene derived from

Blakeslea trispora,a natural food colorant, in F344 rats.

http://www.whfoods.com/genpage.php?tname=george&dbid=107.

5. http://agnews.tamu.edu/dailynews/stories/cfam/nov2901a.htm

6. http://www.whfoods.org

7. http://www.naturesflavors.com/product_info.php?cPath=72&produ

cts_id=4089

8. http://www.cfsan.fda.gov/~lrd/cfr73355.html

9. http://www.cfsan.fda.gov/~lrd/ob-reg.html

10. www.tradingstandards.gov.uk/milton-keynes/

E41%20Colours%20In%20Takeaway%20and%20Restaurant%20F

ood.pdf

27

11. http://www.safinter.com/nses.htm.

12. http://www.palimsest.stanford.edu /don/dt/dt3600.htm/

13. http://www.cspinet.org/new/carmine-8-42-98.htm

14. http://sci-toys.com/ingerdients/ferrous -gluconate.html

15. http://www.titanum.dupont

.com/nasapp/ttportal/mediator?action=2120&locate=en-us

16. . http://www turmeric-curcumin.com. All rights reserved.

17. http://www alternativedr.com/sitemap.htm

18. http://www turmericpowder.net

19. http://www.en.wikipedia.org/wiki/Saffron

Textbook:

1. Ainley Wade & Paul J Weller, 1994, Hand Book of Pharmaceutical

Excipients, 2nd edition. LONDON, 126-133.

2. FAO / WHO Expert Committee, 1994, Summary of Evaluations

On Food Additives (JECFA), Switzerland, 25-67.

3. Remington, 1995, The Science of Practice of Pharmacy, nineteenth

edition, Volume II.

4. Walter Lund, 1994, Pharmaceutical Codex, 12th edition.

LONDON, 36-433

28

Summary of Color Additives Listed for Use in the

United States in Foods and Drugs

Color Additives Approved for Use in Human Food

Name of Coloring agents Uses and Restrictions

Annatto extract Foods generally.

Dehydrated beets (beet powder) Foods generally.

Canthaxanthin

Foods generally, NTE 30

mg/lb of solid or semisolid

food or per pint of liquid food;

May also be used in broiler

chicken feed.

Caramel Foods generally.

-Apo-8'-carotenal Foods generally, NTE: 15

mg/lb solid, 15 mg/pt liquid.

-Carotene Foods generally.

Cochineal extract Foods generally.

Carmine

Sodium copper chlorophyllin

Citrus-based dry beverage

mixes NTE 0.2 percent in dry

mix; extracted from alfalfa.

Toasted partially defatted cooked

cottonseed flour Foods generally.

Ferrous gluconate Ripe olives.

Ferrous lactate Ripe olives.

Grape color extract Nonbeverage food.

Grape skin extract (enocianina)

Still & carbonated drinks &

ades; beverage bases; alcoholic

beverages (restrict. 27 CFR

Parts 4 & 5).

Synthetic iron oxide Sausage casings NTE 0.1

percent (by wt).

Fruit juice Foods generally.

Dried color additive.

Vegetable juice

Foods generally.

Dried color additive, water

infusion.

29

Carrot oil Foods generally.

Paprika Foods generally.

Paprika oleoresin Foods generally.

Riboflavin Foods generally.

Saffron Foods generally.

Titanium dioxide Foods generally; NTE 1

percent (by wt).

Tomato lycopene extract; tomato

lycopene concentrate(3) Foods generally.

Turmeric Foods generally.

Turmeric oleoresin Foods generally.

FD&C Blue No. 1 Foods generally.

Added Mn spec.

FD&C Blue No. 2 Foods generally.

FD&C Green No. 3 Foods generally.

Orange B

Casings or surfaces of

frankfurters and sausages;

NTE 150 ppm (by wt).

Citrus Red No. 2

Skins of oranges not intended

or used for processing; NTE

2.0 ppm (by wt).

FD&C Red No. 3 Foods generally.

FD&C Red No 40 Foods generally.

FD&C Yellow No. 5 Foods generally.

FD&C Yellow No. 6 Foods generally.

. http://www.cfsan.fda.gov/~lrd/cfr73450.html

Color Additives Approved for Use in Drugs

Straight Color Uses and Restrictions

Alumina (dried aluminum

hydroxide) Drugs generally.

Annatto extract Ingested drugs generally; external

drugs including eye area use.

Calcium Carbonate Drugs generally.

Canthaxanthin Ingested drugs generally.

31

Caramel Ingested and topically applied

drugs generally.

-Carotene

Ingested drugs generally.

Externally applied drugs including

eye area use.

Cochineal Extract Ingested and externally applied

drugs. Carmine

Potassium sodium copper

chlorophyllin (chlorophyllin-copper

complex)

Dentrifices that are drugs; NTE

0.1%

Dihydroxyacetone

Externally applied drugs intended

solely or in part to impart a color

to the human body

Bismuth oxychloride Externally applied drugs including

eye area use.

Synthetic iron oxide

Ingested or topically applied

drugs ingested dosage by man

NTE 5 mg/d (as Fe).

Ferric ammonium ferrocyanide Externally applied drugs including

eye area use.

Ferric ferrocyanide Externally applied drugs including

eye area use.

Chromium hydroxide green Externally applied drugs including

eye area use.

Chromium oxide greens Externally applied drugs including

eye area use.

Guanine Externally applied drugs including

eye area use.

Pyrophillite Externally applied drugs.

Mica

Externally applied drugs including

eye area use.

Dentifrices.

Talc Drugs generally.

Titanium dioxide Drugs generally including eye

area use;

Aluminum powder Externally applied drugs including

eye area use.

Bronze powder Externally applied drugs including

eye area use.

31

Copper Powder Externally applied drugs including

eye area use.

Zinc oxide Externally applied drugs including

eye area use.

FD&C Blue No. 1

Ingested drugs generally.

Externally applied drugs.

Eye area use (includes lake).

FD&C Blue No. 2 Ingested drugs.

D&C Blue No. 4 Externally applied drugs.

FD&C Green No. 3 Drugs generally.

D&C Green No. 5 Drugs generally.

Eye area use.

D&C Green No. 6 Externally applied drugs.

D&C Green No. 8 Externally applied drugs (NTE

0.01% (by weight).

D&C Orange No. 4 Externally applied drugs.

D&C Orange No. 5

Externally applied drugs (NTE 5

mg/daily dose of drug).

Mouthwashes and dentifrices.

D&C Orange No. 10 Externally applied drugs.

D&C Orange No. 11 Externally applied drugs.

FD&C Red No. 3 Ingested drugs.

FD&C Red No. 4 Externally applied drugs.

D&C Red No. 6

Drugs such that total with D&C

Red No. 7 NTE 5 mg/daily dose

of drug.

D&C Red No. 7

Drugs such that total with D&C

Red No. 6 NTE 5 mg/daily dose

of drug.

D&C Red No. 17 Externally applied drugs.

D&C Red No. 21 Drugs generally.

D&C Red No. 22 Drugs generally.

D&C Red No. 27 Drugs generally.

D&C Red No. 28 Drugs generally.

D&C Red No. 30 Drugs generally.

D&C Red No. 31 Externally applied drugs.

32

D&C Red No. 33

Ingested drugs, other than

mouthwashes and dentifrices

(NTE 0.75 mg/daily dose of

drug); externally applied drugs,

mouthwashes and dentifrices.

D&C Red No. 34 Externally applied drugs.

D&C Red No. 36

Ingested drugs, other than

mouthwashes and dentifrices,

NTE 1.7 mg/daily dose for drugs

taken less than 1 yr; NTE 1.0

mg/daily dose for drugs taken

more than 1 yr.

Externally applied drugs.

D&C Red No. 39

Quaternary ammonium type

germicidal solutions for external

application (NTE 0.1% (by wt) of

finished drug product).

FD&C Red No. 40 Drugs generally.

Eye area use (includes lake).

D&C Violet No. 2 Externally applied drugs.

FD&C Yellow No. 5

Ingested drugs generally.

Externally applied drugs.

Eye area use (includes lake).

FD&C Yellow No. 6 Drugs generally.

D&C Yellow No. 7 Externally applied drugs.

Ext. D&C Yellow No. 7 Externally applied drugs.

D&C Yellow No. 8 Externally applied drugs.

D&C Yellow No. 10

Drugs generally.

Modification of uses and

restrictions.

D&C Yellow No. 11 Externally applied drugs.

. http://www.cfsan.fda.gov/~lrd/cfr73450.html

33

2-List of food coloring agent that used in Sudan and their

Adverse effects:-

Name Classification Uses Adverse effects Sunset yellow

(FD & C yellow

No 6)

Synthetic Sweets, Ice

cream, drink &

canned fish.

Urticaria (hives), rhinitis, nasal

congestion, allergies hyperactivity,

kidney tumours, chromosomal

damage, abdominal pain, nusea &

vomiting.

Tartrazine

(FD & C yellow

No 5)

Synthetic Drinks, sweets,

jams, cereals,

snack foods &

canned fish.

Hypersensitivity reaction in the

people specially children

consuming of this artificial

coloring has been linked to ADHD

(Attention deficit -

hypersensitivity disorder), Asthma

& inflammatory skin condition

such as urticaria & va topic

dermatitis.

Chlorophyll Natural Deying waxes

& oils.

Anthocyanins

extrated from

edible fruits

Natural

Amaranth

(FD & C Red No

2 )

Synthetic Cake mixes,

fruit- flavoured

filling & jelly

crystals.

Can provoke asthma, eczema &

hypersensitivity, caused birth

defect & foetal death in some

animal tests, possible also cancer.

Panceau 4 R (FD

& C Red No 4)

Synthetic Can produce bad reaction in

asthmatic people.

Brilliant blue

FCF (FD & C

blue dye No 1)

Synthetic Sweets &

drinks

Fast green Synthetic Canned peans,

minit jelly &

sauce

Titanum dioxide Synthetic

Brilliant black Synthetic Brown sauces

& cake mixes.

Azorubine

(carmosile)

Synthetic Jelly crystals Can produce bad reaction in

asthmatic people

Caramel Synthetic Fruit canned

sauces & biscuit

Recommended to avoid.

Curcnim Natural Chesses &

backed sweets.

Beta – carotene Natural

Riboflavin Natural Chess

Annatto

Natural

Use to dye

chess, butter &

snack food.