ANT New Dietary Ingredient Notification for Yung Zip Chemical's Elite Curcumin

ANT
HEALTH SCIENCES INTERNATIONAL
New Dietary Ingredient Notification
for
Yung Zip Chemical's Elite Curcumin
Submitted by:
CANTOX HEALTH SCIENCES
INTERNATIONAL
1011 U .S. Highway 22 West, Suite 200
Bridgewater, New Jersey
08807
On behalf of.-
Yung Zip Chemical Ind . Co., Ltd.
59 Yu Shih Road, Youth Industrial District
Tachia, Taiwan 437, Republic of China
March 2, 2006
CANTOX Offices:
Bridgewater, NJ, USA
908.429.9202
Mississauga, ON, Canada
905.542.2900
Fleet, Hampshire, UK
+44 (0) 870 3513780
CANTOX
HEALTH SCIENCES INTERNATIONAL
SECTION 1
The name and complete address of the manufacturer or distributor of the dietary
supplement that contains a new dietary ingredient, or of the new dietary ingredient .
The manufacturer of the new dietary ingredient is:
Frank Tung
QA Director
Yung Zip Chemical Ind . Co., Ltd .
59 Yu Shih Road, Youth Industrial District
Tachia, Taiwan 437, Republic of China
Phone : 866-4-2681-1344
Fax: 866-4-2682-0920
Direct correspondence to :
David H . Bechtel, Ph.D ., DABT
Managing Director & Senior Scientific Consultant
CANTOX U .S. Inc.
1011 U .S . Highway 22, Suite 200
Bridgewater, NJ 08807
Phone: 908-429-9202
Fax: 908-429-9260
March 2, 2006
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SECTION 2
The name of the new dietary ingredient .
Yung Zip Chemical Ind . Co., Ltd Elite Curcumin
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Description of the dietary supplement or dietary supplements that contain the dietary
ingredient including (i) the level of the dietary ingredient in the dietary supplement, and
(ii) the conditions of use recommended or suggested in the labeling of the dietary
supplement, or if no conditions of use are recommended or suggested in the labeling of
the dietary supplement, the ordinary conditions of use of the supplement .
The dietary supplement containing the Elite Curcumin dietary ingredient will be in capsule,
tablet, granule, and powder form. The curcumin capsules/tablets/sachet will be clearly labeled
and promoted as a dietary supplement . A description of the number of capsules/tablets/sachet
per serving size will appear on the label. Consumption of up to 1500 mg per day will be
suggested or recommended in the label directions, equivalent to 25 mg/kg/day for a 60 kg
person.
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SECTION 4
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The history of use or other evidence of safety establishing that the dietary ingredient,
when used under the conditions recommended or suggested in the labeling of the
dietary supplement, will reasonably be expected to be safe, including any citation to
published articles or other evidence that is the basis on which the distributor or
manufacturer has concluded that the dietary supplement will reasonably be expected to
be safe .
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4.1
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Background
Curcuma longa (or C. domestica), commonly referred to as turmeric, is a perennial herb from
the ginger (Zingiberaceae) family . Turmeric is cultivated extensively in Asia and has a long
history of use in the Chinese and Ayurvedic systems of medicine (Dobelis, 1986 ; Brendler,
1999). The rhizomes of Curcuma longa are dried and used as a food coloring and flavoring
agent. Turmeric has a long history of use as a spice, particularly in curry powders, but has also
been used as a (yellow) coloring agent in foods, cosmetics, materials, varnishes, paper, and
leather (Brendler, 1999) .
Curc,umin (turmeric yellow) is a flavonoid naturally present in and obtained by solvent extraction
of the ground rhizomes of Curcuma longa L. (C. domestica Valeton), with purification of the
resultant extract by crystallization. The commercial product consists essentially of curcumins:
the coloring principle (1,7-bis(4-hydroxy-3-methoxyphenyl) hepta-1,6-diene-3,5-dione), also
known as diferuloylmethane, and its desmethoxy and bisdesmethoxy derivatives in varying
proportions. The structural formula of curcumin is presented in Figure 4-1 .
Figure 4-1 : Molecular structure of curcumin
H
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1,7-bis(4hydroxy-3-methyoxyphenyl)hepta-1,6-diene-3,5-dione
Both turmeric and curcumin are also available in capsules, solutions, and tablets for use as an
herbal supplement, or as ingredients in multiple supplement products (Brendler, 1999) .
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In addition to the isolation of curcumin from the rhizomes of Curcuma longa, synthesis of
curcumin has also been described . Curcumin can be synthesized by condensing vanillin and
acetyl acetone in a medium of ethyl acetate in the presence of tributyl borate .
Curcumin is
isolated from the reaction mixture via acidification and extraction with ethyl acetate, and the
organic layers are washed until neutral, dried, and the solvent removed . The residual product is
purified by chromatography over silica gel using either petroleum or ether as the solvent (Srimal,
1987).
4.2
Elite Curcumin
4.2 .1
Manufacturing Process
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4.3
Safety of Curcumin
Much of the safety data available for curcumin summarized herein was generated in studies
using the flavonoid extracted from turmeric (Curcuma longa) . Although Yung Zip's Elite
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Curcumin is synthetically prepared, it is chemically identical to the flavonoid obtained through
the solvent extraction of turmeric .
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The conclusion of safety is based primarily on animal studies with curcumin itself . Data from
clinical trials with curcumin, its pharmacokinetics and history of food use are considered
supportive of its safety . Curcuma longa and various products derived from turmeric have been
widely used and extensively studied . Thus, data generated for turmeric (approximately 3 to 5%
curcumin), turmeric extracts, and turmeric oleoresin is included to support the safety of Elite
Curr,umin .
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4.3 .1
Curc;umin has a long history of food use . The average daily intake of curcumin through
ingestion of turmeric in India was reported to range from 0 .4 to 1 .5 mg/kg bw/day (Srinivasan
and Satyanarayana, 1980). Similarly, Shah et al . (1999) reported the average daily intake of
curcumin in the diet in India to be approximately 60 to 100 mg curcumin/day based on an
average turmeric intake of 2 to 2 .5 g/day. Commandeur and Vermeulen (1996) estimated the
average daily intake of curcumin by adults in India to range from 80 to 200 mg/day. The
average daily intake of curcumin in France was reported to be 1 mg/kg bw/day, with a
theoretical maximum daily intake of 4.5 mg/kg/day (Verger et al., 1998).
4.3.:?
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History of Use
Regulatory Status
4.3.2. 9 Regulatory Status of Curcumin
A temporary acceptable daily intake (ADI) value of 0.1 mg/kg/day was established for curcumin
in 1978 by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). At its fortyfourth meeting, JECFA evaluated new biochemical and genotoxicity data and the results of
carciinogenicity studies in rats and mice given turmeric oleoresin containing 79 to 85%
curcuminoids (See Section 4.3.4.4). Based on a NOEL of 220 mg/kg bw per day, due to liver
enlargement observed in the carcinogenicity study in mice, and a safety factor of 200, the
Committee increased the temporary ADI to 0 to1 mg/kg bw, and extended it, pending
submission of the results of a reproductive toxicity study with curcumin to be reviewed in 1998
(WHO, 1996). At its fifty-first meeting, the Committee evaluated the results of studies of fertility
in ralts and mice treated with turmeric oleoresin (68.0 to 76.5% curcuminoids) . The low survival
rate of pups in the study in mice and the low rates of pregnancy in rats led the Committee to
conclude that these studies did not provide assurance that the potential reproductive effects of
curcumin had been adequately investigated . The Committee again extended the temporary ADI
until 2001 pending submission of the results of a reproductive toxicity study with a substance
complying with the specifications of curcumin. At its fifty-seventh meeting, the Committee was
informed that a multigeneration study in the rat was in progress, and thus extended the
temporary ADI of 0 to 1 mg/kg bw until 2003 (JECFA, 2004). Most recently, the ADI for
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curcumin was i ncrease d t o 0 to 3 mg /kg b w b ase d on a NOE L of 250 to 320 mg/kg bw/day from
a multigeneration rat study (See Section 4.3.4.6) and the application of a 100-fold safety factor
(JE(:FA, 2004).
4.3.;2.2 Regulatory Status of Turmeric, Turmeric Extracts, and Turmeric Oleoresin
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Turmeric and turmeric oleoresin are also on the U .S. FDA list of color additives approved for
use in human foods (21 CFR 73.600, 73.615) . Turmeric oleoresin is defined as the combination
of flavor and color principles obtained from turmeric (Curcuma longa) by extraction using any
one or a combination of select organic solvents, namely acetone, ethyl alcohol, ethylene
dichloride, hexane, isopropyl alcohol, methyl alcohol, methylene chloride, and trichloroethylene.
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The use of turmeric (Curcuma longa), turmeric extract, or turmeric oleoresin in food for human
consumption is generally recognized as safe (GRAS) by the United States Food and Drug
Administration (FDA) for use as a coloring and flavoring agent in foods such as gelatins and
puddings, condiments, soups, meats, and pickles, either as a powder (1 to 5% curcumin) or the
oleoresin (organic extract containing 40 to 85% curcumin) (Conney et al., 1991 ; HSDB U.S .
Food and Drug Administration, NTP, 1993) when used in accordance with good manufacturing
practice .
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Turmeric, turmeric extract, and turmeric oleoresin are also considered GRAS by the Flavoring
Extract Manufacturers' Association (FEMA) (Hall and Oser, 1965).
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The Natural Health Products Directorate (NHPD) of The Health Products and Food Branch of
Health Canada includes turmeric in its Compendium of Monographs. Ingredients included in the
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NHPD's Compendium of Monographs are considered to be safe and efficacious when used
under the conditions specified in the monograph (Health Canada, 2005). Turmeric root is also
considered an approved herb in the Complete German Commission E Monographs (Blumenthal
et al., 1998).
No A,DI value was allocated for turmeric or turmeric oleoresin by the Joint FAO/WHO Expert
Committee on Food Additives (JECFA). The Committee often declines to allocate ADI's for food
additives devoid of adverse effects such that the intake of substances arising from its use levels
(as determined by good manufacturing practice) and its acceptable background in food does not
represent a hazard to health (Groten et al., 2000). The Committee also noted that turmeric is
often regarded as a food rather than as a food additive (JECFA, 2001, 2003) .
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Pharmacokinetics
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4.3.3.1 In Vitro and Experimental Animal Data
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Early pharmacokinetic studies suggested that oral curcumin was poorly absorbed by the
gastrointestinal tract. Following oral administration of a 1 g/kg bw dose of curcumin to SpragueDavuley rats, 65 to 85% of the dose was excreted in the feces, while negligible amounts were
detected in the plasma and urine (Whalstrom and Blennow, 1978). Fecal excretion was highest
during the first 48 hours, and only 1 to 3% of the administered curcumin was excreted between
48 and 72 hours. Measurements of blood plasma levels and biliary excretion demonstrated that
curc.umin was poorly absorbed from the gut.
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Holder et al. (1978) reported 89.4% and 6 .3% of a 0.6 mg tritiated curcumin dose administered
intragastrically was detected in the feces and urine, respectively, within 72 hours of dosing .
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Later studies with radiolabeled curcumin found 60% of the administered dose was absorbed
and appeared to be transported by the bile, metabolized, and conjugated, and re-excreted into
the gut (Huang et al., 1994).
Following oral administration of 10, 80, or 400 mg of [3H] curcumin to male albino Wistar rats,
no curcumin was detected in the urine. In contrast, the excretion of glucoronide conjugates was
increased above normal levels up to seven days after dosing while the excretion of sulfate
conjugates was significantly increased above normal levels for up to 44 days after dosing, the
last time point at which conjugate excretion was measured . The authors suggested this
prolonged excretion might have resulted from enterohepatic circulation of the metabolites and/or
binding to tissue proteins . The distribution of curcumin was also examined for the period
ranging from fifteen minutes to 24 hours after dosing . No curcumin was detected in heart blood
while traces (< 5 pig/mL) were observed in portal blood. Negligible quantities (< 20 pig/tissue)
were: seen in the liver and kidney . Twenty-four hours after dosing, 1 % of the administered dose
was present in the stomach and small intestine while 38% of the original dose was found in the
cecum and large intestine (Ravindranath and Chandrasekhara, 1980, 1982). These data
suggested significantly more curcumin (60-66%) is absorbed over a range of doses (10 to 400
mg) than suggested by fecal excretion (Ravindranath and Chandrasekhara, 1980, 1982). It was
also noted that differences between these observations and those of Whalstorm and Blennow
(1978) might have been attributed to strain differences or the use of a different vehicle and
dose . Long-term studies in rats reported discoloration of the fur in curcumin-exposed rats and
mice and discolored feces in rats receiving 50,000 mg/kg curcumin (equal to 2 g/kg bw/day)
indicating that significant absorption and bioaccumulation of curcumin occurred at the high
doses employed in the studies (NTP, 1993).
The Ibioavailability of curcumin following oral administration was estimated to be approximately
sixty-five percent. Curcumin inhibits cytochrome P450 isoenzyme 1A1 and is metabolized
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primarily by glucuronidation (Commandeur and Vermeulen, 1996). In vitro studies indicated that
curcurnin was rapidly metabolized when incubated with hepatocytes or microsomal
suspensions, as 90% of the added curcurnin was metabolized within 30 minutes (Wahlstrom
and Blennow, 1978). Metabolism also appeared to be rapid in vivo. When labeled curcumin
was administered to cannulated rats by i.v. injection, 85% of the dose was recovered in the bile
after 6 hours . Major metabolites included the glucuronides of tetra hydrocurcumin and
hexahydrocurcumin, with dihydroferulic acid and ferulic acid present as minor metabolites
(Holder et al., 1978).
In the National Cancer Institute's Chemoprevention Branch-sponsored toxicity studies
discussed in Section 4 .3 .4.3, some ADME parameters were also evaluated . Curcumin was not
detected in plasma following ingrastric administration of up to 3500 mg/kg bw/day (<_ 9.5
mmol/kg bw/day) in rats and up to 1000 mg/kg bw/day in dogs (<_ 2 .7 mmol/kg bw/day)
(Anonymous, 1996) .
Active transport by the bile and extensive metabolism by the liver were demonstrated following
intravenous and intraperitoneal administration of curcurnin (Wahlstrom and Blennow, 1988 ;
Holder et al., 1978) . The major biliary metabolites were glucuronides of tetra- and
hexahydrocrucumin . Dihydroferulic acid was a minor metabolite (Holder et al., 1978).
Asai and Miyazawa (2000) investigated the absorption and metabolism of orally administered
curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) in 7-week-old male
Sprague-Dawley rats. High performance liquid chromatography (HPLC) and liquid
chromatography-mass spectrometry (LC-MS) analyses after enzymatic hydrolyses
demonstrated that the predominant metabolites in plasma following administration were
glucuronides and glucuronide/sulfates of curcuminoids . The plasma concentrations of
conjugated curcuminoids reached a maximum one-hour following administration . The
conjugative enzyme activities for glucuronidation and sulfation of curcurnin were found in the
liver, kidneys and intestinal mucosa. From their results, Asai and Miyazawa (2000) concluded
that orally administered curcuminoids are absorbed from the alimentary tract and are present in
the general blood circulation after largely being metabolized to the form of glucuronide and
glucuronide/sulfate conjugates .
Pan et al. (1999) examined the pharmacokinetics of curcumin following intraperitoneal
administration in the mouse. Following the intraperitoneal administration of 0.1 g/kg, 2 .25
Vtg/rnL was detected in the plasma in the first 15 minutes . One hour after administration, the
levels of curcurnin in the intestines, spleen, liver and kidneys were 177, 26, 27, and 8 ~Ig/g,
respectively, with only traces (0.41 Ng/g) detected in the brain . Curcumin was first
biotransformed to dihydrocurcumin and tetrahydrocurcumin . These compounds were
subsequently converted to monoglucuronide conjugates . These data suggest that curcurnin
glucuronide, dihydro-cuurcumin-glucruonide, tetrahydrocurcumin-glucuronide, and
tetrahydrocurcumin are major metabolites of curcurnin in mice (Lin et al., 2001) .
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Ireson et al. (2002) compared the differences in curcumin metabolism in rats and humans by
examining curcumin conjugation in intestinal and liver tissue . The authors reported that
extensive conjugation of curcumin occurs in the gastrointestinal tract of human, and that there is
more metabolism in human than in rat intestinal tissue . Curcumin conjugation was less
extensive in hepatic fractions from humans than in rats . These findings may explain
hepatotoxicity in rodents and suggest increased susceptibility in rodents (Chainani-Wu, 2003).
4.3.3.2 Clinical Data
In humans, serum levels were either undetectable or very low following oral intake of 2 g
curcumin alone, but serum levels were much higher from 0.25 to 1 hour post-dosing and
bioavailability increased by 2,000% when curcumin was given concurrently with 20 mg piperine,
a known inhibitor of hepatic and intestinal glucuronide conjugation (Shoba et al., 1998).
Fifteen patients with advanced colorectal cancer received an extract of Curcuma (18 mg of
curcumin and 2 mg of the desmethoxy derivative suspended in 200 mg of essential oils derived
from Curcuma spp.) daily for up to 4 months . Three subjects each received doses of extract
equivalent to 26, 72, 108, 144 or 180 mg of curcumin per day. Neither curcumin nor its
glucuronide or sulphate conjugates, or hexahydrocurcumin or hexahydrocurcuminol were
detected in plasma or urine after up to 29 days of treatment. Curcumin was detected in the
feces of all patients. Curcumin sulphate was also detected in the feces of one of the patients
receiving curcumin at a dose of 180 mg/day, which may have been a result of biotransformation
in the gut (Sharma et al., 2001).
Twenty-five patients with conditions associated with a high risk of malignancy were given
curcumin (purity, 99.3%) for 3 months . The starting dose was 500 mg/day, which was
increased stepwise to 1000, 2000, 4000, 8000 and finally 12,000 mg/day. Curcumin was barely
detectable in the serum of patients taking 500 to 2000 mg doses. Serum concentrations of
curcumin peaked at 1 to 2 hours after administration of 4000 to 8000 mg diferuloylmethane and
gradually declined within 12 hours, although a half-life was not determined . No curcumin was
detected in urine . Similar results were obtained in two patients who had taken curcumin for
more than 1 month, indicating that repeated administration did not alter the pharmacokinetic
profile of this substance and that no accumulation had occurred (Cheng et al., 2001).
4.3.4
Toxicity
4.3.4 .1 Acute Toxicity
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Administration of single intragastric doses of 1380 to 3500 mg/kg bw of commercial curcumin to
rats produced no adverse effects aside from discoloring of the feces . The LDSo was thus
considered to be in excess of 3500 mg/kg bw (Anonymous, 1996) . Oral administration of a 2 g
curcumin/kg dose to rats in one study (Shoba et al., 1998) or up to 5 g/kg in another study
(Wahlstrom and Blennow, 1978) did not produce any discernible toxic effects . Additional acute
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oral toxicity studies of turmeric, alcohol extracts, and curcumin in guinea pigs, rats, and
monkeys have revealed a low potential for toxicity (Shankar et al., 1980). Similarly, the acute
oral LDSO of curcumin oil was reported to be in excess of 5 g/kg in rats while the acute oral LDSo
of curcumin in mice was reported to be greater than 2 g/kg (Srimal and Dhawan, 1973 ; Opdyke
and Letizia, 1983) .
4.3.4.2 Subacute Toxicity
The oral administration of 100 mg/kg/day doses of curcumin to rats for 6 days reportedly
induced gastric ulcers in rats . This gastric ulceration was attributed to a reduction in the mucin
content of gastric juice . No ulcerogenic effects were seen when animals were dosed with 50
mg/kg bw/day. Gastric juice secretion was decreased at this dose, while no effects on total
acid, pepsin, or mucin secretion were observed . The decreased gastric juice secretion may be
responsible for reports of antiulcer activity seen at lower doses (Gupta et al., 1980).
4.3.4.3 Subchronic Toxicity
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No adverse effects were reported in an unpublished subchronic toxicity study in which 10 male
rats were administered curcumin at 0.1, 0 .5, 1 or 2% in the diet for 8 weeks (Central Food
Technological Institute and National Institute of Nutrition, 1978). No adverse effects were seen
in rats and monkeys fed 1 .8 g/kg bw/day and 0.8 g/kg bw/day, respectively, for 90 days (Majeed
et al., 1995).
Similarly, no adverse effects on growth, feeding efficiency, or hematologic parameters were
observed in rats fed whole spice turmeric or curcumin at doses equal to or much higher (1 .25- to
125-fold) than those normally consumed by humans for 8 weeks. The decrease in food
consumption and subsequent lower feeding efficiency observed at the highest dosage (10%
curcumin) was thought to perhaps be associated with effects of curcumin on food palatability
(Sambaiah et al., 1982).
The subchronic toxicity of curcumin was evaluated in rats and dogs in two studies funded by the
Chemoprevention Branch of the National Cancer Institute . Colored feces and yellow fur were
seen in rats following the ingrastric administration of curcumin at 1140, 1515, 1995, 2630, and
3500 mg/kg bw for 90 days. Decreased reticuloycyte counts and increased mean corpuscular
hemoglobin were seen in some males but were not considered to be biologically significant.
Minor and statistically insignificant decreases in body weights were observed in males at doses
of 1 515 mg/kg bw/day and above, and in high-dose females. The NOEL was considered to be
>- 3500 mg/kg bw/day (Anonymous, 1996). Following the administration of 250, 500, and 1000
mg/kg bw/day curcumin in a gelatin capsule formulation to dogs for 90 days, significant
elevations in mean corpuscular hemoglobin concentration were seen in mid- and high-dose
females. These elevations were not considered to be biologically relevant, however, as no overt
anemia was detected . The NOEL was thus considered to be > 1000 mg/kg bw/day in male and
female dogs (Anonymous, 1996).
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The National Toxicology Program (NTP) conducted 13-week and 2-year rodent studies using a
turrrieric oleoresin with a high curcumin content (79 to 85%) since sufficient quantities of pure
curc:umin were not available . Data from these studies is summarized below and in Section
4.3.4.4 .
NTF' 13-week study
Groups of 10 male and 10 female B6C3Fj mice and F344 rats received a turmeric extract
containing approximately 79% curcumin the diet at concentrations of 0, 0.1, 0.5, 1 .0, 2 .5, or
5.05'o for 13 weeks . No significant differences attributable to treatment were observed in bodyweight gain, mortality, or histopathology in mice, but a dose-related increase in liver weight
occurred in both sexes. Decreases were observed in lung weight, which achieved statistical
significance in males of the two highest-dose groups only, in thymus weight, significant only at
the :2 .5% level, and in kidney weight, significant in females of the top-dose group only .
Hematological changes observed were not dose-related and the values were within normal
ranges . Clinical chemistry analyses revealed dose-related increases in cholinesterase and
phosphorus, which were significant at the 1 % and higher dose levels in males and at the top two
dose levels (cholinesterase) or top-dose group only (phosphorus) in females . A dose-related
decrease in creatinine levels occurred in females at all but the lowest dose level and in males at
the top three dose levels . The no-effect level with respect to gross and microscopic pathological
changes was 5% of the diet, equal to a time-weighted average of 9280 and 7700 mg/kg bw/day
in females and males, respectively (Lilja et al., 1983).
Likewise, no significant differences due to treatment were observed in body-weight gain,
mortality, or histopathology in rats . A dose-related increase in liver weight was observed in both
sexes, and there was also a treatment-related decrease in heart and lung weights among
females. Hematological examination showed a dose-related increase in polymorphonuclear
lymphocytes at the 2 .5 and 5% dose levels in males while in females there was a small increase
only at the 5% level . In females, erythrocyte counts tended to be lower in a treatment-related,
but riot a consistent dose-related manner; other hematological changes were not dose-related .
Clinical chemistry analyses in males revealed a number of changes at the mid- to high-dose
levels ; SGPT, OCT, total protein, globulin, urea nitrogen, creatinine, and total bilirubin were
lower while the albumin/globulin ratio, direct bilirubin, and chloride tended to be higher than in
controls . Decreased SGOT and LDH were observed only at the highest-dose level. In females,
decreases were observed in LDH, creatinine, total bilirubin, pH, bicarbonate, and total C02,
while phosphorus was increased at the two higher-dose levels . Urinalysis of male rats indicated
that there was a treatment-related increase in casts and an increase in red blood cells at the top
two dose levels . Urine of females showed little or no treatment-related change except for
increased uric acid crystals at all dose levels and a slight increase in red and white blood cells
at the top-dose levels . The no-effect level with respect to gross and microscopic pathological
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changes was 5% of the diet, equal to a time-weighted average of 2760 and 2587 mg/kg bw/day
in females and males, respectively (Lilja et al., 1983).
4.3.4.4 Chronic Toxicity and Carcinogenicity
The National Toxicology Program (1993) conducted a 2-year chronic toxicity and carcinogenicity
study with turmeric oleoresin (79% curcumin) in rats and mice. Male and female F344/N rats
(60 ;animals/sex/group) were administered diets containing 2,000, 10,000, or 50,000 ppm
turmeric oleoresin for 104 weeks (males) or 103 weeks (females). Diets were estimated to
deliver average daily doses of 80, 460, or 2,000 mg/kg to male rats and 90, 440, or 2,400 mg/kg
to female rats . Nine or ten animals from each group were evaluated after 15 months. Survival
rates of male and female rats were unaffected by dietary turmeric . Final mean body weights of
male and female rats receiving 2000 and 10,000 ppm were similar to controls . The final mean
body weights of rats receiving 50,000 ppm were slightly lower (up to 10%) than controls in both
sexes throughout much of the study, although feed consumption was unaffected . At the 15month interim evaluation, significant increases in the absolute and relative liver weights were
seen in female rats at the 10,000 and 50,000 ppm dose levels . No clinical findings related to
toxicity were observed .
Significantly reduced hematocrit values, hemoglobin concentrations, and erythrocyte counts
were seen in high-dose (50,000 ppm) males and females at the 15-month interim evaluation.
Platelet counts were significantly increased in both males and females while a significant
increase in reticulocyte counts was seen in males only at the 50,000 ppm dose level
biologically significant changes were seen in clinical chemistry parameters.
Non-neoplastic lesions were observed in the gastrointestinal tracts of high-dose rats; an
increased incidence of ulcers, hyperplasia, and hyperkeratosis of the forestomach was seen in
males, while both males and females had ulcers, chronic active inflammation, and hyperplasia
Similar lesions were seen in the colon of males. Increased incidences of sinus
ectasia of the mesenteric lymph node were seen in males at the 10,000 and 50,000 ppm dose
levels and in males and females at the 50,000 ppm dose level. These lesions were considered
likely to be regenerative and not neoplastic in nature .
No evidence of carcinogenic activity was seen in male F344/N rats . In females, an increased
incidence of clitoral gland adenomas was seen in all exposed groups. Clitoral gland carcinomas
were observed in one control animal and in four rats at the 2000 ppm dose level . Notably, the
marginal increase of clitoral gland adenoma was neither dose-related nor associated with a
corresponding increase in hyperplasia. No animals at the 10,000 or 50,000 dose level were
affected . The combined incidences of clitoral gland adenoma or carcinoma in all exposed
groups of female rats were similar and did not increase with exposure level . The incidence of
clitoral gland hyperplasia was similar among exposed and control groups of female rats .
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Similarly, the National Toxicology Program conducted a 2-year chronic toxicity and
carcinogenicity study with turmeric oleoresin in mice. Male and female B6C3F1 mice 60
animals/sex/group) were administered diets containing 2,000, 10,000, or 50,000 ppm turmeric
oleoresin for 104 weeks (males) or 103 weeks (females). It was estimated that male and female
mice consumed average daily doses of 220, 520, or 6,000 mg/kg and 320,1,620, or 8,400
mg/kg, respectively . Nine or ten animals from each group were evaluated after 15 months.
Survival rates of male and female mice were unaffected by dietary turmeric . The mean body
weights of females at the 50,000 ppm dose level was slightly lower (up to 12%) than controls
starting from approximately week 25. At the conclusion of the study, significant reductions in
mean body weights were seen at the 50,000 ppm dose males and the 10,0000 and 50,000 ppm
dose, groups in females. The final mean body weights of other exposed groups were similar to
controls, and feed consumption in all exposed groups was similar to controls throughout the
study. At the 15-month interim evaluation, the absolute and relative liver weights were
significantly increased in both males at females in the 10,000 and 50,000 ppm dose groups. No
toxicologically significant clinical findings were observed . There were no biologically significant
differences seen in hematologic parameters . Alkaline phosphatase values were significantly
higher in males and females at the 10,000 and 50,000 ppm levels than in controls after 15
months .
The incidence of hepatocellular ademoma was significantly increased in males and females at
the '10,000 ppm dose level, but not at the 2000 or 50,000 ppm levels . The number of male and
female mice in the 10,000 and 50,000 ppm groups with multiple hepatocellular neoplasms was
significantly greater than that in the controls . The incidences of hepatocellular carcinoma were
similar among exposed and control groups.
There were no chemical related non-neoplastic lesions of the gastrointestinal tract in mice as
had been seen in rats . Three males each in the 2000 and 10,000 ppm dose groups had
carciinomas of the small intestine, however no neoplasms of the small intestine were seen at the
50,000 ppm dose level. A significantly increased incidence of thyroid gland follicular cell
hyperplasia was seen at the 50,000 ppm dose level in females (NTP, 1993).
Summary and Conclusions of NTP Studies
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Gastrointestinal irritation (ulcers, hyperplasia and inflammation) was common in male and
female rats in the high-dose group, but was not observed in mice . The NOEL for
gastrointestinal effects in rats was 10 000 mg/kg in the diet, equal to 440 mg/kg bw/day. After
15 months of treatment, absolute and relative liver weights were increased in both male and
female mice in the mid- and high-dose groups relative to control . The NOEL for liver
enlargement was 2000 mg/kg in the diet, equal to 220 mg/kg bw/day (JECFA, 1994) . The
ingestion of turmeric oleoresin was also associated with thyroid gland follicular cell hyperplasia
in fernales (NTP, 1993).
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It was conc l u d e d th a t un d er th e con diti ons of t h e 2 -year fee di ng studi es conducted by the
National Toxicology Program, there was no evidence of carcinogenic activity of turmeric
oleoresin in male F344 rats administered 2000, 10,000, or 50,000 ppm . In female rats, there
was equivocal evidence of carcinogenic activity based on increased incidences of clitoral gland
adenomas in the exposed groups. There was equivocal evidence of carcinogenic activity in
male B6C3F1 mice based on a marginally increased incidence of hepatocellular adenoma at the
10,000 ppm level and the occurrence of small intestine carcinomas at the 2000 and 10,000 ppm
groups. Likewise, there was equivocal evidence of carcinogenic activity in female mice based
on the increased incidence of hepatocellular adenoma at the 10,000 ppm dose level (NTP,
199:3).
The Joint WHO/FAO Expert Committee on Food Additives reviewed the results of the NTP
studies and concluded that although statistically significant increases in the incidences of
hepatocellular adenomas (mid-dose males and females), small intestinal carcinomas (low- and
mid-dose males) and pituitary gland adenomas (high-dose females) in mice and clitoral gland
adenomas (females) in rats were reported, the effects were not dose-related, and that curcumin
was not a carcinogen (WHO, 1996).
4.3.4.5 Mutagenicify and Genotoxicity
Curc :umin was not mutagenic in the Salmonella Ames assay or the mouse dominant lethal
assay with or without metabolic activation at doses up to the limits of solubility (Ishidate et al .,
19811, 1984 ; Jensen 1982, Mortelmans et al., 1986 ; Vijayalaxmi, 1980 ; Shah and Netrawali,
1988 ; Bonin and Baker, 1980 ; Luck and Rickerl, 1960 ; Nagabhushan and Bhide, 1986), and in
yeast gene conversion test (Sankarnarayanan and Murthy, 1979).
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It was inactive in CHO cells (Au and Hsu, 1979), did not induce micronuclei or dominant lethal
mutations (Vijayalaxmi, 1980). Nagabhusan et al. (1987) had further reported that curcumin
inhibited mutagenicity of tobacco products, tobacco smoke condensates, benzo[a]pyrene and
dimethylbenzo[a]anthracene in presence of S-9 probably by altering metabolic activation and
detoxification of mutagens .
Equivocal results have been reported in some in vitro and in vivo assays of clastogenicity
(Ishidate et al., 1988 ; Giri, 1990). Curcumin was capable of causing clastogenicity with plant
and animal cells both in vivo and in vitro (Abraham et al., 1976 ; Goodpasture and Arrighi, 1976 ;
Ishidate et al., 1984). Kawachi et al. (1980) and Ishidate et al. (1984) reported that curcumin
induced chromosomal aberrations cultured hamster fibroblasts . Tests for the induction of
chromosomal aberrations, micronuclei, or dominant lethal mutations in mice fed 0 .015% in the
diet for 12 weeks were negative (Vijayalaxmi, 1980). Giri et al. (1990) studied sister chromatid
exchanges (SCEs) and chromosomal aberrations induced by curcumin and the synthetic dye
tartrazine on bone marrow cells of 10- to- 12-week old Swiss albino male mice and rats
following acute and chronic exposure via the diet . Curcumin was weakly clasotgenic in vivo in
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mice, but induced SCE in mice following intraperitoneal treatment (Giri et al., 1990). No
significant increase in chromosomal aberrations was observed in the curcumin treated series,
whereas tartrazine showed a significant increase in chromosomal aberrations in some of the
higher concentrations in all the series tested .
Single intraperitoneal injections of 25 to 200 mg/kg bw (0 .07 to 0 .5 mmol/kg bw) to Swiss mice
increased sister chromatid exchanges significantly in bone marrow cells, however, no dose
achieved twice the background rate (Anonymous, 1996) . A 79 to 85% purity preparation
induced chromosomal aberrations and SCEs in vitro. In vivo, a curcumin preparation of
unknown purity administered to mice by intraperitoneal injection did not induce micronuclei in
bone marrow cells, whereas a low level of chromosomal aberrations was reported in the same
cell population (Jain et al., 1987). Growth inhibition due to DNA damage was reportedly
observed in the 8. subtilis Rec assay (Kawachi et al., 1980). Using the sensitive single cell
electrophoresis method (comet assay), Blasiak et al. (1999) observed that curcumin (diferuloyl
methane) at 15, 25, and 50NM caused DNA damage in gastric mucosa cells and human
peripheral blood lymphocytes, however, damaged cells were able to recover within a period of .?
hours .
4.3 .4.5 .1
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Phototoxicity
Curc;umin reportedly exhibited photoxic effects in bacterial systems following irradiation with
visible light (Tonnesen et al., 1987 ; Dahl et al., 1989) .
4.3.4.6 Reproductive and Developmental Toxicity
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No reports of reproductive or developmental toxicity related to curcumin were found in the
literature . No effects on implantation, resorption, live and dead embryos, or skeletal or visceral
abnormalities were seen following the administration of does of 600 and 1600 mg/kg bw,
respectively, to rats and rabbits on days 6 through 15 of gestation (unpublished data cited in
Govindarajan, 1980). Likewise, no adverse effects were seen on pregnancy rate, mean number
of live and dead embryos, or total implants in rats fed diets containing 0.5% or 0.015%
curcuminoids for 12 weeks prior to mating (Govindarajan, 1980). In another study, dietary
administration of 0 .015% curcumin had no effects pregnancy rate, embryo viability, total
implantations, or mutagenic index in rats (Vijayalaxmi, 1980). Inano et al. (2000) reported no
adverse effects on litter size and body weight in pups born to rats treated with 1 % curcumin in
the diet in a study examining the anti-cancer action of curcumin via a standard model of
radiation induced tumor in rat mammary gland .
No evidence of teratogenicity or impaired reproductive capacity was observed in a threegeneration rat study (unpublished data, cited in Wahlstrom and Blennow, 1978). In another
multi-generation study, groups of male and female rats were fed diets containing curcumin at a
concentration of 0, 1500, 3000 or 10 000 mg/kg of diet starting from 10 weeks before the mating
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period and throughout mating . Treatment of females continued throughout pregnancy and
weaning of the offspring . The total periods of treatment were 21 weeks for the parental
generation and 24 weeks for the F, generation . On postnatal day 4, the litter sizes of the F,
offspring were standardized to a maximum of eight . After weaning, 30 male and 30 females of
the IF, generation were selected to become the parents of the F2 generation . Parents were
observed for clinical signs, body weights, food intake, cohabitation interval and duration of
gestation . Pups were weighed on postnatal days 1, 4, 7, 14 and 21 . All parents, F, weanlings
not selected for mating, and all F2 weanlings were subjected to complete necropsy at terminal
sacrifice . The concentrations used corresponded to doses of 0, 130 to 140, 250 to 290 or 850
to 960 mg/kg bw per day in males, and 0, 160, 310 to 320 or 1000 to 1100 mg/kg bw per day in
females (Ganiger, 2002).
There was a dose-related decrease in body-weight gain in the dams of the parental generation
during days 10 to 15 of gestation, which was statistically significantly different from that of
controls (body-weight gains, >80% that of controls) at the intermediate and highest doses . At
this time, body weights were reported to be below the range of values for the historical controls .
However, maternal body weights did not differ significantly between groups at the end of
gestation. The mean body weights of the F2 offspring (both sexes combined) were significantly
decreased on postnatal days 1 and 7 at the intermediate dose, and on postnatal days 7, 14 and
21 at the highest dose . A dose-related trend was apparent, but the effect was small, with
average body weights being >90% that of the control pups, and the observed changes were
reported to be within the range of the data for historical controls . There were no other effects on
general health, body weight, pup survival and fertility indices in either generation . The effects at
the intermediate dose were observed at isolated time-points only and were considered to be
incidental ; and therefore this dose, equal to 250 to 320 mg/kg bw per day for the F, generation,
was established as the NOEL (Ganiger, 2002).
4.3.5
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Clinical Data
In addition to its history of use in foods, additional evidence to support the safety of curcumin is
available from clinical trials . Data from several such studies are summarized in Table 4-1 and a
discussion of the relevant findings follows.
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HEALTH SCIENCES INTERNATIONAL
During the course of clinical trials, single oral doses up to 2 g curcumin have been administered
to healthy human volunteers, with no evidence of adverse health effects (Anonymous, 1996 ;
Sholba et al., 1998). Soni and Kuttan (1992) reported no adverse effects among ten subjects
administered 500 mg of curcumin (98% purity) daily via capsules for 7 days . Multiple doses of
600 mg turmeric oil mixed with 3 g turmeric ethanol extract per day or 375 mg curcumin three
times daily have also been used in three-month long clinical studies (Hastak et al., 1997 ; Lal et
al., 1999) .
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Subjects consuming 200 mg of a hydroalcoholic extract of Curcuma longa (approximately 20
mg/day curcumin) for 15 to 60 days reported no side effects such as nausea, diarrhea, or
constipation during the treatment period (Ramirez-Bosca et al., 1997 ; 2000) . In earlier studies,
the same treatment regimen (approximately 20 mg/day curcumin for 15-60 days) produced no
sign of apparent liver or kidney toxicity as measured by glutamic-oxaloacetic transaminase
(GOT), glutamic-pyruvic transaminase (GPT), y-glutamyltransferase (GGT), alkaline
phosphatase, and total bilirubin . Blood coagulation parameters were likewise unaffected
(Rarnirez-Bosca et al, 1995, 1997).
Twenty-five patients with conditions indicating a high risk of malignancy were given
diferuloylmethane (99 .3% purity for 3 months . The starting dose was 500 mg/day, which was
increased stepwise to 1000, 2000, 4000, 8000 and finally 12,000 mg/day . The patients received
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regular follow-up, including physical examination, and analysis of blood counts and biochemistry
parameters. No adverse effects were reported at doses of up to 8000 mg/day . The highest
dose of 12,000 mg/day was not acceptable to the patients because of the bulky volume of the
tablets (Cheng et al., 2001) . Five other trials demonstrated the safety of curcumin at doses
ranging from 1125 to 2500 mg/day . Curcumin was administered orally to rheumatoid arthritis
patients at a dose of 1 .2 g/day without signs of toxicity . Blood pressure, pulse, erythrocyte
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sedimentation rate, and renal and hepatic function were likewise unaffected (Deodhar et al.,
198CI) . Doses of 1500 mg/day for 4 to 6 weeks produced subjective improvement in
osteoarthritis symptoms, and no side effects were reported (Srimal and Dhawan, 1985) . Lal et
al. (1999, 2000) reported no adverse effects in clinical studies using doses of 1125 mg/day .
Forty-five past-surgical patients received either curcumin (1200 mg/day), phenylbutazone (300
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mg/clay) or placebo for 5 days . One patient in the curcumin group reported mild transient
giddiness on postoperative day 3 while 1 patient in the placebo group complained of nausea on
the first postoperative day . No changes in blood tests were noted (Satoskar et al., 1986).
Among 19 HIV patients given 2500 mg curcumin/day (duration not specified), two subjects
reported some gastric irritation, including one with a past history of peptic ulcers . No adverse
reactions or changes in blood test parameters were noted (James, 1994) . Thamlikitkul et al.
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(198'9) reported no adverse side effects in dyspeptic patients treated with 250 mg Curcuma
domestica Val . four times daily for 7 days (corresponding to daily doses of approximately 50 mg
curcumin four times daily) . In a randomized, double-blind, crossover study, Rasyid and Lelo
(1998) examined the effects of 20 mg curcumin on gall-bladder volume and function in healthy
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human volunteers . Curcumin was shown to stimulate contraction of the gall bladder, and none
of the subjects reported experiencing adverse side effects.
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Fifteen patients with advanced colorectal cancer received an extract of Curcuma (18 mg of
curc:umin and 2 mg of the desmethoxy derivative suspended in 200 mg of essential oils derived
from Curcuma spp .) daily for up to 4 months. Three subjects each received doses of extract
equNValent to 26, 72, 108, 144 or 180 mg of curcumin per day. Gastrointestinal symptoms were
reported by 3 subjects . During the first month of treatment, one patient receiving 108 mg
curc:umin per day experienced nausea, which resolved spontaneously without discontinuing the
treatment. Two patients, who received curcumin at a dose of 72 or 180 mg per day,
respectively, experienced diarrhea . In the absence of controls, and in view of the clinical
conditions of the patients however, it is not clear whether these symptoms were related to
treatment (Sharma et al., 2001).
Allergenicity
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One case of allergic contact dermatitis to Curcuma longa in a 64-year old male Indian spice
worker was been reported . Although no quantitative estimate of exposure was provided, the
worker was reportedly exposed to 7 different spices and worked in a dusty place laden with
spice powders. The authors concluded that turmeric is a weak sensitizer and that allergic
contact dermatitis to it is uncommon (Goh & Ng, 1987). Other case reports of allergic contact
dernnatitis due to curcumin were also available (Hata, 1997 ; Kiec-Swierczynska, 1998) .
However, Futrell and Rietschel (1993) patch tested 55 patients with suspected contact
dermatitis for sensitivity to a number of spices and observed only two reactions to turmeric at a
concentration of 25% in petroleum ; no reactions were observed at the lower (10%)
concentration . The authors noted that it was unclear whether this was indicative of a threshold
for detecting true allergy or a marginal irritant reaction . Although some reactions have been
reported in double-blind, placebo controlled food challenges involving mixtures of natural
colorings, it was not possible to determine which of the food colorants may have triggered the
adverse reactions. Thus, no convincing evidence exists of allergic reactions to turmeric or
curcumin (Lucas et al., 2001) .
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Biological Effects and Pharmacology
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There exists an extensive database related to the pharmacological effects of curcumin and
turmeric . Although not expressly related to safety, a brief overview of the available data has
been provided . Pharmacological actions of curcumin reportedly include antioxidant, antiinflammatory, anti-cancer, and antiatherogenic effects (Anonymous, 1996). Due to these
activities, the NCI Chemoprevention Branch reportedly considered curcumin for clinical
development (Anonymous, 1996).
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Gurc :um i n h as been s h own t o i n d uce some forms o f detoxifying phase 1 metabolic enzymes
(cytochrome PaSO) while inhibiting other forms involved in the activation of carcinogens
(Sarnbaiah and Srinivasan, 1989 ; Deshpande and Maru, 1995 ; Singh et al., 1995 ; Firozi et al.,
1996 ; Oetari et al., 1996 ; Ciolino, et al., 1998 ; Thapliyal and Maru, 2001 ; Thapliyal et al., 2001).
Curr,umin has also been shown to increase the levels of glutathione (GSH), a protein that, along
with the phase II metabolic enzyme glutathione-S-transferase is involved in the metabolism of
chemical substances via conjugation, by over 40% in rat liver cells in vitro at non-cytotoxic
concentrations (White et al., 1998 ; Piper et al., 1998 ; Singh, et al. 1998). Induction of phase I
and phase II metabolic enzymes by turmeric and curcumin has also been observed in lactating
mice ; and their suckling offspring (Singh et al., 1995) .
There have been several reports of curcumin ' s antiatherogenic effects in both experimental
animals and humans. Curcumin at a level of 0.1% in the diet was reported to lower serum and
li ver c h o les tero l i n ra ts fe d 1 % c h o l es tero l -con ta i n i ng di ets for 7 weeks (Rao et al., 1970).
Similarly, Kamal-Eldin, (2000) reported that curcumin, administered ad libitum to rats for 4
weeks at 4 g/kg diet significantly lowered both plasma and hepatic total cholesterol.
Hyperlipidemic rats fed 3000 mg/kg bw of an ethanolic extract (50% v/v) of defatted Curcuma
longa had lower levels of serum cholesterol and triglycerides and elevated high-density
lipoprotein (HDL)-cholesterol compared to controls (Dixit et al., 1988). Curcumin has also been
reported to counteract the hypercholesterolemic action of increased dietary cholesterol, but did
not reduce cholesterol in normal-fed rats . Lower cholesterol levels seen in rats were attributed
to increased fecal extraction of bile acids and cholesterol (Subba Rao et al., 1970) .
Ramiirez-Bosca et al. (1995, 1997, 2000a,b) reported that oral administration of the
hydroalcoholic extract of Curcuma longa (corresponding to approximately 20 mg/day curcumin)
to healthy human subjects resulted in significant decreases in the LDL and apo B levels and
significant increases in the HDL and apo A levels of healthy subjects . Decreases in the levels of
blood lipid peroxides, oxidized lipoproteins and fibrinogen were also reported .
Based on experimental animal studies, curcumin is believed to have hepatoprotective activity.
It is also considered to possess potent anti-inflammatory and antioxidant activities and can
suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation
associated with Alzheimer's disease (Rao et al., 1995 ; Luper, 1999 ; Yang et al., 2005). Orally
admlinistered curcumin reportedly reduced inflammation in laboratory animals and reduced
discomfort in rheumatoid arthritis patients (Deodhar et al., 1980 ; Mukhopadhyay et al., 1982 ;
Srimal and Dhawan, 1973) .
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Antipsoriatic effects have been reported in both animal models (Bosman, 1994) and human
subjects (Heng et al., 2000).
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Of 1,130 traditional herbs, turmeric was among six with high human estrogen receptor- (ER) and
progestin receptor- (PR) binding activity in human breast cancer cells (Zava et al., 1998).
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Verrna et al., (1997, 1998) showed that curcumin and the isoflavonoid genistein, alone and in
combination, inhibited the growth cultured human breast cancer cells induced by pesticides and
environmental chemicals .
The inhibitory effects of curcumin on carcinogenesis has been demonstrated in several animal
models of tumors induced by irradiation or standard chemical carcinogens, and the
chernopreventative activity of curcumin was apparent when administered prior to, during, and
after carcinogen treatment, as well as when it was given only during the promotion/progression
phase, and these studies have demonstrated tumor prevention in animal models of carcinogeninduced colon, duodenum, forestomach, mammary gland, oral cavity, and skin models (Huang
et al., 1988 ; Huang et al., 1992 ; Bhide et al., 1994 ; Huang et al., 1994 ; Huang et al., 1997 ;
Limtrakul et al., 1997 ; Tanaka et al., 1994 ; Rao et al., 1995 ; Anonymous, 1996 ; Takaba et al.,
1997 ; Singh et al., 1998 ; Inano et al., 2000 ; Aggarwal et al., 2003; Miquel et al., 2002; Joe et al.,
2004).
Jee et al. (1998) found that curcumin induced apoptosis in human basal cell carcinoma cells
while Kuo et al., (1996) observed a similar effect in human leukemia cells. The favorable effects
of cUrcumin in some of these cancer studies may be related to the protective effects against
dermal inflammatory dermatitis (Ishizaki et al., 1996) or a favorable immunomodulation
(Bhaumik et al., 2000) .
A number of small clinical trials designed to demonstrate the efficacy of curcumin or turmeric in
the treatment of arthritis, postoperative inflammation, or other inflammatory conditions provide
data to support the safety of curcumin . In a preliminary study in HIV-seropositive individuals, no
adverse effects have been reported following the administration of an average dose of 2000
mg/day for an average of 127 days (Copeland, 1994) . Daily doses of 500 mg (0 .02 mmol/kg
bw) for seven days decreased serum lipid peroxides and total cholesterol and increased HDLcholE:sterol without adverse effects (Soni and Kuttan, 1992). Curcumin at doses of 1800 to
2100 mg/day for 5 to 6 weeks resulted in significant improvement in rheumatoid arthritis
symptoms without any side effects. Similarly, doses of 1500 mg/day for 4 to 6 weeks produced
subjective improvement in osteoarthritis symptoms, and no side effects were reported (Srimal
and Dhawan, 1985). Likewise, no adverse effects were reported in clinical trials in which
comparable doses of curcumin were administered to patients suffering from acute inflammation
related to various medical or surgical procedures including episiotomy, hernia operations, nasal
fractures etc. (Srimal and Dhawan, 1985).
In a randomized, double-blind, crossover study, Rasyid and Lelo (1998) examined the effects of
20 m~g curcumin on gall-bladder volume and function in healthy human volunteers . Curcumin
was :shown to stimulate contraction of the gall bladder.
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4.3 .6
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An overview of information related to the safety and toxicity of turmeric and turmeric extracts is
presented here for the sake of completeness and to support the safety of Elite Curcumin .
However, it should be noted that these data are not the primary source upon which the
conclusion that Elite Curcumin can reasonably be anticipated to be safe when used in
accordance with label instructions was based . Curcumin is present at 3 to 5% in turmeric and
higher percentages in turmeric extracts . However other components and impurities present in
turmeric not found in synthetic curcumin may be responsible for some effects noted in these
studies .
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Supporting Data with Turmeric and Turmeric Extracts
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4.3. 6 .1 Acute Toxicity
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The acute oral LDSO of a turmeric extract containing an estimated 79% curcumin was reported to
be greater than 10 g/kg bw in both rats and mice (Lilja et al., 1983). The short-term studies in
rats and mice on test material containing approximately 79% curcumin indicated a low shortterm toxicity, although evidence of minimal hepatotoxicity and nephrotoxicity was seen in the
high-dose acute toxicity study by gavage (WHO, 1987).
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No toxicity was seen 1 day or 3 weeks following a single, acute administration of 2.5 g/kg bw
powdered turmeric (containing approximately 2.5% curcumin) or 300 mg/kg bw of the alcoholic
extract of turmeric in the diet for 1 day to rats, guinea pigs, or monkeys. No treatment-related
gross or histopathologic lesions were seen in the liver, kidney, or heart (Shankar et al ., 1980).
Data from multiple studies suggest that the mouse is a species particularly susceptible to
turmeric-induced toxicity. Acute oral administration of 0.5, 1, and 3 g of an ethanolic Curcuma
longa extract per kg body weight produced no significant mortality, relative to control, but oral
administration of 100 mg/kg body weight/day for 90 days resulted in lower body weight gains,
changes in some organ weights, and decreased white blood cell and red blood cell levels,
relative to control animals (Qureshi et al., 1992) . Kandarkar et al. (1998) observed liver toxicity
(necrosis with regeneration) in mice given turmeric (0.2%, 1 %, or 5%) or an ethanolic turmeric
extract (0.055 or 0.25%) in the diet for 14 days.
4.3.6.2 Subacute Toxicity
Similar results (reduced body weight gain, changes in absolute and/or relative liver weights, and
hepatotoxicity) were described by Deshpande et al. (1998) . Mice and rats were fed diets
containing 0.05 or 0 .25% of a 5% ethanolic turmeric extract (ETE) for 14 days . Approximately
98% of the 5% extract was made up of curcumin, demethoxycrucrumin and bisdemethoxycurcumin . Growth was not affected in either species, and there were no dose-related
chang es in absolute or relative liver weights . Mice were more susceptible to ETE-induced
effects than rats . Hemoglobin levels were unaffected by mice treated with 0 .05 or 0.25% ETE .
No dose-related significant changes were seen in mice in markers of either liver function (e.g.,
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serurn glutamate oxaloacetate aminotransferase and serum glutamate pyruvate
aminotransferase) or kidney function (urea, creatinine). Levels of serum proteins and serum
albumin were significantly elevated in mice at both dose levels . There were no significant
hematological or clinical chemistry effects observed in ETE-treated rats . No histopathological
changes were observed in the lungs, forestomachs, or brains of mice while focal necrosis of the
spleen was observed in both the low- and high-dose groups. No effects on the kidneys were
observed in mice at the 0.05% level, minimal focal necrosis of the cortex, glomeruli and/or
tubules was seen in some high-dose animals . Three of twelve mice at the 0.05% level showed
focal necrosis of the liver with regeneration while four of twelve exhibited necrosis only.
Similarly, at the 0.25% level, three mice showed focal necrosis with regeneration while an
additional three mice showed focal necrosis only . No histopathological changes were observed
in the liver, lungs, kidney, forestomach, spleen or brain of rats treated with 0 .05% or 0 .25%
ethanolic turmeric extract for 14 days when compared with controls (Deshpande et al., 1998) .
Kandarkar et al. (1998) further examined the histopathological and ultrastructural effects of ETE
on the liver. Female mice were administered 0.05% or 0.25% ETE in the diet for 14 days. No
effects on body weight or absolute or relative liver weights were reported, and no macroscopic
changes to the livers, lungs, or forestomachs were seen . Likewise, no significant
histopathological effects were observed in the lungs or forestomach . Coagulative necrosis
accompanied by a zone of regenerating parenchymal cells of the liver was seen in 3 of 6 mice in
each group. The observed ultrastructural changes to the liver were considered to be consistent
with a non-specific reaction to injury . The authors suggested that mice may be more
susceptible to these effects since the subchronic administration of turmeric and its components,
including curcumin, produced no adverse effects in rats, guinea pigs, dogs, and monkeys at
similar concentrations . The authors also noted that although the concentrations in the diet were
similar, mice were exposed to higher doses on a bodyweight basis than other species.
4.3.6.3 Subchronic Toxicity
The administration of turmeric oleoresin (15% curcumin) to pigs in the diet at 60, 296, and 1,551
mg/kg body weight/day (corresponding to doses of 10.5, 51 .8, and 271 .4 mg curcumin/kg,
respectively) for up to 109 days resulted in statistically significant dose-related increased in liver
and thyroid weights . No changes in gross pathology considered to be related to dosing were
seen at necropsy, but upon microscopic examination, changes in thyroid, kidney, and urinary
bladder histology (e.g., pericholangitis, hyperplasia of the thyroid, and epithelial changes in the
kidney and urinary bladder) were observed at the two higher dosages . No dose-related
significant changes in hematological or biochemical parameters were reported . At 1,551
mg/kg/day, reduced weight gain and food-conversion efficiency were observed . The authors
concluded that the lowest level at which there was a clear effect was 296 mg/kg bw/day,
corresponding to an intake of 51 .8 mg curcumin/kg/day since histological changes in the liver,
kidney, and urinary bladder were clear at this level . It was not clear whether 60 mg turmeric
oleoresin/kg bw/day, corresponding to a curcumin intake of 10.5 mg/kg bw/day, can be
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considered a no-adverse effect level. At this dose, increased absolute and relative thyroid
weights were reported . These changes corresponded to the histological changes visible at
higher doses, however it was not clear whether this finding was indicative of a reversible
adaptive response (Bille et al., 1985) .
In additional studies in the mouse, acute oral administration of 0 .5, 1, and 3 g of an ethanolic
Curcuma longa extract per kg body weight (curcumin content not specified) produced no
significant mortality and no signs of toxicity relative to control. Oral administration of 100 mg
extract/kg body weight/day for 90 days resulted in lower body weight gains, changes in heart
and Ilung weights, and decreased white blood cell and red blood cell levels relative to control
animals (Qureshi et al., 1992) .
Oral administration of 100 mg of an ethanolic Curcuma longa extract per kg body weight
(curc;umin content not specified) for 90 days to male rats resulted in no spermatotoxic effects.
The incidence of sperm abnormalities was significantly lower than in controls, an effect the
authors attributed to the antioxidant activity of Curcuma longa. Increased caudae epididymidies
weights and significantly higher sperm motilities were observed in extract-treated males relative
to control, indicating a possible androgenic activity. The sperm count elevation was not
statistically significant however (Qureshi et al., 1992) .
As part of a study designed to examine the modifying effects of curcumin on the initiation and
post-initiation phases of 4-nitroquinoline 1-oxide induced oral carcinogenesis, control male F344
rats were fed diets containing 500 ppm curcumin for 22 weeks. No histopathoglcoial findings
indicative of liver, kidney, or lung toxicity were seen (Tanaka et al., 1994).
In contrast to Desphende et al. (1988) and Kandarkar et al ., (1998), Miquel et al. (1995)
reported no toxic effects on physiological, behavioral, or biochemical parameters in mice fed 4
mg/kg bw/day of a hydroalcoholic extract of turmeric (equivalent to 0.4 mg/kg bw/day curcumin)
for 4 weeks. A decrease in plasma and liver lipid peroxides was reported, consistent with other
reports of curcumin's antioxidant effects.
4.3.6.4 Mutagenicity and Genotoxicity
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Turmeric and turmeric derivatives were not found to be mutagenic in the Ames bacterial
mutagenicity assay using several Salmonella typhimurium strains in the presence or absence of
rodent liver metabolic fractions (Mortelmans et al., 1986 ; NTP, 1993). The effects of turmeric
and curcumin on chromosome integrity are not clear. For example, Acute oral administration of
turmeric (5, 2.5 and 1 .25 g/kg bw) to male and female mice failed to induce a significant
increase in the yield of micronuclei in polychromatic erythrocytes (PCEs) in one study (Abraham
and Kesavan, 1984), while chromosome aberrations were reported to occur in vitro following
treatment with extracts from fresh Curcuma longa rhizomes in another study (Abraham et al.,
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1976). Arujo et al. (1999) found that turmeric and curcumin potentiated radiation induced
clastogenicity in Chinese hamster ovary cells .
4.3.6 .5
Clinical Toxicity
Data from clinical studies conducted with turmeric and turmeric extracts are summarized in
Table 4-2. In addition, Kuttan et al. (1987) evaluated the use of an ethanolc extract of turmeric
(curc,umin content 0 .5%) or a 0 .5% curcumin ointment for topical application to external
cancerous lesions of 62 patients . Most subjects reported symptomatic relief . A single adverse
effect, local itching that authors believed my have been an allergic reaction to curcumin, was
reported .
Polasa et al. (1992) evaluated some safety parameters in a study of the effects of turmeric on
urinairy mutagens in smokers. No adverse effects on serum aspartate aminotransferase,
alanine aminotransferase, blood glucose or creatinine levels were seen following consumption
of 1 .!5 g turmeric (curcumin content not specified) daily for 30 days . Serum cholesterol and HDL
and triglyceride levels were likewise unaffected .
Data from clinical studies with turmeric and turmeric extract are summarized in Table 4-2.
'
March 2, 2006
30
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CANTOX
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HEALTH SCIENCES INTERNATIONAL
SUMMARY
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The information presented herein shows that :
(i)
Synthetically produced curcumin 1,7-bis(4-hydroxy-3-methoxyphenyl) hepta-1,6diene-3,5-dione) is well characterized, and the process for manufacturing the
nature-identical compound yields a product demonstrated to reproducibly meet
compositional specifications .
(ii)
There is a long history of food use for both turmeric and curcumin, thus humans have
previously been exposed to curcumin without reports of significant adverse effects.
Turmeric is considered GRAS by FDA, FEMA .
(iii)
No adverse effects were reported in an unpublished subchronic toxicity study in
which 10 male rats were administered curcumin at 0 .1, 0 .5, 1 or 2% in the diet for 8
weeks. Similarly, no adverse effects on growth, feeding efficiency, or hematologic
parameters were observed in rats fed whole spice turmeric or curcumin at doses
equal to or much higher (1 .25- to 125-fold) than those normally consumed by
humans for 8 weeks. The decrease in food consumption and subsequent lower
feeding efficiency observed at the highest dosage (10% curcumin) was attributed to
effects of curcumin on food palatability .
(iv)
The No-Observed-Effect Levels (NOELs) in dogs and rats in the 90-day
Chemoprevention Branch studies were in excess of 1000 mg/kg bw/day and 3500
mg/kg bw/day, respectively, the highest dose level administered to each animal . In
13-week feeding studies in rats and mice conducted by the National Toxicology
Program, the no-effect level with respect to gross and microscopic pathological
changes was 5% of the diet. This level was equivalent to a time-weighted average of
7700 and 9280 mg/kg in male and female mice and 2587 and 2760 mg/kg bw/day in
male and female rats. In Chemoprevention Branch-funded studies of commercial
grade curcumin, minor changes in body weights in rats and hematological values in
rats and dogs were not considered biologically significant . An intake of 1500
mg/day, the level suggested or recommended on Elite Curcumin product label, is
equivalent on a body weight basis to 25 mg/kg bw/day in a 60 kg adult. Thus, there
is over a 100-fold safety factor from the NOEL in rats and a 300-fold safety factor
.
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from the NOEL in mice .
,
(v)
Although evidence of hepatotoxicity has been reported in rodent studies,
pharmacokinetic studies demonstrate that metabolism of curcumin differs in humans
and that rodents might be particularly susceptible to effects on the liver.
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(vi)
Curcum i n was repor t e dl y non-carci nogen i c over th ree genera ti ons i n ra t s, h owever,
the data were unpublished and the details of this study were not available for review .
Turmeric oleoresin containing 79 to 85% curcumin produced equivocal responses
after two-year bioassays in rats and mice. Increased incidences of clitoral gland
adenomas in female rats, hepatocellular adenomas in female and male mice, and
small intestinal carcinomas in male mice were observed, but these effects were not
dose related.
(vii)
Curcumin was not mutagenic in the S a lmone lla Ames assay or t h e mouse d om i nan t
lethal assay with or without metabolic activation at doses up to the limits of solubility .
Growth inhibition due to DNA damage was reportedly observed in the B. subtilis Rec
assay. Curcumin (diferuloyl methane) caused DNA damage in gastric mucosa cells
and human peripheral blood lymphocytes in the comet assay, however damaged
cells were able to recover within a period of 2 hours . Equivocal results have been
reported in in vitro and in vivo assays of clastogenicity .
(viii)
Clinical studies conducted with curcumin showed that the test material generally had
no adverse effects. Small efficacy trials suggested that ingested doses of
approximately 2000 mg/kg/day for 18 weeks was without adverse effects . Results
from a Phase I clinical trial in which no evidence of toxicity was seen in 25 subjects
using up to 8000 mg/day of curcumin for 3 months provides an ample margin of
safety above the recommended dose for Elite Curcumin .
(ix)
Data from preclinical studies and clinical trials, pharmacokinetics, history of food use,
etc. regarding turmeric and turmeric extracts and oleoresins is considered supportive
of the safety of curcumin since these products contain curcumin in varying amounts .
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CONCLUSION
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Based on the aforementioned evidence provided above, including results of preclinical safety
studies conducted with curcumin, the presence of a safety factor of at least 100- to 300-fold that
exists between the NOAELs from the 90-day repeated dose toxicity studies in rodents and the
maximum recommended dose to consumers, the long history of use of curcumin and turmeric in
foods, and clinical studies of curcumin in which no significant adverse effects were reported,
Yung Zip concludes that the chronic use of curcumin in dietary supplements at an intake of up
to 1500 mg per day is reasonably expected to be safe.
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