Download S E P 14 2006 Memorandum

Public Health Service
DEPARTMENT OF HEALTH & HUMAN SERVICES
Food and Drug Administration
Memorandum
Date:
-
S E P 14 2006
From :
Consumer Safety Officer, Division of Dietary Supplement Programs , Office of
Nutritional Products, Labeling and Dietary Supplements, HFS-810
Subject :
75-Day Premarket Notification of New Dietary Ingredients
To:
Dockets Management Branch, HFA-305
Subject of the Notification : , "BeneFlaxTM Flax Lignan Extract"
Firm: Natural ASA
Date Received by FDA :
June 8, 2006
90-Day Date:
September 6, 2006
In accordance with the requirements of section 413(a) of the Federal Food, Drug, and
Cosmetic Act, the attached 75-day premarket notification and related correspondence for the
aforementioned substance should be placed on public display in docket number 955-0316 as
soon possible since it is past the 90-day date . Thank you for your assistance .
-Victoria Lutwak
i9~Y-s- 03i6
S~ .S
gJ
nr, .pARTMENT OF HEALTH AND HUMAN SERVICES
Luis A. Mejia, Ph.D .
Public Health Service
Food and Drug Administration
5100 Paint Branch Parkway
College Park, Maryland 20740
AUG 18 2006
Director, Regulatory and Scientific Affairs
Archer Daniels Midland Company
1001 N. Brush College Rd.
Decatur, Illinois 62521
Dear Dr. Mejia:
dated June 6, 2006, that you submitted pursuant to
This is to inform you that the notification,
the Federal Food, Drug, and Cosmetic Act (the
21 U.S .C. 350b(a)(2)(section 413(a)(2) of
(FDA) on June 8, 2006 . Additional
Act)) was filed by the Food and Drug Administration
7 2006. Your notification concerned
information was received on June 27, June 28, and July
Lignan Extract" that you produce from Linum
the substance that you called "BeneFlaxTM Flax
dietary ingredient .
usitatissimum L and that you intend to market as a new
be sold in bulk form to finished product
According to your notification, your ingredient "will
supplement which will be manufactured
manufacturers of dietary supplements . . . . The dietary
hard-shell capsule form, each pill containing
by our customers may be in a tablet or a 2-piece
[secoisolariciresinol diglucoside] as the active
a dose ranging from 30-300 mg of SDG
86-860 mg of BeneFlaxTM Flax Lignan
ingredient which will be provided by approximately
on the package label may be as
extract. . . . [T]he suggested use of the dietary supplement
follows : `take 1-4 tablets or capsules a day."'
distributor of a dietary supplement containing a
Under 21 U.S.C . 350b(a), the manufacturer or
in the food supply as an article used for food
new dietary ingredient that has not been present
chemically altered must submit to FDA, at least 75
in a form in which the food has not been
or delivered for introduction into interstate
days before the dietary ingredient is introduced
the manufacturer or distributor has
commerce, information that is the basis on which
such new dietary ingredient will reasonably
concluded that a dietary supplement containing
to determine whether it provides an
be expected to be safe . FDA reviews this information
350b (a) (2), there must be a history of
adequate basis for such a conclusion. Under 21 U.S.C .
that the new dietary ingredient, when used under
use or other evidence of safety establishing
the labeling of the dietary supplement, will
the conditions recommended or suggested in
is not met, the dietary supplement is
reasonably be expected to be safe. If this requirement
(1) (B) because there is inadequate
considered to be adulterated under 21 U.S.C . 342(f)
new dietary ingredient does not present a
information to provide reasonable assurance that the
.
significant or unreasonable risk of illness or injury
period that FDA intends to complete
This letter is to alert you within the 75-day notification
response to your notification . Please note
its evaluation within a few weeks and send you a
the 75-day timeframe does not constitute a
that a lack of a response to a notification within
Page -2- Dr. Luis A. Mejia
the ingredient is safe or is
finding by the agency that the ingredient or a product that contains
not adulterated under 21 U.S .C . 342. See 21 C .F.R. 190.6(fl.
June 8, 2006 .
Your notification will be kept confidential for 90 days after the filing date of
at FDA's Docket
After the 90-day date, the notification will be placed on public display
to identify
Management Branch in docket number 955-0316 . Prior to that date, you may wish
trade secret or otherwise
in writing specifically what information you believe is proprietary,
confidential for FDA's consideration.
If you have any questions concerning this matter please contact Victoria Lutwak
at (301) 436-1775 .
Sincerely yours,
~-
,
fv
inda S. Pelli ore, Ph.D .
Supervisory Team Leader, Senior Toxicologist
Division of Dietary Supplement Programs
Office of Nutritional Products, Labeling
and Dietary Supplements
Center for Food Safety and Applied Nutrition
Public Health Service
Food and Drug Administration
DEPARTMENT OF HEALTH & HUMAN SERVICES
Memorandum
Date :
OCT
6 2006
From :
Consumer Safety Officer, Division of Dietary Supplement Programs , Office of
Nutritional Products, Labeling and Dietary Supplements, HFS-810
Subject:
75-Day Premarket Notification of New Dietary Ingredients
To :
Dockets Management Branch, HFA-305
Subject of the Notification :
BeneFIaXTM Flax Lignan Extract
Firm : Archer Daniels Midland Company
Date Received by FDA: June 8, 2006
90-Day Date : September 9, 2006
Please append this letter to Report 355 . In accordance with the requirements of section
413(a) of the Federal Food, Drug, and Cosmetic Act, the attached 75-day premarket
notification and related correspondence for the aforementioned substance should be placed
on public display in docket number 955-0316 as soon possible since it is past the 90-day
date . Thank you for your assistance .
-Victoria Gutwak
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
5100 Paint Branch Parkway
College Park, Maryland 20740
Luis A. Mejia, Ph.D .
Director, Regulatory and Scientific Affairs
Archer Daniels Midland Company
1001 N. Brush College Rd.
Decatur, Illinois 62521
SEP ~ 8 2006
Dear Dr. Mejia:
This is to inform you that the notification, dated June 6, 2006, that you submitted pursuant to
21 U.S .C. 350b(a)(2)(section 413(a)(2) of the Federal Food, Drug, and Cosmetic Act (the
Act)) was filed by the Food and Drug Administration (FDA) on June 8, 2006. Additional
information was received on June 27, June 28, and July 7 2006. Your notification concerned
the substance that you called `BeneFlaxTM Flax Lignan Extract" that you produce from Linum
usitatissimum L and that you intend to market as a new dietary ingredient.
According to your notification, your ingredient "will be sold in bulk form to finished product
manufacturers of dietary supplements . . .. The dietary supplement which will be manufactured
by our customers may be in a tablet or a 2-piece hard-shell capsule form, each pill containing
a dose ranging from 30-300 mg of SDG [secoisolariciresinol diglucoside] as the active
ingredient which will be provided by approximately 86-860 mg of BeneFlaxTM Flax Lignan
extract. . . . The suggested daily dose of SDG is 30-600 mg as the active ingredient which will
be provided by approximately 86-1720 mg of BeneFlaxTM Flax Lignan extract. . . . [t]he
suggested use of the dietary supplement on the package label may be as follows : `take 1-4
tablets or capsules a day."'
Under 21 U.S.C . 350b(a), the manufacturer or distributor of a dietary supplement containing a
new dietary ingredient that has not been present in the food supply as an article used for food
in a form in which the food has not been chemically altered must submit to FDA, at least 75
days before the dietary ingredient is introduced or delivered for introduction into interstate
commerce, information that is the basis on which the manufacturer or distributor has
concluded that a dietary supplement containing such new dietary ingredient will reasonably
be expected to be safe. FDA reviews this information to determine whether it provides an
adequate basis for such a conclusion . Under 21U .S.C .350b(a)(2), there must be a history of
use or other evidence of safety establishing that the new dietary ingredient, when used under
the conditions recommended or suggested in the labeling of the dietary supplement, will
reasonably be expected to be safe. If this requirement is not met, the dietary supplement is
considered to be adulterated under 21U .S .C .342(fl(1)(B) because there is inadequate
information to provide reasonable assurance that the new dietary ingredient does not present a
significant or unreasonable risk of illness or injury .
.
Page -2- Dr. Luis A. Mejia
FDA has carefully considered the information in your submission and the agency has
concerns about the evidence on which you rely to support your conclusion that "BeneF1axTM
Flax Lignan Extract" will reasonably be expected to be safe.
FDA has been unable to determine the relationship between the material that you intend to
market and the substances that are analyzed or used in safety information included in your
notification . For example, you have informed FDA that the manufacturing procedure used to
produce the material used in clinical safety studies was different than your current
manufacturing procedure. Your notification does not address how the differences in these
two manufacturing procedures affect the composition of your ingredient (other than the
content of SDG) or how alterations in the 67.1 % of your ingredient that are not SDG affect
the safety profile of "BeneFlaxTM Flax Lignan Extract" . In addition, your notice included in
vitro and rodent in vivo toxicology studies. While these studies were said to be conducted
using "flaxseed extract containing secolariciresinol diglucoside (SDG)", the descriptions of
the test material vary from study to study and there are no certificates of analysis or other
information that establish the relationship between the test material(s) and the product you
intend to market. Your notice contains a description of the methods that you used to analyze
cyanogenic glycosides and the results of these analyses, but analytical results of what appear
to be the same lot of material in tables 4a and 4c of your notice are not consistent. As a result,
in us unclear to FDA that your notification establishes the quantity of these toxins in your
product. It is therefore unclear to FDA how the ingredient you intend to market is
qualitatively or quantitatively similar to the substances described in the information that you
present as evidence of safety for your new dietary ingredient, or how that information is
relevant to evaluating the safe use of your new dietary ingredient under the recommended
conditions of use
For the reasons discussed above, the information in your submission does not provide an
adequate basis to conclude that "BeneFlaxTM Flax Lignan Extract", when used under the
conditions recommended or suggested in the labeling of your product, will reasonably be
expected to be safe. Therefore, your product may be adulterated under 21 U.S.C . 342(fl(1)(B)
as a dietary supplement that contains a new dietary ingredient for which there is inadequate
information to provide reasonable assurance that such ingredient does not present a significant
or unreasonable risk of illness or injury. Introduction of such a product into interstate
commerce is prohibited under 21 U.S .C . 331(a) and (v).
Your notification will be kept confidential for 90 days after the filing date of June 8, 2006.
After the 90-day date, the notification will be placed on public display at FDA's Docket
Management Branch in docket number 95S-0316 . Prior to that date, you may wish to identify
in writing specifically what information you believe is proprietary, trade secret or otherwise
confidential for FDA's consideration.
t-
~
Page -3- Dr. Luis A. Mejia
If you have any questions concerning this matter please contact Victoria Lutwak
at (301) 436-1775 .
Sincerely yours,
.
.
ejw
2.~
Linda S . Pellicore, Ph.D.
Supervisory Team Leader, Senior Toxicologist
Division of Dietary Supplement Programs
Office of Nutritional Products, Labeling
and Dietary Supplements
Center for Food Safety and Applied Nutrition
t ,.~~
~
James R. Randall Research Center
*M
nDM
Y-.
f
6
r=G,~G~
JUN - 8 2006
June 6, 2006
Dr. Susan Walker
Director, Division of Dietary Supplements Program
Office of Nutritional Products, Labeling and Dietary Supplements (HFS-810)
Center for Food Safety and Applied Nutrition
Food and Drug Administration
5 100 Paint Branch Pkwy,
College Park, MD 20740
Re : ADM -~ Ne.-; Dietary Ingredient Notification - BeneFlaXTm Flax Lignan Extract
Dear Dr. Walker,
We are submitting a new Notification for the Marketing of a New Dietary Ingredient, namely BeneFlaXTm Flax
Lignan extract pursuant to 21CFR 190.6 (Requirements for Premarket Notification). In this new notification,
we have addressed the questions which you had raised in your response letter dated February 17, 2006
regarding our earlier notification dated December 2, 2005 . The questions pertained to the identity of
"BeneFIaXTM Flax Lignans", description of 57% of the material listed as "other natural components" and
description of the method for identifying or quantifying the cyanogenic glycosides . We then sought
clarification on these questions and advice from your staff, Dr Linda Pellicore and Ms. Vicky Lutwak during a
telephone conference call in late February, 2006 . We believe that the enclosed information in this new
notification will clearly establish that BeneFlaXTm Flax Lignan extract will reasonably be expected to be safe
as a new dietary ingredient in the U.S . market .
BeneFlaXTm Flax Lignan extract is manufactured by extraction and purification of flax lignans derived from
defatted flaxseed meal . The product is an extract which contains at least 35% of the major lignan, namely
secoisolariciresinol diglucoside (SDG), and other natural occurring components of flaxseed . This new dietary
ingredient will be sold in bulk to manufacturers for use in their finished dietary supplement products .
We kindly ask you to please acknowledge the receipt of this notification and let us know if you have any
q u I stions
*
. "L'ou may contact me at 217-4 .5 1 -2201, or Dr. James How at 217-45 1-2469 .
Thank you for your kind attention to this matter. Best regards .
Sincerely,
r
,
I
Luis A. ejia, Ph.D .
Director, Regulatory an Scientific Affairs
Tel: 217-451-2201 ; Fax : 217-451-7098
Email: mejia@admworld .com
Enclosures :
3 complete sets of:
Binder 1 - One original NDI notification with appendices,
Binders 2 & 3 - Copies of reference papers cited in the text of the NDI notification .
Archer Daniels Midland Company
1001 N . Brush College Rd .
Decatur, IL 62521
CONFIDENTIAL
Notification of the Marketing of a New Dietary Ingredient (NDI):
BeneFlaxTM Flax Lignan Extract
Submitted to
Office of Nutritional Products, Labeling and Dietary Supplements (HFS-810)
Center for Food Safety and Applied Nutrition
Food and Drug Administration
5 100 Paint Branch Pkwy,
College Park, MD 20740
By
Archer Daniels Midland Company
4666 Faries Parkway
Decatur, Illinois 62526, USA
Compiled BE.
James S. How, Ph.D.
Senior Manager, Regulatory and Scientific Affairs
Tel: 217 4512469; Fax: 217 451 7098
Email : how(~a,admworld .com
Contact Person:
Luis A. Mejia, Ph.D.
Director, Regulatory and Scientific Affairs
Tel : 217 451 2201 ; Fax 217 451 7098
Email: mejia a~admworld .com
0001
Table of Contents
.
-
Introduction ..... . . . . . . . . . . .. ....... ..... .. . . . . . . .......... .. . . . . . . . . . . . . . .. .. .. ......... .. . . . . . . . . . .. ........... . . . . . . . ..... ......... .. . . . . . . . . . . .
. 0004
1.0
Product Identity and Description of New Dietary Ingredient .... .. . . . : . . . .. .. ........., .. .. . . 00 05
1.1
Trade Name ..... .. . . . . . . . . . . . .......... .. . . . . . . .. ............ ...... ... . . . . . . . . . . . ...... .. . . . . . . . . . . . ........ . . .. . . . . . . . . . . ..... ... 0005
1 .2
Common Name . .. .. . . . . . . . . . . : ...........: .. . . . . . . . . .. . . .. ..... ...... .. . . . . . . . . . . .. ........ ..... . . . . . ............ . . :. . . . . . . .. .... 0005
1 .3
Scientific Name .... .. .. . . . . . . . . . .. . . . . .. . . .... .. . . . . . . . . . . . . . . .. ... . . ..... . . . . . . . . . .. ........... .. . . . . . .. .. ...... .. .. .. . . . . .. . ... 0005
1 .5
Properties of BeneFlaxTM Flax Lignan Extract. . . . .. .......... .. . . . . . . . .:...,..... . . . . . .,. ,_ ._, 0005
1..6
Flaxseed as the Source for BeneFlaxTM Flax Lignan Extract . . . . . . . . . ....... . . . . . . . . . . . . . .... ....., .. .. . . 0006
1 .6.1 .
Composition of Flaxseed . . . . . . . .. .. .............. .. . . . . . . .. .............. . . . . . . . . . . . . . . .... . . . . . . . . . . . .. .. ..... . .. .. 0006
1 .6.2.
Flaxseed Lignans . .. .. ... .. .. .. . . . . . . . . . ................... . . . . . .. .. ............ .. . . . . . . . . . .... ... .. .. . . . . . . . .. ........ .. 0008
2.0
Product Specifications and Quality Attributes .. .......... . . . . . . . . .. ........., .. . . . . , . . ., . _... : ,. , . . . ,. ,. 0010
2 .1
Product Specifications . . . . . ...........:. . . . . . . . . . . . . . . . . . . . .. ........... . .. . . . . ...... . .. .. . . . . . . . . . . . ....... .. . . . . . . . . . . . .. 0010
2.2
Labeling . . . . . . . . . . .. ........ .. .. . . .. . .... .. ..... .. . . . . . . . . . . . . . . . . . .. .............. .. . . . . . . ..... ....... . . . . . . . . . .. .. . ........ . . . . . . . . . 0010
2.3
Packaging . . . , . . : .: : .. .. ........ .. . . . . . . . . . . . ......... . . . . . . . . . . . . . . . .. .. ............ . . . . . . . . ........... . . . . . . . . . . .. ........... . . . . . . .0010
2.4
Storage and Shelf Life ...... . . . . . . . . . . . . . ....... .. .. .. . . . . . . . . . .. ........... ... .. . . . . . . . . . . ...... .. . . . . . . . . . . . . .......... .. . . . 0011
3 .0
Method of Manufacture (Confidential) .............~~.... . . . . . . . .......... .. . . . . . . . . . . . . .. ..... . . . . . . . . . . .. .. . ...... .. . . . 0012
3 .1
Process Description (Confidential) . . . . . . .. ............. .., . . . . . .,. ...... . . ., . , . . . . .. .,, . . . .. .. .. . . . . . . . . . . ....... ., 0012
3 .2
Batch Analyses and Composition of BeneFlaxTM Flax Lignan extract . ............ . . . . . . . . . . . .... .. 0014
3 .2.1
Batch Analysis .. . . . . . ..........:.. . . .. . . . . . . . . . .. .. .... ....... . . . . . . . . . . . . . ........ .... .. . . :. .......... .... .. . . .. . . . . . . . . . 0014
3.2.2
Chemical Composition ...i....... . . .. . . . . . . . . . . . .. .. ..... .. .. . . . . . . . . . . . .. ............ . . . . ................ .. . . . . . . . . . 0014
3.2 .3
Compositional changes in BeneFlaxTM Flax Lignan extract during processing . . . . . . . . . 0019
3.2.4
Impurities Testing . .. :. . . . . .. . . . ......... :... .. .. . . .. . . . . . . . .......... . . . . . . . . . . .. .. ......... . . . . . . . .............. . . . . . . . 0029
3.2:5
Comparative composition of commercial flax products . . . . .. .. .......... .. . . . . . . .. ............ . . . ., 0029
4.0
Intended Use .... . . . . . . . . ... .......... . . . . . . . . . . . . .. ............... . . . .. . . . . . . . ......... .. . . . . . . . .. .. .......... .. . . . . . . .. ............. .. 0033
SA
Safety Overview .. . . . . . . . . . . . . ......... . . . . . . . . .. .................. .. . . . . . . . . . . . .. ....... .. . . . . . . . .. ............ .. .. . . . . . . ......... .. 0033
5.1
Absorption, Distribution, Metabolism and Excretion. . . . . .. ...:... .. .. . . . . . . . .......... .. .., . . . . . . .,....., 0034
5 .1 .1
Lignan metabolites . . . . .......... .. .. . . . . .. .. :............. .. .. . . . . . . . . . . . . . . ...... .. . . : . . . . ............ . . . . . . . . . . .. .. .. . 0034
5 .1 .2
Dose response . . . . . . . . . . . . . .. .. .. . .. . .. .. .. . . . . . . . . . . . . .. ........ .. . . . . . . . .: .. ... .. . ....... . . . .. ............ .. .. . . . . . . .. . . . 0035
5 .1 .3.
Distribution of metabolites . . ....... .. . . . . . . . . . . . . .......... .. .. . . . . . . . .. . .. . . ...... .. . . . . . . . .. .......... ... . . . . . . . . 0036
5 .2
History and Current Human Exposure to Flaxseed and Flax Lignan products . .......... . . . . ... 0038
5 .3
Human Studies on Flaxseed and Flax Lignans . . . . . . . .. .......... .. . . . . . . . ..,. ...., .. . . . . . . . ., ....., . 0040
5 .4
Human Clinical Studies Using BeneFlaxTM Flax Lignan extract . . . . . . . .... . . . . . . . . . . . . . . . .. .. ......:. , 0042
5 .5
Genotoxicity Study on Flax Lignans .. ................ . . . . .. .. ............ .. . . . : . . . . . . . ..... .. .. . . . . . . . . . .. .. ........ . 0047
5 .6
Mutagenicity Study of BeneFlaxTM Flax Lignan extract (Confidential) ...... .. . . . . . . . .. .. ........ . 0048
5.7
Animal Studies on BeneFlaxTM Flax Lignan extract (Confidential) . . . . . .. .... ... . . . . . . . . . . . .. ...... . 0049
5.8
Potential Safety Concerns Regarding Natural Components in Flaxseeds . ......... . . . . . . . . . .. .. .. . 0050
5.8.1
Cyanogenic glycosides .......... .. . . . . . . . . . . . . . . . . . .. ........ .. .. . . . . .. .... .... .. .. . . . . . . . . . . . . . ..... .. .. . . . . . . . .. . . . 0050
5.8.3
Phenolic acids ...... . . . . . . . .... ..... . . .. .. . . . . . . . . :. . . . . . .. .. .......... .. . . . . . . ....... . . . . . . . . . . . . . . . . .. ........... . . . . . . . . 0054
5.8.4
Hydroxymethylglutaric Acid (HMGA) . . . . . . ................ . . . . . . .. .......... . . . . . . . . . .. .. ........... . . .. . . 0058
5.8.5
Herbacetin . . .. ............ . . . . . . . . . . . . . ......... .. . . .. . . . . . . . . . .............. . . . . . . .. .. .. ...... . . . . . . . . . . . .. ... .......... .. . .0058
5 .9
Safety of Chronic Exposure . . . . . . . . . . ... .......... . . .. . . . . . . . .. ............ .. . . . . . . .. . . ....... . . . . . . . . . . .... ......... .. . . 0059
6.0
Conclusion ......... . . . . .. .. ................ .. .. . . . . . .. . . .. ............. . . . . . . . .... .:...... .. . . . . . . . . . . . . .. . .. . . . .. . . . . . . . . . . . .. ........ . 0062
7.0
References ............ . . . . . . .. .. ............ .. .. . . . : . . . . . .. . . .. . . . . .. . . . .. . . . . . . . . . .......... . . . . . . . . . . . . ...... .... .. . . . . . . . . . .. ..:..... .0063
0002
Appendices
A.
Chemical structure of SDG and its metabolic conversion to
enterodiol and enterolaetone .
B.
Selected key papers cited in this NDI notification dossier.
C.
BeneFlaxTM Flax Lignan extract technical datasheet and
certificate of analysis for 3 production lots.
D.
Analysis of BeneFlaXTm Flax Lignans, flaxseed and flax meal
for FDA-NDI submission .
E.
Determination of compounds present in flax lignans by LC-PDA-MS .
F.
Averaged numeric values for four process lots used to graph ratios of
flax component concentrations at sequential SDG processing steps.
G.
Outside laboratory pesticides testing reports for 3 production lots
(0602081, 0602231 & 0603031) and 2 pilot lots (K0546A &
K0548A) of BeneFlaXTm Flax Lignan extract.
(
Outside laboratory dioxins/PCB's testing reports for 3 production lots
(0602081, 0602231 & 0603031) and 3 pilot lots (K0544B, K0546A &
K0548A) of BeneFlaXTm Flax Lignan extract .
H.
I.
Outside laboratory mycotoxins testing report for 3 production lots
of BeneFlaXTm Flax Lignan extract .
J.
Online search of FDA website on flaxseeds and flaxseed lignans.
K.
Medline° and CAplus literature search on flaxseed lignans safety
and toxicity.
L.
Summary of literature review on animal and human studies using
flaxseeds or flax lignans.
M.
Independent report on "The potential estrogenicity of SDG flax
lignan extract" .
N.
Global new products database showing products containing flax or
flax lignans and commercial products containing flax ingredients.
O.
FDA's letters on history of safe use of flaxseeds and flax products
0003
Introduction
The information contained in this document is submitted to the Food and Drug Administration for the
purpose of complying with the Notification for the Marketing of a New Dietary Ingredient, namely
BeneFlaxTM Flax Lignan extract (a natural extract from flaxseeds containing secoisolariciresinol
diglucoside (SDG) as the active component), pursuant to 21CFR 190 .6 (Requirements for Premarket
Notification).
The Archer Daniels Midland Company (ADM) is .the manufacturer of this new dietary ingredient
which will be sold in bulk form to finished product manufacturers of dietary supplements .
Name of the new dietary ingredient : BeneFlaxTM Flax Lignan extract
Botanical source:
Seed of the flax plant.
'
Latin binomial nafne for flax plant: Linum usitatissimum L.
Author: Carl Linnaeus (Carl von Linne); (1707-1778).
use
Description of the dietary supplement that contains the new dietary ingredient, including
in
the
level of the ingredient in the dietary supplement and the conditions of use recommended
labeling of the dietary supplement:
"
The dietary supplements which will be manufactured by our customers may be in a tablet or a
2-piece hard-shell capsule form, each pill containing a dose ranging from 30 - 300 mg of SDG
as the active ingredient which will be provided by approximately 86 - 860 mg of BeneFlaxTM
plus
Flax Lignan extract. Each pill containing the BeneFlaxTM Flax Lignan extract ingredient
excipients, fillers and other ingredients may weigh between 250 mg - 1 .5 g depending on the
-
formula of the finished dietary supplement.
"
The suggested daily dose of SDG is 30 - 600 mg as the active ingredient which will be
on
provided by approximately 86-1720 mg of BeneFlaxTM Flax Lignan extract. Depending
affect the size
how much SDG is in the formula of the finished dietary supplement which will
may
of the tablet or capsule, the suggested use of the dietary supplement on the package label
be as follows: "Take 1 - 4 tablets or capsules a day".
0004
1 .0
Product Identity and Description of New Dietary Ingredient
1.1
Trade Name
BeneFlaxTM Flax Lignan extract
1.2
Common Name
Natural flax lignan complex containing secoisolariciresinol diglucoside (SDG) as the
active and major lignan component.
1.3
Scientific Name
The chemical name for SDG, the major'rignan component of BeneFlaxTM Flax
Lignan extract is P-D-Glucopyranoside, 2,3-bis[(4-hydroxy-3-methoxyphenyl
methyl]-1,4-butanediyl bis-,[R-(R*,R*)]
f
Formula:
C3a Ha6 0i6
Molecular weight:
686.7
CAS number :
158932-33-3
The chemical structure of SDG, and its metabolic conversion to enterodiol and
enterolactone by gut microflora, is shown in Appendix A.
1.5
Properties of BeneFlaxTM Flax Lignan Extract
Table 1 - Properties of BeneFlaxTM Flax Lignan extract
Form :
Color:
Odor :
Taste:
Solubility :
Hygroscopicity :
,powder
brown
"tea" like aroma
"tea" like flavor
- Slightly soluble in water at neutral pH,
- Moderately soluble in 70% ethanol
low
0005
1.6
,
Flaxseed as the Source for BeneFlaxTM Flax Lignan Extract
on the
The composition of flaxseed itself is discussed in this section to provide a background
which is the
origin and presence of naturally, occurring components including flax lignan
constituent of interest in this notification .
1 .6.1. Composition of Flaxseed
overall
Reported flax compositions are variable . The following are some of these reports. The
(24%), fiber
composition of whole flaxseed consists of fat (36%), protein (24%), carbohydrate
Mazza (1998)
(6%), water (5 .5°Io) and ash (3 .4°Io) as reported by Prasad, (2000a) . Oomah and
shown
compared the . composition of different flaxseed products, whose main components are
processed
in Table 2. Dehulling and lipid removal significantly changes the composition of
products .
(9 .2°Io) and
Flaxseed protein is high in glutamic acid (19 .6%), aspartic acid (9.3%) and arginine
about 5%
low in cystine (1 .1°Io), and methionine (t .5%). Flaxseed lipid is comprised of
:2n-6) and 59%
palmitic acid, 3% stearic acid, 17% oleic acid (18:1n-9), 15% linoleic acid (18
reported by
a-linolenic acid (ALA ; 18 :3n-3) . The sugar composition of flaxseed meal has been
xylose,
Bhatty and Cherdikiatgumchai (1990) . Glucose was the major sugar followed by
.5% .
galactose, arabinose; rhamnose and fucose . Total sugar content of the seed meal was 28
and total
Flaxseed meal is high in crude, acid detergent (cellulose and lignin), neutral detergent
meal was
fiber (cellulose, lignin and hemic.ellulose) . The total dietary fiber content of flaxseed
or mucilage;
39-45% (Bhatty and Cherdikiatgumchai, 1990). Flaxseed polysaccharides (gum
whole seed or meal .
5-S°Io of the seed weight) may be isolated via aqueous extraction of the
Flaxseed gum is a mixture of acidic and neutral polysaccharides.
of
Shahidi (2002) reported the following minor components of flax which are comprised
phytic acid,
phytochemicals such as tocols, phenolic acids, lignans, phospholipids, phytosterols,
phytochemicals,
carotenoids, enzyme inhibitors, oligosaccharides and cyanogens. These
Oomah and Mazza
considered as bioactive components of flaxseed, have been reviewed by
(2000) .
0006
Table 2 . Composition of Flaxseed Products (°Io)
Protein
(N X 6 .25)
Lipid
Carbohydrate
Ash
Whole flaxseeds
23 .5
43.8
9 .9
4 .81
Commercial flaxseed meal
39 .2
13 .6
NR
5 .58
Defatted flaxseed meal
42 .2
0 .6
17.8
7 .42
Flaxseed Product
NR = not reported
Source : Oomah and Mazza, (1998)
Flaxseed is one of the richest sources of lignans used in the human diet. The~major lignan in
flaxseed is secoisolariciresinol, which is present-as a diglucoside (SDG). SDG is part of a
covalently bonded complex containing SDG and hydroxymethylglutaric acid (HMGA) (Ford et
al., 2001 ; Kamal-Eldin et al ., 2001) . The SDG content in flaxseed has been reported to vary
from 6100 to 13300 mg/kg (Johri son et al., 2000). HMGA has been reported to be a putative
inhibitor of mevalonate biosynthesis and hence also of cholesterol (Lupien et al., 1979).
However studies have not shown this conclusively . Flaxseed also contains small amount of
matairesinol, pinoresinol, lariciresinol, and isolariciresinol (Mazur et al., 1996; Qiu et al., 1999 ;
Sicilia et al., 2003).
The phenolic acid content of flaxseed is considerably lower than that of other oilseeds
(Dabrowski and Sosulski, 1984) . Flaxseed contains 8-10 g/kg of total phenolic acids, -5 g/kg
of esterified pfienolic acids, and 3 .5 g/kg of etherified phenolic acid . The levels of total and
esterified phenolic acid are 81 and 73 .9 mg/100 g, respectively, for dehulled defatted flaxseed
meal (Dabrows.ki and Sosulski, 1984). Trans-ferulic acid (46%) was the predominant phenolic
acid present, but trans-sinapic (36%), trans-p-coumaric (7.5°Io), trans-caffeic (6 .5%) and phydroxybenzoic acids were found in smaller amounts . In addition, presence of o-coumaric,
genistic, and vanillic acid was reported . Ferulic acid (10.9 mg/kg), chlorogenic acid (7S
mg/kg), gallic acid (2 .8 mg/g), and traces of 4-hydroxy benzoic acid were identified in defatted
flaxseed powder (Harris and Haggerty, 1993).
0007
the
Phytic acid is a natural plant inositol hexaphosphate commonly found in seeds ; it represents
variety of
principal form of stored phosphate. Phytic acid has been reported to exhibit a
physiological effects including hypocholesterolemic, antioxidative, anticarcinogenic,
hypolipidemic, and hypoglycemic effects (Oomah and Mazza, 2000). Flaxseed contains 23-33
1996).
g phytic acid per kg meal, depending on the cultivar and environment (Oomah et al.,
Defatted flaxseed contains 1 .8-3 .0% phytic acid, representing -70% of the total phosphorous.
(Bhatty and Cherdikiatgumchai, 1990).
1.6.2. Flaxseed Lignans
formed by
Flax is one of the richest sources of plant lignans which are phenolic compounds
is
the union of two cinnamic acid residues . They 4re related to lignins in that their synthesis
by-products of
presumed to occur by a similar pathway ; however it is probable that lignans are
substances found
the pathway for lignin synthesis. Lignin is one of the most abundant organic
lignans (Setchell,
and consequently almost all plants may potentially contain the derivative
1995) .
Flax is particularly rich in the lignan, 2,3-bis(3-methoxy-4-hydroxybenzyl)butane-l,4-diol,
as a
commonly referred to as secoisolariciresinol (SECO) which occurs naturally in flaxseed
diglucoside, P-D-Glucopyranoside, 2,3-bis[(4-hydroxy-3-methoxyphenyl) methyl]-1,4small
butanediyl big,-[R(R*,R*)] commonly known as SDG. Besides SDG, flax also contains
been
amounts of the lignans matairesinol, pinoresinol and isolariciresinol . Flaxseed has
. Lignans are
reported to contain 301 mg/l00 g lignans as aglycone forms (Milder et al., 2005)
-
brassica vegetables
also present in many plant sources such as sesame seeds (29.3 mg/ 100 g)
and also in legumes such
(2.3 mg/100 g), pumpkin seeds, grains such as wheat, barley and oats
as beans, lentils, soybeans, fruits and other vegetables .
year, extraction method,
The lignan content of flaxseeds are affected by variety, location, crop
been reported by
hydrolysis and analytical techniques . The SDG content in flax products has
f
flaxseed diet
several authors to contain 29-1055 mg/100 g seed, 200-1300 mg/100 g
seed (Mazur et al.,
(Thompson, 2003), 600-1800 mg/100 g seed (Prasad, 2000a), 370 mg/100 g
meal (Obermeyer et a1.,
1996), 228 mg/100 g seed and 82 mg/100 g seed; 226 mg/100 g flax
mg/100 g) in ten
1995). SDG content ranged from 0.96-3 .15 Itmoles/g (equivalent to 66-216
0008
varieties of flax. Johnsson et al ., (2000) analyzed SDG from fourteen Swedish and fifteen
Danish flax cultivars and reported that the SDG ranged from 1170-2410 mg/100 g in defatted
flour compared to 610-1330 mg/l00 g in the seed. Milder et al (2005) reported 294 mg SECO
/100 g in composite samples of flaxseed samples. Commercial methods for extracting and
purifying the .lignans in flax are now available, thus making it possible for food companies to
add purified SDG to food products or to supplements.
Many lignans have been reported to have antitumor, antimitotic, antioxidant and weak
estrogenic activities (MacRae and Towers, 1984 ; Prasad, 2000b) . Thompson and Ward (2002;
book chapter included in Appendix B) in their review on the health benefits, bioavailability-and
safety of flaxseed lignans, reported that the metabolism and availability of lignans in a 2.5-10%
human
flaxseed diet or of equivalent levels of purified lignans (i .e. SDG), as seen in animal and
of
studies, are sufficiently high to produce health benefits . The benefits may include reduction
cancer risk, cardiovascular disease, diabetes, kidney disease, osteoporosis and menopausal
symptoms and improvement of benign prostatic hyperplasia (BPH) .
0009
PAGES 10 THROUGH 32
23 PAGES
TOTAL
REDACTED IN ITS
ENTIRETY
CONTAINS
TRADE
SECRET
CONFiDENT1AL
COMMERICAL
INFORMATION
4.0
Intended Use
BeneFlaxTM Flax Lignan extract is intended for use as an ingredient in dietary supplements .
This new dietary ingredient will be sold in bulk to the finished dietary supplement
manufacturers. Suggested dose per day is approximately 86 - 1720 mg of the BeneFlaxTM Flax
Lignan extract containing 30 - 600 mg of SDG.
This suggested dose range was established based on the observed efficacy in lowering total
cholesterol and low density lipoprotein cholesterol and relieving BPH symptoms in two ADM
sponsored human clinical studies using BeneFlaxTM Flax Lignan extract. Both of these studies
used treatment doses of up to 1720 mg of BeneFlaxTM Flax Lignan extract equivalent to 600
mg SDG per day (Zhang et al :, 2006a, 2006b) .
These studies are discussed in detail in
Sections 5 .4.
5.0
Safety Overview
Numerous commercial flax products including flaxseeds and its derivatives such as flaxseed
flour, flaxseed oil and flaxseed lignans are being sold in the United States market
where these products are regularly consumed as foods or dietary supplements .
An online search of the FDA website did not show any adverse events or warning letters
other than those related to claims pertinent to flaxseed or flaxseed lignans (Appendix J).
An extensive literature search was conducted on "flaxseed and lignans, toxicity or safety or
adverse effect" using CAplus and Medline° databases (Appendix K). Forty five relevant
references were found. No adverse or toxic effects were reported on the feeding trials of
flaxseeds or flax lignans in either animals or humans. However, it is generally recognized that
flaxseed may have adverse effects in animals when consumed in very large quantity as part of
improperly processed feed rations.
A literature review was also conducted on 44 key studies (21 human studies and 23 animal
studies) . The summary of each study is shown on Appendix L. There were no reported toxic
0033
or adverse effects . Some of the selected animal and human studies are discussed later in this
Section.
An independent review on the potential estrogenicity of SDG flax lignans extract concluded
that the data from a 90-day rat study using BeneFlaxTM Flax Lignan extract (Covance, 2002)
showed it is unlikely that adverse estrogenic activity will be observed in adults consuming SDG
products at the levels of 500-700 mg/person/day (Borzelleca, 2005; Appendix M) . These data
are supportive of the safety of flax lignans reported in the literature.
Potential safety concerns regarding the levels of naturally occurring components in
flaxseeds, notably cyanogenic glycosides and relevant phenolic acids will be discussed
in Section 5.8.1 .
5.1
Absorption, Distribution, Metabolism and Excretion
f
For the purpose of evaluating safety, all sources of dietary flax lignans will be discussed. The
-
analysis, metabolism and bioavailability of flaxseed lignans has been reviewed by Thompson
(2003 ; paper included in Appendix B) and Thompson and Ward (2002) ; paper included in
Appendix B).
5.1 .1
Lignan metabolites
It is established that plant lignans such as SDG and matairesinol are converted to the
mammalian lignans enterodiol (ED) and enterolactone (EL) by the bacterial flora in the colon
_
(Setchell, 1995 ; see also Appendix A) . These mammalian lignans undergo enterohepatic
circulation -with a portion reaching the kidney and are excreted in the urine (Setchell, 1995;
Axelson and Setchell, 1981) . Urinary excretion of ED and EL have been used as indicators of
production and availability of mammalian lignans in animals and humans (Setchell, 1995;
Nesbitt et al., 1999). ED and EL are also chemically similar to 17-(3 estradiol and are
considered both agonistic and antagonistic to the estrogen receptor system (Tan et al ., 2004 ;
Xie et al ., 2003). The chemistry, quantitative analysis, biological properties and health effects
of ED and EL has been reviewed by Wang (2002 ; paper included in Appendix B) .
Although ED and EL are the main mammalian lignans analyzed in urine, other
0034
metabolites have recently been identified (Jacobs and 1Vletzler, 1999) . ED has been
shown to be metabolized in vitro by rat liver microsomes to three aromatic and four
aliphatic monohydroxylated compounds, and EL to six aromatic and six aliphatic
monohydroxylated compounds (Jacobs and Metzler, 1999). Many of these metabolites
have also been detected in the bile of bile duct-catheterized rats administered ED or EL
(10 mg/kg body) intraduodenally, and in the urine of rats gavaged with ED or EL or fed a
diet containing 5% flaxseed (Niemeyer et al., 2000) . In four human subjects fed flaxseed
(16 g) for 5 days, however, only the aromatic monohydroxylated metabolites of ED and
EL were detected (Jacobs et al., 1999) . These metabolites were estimated to represent
<5% of the total urinary lignans in the human subjects (Jacobs et al., 1999) or <3% of the
parent lignans ED or EL fed to rats (Niemeyer et al., 2000).
In contrast, when radiolabeled SDG (3H-SDG) was fed to rats (Rickard and Thompson,
2000), only ED, EL, secoisolariciresinol (SECO; aglycone of SDG), and four other
unidentified metabolites, none o~ which had mass spectra that matched those observed by
Metzler and colleagues (Jacobs et al., 1999; Jacobs and Metzler, 1999 ; Niemeyer et al., 2000),
were found in the urine. Two of the unknown metabolites were observed in the urine of rats
fed non radioactive flaxseed or SDG (Rickard and Thompson, 2000). The other metabolites
from SDG, ED or EL, although formed, may have been present at too low levels to be
detectable .
5 .1.2
,
Dose response
When rats were fed diets containing 2 .5, 5, or 10% flaxseed, the urinary excretion of total
lignans (ED + EL + SECO) was linear up to 5 % and then started to level off, suggesting a
threshold response (Rickard et al., 1996). A similar pattern of results was observed when
SDG was gavaged at levels (1 .2, 2.2, and 4.4 mol SDG/day) equivalent to the amounts
consumed in the 2 .5, 5, and 10%a flaxseed diet (Rickard et al., 1996) . The urinary lignans
leveled off after an intake of 2.2 moUday. In agreement with the rat study, a dose-related
linear increase in urinary lignans (ED + EL + SECO) excretion was observed in premenopausal
women fed 0, 5, 15, and 25 g flaxseed (Nesbitt, et al., 1999) and in postmenopausal women fed
0, 5, and 10 g flaxseed (Hutchins, et al., 2000). The intake of 5% flaxseed diet by rats was
equivalent to an intake of about 25 g flaxseed by humans, thus no leveling off of urinary lignan
0035
excretion was observed in the human trial as the amount fed
was below the threshold where
leveling off was expected .
5.1.3. Distribution of metabolites
The pharmacokinetics of EL and ED were recently evaluated in
healthy men and women
consuming a single dose of purified SDG (1 .31 Amolelkg body weight)
(Kuijsten et al., 2005 ;
paper included in Appendix B). The dose of SDG was equivalent to 0.90
mg/kg body weight or
63 mg daily intake of SDG by a 70 kg person . EL and ED appeared
in plasma 8-10 hours after
ingestion of the purified SDG. The mean elimination half life of ED
(4.4. + 1 .3 hours) was
shorter than that of EL (12 .6 + 5 .6 hours) . Within 3 days, up to 40% of the
ingested SDG was
excreted as ED and EL via urine, with the majority (58%) as EL. This
study"concluded that the
levels of enterolignans in plasma are good biomarkers of lignan
intakes.
`
The body distribution and excretion of the SDG metabolites was determined at
various
times for up to 48 hours after rats were gavaged with 3H-SDG (Rickard and Thompson,
1998).
After 48 hours, most of the recovered radioactive dose was excreted i .e .,
>60% of
recovered dose- in the feces and 28 - 32% of recovered dose (at least 70% of the
absorbed
dose) in the urine . The total recovery did not vary with acute (single treatment) Vs.
chronic (after treatment with 1 .5 mg SDG/day for 10 days) intake, but there was a delay in the
fecal excretion with chronic intake . The fecal excretion was almost complete after 12 hours
in
the acute group, whereas the fecal radioactivity in the chronic group was negligible
after 12
hours and approached the level excreted in the acute group only after 24 hours . This was
attributed to increased enterohepatic circulation of the lignans after chronic treatment,
which in
turn was related to increased (3-glucuronidase activity due to the Iignans (Jenab and Thompson,
0036
.
1996 ; Jenab et al., 1999) . The urine radioactivity excreted after 24 hours (12%)
was in
agreement with a previous report of 11 .4% recovery of ED and EL in rats fed 1 .5 mg
SDG/day
for 2 weeks (Rickard, et al., 1996), suggesting that the recovered activity is primarily
metabolites of SDG. Later analysis of the urine confirmed that the majority of the radioactivity
in the samples were from ED, EL, and SECO with minor amounts from four unidentified
lignan metabolites (Hutchins et al., 2000).
Radioactivity was detected in all analyzed tissues (heart, liver, kidney, spleen, lung,
adipose, mammary gland, ovaries, uterus, skin, muscle, brain, stomach, small intestine,
cecum, and colon), but the highest levels were found in those involved in lignan
metabolism, i.e. gastrointestinal tissues (3-7% of recovered dose), the liver, and kidney
levels were five times higher than in other non gastrointestinal tissues (Rickaid and Thompson,
1998). Although appreciable amounts were also detected in estrogen-sensitive tissues
such as the uterus and ovary, low levels were found in the mammary gland, indicating
that a putative protective effect of lignans is not only through their direct binding to this tissue .
f
Chronic intakes increased the radioactivity level in the liver and adipose tissue but not in the
other tissues. The radioactivity level in the blood was <1% of recovered dose, most of which
was present in the plasma (Rickard and Thompson, 1998) . Plasma lignan concentration was
estimated to be - 1 AmoUL in rats fed 1 .5 mg/d SDG, a value -3000 times higher than peak
estrogen levels in rats . The level peaked 9 hours after 3H-SDG intake and remained steady up
to 24 hours in the chronic group but had dropped, although still not lower than that at the 12hour time point, in the acute group (Rickard and Thompson, 2000). Similar results were
obtained in premenopausal women fed 25 g raw flaxseed once (acutely) or daily for 8 days
(chronic) in which plasma levels peaked at 9 hour post consumption (Nesbitt et al., 1999). The
plasma lignan level in the women was higher on day 8 than on day 1 of intake. The plasma
concentration stabilized by the eighth day of intake suggesting that consumption of flaxseed or
other Iignan sources, once a day, may be sufficient to maintain plasma lignan concentrations .
Phytoestrogens have been shown to exert distinct agonistic and/or antagonistic activity
on human estrogen receptors, ERa and ER(3 by their relative binding affinities (RBA) .
As reported by Mueller et al., (2004) lignan enterolactone (EL) has a weak RBA of 0 .01 on
ERa and a RBA of 0.07 on ERP when compared to i) estrogen 17(3-estradiol (E2) which has a
0037
RBA of 107 on ERa and 82 on ERP and, 2) synthetic estrogen diethylstilbestrol
(DES) which
has a RBA of 100 on ERa and 100 on ER(3.
Plasma concentrations of ED and EL found in a clinical study of BeneFlaxTM
Flax Lignan
extract were on the order of 230 and 40 ng/ml (Zhang, 2006a, Table 11). These
values
represent a concentration ; respectively, of 8000 and 1300 times the estradiol
concentration
typically found in humans (30 pg/rnl) . With respect to EL itself, the binding efficiencies
for EL
are 1000 to 10,000 times weaker than estradiol for ER(3 and ERa, respectively,
suggesting that
any estrogenic effect will not be significantly greater than estradiol itself. Based on
the data
from the rodent toxicology study (Covance, 2002), it was determined that the consumption
of
BeneFlaxTM Flax Lignan extract did not present an estrogic effect of concern (Borzelleca,
Appendix H) .
5.2
History and Current Human Exposure to .Flaxseed and Flax Lignan products
f
Plant lignans are present in many plant sources such as oilseeds, nuts, grains, fruits and
vegetables which are regularly consumed as normal components of the human diet. Plant
sources containing lignans include flaxseed, sesame seeds, brassica vegetables, pumpkin seeds,
wheat, barley and oats, legumes such as beans, lentils and soybeans, fruits and other vegetables.
,
_
Much of the foundation for flax usage had been laid during the Egyptian times, with the Greek
and Roman civilizations continuing to praise its merits as a food, a fiber and a medicine .
Traditional food and medicinal uses of flaxseed have been described by Pengilly (2003) .
Flaxseed has historically been consumed as a cereal and valued for its medicinal qualities,
while the oil from the seed has been used as a frying medium for food (Vaisey-Genser and
Morris, 2003) . Flaxseed was reported to be used in breads in Jordan and Greece as early as
1000 B.C . The people of the southern Nile region in Ethiopia to this day still plant many acres
with flax (also known as linseed) . They consume the seed, often roasted in a stew, wat, as a
porridge, gufmo, and also as a drink, chilka . (Siegenthaler, 1994). Ground and whole flaxseeds
continue to be used in baked goods and other foods in Europe and Asia (Carter, 1993).
Flaxseeds have been used for hundreds of years as a substantial part of the diet in some parts of
Russia as mentioned in FDA's precedent files (Vanderveen, 1995). People in India and China
use flaxseed oil in their cooking (Pan, 1990) .
0038
Currently, many food products, functional foods and dietary supplements
containing flaxseed
or flaxseed derivatives as ingredients are available commercially in the United
States, Canada,
the United Kingdom and other European countries. These flaxseed derivatives
include milled
flaxseed, flax meal, defatted flax flour, flax oil, flax lignans and flax fiber.
Flaxseed is an
excellent source of functional food components such as dietary fiber - both soluble
and
insoluble, a-linolenic acid (ALA) and lignans.
According to the Global New Food Products Database (GNPD) tracking service provided
by
Mintel, there were 196 new food products containing flax in 2005 as compared to 51 new
products in 2000 (Appendix N),. The majority of new products introductions are in the U.S.
(166), Canada (57) and Europe (22) (Appendix N) . Out of the 420 recorded food products
listing flax, the top 5 food categories are as follows : bakery, 192; snacks, 82; breakfast cereals,
64; and dairy, 17. Flax ingredients are used in ready-to-eat flaxseeds and health bars, and as an
ingredient (e.g. flax meal and de$atted flour) in food recipes. It can also be seen in Appendix N
that there were a total of 25 new dietary supplements containing flax lignans from 2000-2005
and a total of 21 new food products containing flax lignans which were introduced from 20002005. A sample list with a brief description of commercial food products containing flax
ingredients is also shown.
-
Vanderveen (1995) ; citing FDA's precedent files, reported that the agency received information
in 1983 indicating the use of untreated flaxseed as a food ingredient in baked goods prior to
_
1958 . Based on the historical information and FDA's own research, the agency concluded that
it will not object to the use of 12% flaxseed (whether defatted or heat treated) in foods . This
policy has been communicated to the food industry, including Harvest Foods Ltd. (Canada) in
1983 and to French American Ice Cream Company, Inc . (California, U.S.) in 1990 (see
Appendix O).
According to the available research, flaxseed and flaxseed oil supplements appear to be well
tolerated, and there is long-standing historical use of flaxseed products without significant
reports of side effects (Mayo Clinic Website, 2006 ; NLM/NIH Website, 2006) . The advisory
states that adults (18 years or older) may take flaxseed oil available in a capsule form, which
often contains 500 milligrams alpha-linolenic acid per gram capsule or 10 to 60 grams of
0039
flaxseeds. It cautions, however, that daily doses of 45 grams may have laxative
effects and
women should not take flaxseed or flaxseed oil during pregnancy and
breastfeeding because of
possible estrogenic effects . Consequently, obtaining lignans from supplements
rather than oil
containing flax products may be beneficial .
5.3
Human Studies on Flaxseed and Flax Lignans
Various human clinical studies to determine the physiological effects of flaxseed or
flaxseed
components have been reviewed by Oomah (2001 ; paper included in Appendix B). The
highest level of flaxseeds or flaxseed components reported was 50 g/day of defatted flaxseed
(Jenkins et al., 1999), 50 glday of flax flour (Cunnane et al., 1993) and 50 gl.day of flaxseed
(Cunnane et al., 1995) ; these levels were well tolerated by humans.
Thompson et al., (2000) reported that feeding 25 g flaxseed in a muffin formulation to
patients
with newly diagnosed breast can~er from the time of diagnosis to the time of surgery resulted
in
significantly lower tumor cell proliferation compared with those fed the placebo muffin without
flaxseed .
Human subjects consuming SO g flaxseed per day have shown no effects on vitamin B6 or
metabolism (Cunnane et a1., 1993; Mazza and Biliaderis,1989) . Consumption of 50 g of
milled flaxseed per day has not been associated with toxicity symptoms in adults which
suggested that cyanogenic compounds in this amount of flaxseed seem likely to be well
_
tolerated (Jenkins, 1995). The equivalent amount of SDG in 50 g of flaxseed diet would be
equal to 650 mg when calculated based on the highest level of SDG (1330 mg/100 g) reported
by Johnsson et al., (2000) .
Results from animal feeding trials using much higher flaxseed intake including 20% and 40%
flaxseed diet for 90 days in weanling Sprague-Dawley rats (body weight 57.9±2.3 g ) confirm
the safety of flaxseed observed in these human studies (Ratnayake et. al., 1992).
Thompson and Ward (2002) in their review on the health benefits, bioavailability and
safety of flaxseed lignans, reported that the metabolism and availability of lignans in a
0040
~
2.5-10% flaxseed diet as seen in animal and human studies, are
sufficiently high to produce
health benefits . The benefits may include reduction of cancer risk,
cardiovascular disease,
diabetes, kidney disease, osteoporosis, and menopausal symptoms . This
2.5-10% flaxseed diet
would contain 0.76-3.02 mg SDG/day fed to rats as calculated based
on the study by Rickard et
al., (1996) . This is equivalent to the consumption of 3 .35=13 .3 mg
SDG/kg body weight/day .
In humans, the daily intake would be equivalent to 235-930 mg per day
based on an average
body weight of 70 kg.
Nesbitt et al. (1999) studied nine women who supplemented their diets with
5, 15, or 25 g raw
flaxseed or 25 g processed flaxseed cooked into a muffin or bread for 7 days
to examine
lignan urinary excretion in a randomized cross-over study . The raw flaxseed contained
2.93
Itmol SDG/g (201 mg/100 g) when analyzed by~HPLC. All flaxseed supplementation
resulted
in greater urinary lignan excretion . No difference in excretion was seen by
preparation of the
flaxseed into muffins or bread. There were no reports of adverse effects during the trial.
f
Hutchins, et al., (2000) studied 31 healthy postmenopausal women who were fed 0, 5, or
10 grams of ground flaxseed per day for 7- week feeding periods in a randomized, cross-
over trial to examine urinary excretion of metabolites . Consumption of flaxseed significantly
increased the excretion of enterodiol, enterolactone, and total lignans in a linear; doseresponsive manner. No record of adverse effects were noted during this trial.
Stuglin and Prasad (2005) studied the effect of flaxseed consumption on blood pressure,
serum lipids, hemopoietic system and liver and kidney enzymes in healthy humans. Their
_
results suggested that daily consumption of 32 .7 g of total flaxseed for 4 weeks does not
have any deleterious effects on the hemopoietic system or renal and hepatic function .
In a study to examine blood lipid profiles and markers of bone metabolism, Lucas et al., (2002)
conducted a double blind randomized trial of 58 postmenopausal women who were separated
into two treatment groups of either 40 g of ground whole-flaxseed or wheat based control.
Their diets were supplemented with these treatments for 3 months . There were no significant
changes in circulating IGF-I, IGFBP-3, AP, BSAP, TRAP, calcium, E1, E2, FSH and SHBG.
There were no changes in urinary Dpd or helical peptide between treatments . There were
improvements in serum lipid markers including reductions in total cholesterol, non-HDL
0041
cholesterol, Apo A-1 and Apo B . There was also a moderate reduction in HDL.
There was no
documented evidence of ill side effects.
A randomized cross over trial compared the effect of flaxseed supplementation
to hormone
replacement therapy in hypercholesteroiemic menopausal women. Participants
supplemented their diet with 40 g crushed flaxseed, there were mild favorable effect
of flax
supplementation on markers related to cardiovascular health (Lemay et al., 2002).
Brooks, et al., (2004) used a randomized, double-blind, parallel, placebo-controlled
design on supplementation of either placebo, 25 g soy flour, or 25 g ground flaxseed
in
postmenopausal women to examine the effects of supplementation on menopause symptoms
The treatments were administered in a muffin for 16 weeks. Blood and urine
samples were
collected for baseline analysis before treatment and at the end of the treatment period
.
.
.
Phytoestrogens, estrogen metabolites, and serum hormones were analyzed, as well as, serum
and urine biochemical markers of bone metabolism . No significant change in serum
hormones
or biochemical markers of bone metabolism were seen between treatment groups . There
was
an increase in urinary lignan excretion in the flaxseed treated group. There was
no report of
adverse effects.
5.4
Human Clinical Studies Using BeneFlaxTM Flax Lignan extract
0042
PAGES 43 THROUGH 49
8
PAGES
TOTAL
REDACTED IN ITS
ENTIRETY
CONTAINS
TRADE
SECRET
CONFIDENTiAL
COMMERICAL
INFORMATION
5.8
Potential Safety Concerns Regarding Natural Components in Flaxseeds
5 .8 .1
Cyanogenic glycosides '!
Flax, as well as, other edible plants such as, sorghum, wheat, barley, oats, rye, lima beans,
kidney beans, apples, cassava, and bamboo shoots, may contain significant amounts of
cyanogenic glycosides ranging from 6 to 8000 mg/kg (Oomah et al ., 1992; WHO, 1999, Jones
0050
1998). These naturally occurring compounds when digested release cyanide, which
could
potentially cause cyanide toxicity (Jones, 1998) . However, mammals are capable of
detoxifying cyanide by its conversion to thiocyanate mediated by the enzyme
thiosulfatecyanide sulfur transferase (Jones 1998). Thus, cyanide commonly acquired from dietary
sources is readily excreted as thiocyanate in the urine (WHO, 1999). This natural detoxification
mechanism protects the body against cyanide toxicity and toxicity only occurs when
the rate of
absorption of cyanide is such that the metabolic detoxification capacity of the body is
exceeded.
In flax, the total cyanogenic glycosides content (comprising of linamarin, linustatin
and
neolinustatin) has been reported to range from 365-550 mg per 100 grams of seeds in ten
cultivars (Mazza and Oomah, 1995). Jenkins, 1995 has also reported a level of cyanogenic
glycosides of 457 mg per 100 grams of whole flaxseeds (paper included in Appendix B).
Furthermore, he also showed a lower content of-cyanogenic glycosides in baked products .
In
addition, virtually no cyanide was detected when boiling flaxseeds before analysis (Chadha et
al., 1995). Lower cyanogenic glycosides content in baked flaxseed products has also been
reported .
It has been reported from human clinical studies that consumption of up to 50 g/day of milled
flaxseeds (containing about 230 mg of cyanogenic glycosides) or partially defatted flaxseeds,
incorporated into foods, fed to adult subjects for up to 4 weeks (Cunnane et al., 1995 ; Jenkins,
1995 ; Jenkins et al, 1999) was not associated with toxicity symptoms, indicating that
cyanogenic compounds in this amount of flaxseed are well tolerated (Jenkins, 1995; paper
included in Appendix B) .
_
A detailed chemical analysis of cyanogenic glycosides for a115lots (3 production and 2 pilot
lots) of BeneFlaxTM Flax Lignan extract evaluated in this notification is shown in Tables 4A,
4B and 4C.
'
The levels of cyanogenic glycosides and of HCN equivalents of 5 lots of BeneFlaxTM Flax
Lignan extract are summarized in Table 10.
0051
Table 10 . Summary of cyanogenic glycosides (CG) content and corresponding HCN
equivalents in 3 Production Lots and 2 Pilot of BeneFlaXTm Flax Lignan extract*
Lot No .*
46 A
48 A
602081
602231
603031
Average
(Range)
Linamarin
mg/kg
0
0
14
9
40
13
(0-40)
Linustatin
mg/kg
50
10
212
70
137
96
(10-212)
Neolinustatin
mg/kg
200
140
182
60
164
149
(60-200)
Total CG's
mg/kg
250
140
408
139
304
248
(139-408)
Total HCN
Equivalents"
15.6
8.7
26.0
9.0
19.0
15.7
(8.7-26.0)
* Same lots presented in Table 4C .
** Calculated based on the molecular weight (MW) of each compound as follows:
(Amount of Compound (mg)) X (MW of CN) / (MW of Compound (mg)).
The cyanogenic glycosides consist primarily of linustatin and neolinustatin and trace amounts
of linamarin. As shown on Table 10, the average level of total cyanogenic glycosides in
BeneFlaXTm Flax Lignan extract yvas 248 mg/kg (or 24.8 mg per 100 g) with a range of 139 t
408 mg/kg . Considering the highest observed level of total cyanogenic glycosides of 408
mg/kg in BeneFlaXTm Flax Lignan extract, it can be estimated that the amount of total
cyanogenic glycosides, at the highest recommended dose of the product of 1 .72 g/day
(containing 600 mg of SDG), will be only 0.70 mg/day. This very low level of total
cyanogenic glycosides in BeneFlaxTM Flax Lignan extract is significantly below the estimated
intake of 230 mg of cyanogenic glycosides when feeding whole flaxseed to humans without
adverse effects (Jenkins, 1995).
Since cyanide is the toxic end product released, upon digestion of the cyanogenic glycosides,
the safety and toxicological information of these compounds is commonly reported as mg/kg of
hydrogen cyanide (HCN) equivalents. The levels of HCN equivalents and cyanogenic
glycosides of 5 lots of BeneFlaXTm Flax Lignan extract are also shown in Table 10. On
average, BeneFlaXTm Flax Lignan extract contained 15 .7 mg/kg (range : 8.7 - 26.0 mg/kg) of
HCN equivalents.
A comprehensive description of the safety of cyanogenic glycosides has been reported by
WHO (WHO, Food Additive Series 30, 1999). The toxicity of these compounds has also been
evaluated by JECFA and EFSA (JECFA, 1992 ; EFSA, 2004), which in conclusion did not set a
0052
safe level of intake of cyanogenic glycosides due to the lack of reliable quantitative
consumption data . Therefore, a safe level of intake or NOAEL was not established and JECFA
only concluded that a level of up to 10 mg/kg of HCN in the Codex Standard 17$ for edible
Cassava flour was not associated with acute toxicity (Codex, 1989). However, WHO
monograph reported lethal doses of HCN from 2.0 mg/kg,BW in cats, cattle and sheep to 4 .0
mg/kg BW in dogs . The LDso~s of cyanogenic glycosides, as determined by IN. route, were
determined by EPA in 1990 as 0.66-1 .43 mg/kg body weight in several animal species. The
LDso per oral route has only been determined in a rat model by WHO (1965, cited by WHO,
Food Additive Series 30, 1999), and was reported at the HCN level of 10-15 mg/kg body
weight (WHO, Food Additive Series 30, 1999) . If this is extrapolated to humans, the rat oral
LD50 would be equivalent to 700 - 1050 mg/day of HCN for a reference person weighing 70
kg.
Considering the highest level of HCN equivalent of 26 mg/kg of product found in the analysis
of 5 final BeneFlaxTM Flax Lignqn extract lots, the corresponding level of HCN present in 1 .72
g of maximum suggested daily dose of BeneFlaxTM Flax Lignan extract would amount to only
0.04 mg. This level is well below the lethal doses and LDso~s for cyanogenic glycosides
reported for all animal species evaluated, either IN. or by oral route. Furthermore, this 0.04
mg value is only 0.0006 mg/kg on a body weight basis when compared to a 70 kg reference
person (0.04/70 kg). In addition, it can be calculated that the amount of HCN in a 200 g daily
portion of Cassava flour (EFSA, 2004), which meets the Codex Standard for edible Cassava
flour (Codex Standard 176, I989/1995) is 2.0 mg. This amount of cyanide, likely to be
consumed by a person in the developing world where Cassava is a staple food, without toxic
effects, is much higher than the 0.04 mg of HCN contained in 1 .72 g of BeneFlaxTM Flax
_
Lignan extract (the maximum suggested dose of the product).
Consequently, it can be concluded that very low levels of HCN present in a daily dose of
BeneFlaxTM Flax Lignan extract when used as an ingredient in dietary supplement are
insignificant and do not pose a safety concern when consumed at the suggested dosage.
0053
5.8.3
Phenolic acids
Phenolic acids are ubiquitous in the plant kingdom and can be present in considerable amounts
in the human diet. They include primarily caffeic, chlorogenic, cinnamic, ferulic and coumaric
acids. The main dietary sources of these compounds are fruits, fruit juices, coffee, wine, tea
and to a lesser extent, vegetables and cereals (King and Young, 1999) . Rich sources of
phenolic acids are blueberry (1,881-2,112 mg/kg), cherry (290-1,280 mg/kg), pear (44-1,270
mg/kg), apple (2-258-mg/kg), orange (21-182 mg/kg), potato (100-190 mg/kg) and coffee
beans (56 g/kg/Dry Weight) . Thus, the consumption of fruit juices and coffee contribute
significantly to the dietary intake . Cereals, particularly when consumed as whole grain, are
also significant dietary sources of cournaric and ferulic acids (Clifford, 1999) . The attention of
these compounds has been primarily focused on the beneficial antioxidant effects . Due to their
ubiquitous presence in plant foods, it is believed-that their consumption may be up to hundreds
of milligrams per day (King and Young, 1999; Clifford, 1999). For example, a consumption
study conducted in Germany in a limited sample of men and women estimate an average
phenolic acid intake of 222 mg/day, the majority from coffee drinking (Radtke, 1998). Another
study also estimated, based on different dietary patterns, that the consumption of phenolic acids
can range from 25 mg to 1 .0 g/day (Clifford, 1999).
Flaxseed is a rich source of phenolic acids, containing 800-1,000 mg of phenolic acids per 100
g of seeds (Shahidi and Naczk, 2003). The main phenolic acids that have been reported in
dehulled and defatted flaxseed meal are ferulic (46%), sinapic (36%), coumaric (7.5%) and
caffeic (6 .5%) (Dabrowski and Sosulski, 1984). Other reported phenolic compounds reported
in flaxseeds include a SDG isomer, pinoresinol diglucoside, isolariciresinol, metairesinol,
genistic and vanillic acids in free or bound form (Dabrowski & Sosulski, 1984 ; Johnsson et al.,
'
2002).
-
Ferulic Acid
Ferulic acid is considered an antioxidant and anti-inflammatory agent derived from plants . It is
found, along with coumaric acid, chiefly in the cell wall and external layers of cereals such as
barley, rice, maize, wheat and in flax (Clifford, 1999). Cereal bran products are particularly
rich in this compound . Barley bran, for example, contains, approximately 50 mg/kg of ferulic
acid (Clifford, 1999).
0054
Several animal studies have demonstrated a protective effect of ferulic acid against alcohol
liver toxicity (Rukkumani et al., 2004), the formation of nitrosamines (Kuenzig et al., 1984),
the toxicity of Abeta 42 (1- (a beta-amyloid peptide) to brain cells (Yan, 2000) and carbon
tetrachloride-induced toxicity (Srinivasan et a1., 2005). None of these studies suggested toxic
effect of ferulic acid . Srinivasan et al.; (2005) studied the protective effect of this natural
substance on carbon tetrachloride induced toxicity in rats for a treatment period of 90 days .
They reported that ferulic acid, at a dose of 20 mg/kg body weight per day, was effective in
preventing heptatoxicity without side effects. In our batch analyses, the ferulic acid content
(including the acid equivalent from the hydrolysis of the glucoside form) was found to be 6,286
mg/100g (average of 5 lots in Table 4C). However, when consuming the highest
recommended dose of BeneFlaxTM Flax Lignan extract of 1 .72 g, the estimated amount of
ferulic acid intake would be only 108 mg/day, or equivalent to eating several apples . In
humans, this level of ferulic acid intake would be equivalent to 1 .54 mg/kgBW/day for a person
weighing 70 kg. This intake of ferulic acid should not pose a safety concern, as it is lower than
the aforementioned dose reporteq by Srinivasan et a1. (2005), and far below the LDLo (Lethal
Dose Low) of 1200 mg/kg BW for ferulic acid reported by the Sax's Handbook, as determined
in mouse by parental administration (Lewis, Sr., 2004) .
n-Coumaric Acid
p-Coumaric and ferulic acids are found primarily in the cell walls and external layers of cereals,
such as barley, rice, maize, wheat and flax (Clifford, 1999) . Cereal bran products are
particularly rich in these compounds where these are associated with dietary fiber: Barley bran,
for example, contains = 30 mg/kg of p-coumaric acid (Clifford, 1999) .
'
Khelifi-Touhami et al . (2003) studied the effects of caffeic, ferulic and p-coumaric acids on the
rat thyroid gland in a 3-week oral treatment period . The dose level for each of the phenolic
acids, administered by gastric tube and not as part of the diet, was 0.25 jimollkg/day (i.e . 41 .04
ttg equivalent to 0.0410 mg/kg/day) . The results of this single study indicated that
administration of p-coumaric acid at this dose induced goiter in rats . However, the use of the
rat as experimental model for goitrogenic studies is questionable because, in comparison with
humans, rodents are more sensitive to goitrogens , the rat lacks high-affinity binding globulin
and the plasma T4 in rats is shorter (Dohler et al., 1979). In contrast, Yeh and Yen (2006)
tested ferulic acid and p-coumaric acid at a significantly higher dosage of 100 mg/kg BW/day
0055
for 14 days in rats and found no adverse effects and that these phenolic acids significantly
induced phase II hepatic antioxidant enzyme and increased the antioxidant status of the liver.
Furthermore, our own 90-day sub-chronic rat feeding study (Covance, 2002) did not find any
adverse effect on thyroid parameters using BeneFlaxTM Flax Lignan extract. In our batch
analyses, the amount of p-coumaric acid (including the acid equivalent from the hydrolysis of
the glucoside form) is 6,156 mg/l00 g in BeneFlaxTMFlax Lignan extract (average of S lots in
Table 4C). However, the amount of p-coumaric acid in BeneFlaxTM Flax Lignan extract when
consumed at the highest proposed daily dose (1 .72 g of product) is estimated to be only 106 mg .
This intake level of p-coumaric acid should not pose a safety issue, as it is lower than the
aforementioned dose reported by Yeh and Yen (2006) . Furthermore, this level of coumaric
acid in 1 .72 g of BeneFlaxTM Flax Lignans extract is significantly lower than the LDso value of
657 mg/kg BW determined in the mouse when administering coumaric acid by intraperitoneal
route (Lewis Sr., 2004).
Caffeic Acid
`
Caffeic acid is a naturally occurring phenolic acid present in a wide variety of commonly
consumed plant foods, such as vegetables, fruits, fruit juices, coffee and spices . Caffeic acid
(free and conjugated) has been found in significant concentrations in foods such as lettuce
(767-1570 mg/kg), celery (89-104 mg/kg), potato (163-280 mg/kg) and blueberry (83-588
mg/kg) (IARC Monograph, 1993). Spices such as thyme, basil, aniseed, caraway, rosemary,
tarragon, mejorana and sage have been found to contain more than 1000 mg/kg (Hayase and
Kato, 1984).
Caffeic acid is often found esterified to quinic acid to form chlorogenic acid which is widely
distributed in fruits and vegetables but notable for its high concentration in seeds, particularly
coffee beans (King and Young, 1999). Depending on the coffee species, green coffee beans
contains 6-10% chlorogenic acid and it has been estimated that a 200 ml cup roast and ground
coffee may supply from 20 to 675 mg , depending on the coffee strength (Clifford, 1999).
Some early studies have associated high dietary levels of caffeic acid (2°Io in the diet) with the
development of cancerous lesions in the forestomach of rats and mice (IARC 1993 ; Hirose et al.
1987, Hagiwara et al . 1991, Hirose et al. 1992, Hirose et al. 1991, Ito et al. 1993, Hirose et al.
0056
1997). However, more recent investigations have reported a protective effect of caffeic acid
against liver cancer in the rat (Hagiwara et al. 1996) and as a potent antioxidant preventing the
formation of reactive oxygen and free radicals (Gulcin, 2006) . In addition, both caffeic acid
and chlorogenic acid have been' found to inhibit DNA methylation in human cancer cells, thus
preventing the promotion of carcinogenesis (Lee & Zhu, 2006).
This contrasting information on the effect of caffeic acid in experimental animals can be
explained by the study of Lutz et al., (1997), who investigated the carcinogenic dose response
to various intake levels of this compound . Using the rat as experimental models, it was found
in this investigation that there was a J shape response to various levels of caffeic acid ; high
consumption (> 100 mg/kg BW/day) led to hyperplasia of the forestomach, while low intake
levels (<
_ 35 mg/kg BW/day) had a protective effect.
In the analysis of BeneFlaxTM Flax Lignan extract, the amount of caffeic acid (including the
acid equivalent from the hydrolyfis of the glucoside form) was found to be 2,154 mg/100 g
(average of 5 lots in Table 4C) . However the estimated amount of caff`eic acid is only 37 mg
when consuming 1 .72 g of BeneFlaxTM Flax Lignan extract which is the highest suggested dose
per day . In humans, this level of caffeic acid intake would be equivalent to 0.53 mg/kg
BW/day for a person weighting 70 kg. This intake level of caffeic acid should not pose a safety
issue as it is 66 times lower than the aforementioned dose of < 35 mg/kg BW/day reported by
Lutz et al., (1997) . Most importantly, this small amount of caffeic acid in 1 .72 g of
BeneFlaxTM Flax Lignan extract is far below the reported LDLo (Lethal Dose Low) of 1,500
mg/kg BW as determined in the rat by administrating caffeic acid by intraperitoneal route
(Lewis, Sr, 2004).
On the basis of all existing data combined, it can be concluded that the cancer risk for humans
associated with the intake of caffeic acid is negligible (Ito and Hirose, 1989, Lutz et al., 1997).
The proliferative lesions in the forestomach of rats and mice induced by high intakes of caffeic
acid are largely reversible, in contrast to those induced by genotoxic carcinogens, which
generally persist and develop into cancer. Furthermore, the significance of reported
tumorgenicity of caffeic acid to the development of human cancer is limited because humans
`
do not have a forestomach. Based on more recent literature, it is more likely that caffeic acid
0057
(either free or conjugated as chlorogenic acid) is a beneficial substance, both as
chemopreventive and as an antioxidant, rather than a potential toxic compound .
5.8.4
Hydroxymethylglutaric Acid (HMGA)
Although HMGA may function as a competitive inhibitor of HMG-Coenzyme A, its
contribution to the health benefits of flaxseeds has not yet been demonstrated (Muir and
Westcott, 2003) . Lupien et al., (1979) studied the effects of HMGA on plasma and low density
lipoprotein cholesterol level in familial hypercholesterolemia in 36 patients randomly assigned
to five groups with each group receiving one of the following treatments : placebo, HMGA 750
mg, 1500 mg, 2250 mg or 3000 mg per day. The possible toxic effects at each dose level were
also investigated . As compared to the placebo, the mean plasma cholesterol levels during the
eight-week treatment period were 11 and 13 percent lower in the 2250 mg and 3000 mg treated
groups . Furthermore, there were no clinical side effects throughout the study, and various
hematologic, hepatic, renal and metabolic function tests were clinically unaltered. The HMGA
content is 12.3 g/100 g in BeneF~axTM Flax Lignan extract (average of S lots in Table 4A).
However, the estimated consumed amount of HMGA is only 211 mg when derived from 1 .72 g
of BeneF1aXTM Flax Lignan extract at the highest suggested daily dose . This intake level of
HMGA should not pose a safety issue as it is significantly lower than the levels used in the
aforementioned Lupien et al . (1979) study. In addition, it is significantly lower than the LDso
of 7330 mg/kg BW as determined in the mouse by oral route (Lewis Sr . 2004) .
5.8 .5
Herbacetin
Herbacetin (3,8-0-diglucosyl herbacetin) is a flavonoid typically found in flaxseeds which also
mediates antioxidant activity (Qiu, et a1., 1999) . A literature search regarding this compound
_
failed to reyeal any suggestion of toxicity. Studies found were focused primarily on its
chemical identification and characterization in exotic plant sources (Lee et al ., 2000) . In
addition, in our product analysis, the levels of herbacetin in BeneFlaxTM Flax Lignan extract
were significantly lower than the other phenolic acids found in the product (Table 4A). Hence,
it would appear that the presence of small amounts of herbacetin in BeneFlaxTM Flax Lignan
extract does not represent a safety concern. On the contrary, due to its antioxidant properties, it
may be beneficial .
0058
5.9
Safety of Chronic Exposure
Safety data on the effect of chronic exposure to high levels of flax lignans in humans are not
available beyond 16 weeks (Zhang et al., 2006c). However, based on the metabolism of
lignans and the pharmacokinetics of enterolignans (enterolactone and enterodiol produced by
bacterial conversion of lignans in the colon), it is unlikely that chronic exposure to lignans
present a safety risk . The kinetics of enterolignans have been studied in humans by Mazur et
al ., (2000), and more recently by Kuijsten et al., (2005) . Mazur et al., (2000) determined the
pharmacokinetics and urinary excretion of enterolactone in five healthy women and two men
after consumption of a single strawberry meal containing a known amount of lignans. Basal
and post-meal blood and urine samples were collected at short intervals. This strawberry meal
increased the concentrations of enterolactone in blood plasma after $-24 hours, and in urine
samples collected at 13-24 and 25-36 hours after the meal . Most importantly, the amount of
enterolactone excreted in urine collected for 48 hours post-meal was, on average, 114% of the
amount of lignan consumed in the meal, indicating rapid clearance and practically no
accumulation of enterolignans.
`
Kuijsten et al., (2005) studied the pharmacokinetics of enterolignans in healthy men and
women consuming a single dose of secoisolariciresinol diglucoside (SDG), the major lignan in
flax . Six men and six women participated in the study . After an overnight fast, they were
given 1 .31 jLmol SDG/kg BW (or 0 .9 mg SDG/kg BW) in water, just before having their
breakfast . Blood samples were collected at various time points up to 96 hours. Urine samples
'
were collected 24 hours prior to the intake of SDG until 72 hours after the intake of SDG. Both
enterolactone and enterodiol were measured in the samples. It was found that it took = 8-10
hours before enterolignans appeared in plasma . The maximum concentration of enterodiol was
reached 14.8 hours after consumption of SDG, while the maximum concentration of
enterolactone was reached at 19 .7 hours post-dose. The elimination half life of enterodiol was
4.4 ± 1 .3 hours, and for enterolactone 12.6 ± 5 .6 hours . Thus, the residence time of enterodiol
was about 21 hours and that of enterolactone was about 36 hours. Furthermore, most of the
enterolignans were excreted in the urine within the first two days. These data together indicate
that in humans, plasma levels can reach a steady state of enterolignans after 5-10 hours and that
their body clearance is rapid. This kinetic feature indicates a low possibility that tissue
enterolignans could reach high levels that may be of safety concern.
0059
In regard to chronic dietary exposure, consumption data of flax or flax products were not
available . We reviewed several dietary national surveys in the United States and other flax
producing countries, including Canada, Argentina and countries in Eastern Europe and found
that flax products were not part of their dietary data bases. On the other hand, lignans intake
has been estimated to be low in Western societies. Studies conducted in the United States (de
Kleijn et al 2001, Valentin-Blasini et al, 2005), Finland (Valsta et al., 2003) and Sweden
(Hedelin et al ., 2006) have shown that in the general population, the daily consumption of
lignans is less than 1 .0 mg/day. Therefore, chronic lignan consumption at these low levels is
not representative of consuming higher level of lignans as suggested for BeneFlaxTM Flax
lignan extract. However, dietary exposure to higher levels of lignans has been studied by
Adlercreutz et al. by measuring the urinary excretion of lignans in selected U.S. population
groups with contrasting levels of lignans intakes from dietary sources (Adlercreutz et a1., 1995).
For example, these investigators found that oriental women living in Hawaii had a low lignan
urinary excretion of less than 1 itmol/24 hrs while a group of individual consuming a
macrobiotic diet, rich in whole pains and fruits, had a mean urinary excretion of urinary
lignans of 28 Amoll24 hrs (approximately a 28 fold difference) . Although the Adlercreutz et al.
study did not measure plasma lignan concentrations, if one assumes urinary excretion levels
parallel plasma levels, then one would expect there to be a 28-fold difference between plasma
levels of omnivores in the general population and macrobiotic diet consumers. Interestingly;
the observed 28-fold difference in urinary lignan excretion between low lignan consumers
(Oriental women) and high lignan consumers (macrobiotic diet group) is similar to the
observed difference in plasma enterolignans (enterodiol and enterolactone) in subjects
(see
consuming 600 mg of SDG/day versus the control group, in our China cholesterol trial
Table 11). In this study, the plasma level of enterodiol was an average of 8.1 ng/ml in all ,
subjects in the control group and 229.8 nglml in all subjects receiving 600 mg of SDG
throughout the supplementation period (also a 28-fold difference) . This would suggest that
plasma value increases are then the same in the China study and the macrobiotic diet study. In
extract
the absence of other data, this relation suggests that consuming BeneFlaxTM Flax Lignan
would present a plasma exposure level similar to those consuming a macrobiotic diet .
issues .
Macrobiotic diets rich in whole grains are considered healthy and do not present safety
0060
0061
..:~,.
6.0
Conclusion
Total product characterization, composition, specifications and
quality attributes of BeneFlaxTM
Flax Lignan extract have been well established. This includes a
clear characterization for
absence or inconsequentially low levels of potentially toxic substances,
such as cyanogenic
glycosides . We have also shown that upon processing of BeneF1aXTM Flax
Lignan extract; we
do not concentrate any undesirable naturally occurring compound
or contaminants, or introduce
any extraneous potentially toxic compounds. On the contrary, we show
that potentially toxic
substances, like cyanogenic glycosides, are drastically reduced to very low
levels which are
below other commercially available products, and do not pose any
safety concern.
The safety of BeneFlaxTM Flax Lignan extract ltas been demonstrated by toxicity
testing the
product, following FDA Red Book guidelines, in a mutagenicity study and a 90-day
rat feeding
study, the results of which show no negative effects. Additionally, four
human clinical studies
using this new dietary ingredienti for periods up to 16 weeks at a daily dose
as high as 600 mg
SDG, conducted by independent investigators, did not show any adverse clinical,
metabolic or
functional effects.
Furthermore, a thorough literature review of animal and human studies using flax,
flax products
and lignans, as well as each major safety relevant component found in the
characterization of
the BeneFlaxTM Flax Lignan extract, showed the absence of any significant adverse
effects at
the suggested dose ranges that could be potentially attributed to the product components
.
A thorough and careful assessment of all these safety information form the basis on
which
Archer Daniels Midland Company has concluded that BeneFlaxTM Flax Lignan
extract
containing SDG will reasonably be expected to be safe as a new dietary ingredient
for use in
dietary supplements and thus should be permitted for introduction in the U.S . market.
0062
7 .0
References
Adlercreutz, H.C ., Goldin, B.R., Gorbach, S .L.,
Hockerstedt, K.A.V., Watanabe, S .,
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