s MAR 3 2006 Memorandum

DEPARTMENT OF HEALTH & HUMAN SERVICES
s
Food and, Drug Administration
Memorandum
/
~ d 3~r~~G ~
MAR 3 2006
Date :
From :
subject:
o:
Public Health Service
Consumer Safety Officer, Division of Dietary Supplement Programs , Office of
Nutritional Products, Labeling and Dietary Supplements, HFS-810
75-Day Premarket Notification of New Dietary Ingredients
Dockets Management Branch, HFA-305
Subject of the Notification :
BeneFlaxTM Flax Lignans
Finn: Archer Daniels Midland Company
Date Received by FDA : December 5, 2005
90-Day Date : March 5, 2006
0
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 95S-0316 as
soon possible since it is past the 90-day date. Thank you for your assistance.
-Victoria Gutwak
*
,qq 5 5 -o3/6
,~p T 3ac2
~~^"s`""~s~,
/
DEPARTME NT OF HEALTH AND HUMAN SERVICES
Public Health Service
F E B 1 7 2006
James S . How, Ph .D .
Senior Manager
Regulatory and Scientific Affairs
Archer Daniels Midland Company
1001 N. Brush College Rd.
Decatur, Illinois 62521
Dear Dr. How:
This is to inform you that the notification, dated December 2, 2005, 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 toy the Food and Drug Administration (FDA) on December 5, 2005 . FDA also
received additional information dated December 7 and December 8 . Your notification concerned
the substance that you identified as "BeneFlaxTM Flax Lignans" that you produce from an extract
of the seeds from Linum usitatissimum L.
40
According to your notification, your new dietary ingredient will be marketed "in a tablet form
containing . . . 280 - 580 mg of BeneflaxTM Flax Lignan ingredient ." Concerning the conditions of
use for your ingredient, your notification states that the "[r]ecommended total daily dose [will be]
. . . 860-1720 mg of BeneflaxTM Flax Lignan ingredient . Recommended conditions of use of the
dietary supplement on the package label may be: 1) Take two tablets once a day, or 2) Take two
tablets twice 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 section 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 21
U .S .C . 342(t) (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
inj ury .
0
-
Food and Drug Administration
5100 Paint Branch Parkway
College Park, Maryland 20740
Page -2- Dr. James S . How
"
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 a dietary supplement
containing "BeneFlaXTm Flax Lignans" will reasonably be expected to be safe .
FDA was unable to establish the identity of "BeneFlaXTm Flax Lignans" . While your notification
describes the presence of the flax lignan secoisolariciresinol as comprising 37% of the
ingredient, 57°ro of the material in the product is not adequately described . In addition, your
notification did not cite a method or describe how cyanogenic glycosides were identified or
quantified . Therefore, FDA is unable to determine the levels of cyanogenic glycosides that will
be present in dietary supplement products containing "BeneFlaXTm Flax Lignans" . Because the
identity of "BeneFlaXTm Flax Lignans" is unclear, it is unclear how your ingredient is
qualitatively or quantitatively similar to the substances described in the information that you rely
on for the safety for "BeneFlaXTm Flax Lignans" .
For the reasons discussed above, the information in your submission does not provide an
adequate basis to conclude that "BeneFlaXTm Flax Lignans" 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(f)(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).
is
Your notification will be kept confidential for 90 days after the filing date of December 5, 2005 .
After the 90-day date, the notification will be placed on public display at FDA's Docket
Management Branch in docket number 955-0316 . 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.
If you have any questions concerning this matter, please contact Linda S . Pellicore,
Ph.D. at (301) 436-2375 .
Sincerely yours
-99~,
Susan J. Walker, M.D.
Director
Division of Dietary Supplement Programs
Office of Nutritional Products, Labeling
and Dietary Supplements
Center for Food Safety and Applied Nutrition
0
1
James R. Randall Research Center
IY
~
ODM
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~, L% l `
.
December 2, 2005
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:
New Dietary Ingredient Notification - BeneFlaxTM Flax Lignans
Enclosed please find an original, three copies and a redacted copy (without the
Confidential information) of the "Notification of the Marketing of a New Dietary
Ingredient : BeneFlaxTM Flax Lignans" submitted pursuant to 21CFR 190.6 (Requirements
for Premarket Notification) .
The enclosed information forms the basis on which Archer Daniels Midland Company has
concluded that BeneFlaxTM Flax Lignans will reasonably be expected to be safe as a new
dietary ingredient in the U.S . market .
"
BeneFlax'M Flax Lignans is manufactured from extraction and purification of defatted
flaxseed meal . The product is a concentrate which contains at least 35% of the major
lignan, secoisolariciresinol diglucoside (SDG) . This ingredient is a natural component of
flaxseeds . Flaxseed ingredients are commonly found in food products.
Kindly acknowledge the receipt of this NDI. If you have any questions regarding this
notification, please contact me at the telephone number below .
Thank you for your kind attention to this matter. Best regards.
Sincerely,
J~mes S . How . Ph .D .
Senior Manager
Regulatory and Scientific Affairs
Tel: 217 451 2469 ; Fax: 217 451 7098
Email : how@admworld .com
.
Enclosures :
Binder 1 - Original NDI
Binder 2, 3, 4, - Copies of NDI
Binder 5- Redacted copy of NDI (without Confidential information)
Archer Daniels Midland Company
1001 N. Brush College Rd .
Decatur, IL 6252 1
James R. Randall Research Center
r~
~p M
Ms. Victoria Lutwak
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
By Overnight Courier
December 8, 2005
Re:
0
New Dietary Ingredient Notification of BeneFlaxTM Flax Lignans
Enclosed please find the original and two copies of my letters dated December 7 and 8.
Thank you for your kind attention to this matter .
Best regards.
Sincerely,
am~~s S . How, Ph .D .
Senior Manager
Regulatory and Scientific Affairs
Tel: 217 451 2469 ; Fax : 217 451 7098
Email: how4~i'admw°orld .com
"
Archer Daniels Midland Company
1001 N. Brush College Rd .
Decatur, IL 6?521
00,
James R. Randall Research Center
0
*DM
Ms. Victoria Lutwak
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
S 100 Paint Branch Pkwy,
By Overnight Courier
College Park, MD 20740
December 7, 2005
Re :
New Dietary Ingredient Notification of BeneFlaXTm Flax Lignans
Thank you very much for telephoning me to confirm the receipt of the NDI documents on
BeneflaxTM Flax Lignans . You have informed me that the filing date was December 5th,
2005 and the anticipated 75th day shall be February 18th, 2006 .
"
I would like to clarify that Archer Daniels Midland Company (ADM) is notifying FDA of
the BeneFlaXTm Flax Lignans product as a new dietary ingredient . ADM is the supplier of
BeneFlaXTm Flax Lignans ingredient . Our customers will use BeneFlaXTm Flax Lignans as
an ingredient in their finished dietary supplement products .
I have enclosed with this letter the following additional information you have requested for
the NDI dossier regarding : 1) Botanical name and description of Flax and 2) description of
the intended use of BeneFlaXTm Flax Lignans in a finished dietary supplement product.
I would also like to enclose the corrected Table 3 found on page 7 of the NDI dossier; the
superscripts 2 and 3 were accidentally switched at the bottom of the table.
I trust that this additional information will complete the documentation of our NDI dossier.
Kindly advise if you have any questions .
Thank you for your kind attention to this matter . Best regards.
Sincerely,
"
,'
qames S . How, Ph.D.
Senior Manager
Regulatory and Scientific Affairs
Tel : 217 4512469 ; Fax: 217 451 7098
Email : howC admworld .com
"
Enclosures :
1) Addendum to the NDI dossier,
Archer Daniels Midland Company
2) Corrected Page 7 of the NDI dossier
1001 N. Brush College Rd .
Decatur, IL 62521
/ ~/
James R. Randall Research Center
DM
Enclosure 1
Addendum to the Notification of New Dietary In~zredient (NDI) of
BeneFlaxTM Flax Li nans
Name of the new dietary ingredient : BeneFlaxTM Flax Lignans
Botanical source:
Seed of the flax plant.
Latin binomial name for flax plant:
Linum usitatissimuni L.
Author: Carolus Linnaeus (Carl von Linne) ; (1707-1778)
Description of the dietary supplement that contains the new dietary ingredient
including use level of the ingredient in the dietary supplement and the conditions of use
recommended in the labeling of the dietary supplement.
The dietary supplement will be in a tablet form containing a typical range of 100 "
200 mg SDG as active ingredient which is equivalent to approximately 280 - 580 mg of
Benc:FlaxTM Flax Lignan ingredient. Each tablet containing the BeneFlaxTM Flax Lignan
ingredient, excipients, fillers and other ingredients will weigh between 500 mg - 1 .5 grams,
depending on the formulation of the finished dietary supplement customer.
Recommended total daily dose of 300 - 600 mg SDG which is equivalent to
approximately 860-1720 mg of BeneFlaxTM Flax Lignan ingredient . Recommended
condition of use of the dietary supplement on the package label may be : 1) Take two tablets
once a day, or 2) Take two tablets twice a day.
"
Archer Daniels Midland Company
1001 N. Brush College Rd .
Decatur, IL 62521
Oilo
0
James R. Randall Research Center
DM
Enclosure 2
Corrected Page 7 of the Notification of New Dietary Ingredient (NDI)
of BeneF'laxTM Flax Lignans
Table 3 - Product analysis of 5 representative batches of BeneFlaxT"" Flax Lignans
.
1 .6 .2
Labeling :
13eneFlaxT'" Flax Lignans (containing-351/'o SDG).
1 .6 .3
Packaging:
20 kg net (44 lb) polylined, poly drums
".
5 -kg net (11 lb .) polylined, poly drums
1 kg net (2 .2 lb) polylined, poly drum
Archer Daniels Midland Company
1001 N. Brush College Rd .
Decatur, IL 62521
0
BINDER #1 : ORIGINAL COPY
Notification of the Marketing of a New Dietary Ingredient (NDI) :
BeneFlaxTM Flax Lignans
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
Contact Person
James S . How . Ph .D.
Senior Manager, Regulatory and Scientific Affairs
Tel : 217 451 2469 ; Fax : 217 451 7098
Email : how &,admworld.coin
0
Notification of the Marketing of a New Dietary Ingredient (NDI) :
_
BeneFlaxTM Flax Lignans
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
Contact Person
James S. How . Ph .D .
Senior Manager, Regulatory and Scientific Affairs
Tel : 217 451 2469 ; Fax : 217 451 7098
Email : how@admworld .com
"
BeneFlaxll" Flax Lignans ND[
Page 1/32
Table of Contents
0
Product Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . .......... .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. .. .. .. 3
1 .0
1 .1
1 .2
1 .3
Flaxseed Lignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. ............ .... .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. ..3
Common Name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... ............ .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . ..4
Trade Name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ............ .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Scientific Name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. . .. ... .... .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1 .4
1 .5
Properties of BeneFlaXTm Flax Lignans . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ............ .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1 .6
Product Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. ............ .. .. .. . . . . . . . . . . . . . . . . . . . . . .5
1 .6 .1
Batch Analyses . .. . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .......... .. .... .. . . .. . . . . . . . . . . . . . . . . 6
1 .6 .2
Labeling: .. ...... ..... .... .. .. .. .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. .... .. .......... .. .. .. . . . . . . . . . . . . . . . .7
1 .6 .3
Packaging: ... .. .... .. .... .. ... . . ... . .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. ...... .......... . . .. . . . . . . . . . . . . . .7
1 .6 .4
Storage and shelf life : . ... . .... .. .... .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. .. .. .. .. ........ .. .. .. .. . . .. . . . . 8
2 .0
Method of Manufacture (Confidential) . .... .. . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .... ............ .. ..-. .. . . 9
2 .1
Process Description (Confidential) .. .. ... .. .. .. .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. .... .... .......... .... .. . . 9
BeneFlaXTm Flax Lignans Process Flowchart (Confidential) . . . . . . . . . . . . . .. . . .. .. .. ............ .. 10
22
Intended Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. ....... .. .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ............ l l
3 .0
4.0
Product Safety Information . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .... . .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .... ........ 11
4.1
Absorption, Distribution, Metabolism and Excretion .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ...... 13
Lignan metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. .. ..... .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. 13
4.1 .1
4 .1 .2
4.1 .3 .
4.2
4 .3
Dose response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ..... .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. 14
Distribution of metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ... .. .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Genotoxicity Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. ..... .. .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Mutag,enicity Study of BeneFlaXTm Flax Lignans (Confidential) .... .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Animal Studies ... .... .. .. .. .. . . .. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... ....... .. ... . . . . . . . . . . . . . . . . . . . . . . 18
4 .4
4 .4 .1
Rat feeding study using BeneFlaXTm Flax Lignans (Confidential) .. . . .. . . . . . . . . . . . . . . . . . 18
4 .4 .2 .
Animal studies using flaxseeds or flax lignans . . . . . . . . . . . . . . . . . . . . . .. .. .. ..... .... .. . . .. . . . . . . . . . . . 20
4 .5
Human Studies . .. .... .. .... .. .................. .... .. . . .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ..... .. .. . . . . . . . . . . . 20
4.5 .1
Clinical studies using flaxseeds or flax lignans . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ..... .... .. .. .. . . . . . 20
4 .5 .2
Clinical studies using BeneFlaXTm Flax Lignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ..... .... .. .. . 23
5 .0
C'onclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. ...... ...... .. .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . ........... .. . 24
6.0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. .... .. ...... .... .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .......... 27
Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ................ .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .... 32
7.0
0
BeneFlaxT" Flax Lignans NDI
Page 2/32
0
1 .0
Product Description
1 .1
Flaxseed Lignans
Flaxseed libnarls are derived firom [lie seed of the flax (Linwm usitatis.sirvusn) plant or
linseed plant as it is colnmoiily knoU,7i.
The overall composition of whole flaxseed
consists of fat (169,o), proteul (24",,0), carbohWrate (24~'0), fiber !,6°,'0), ~~~ater (5 .5°0) and ash
(; .4(?«) as reported by Prasad, 2000a.
Flax is one of the richest sources of plant lignans, and is particularly rich in the lignan,
2,3-bis(3-methoxy-4-hydroxybenzyl)butane-l,4-diol which is commonly referred to as
secoisolariciresinol (SECO) which occurs naturally in flaxseed as a diglueoside, p-DGlucopyranoside, 2,3-bis[(4-hydroxy-3-methoxyphenyl)methyl]-1,4-butanediyl bis,[P,(R*,R*)] which is commonly known as SDG . Besides SDG, flax also contains small
amounts of the lignans matairesinol, pinoresinol and isolariciresinol . Lignans are found
in pumpkin seeds, fiber-rich plants, including grains such as wheat, barley and oats ;
legumes such as beans, lentils and soybeans ; and vegetables such as garlic, asparagus,
broccoli and carrots. Lignans are phenolic. compounds formed by the union of two
cinnamic acid residues . They are related to lignins in that their synthesis is presumed to
occur by a similar pathway; however it is probable that lignans are by-products of the
pathway for lignin synthesis . Lignin is one of the most abundant organic substances
found arid consequently almost all plants may potentially contain the derivative lignans
(Setchell, 1995).
The analyzed lignan content of flaxseeds are affected by variety, location, crop year,
extraction method, hydrolysis and analytical techniques . The SDG content in flax
products has been reported to contain 29-1055 mg/100g seed, 200-1300 mg/100g
flaxseed diet, 200-1300 mg/100g (Thompson, 2003), 600-1800 mg/100g seed (Prasad,
2OOOa) ;, 370 mg/100g seed (Mazur et al ., 1996), 228 mg/100g seed (Degenhardt et al.,
2:002) and 82 mg/100g seed; 226 mg/100g flax meal (Obermeyer et al., 1995) . SDG
"
content range from 0.96-3 .15 pmoles/g (equivalent to 66-216 mg/100g) in ten varieties of
flax (Thompson et al., 2000). Johnsson et al ., (2000) analyzed SDG from fourteen
Swedish and fifteen Danish flax cultivars and reported that the SDG ranged from 1170BeneFlaxT" Flax Lignans NDI
Page 3/32
2410 mg/100g in defatted flour versus 610-1330 mg/100g in the seed .
is
Milder et al
(:?005) reported 294 mg SECO /100g 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 liE;naus have been reported to have antitw»our, antimitotic, antioxidant and weak
e,trogenic activities (ti'(acRae and Towers . (984 ; Prasad, 2000b) . Thompson and Ward
(2002: puuhlcche(l pczper in ,9pperlcli.r- t'I) in their review on the health benefits,
bioa\ailabiiity and safety of flaxseed li`mauls, reported that the metabolism and
~ Ta It,ability
I I of lignans
I
Iin 1 2 .5-10`0 flaxseed diet or of equivalent levels of purified
lignans (i .e. SDG), as seen in aninnal and human studies, are sufficientlv high to produce
health benefits . The benefits rnay include reduction of cancer risk, cardiovascular disease,
diabetes, kidney disease, osteoporosis and menopausal symptoms and improvement of
prostate and BPH condition . Rickard et al (1996) reported the following amount of
flaxseed diet fed to rats : 2 .~"o flaxseed diet or ( .l pmole SDG,'day, 5°o flaxseed diet or
2 .2 Eamole SDCiiday and 10°~~ flaxseed diet or 4.4 pmole SDGiday . The SDG levels of
these flaxseed diets are eyumalent to 0.76 . 1 ._51 and 3 .02 mg/day respectively. Using the
average weight 227g of the rats used in this study the consumption of SDG by the rats
~vould be equivalent to 3 .315, 6 .65 and t33 mg%l<g body weight per day .
This will be
equi\-alent to 235, 466 and 930 mg/day for a human adult weighing 701<g .
Flaxseed lignans, in particular SDC7, are precursors which are metabolized by the
bacterial
flora in
the colon of humans
and animals
to the marnmalian
lignans
enterolactone (EL) and enterodiol (ED) (Axelson et al ., 19R2) . The metabolic pathway is
slho\N n in .AI)pendir 1.
1 .2
Common Name
Natural flax lignan complex whose major lignan component found is SDG
(Secoisolariciresinol Diglucoside) .
0
BeneFlaxT"' Flax Lignans NDI
Page 4/32
1 .3
"
Trade Name
The product being notified will be marketed as BeneFlaxTM Flax Lignans by
Archer Daniels Midland Company (ADM) .
1 .4
Scientific Name
The chemical name for SDG, the major lignan component of BeneFlaxT'" Flax
Lignans is (3-D-Glucopyranoside, 2,3-bis[(4-hydroxy-3-methoxyphenyl)
methyl ]-1,4-butanediyl bis-,[R-(R*,R*)]
1 .5
"
Formula :
C32 H46 O16
Molecular weight :
686 .7
CAS number:
158932-33-3
Properties of BeneFlaxT"' Flax Lignans
Table 1
Form:
Color:
Odor :
-
Taste
Solubility :
Hygroscopicity:
1 .6
powder
brown
"tea" like aroma
"tea" like flavor
- Slightly soluble in water at neutral pH,
- Moderately soluble in 70% ethanol
low
Product Specifications
BeneFlaxT"11 Flax Lignans NDI
Page 5/32
'Table 2- BeneFlaxT"' Flax Lignans Product Specifications
Appearance
Total flax lignan (SDG'), %, as is
Protein, (%N x 625), as is
Fat, %, as is
Moisture, °io
Heavy rnetals ;, Min
:Standard plate count, per gram
Yeast and mold, per gram
Coliforrns, per 10 grams
E. coli, per 10 grams
Salmonella, per 10 grams
Staph . aurcus, per 10 grams
!Particle size, mesh, °ro through #40
"
1 .6 .1
Batch Analyses
The product analyses of 5 representative batches of BeneFlaxT"' Flax Lignans are shown
E.n the following Table 3 .
"
BeneFlaxT" Hax Lignans NDl
Page 6/32
Table 3 - Product analysis of 5 representative batches of BeneFIaxT"" Flax Lignans
"
"
1 .6.2
Labeling :
BeneFlax7"' Flax Lignans (containing 35% SDG) .
1 .6.3
Packaging :
20 kg net (441b) polylined, poly drums
5 kg net (1 1 lb.) polylined, poly drums
1 kg net (22 lb) polylined, poly drums
BeneFlax"' Flax Lignans NDI
Page 7/32
1 .6.4
-
Storage and shelf life :
E3eneFlax TM Flax Lignans is a powder which is packaged in sealed double polyethylene
bags and placed inside a fiber drum . These drums are stored under cool and dry condition
in the warehouse to prevent contamination with atmospheric moisture and microbial
organisms . A shelf life of three years is expected with storage at room temperature i .e .
below 77° F (25° C) as shown n Table 4, below.
Table 4- Shelf life data of BeneFlaxTM Flax Lignans
SDG content (mg)
500 r
-* - 4 Deg C -M- Room Temp
400
"
300
200
100
0
O~ O~
~`a'~'~`~{.
O~
O~
O~
O~
iz;v
iz;v
qz;v
Oti
I~v
ON'
O~
O~
O~
O~
O~
O~
O~`
Time (months)
0
BeneFlaxT" Flax Lignans NDl
Page 8/32
O~`
.
PAGES 9
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SECRET
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0
"
3 .0
Intended Use
BeneFlaxTM Flax Lignans is intended for use as ingredient in dietary supplements.
Recommended dose per day is approximately 860-1720 mg of the BeneFlaxTM
Flax
Lignans product which is equivalent to providing 300-600 mg of SDG .
4 .0
Product Safety Information
Numerous commercial 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 flax products are regularly consumed as foods or dietary supplements .
The conversion of flax lignans containing secolariciresinol diglucoside (SDG) to
enterodial (ED) and enterolactone (EL) for distribution, absorption and excretion in the
body will be discussed in the next section 4 .1 .
Genotoxicity, mutagenicity, animal and human studies on flaxseed and/or flax lignans
have shown absence of adverse effect or safety concerns . These studies including studies
using BeneFlaxTM Flax Lignans will be discussed in the following sections : 4 .2, 4 .3 and
4. .4, respectively .
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 II) .
An extensive literature search was conducted on "flaxseed and lignans, toxicity or safety
or adverse effect" using CAPLUS and MEDLINE database (Appendix II1). 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 .
A literature review was conducted on 43 key studies (19 human studies and 23 animal
studies) . The summary of each study is shown on Appendix IV.
BeneFlaxTm Flax Lignans NDI
There were no reported
Page 11/32
toxicology or adverse effects .
Some of the selected animal and human studies are
discussed in sections 4.4.2. and 4 .5 .1
A .n independent review on the potential estrogenicity of SDG flax lignans extract
concluded that the data from the rat study using BeneFlaXTm Flax Lignans (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 V). These data are supportive of the safety of flax lignans reported in the
literature.
P~~ potential safety concern of flaxseeds is the cyanogenic glycoside levels which may
give rise to potential safety concerns . The total cyanogenic glycosides content
(comprising of linamarin, linustatin and neolinustatin) ranged from 365-550 mg per 100
grams of seeds in ten flax cultivars (Mazza and Oomah, 1995) and was also reported to
be 457 mg per 100 grams of whole flaxseeds by Jenkins, 1995 ( published paper in
Appendix VI). Jenkins (1995) also showed a lower content of cyanogenic glucosides in
S
baked products. Virtually no cyanide was detected on boiling either a homogenate or the
flaxseeds before analysis (Chadha et al . 1995). The decrease in cyanide on boiling and
lower cyanogenic glycosides content in baked flaxseed products indicates these
glycosides are labile to heat .
Consumption of up to 50 grams per day of milled flaxseeds or partially defatted flaxseeds
incorporated in foods tested in human studies (Cunnane et al., 1993 ; Mazza and
Biliadaris, 1989 ; Jenkins et al., 1999) have not been not associated with toxicity
symptoms in adults which indicated that cyanogenic compounds in this amount of
flaxseed seem likely to be well tolerated (Jenkins, 1995 ; published paper in Appendix
L'I). BeneFlaXTm Flax Lignans contains about 50 mg of total cyanogenic glycosides per
100 grams of product (Table 3). When BeneFlaXTm Flax Lignans is consumed at the
intended dose of up to 2 grams a day as described in Section 3, the estimated amount of
cyanogenic glycosides intake
is about 1 mg
per day compared to about 229 mg
estimated from the consumption of 50 grams of whole flaxseeds per day (Jenkins, 1995) .
This very low level of cyanogenic glycosides in BeneFlaXTm Flax Lignans consequently
does not raise a safety issue.
BeneFlaxT"' Flax Lignans NDI
Page 12/32
4.1
Absorption, Distribution, Metabolism and Excretion
The analysis, metabolism and bioavailability of flaxseed lignans has been reviewed by
T'hompson (2003; published paper in Appendix VI) . and Thompson and Ward (2005 ;
published paper in Appendix VI) .
4.1 .1
Lignan metabolites
It: is established that plant lignans such as SDG and matairesinol are converted to the
mammalian lignans ED and EL by the bacterial flora in the colon (Setchell, 1995 ;
Appendix I). These mammalian lignans undergo enterohepatic circulation with a portion
reaching the kidney and excreted in the urine (Setchell, 1995 ; Axelson and Setchell,
1981).
Urinary excretion of ED and EL has been used as indicators of production and
availability of mammalian lignans in animals and humans (Setchell, 1995; Lampe et al.,
1994 ; 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; published paper in
Appendix VI) .
Although ED and EL are the main mammalian lignans analyzed in urine, other
metabolites have recently been identified (Jacobs and Metzler, 1999). ED has been
shown to be metabolized in vitro by rat liver microsomes to three aromatic and four
aliphatic monohydroxylated compounds and the 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
(l0 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,
BeneFlaxT" Flax Lignans ND[
Page 13/32
2000), only ED, EL, secoisolariciresinol (SECO ; aglycone of SDG), and four other
is
unidenti fied metabolites, none of 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 nonradioactive flaxseed or SDG (Rickard and Thompson, 2000) . The
other metabolites from SDG, ED or EL, although formed, may have been present at too
low a level to be detectable .
4 .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, 22, and 4 .4 mol SDG/day) equivalent to the amounts
consumed in the 2.5, 5, and 10% flaxseed diet (Rickard et al., 1996) . The urinary lignans
leveled off after an intake of 2 .2 mol/day. In agreement with the rat study, a dose-related
0
linear increase in urinary lignans (ED + EL + SECO) excretion was observed in
premenopausal women fed 0, S, 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 is equivalent to an intake of -25 g flaxseed by humans, thus no
leveling off of urinary lignan excretion was observed .
4 .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 pmole/kg body weight) (Kuijsten et al.,
2005 ; published paper in Appendix VI). 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%)
is
as EL. This study concluded that the levels of enterolignans in plasma are good
biomarkers of lignan exposure .
BeneFlax'"' Flax Lignans NDI
Page l4/32
Zhang (2005a) conducted a clinical trial to study the effect of dietary flaxseed lignans
(using BeneFlaxTM Flax Lignans) on plasma lipids in hypercholesterolemic subjects in
China . The blood data showed that ED and EL reached steady state after 4 weeks of daily
consumption of either 300 mg or 600 mg SDG of dietary flax lignans (using BeneFlaxTM
Flax Lignans) indicating no significant accumulation of these metabolites in plasma .
Other parameters observed in the blood data are discussed in details later in Section 4.5.2.
The body distribution and excretion of the SDG metabolites was determined at various
times for up to 48 h 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 lignans (Jenab and Thompson, 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
SEC,O with minor amounts from four unidentified lignan metabolites (Huchins 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,
c~ecum, and colon), but the highest levels were found in those involved in lignan
metabolism, i.e . gastrointestinal tissues (3-7°io of recovered dose), the liver, and kidney
(levels 5 times higher than other non gastrointestinal tissues (Rickard and Thompson,
10
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
BeneFlaxT-`" Flax Lignans NDI
Page 15/32
that the effect of lignans is not only through their direct binding to this tissue .
Phytoesterogens 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 ER(3 when compared to 1) estrogen 17(3-estradiol (E2)
which has a RBA of 107 on ERa and 82 on ERR and, 2) synthetic estrogen
diethylstilbestrol (DES) which has a RBA of 100 on ERa and 100 on ER(3 .
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 pmol/L 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 12-hour time point, in the acute group (Rickard and
Thompson, 2000). Similar results were obtained in premenopausal women fed 25g raw
!
flaxseed once (acutely) or daily far 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 lignan sources,
once a day, may be sufficient to maintain plasma lignan concentrations .
4.2
Genotoxicity Study
Flax lignans were tested for genotoxicity because of their chemical structural similarity to
diethylstilbestrol, a known carcinogen (Metzler et al., 1998) . EL, ED, matairesinol, and
SECO were tested at 200 umol/L on cell-free microtubule assembly and at 100 pmol/L in
cultured male Chinese hamster V79 cells at five different genetic end points, i.e.
disruption of the cytoplasmic microtubule complex, induction of mitotic arrest, induction
of micronuclei and their characterization by CREST staining, and mutagenicity at the
hypoxanthine phosphoribosyltransferase (HPRT) locus Kulling, et al., 1998)
Results
showed no aneuploidogenic and clastogenic potential at the levels of lignans used
BeneFlaxT" Flax Lignans NDI
Page 16/32
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4.4.2.
Animal studies using flaxseeds or flax lignans
A summary of the literature review on animals studies using flaxseeds or flax lignans are
listcd in Appendix IV. Some notable studies are mentioned below.
Exposure of offsprings in rats to lignans at a level of 10% flaxseed diet during lactation
or postweaning produced no adverse effects on reproductive indices (Tou et. al, 1998;
l')99) .
Exposure: of flaxseed (10% diet) or its purified lignan (equivalent to 1 .772 mg
SDG per g flaxseed ) during suckling only or continuously did not alter reproductive
indices in male and female offspring rats (Ward et al ., 2001).
"
Four week supplementation of a diet with flaxseed (2 .5, 5, or 10%) or the equivalent SDG
(0 .75, 1 ._5 or 3 .0 mg/day) fed to rats were observed to be antiestrogenic without gross tissue
toxicity (Orcheson et al ., 1998) .
4.5
Human Studies
The summary of literature review on human studies using flaxseeds or flax lignans is
listed in .Appendix IV. Some notable studies are discussed in the following section, 4.5 .1 .
Clinical studies using BeneFlaxTM Flax Lignans will be discussed in section,
4 .5 .2 .
4 .5.1
Clinical studies using flaxseeds or flax lignans
Morris (2004) in her review on the health and nutrition aspects of flax did not find any
toxic or adverse effects resulting from the consumption of flaxseeds or flaxseed lignans .
BeneFlax-l ^' Flax Lignans NDi
Page 20/32
Thompson et al ., (2000) reported that feeding 25g flaxseed in a muffin formulation to
patients with newly diagnosed breast cancer from the time of diagnosis to the time of
surgery resulted in significantly lower tumor cells proliferation compared with those fed
the placebo muffin without flaxseed. Human subjects consuming SOg flaxseed per day
have shown no effects on vitamin B6 or metabolism (Cunnane et al., 1993 ; Mazza and
Etiliadaris, 1989). Consumption of SOg 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 SOg of flaxseed diet would equate to 650 mg when calculated from the
highest level of SDG (1330 mg/100g) reported by Johnsson (2000) .
Results ftom 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 .3g )
confirm the safety of flaxseed observed in these human studies (Ratnayake et. al ., 1992).
T'hompson and Ward (2002) in their review on the health benefits, bioavailability and
41
safety of flaxseed lignans, reported that the metabolism and availability of lignans in a
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) . As discussed in Section 1 of this document,
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
grams raw flaxseed or 25 g processed flaxseed cooked into a muffin or bread for 7 days
to examine (ignan urinary excretion in a randornized cross-over study. The raw flaxseed
contained 2.93 fcmol SDG/g (201 mg/100g) 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 report of
adverse effects during the trial .
BeneFlaxT'I' Flax Lignans NDI
Page 21/32
H[utchins, 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, crossover trial to examine urinary excretion of metabolites. Consumption of flaxseed
s Ii Igniificantly increased the excretion of enterodiol, enterolactone, and total lignans in a
linear, dose-responsive manner. No record of adverse effects 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 .7g 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.,
(?_002) 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 diet 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 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 hypercholesterolemic 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
is
samples were collected for analysis a baseline and at the end of the treatment period .
Fhytoestrogens, estrogen metabolites, and serum hormones were analyzed, as well as,
serum and urine biochemical markers of bone metabolism. No significant change in
BeneFlaxT"' Flax Lignans NDI
Page 22/32
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 .
4 .5.2
C,'linical studies using BeneFlaxTM Flax Lignans
ADM sponsored a recent clinical trial in China (Zhang, 2005a) to study the effect of
dietary flaxseed lignans (using BeneFlaxTM Flax Lignans) on plasma lipids in
hypercholesterolemic subjects
(20 women; 35 men, ages 28-79) using a randomized,
placebo controlled double blind design for 8 weeks.
BeneflaxTM Flax Lignans was
formulated into dietary supplement tablets to provide the following equivalent dosage of
SDG in the amount of 0 mg (placebo), 300 mg or 600 mg administered to each subject
per day respectively . Total cholesterol (TC) and low density lipoprotein cholesterol
(LDLC) were significantly reduced for the 300 mg and 600 mg SDG treatment doses
when compared to the placebo. Levels of creatinine, blood urea nitrogen (BUN), alanine
aminotransferase (ALT) and gamma glutamyl transferase (GGT) were observed to be
similar among treatment groups and all these parameters are within normal range (Table
5). This demostrates that BeneflaxTM Flax Lignans has no noticeable adverse effect on
kidney or liver function .
Z;hang (2,OOSb) also conducted another clinical trial in China to study the effect of dietary
flaxseed lignans (using BeneFlaxTx` Flax Lignans) on benign prostatic hyperplasia (BPH)
in 60 men who have had the BPH condition. A randomized placebo controlled double
blind design was used.
The amount of BeneFlaxTM Flax Lignans was formulated in
dietary supplement tablets to provide 0 mg (placebo), 300 mg or 600 mg SDG daily doses
for the subjects over a period of 4 months . Levels of creatinine, blood urea nitrogen
(BUN), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in blood
were measured at 0, 2 and 4 months . There were no difference in concentration levels of
these parameters among the treatment groups . The results of this study also indicate that
BeneFlaxTM Flax Lignans did not adversely affect kidney or liver function (Table 6).
.
In the literature, Hallund et al. (2005) reported that six weeks consumption of a low fat
muffin enriched with a flax lignan complex (BeneFlaxT"' Flax Lignans), which provides
BeneFlax''" Flax Lignans ND[
Page 23/32
500 mg SDG per day significantly increased serum enterolactone (EL) and urinary EL
excretion in healthy postmenopausal women, but had no effect on plasma lipid
49
concentrations, serum lipoprotein oxidation resistance or plasma antioxidant capacity .
The study was performed on twenty-two women using a randomized double blind
placebo controlled crossover design . No noticeable adverse effects were observed .
5 .0
Conclusion
The product characteristics and quality specifications of BeneFlaxTM Flax Lignans have
been established. The safety of BeneflaxTM Flax Lignans has been demonstrated by
evaluating the product in a mutagenicity study, rat feeding study and three human clinical
studies conducted by independent investigators. A thorough literature review of animal
and human studies using flaxseeds or flax lignans showed the absence of any adverse
effects by lignans . There were no adverse events reported by the FDA on products
containing flax lignans which are already in the market.
0
The information contained in this NDI dossier forms the basis on which Archer Daniels
Midland Company has concluded that BeneFlaxTM Flax Lignans containing SDG will
reasonably be expected to be safe as a new dietary ingredient for introduction in the U.S .
market.
0
BeneFlaxT~ Flax Lignans NDI
Page 24/32
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6 .0
References
Axelson, M. and Setchell, KDR, 1981 . the excretion of lignans in rats- evidence for an
intestinal bacterial source for this new group of compounds . FEBS Letters,
vol . 123, number 2, pp 337-342 .
Pixelson, M., Sjovall, J ., Gutafsson, BE, Stetchell, KDR. 1982 . Origin of lignans in
mammals and identification of a precursor from plants . Nature 298 :659-660 .
E3hathena SJ, Velasquez MT . 2002 . Beneficial role of dietary phytoestrogens in obesity
and diabetes . Am. J. Clin . Nutr. 76 : 1191-1201 .
Bowen, P .E. 2001 . Evaluating the Health Claim of Flaxseed and Cancer Prevention .
Nutrition Today 36(3):144-158 .
Brooks, Jennifer D ., Ward, Wendy E., Lewis, Jacqueline E., Hilditch, John, Nickell,
Leslie, Wong, Evelyn, and Thompson, Lilian U. 2004 . Am. J. Clin . Nutr.
79:318-325 .
"
Chadha, R.K ., Lawrence, J.F ., and Ratnayake, W.MN., 1995 . Ion chromatography
determination of cyanide released from flaxseed under autohydrolysis conditions .
Food Additives and Contaminants, vol. 12 No . 4, 527-533 .
Chen, J ., Tan, KP, Ward, WE . and Thompson, LU. 2003 . Exposure to Flaxseed or its
Purified Lignan during Suckling Inhibits Chemically Induced Rat Mammary
T'umorigenesis . Exp. Biol . Med. 228 :951-958 .
Covance, 2002 . Mutagenicity study and a 13-week oral gavage feeding study in
rats using the BeneflaxTM Flax Lignans as the test article. Confidential
client report for the Archer Daniels Midland Company. (Unpublished)
Cunnane, S.C ., Ganguli, S ., Menard, C ., Liede, A.C ., Hamadeh, M.J., Chen, A.-Y.,
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Hallund, J ., Ravn-Haren, G., Bugel, S ., Tholstrup, T. and Tetens, I. 2005 . A lignan
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(unpublished).
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Postmenopausal Women. Cancer Epidemiology, Biomarkers & Prevention
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Jacobs, F;., and Metzler, M. 1999. Oxidative metabolism of mammalian lignans
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Food Chem. 47, 1071-1077 .
Jacobs, E., Kulling, S .E ., and Metzler, M. 1999 . Novel metobolites of the mammalian
lignans enterolactone and enteroldiol in human urine. J. Steroid Biochem. Mol.
Biol, 68, 211-218.
Jenab, M[ ., and Thompson, L.U . 1996. Influence of flaxseed and lignans on colon
carcinogenesis and beta-glucuronidase activity . Carcinogenesis 17, 1343-1348.
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increase cecal beta-glucuronidase activity inrats . Nutr. Cancer 33, 154-158 .
Jenkins, D.J.A., 1995 . Incorporation of flaxseed of flaxseed components into cereal foods .
Chapter 10 . In "Flaxseed in Human Nutrition." Editors: Cunnane, S. and
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"
Jenkins, D.J.A . . Kendall, C.W .C ., Vidgen, E., Agarwal, S ., Rao, A .V ., Rosenberg, R.S .,
L)iamandis, E.P., Novokmet, R., Mehling, G.C ., Perera, T., Giffiin, L .C., and
Cunnane, S . 1999 . Health aspects of partially deffated flaxseed, including effects
on serum lipids, oxidative tneasures, and ex vivo androgen and progestin activity :
a controlled crossover trial, Am J Clin Nutr 69 :395-402 .
Johnssoti, P ., Kamal-Eldin, A., L., Lennart, N., and Aman, P. 2000. HPLC Method for
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48 :5216-5219 .
Kuijsten, A., Arts, I.C .W., Vree, T.B . and Hollman, P.C .H . 2005 . Pharmacokinetics of
enterolignans in healthy men and women consuming a single dose of
secoisolariciresinol diglucoside. J. Nutr. 135 : 795-801 .
Kulling, S .E., Jacobs, E., Pfeiffer, E ., and Metzler, M . 1998 . Studies on the Genotoxicity
of the Mammalian Lignans Enterolactone and Enterodiol and their Metabolic
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Lampe, J.W ., Martinie, M.C., Kurzer, M.s ., Adlercretz, H ., and Slavin, J.L., 1994.
Urinary lignans and isoflavonoid excretions in premenopausal women consuming
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Lucas, EA., Wild, RD, Hammond, LJ, Khalil, DA., Juma, S., Daggy, BP, Stoecker, BJ,
and Arjmandi, BH 2002 . Flaxseed Improves Lipid Profile without Altering
Biomarkers of Bone Metabolism in Post-menopausal Women. The Journal of
Clinical Endocrinology & Metabolism . 87(4):1527-1532 .
MacRae, W.D ., Towers, G.H .N . 1984. Biological activities of lignans. Phytochemistry
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Food Sci. 54:1302 .
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In "Flaxseed in Human Nutrition ." Editors : Cunnane, S . and
Thompson, L.U . Published by AOCS Press .
Mazur, `V., Fotsis, T., Wahala, K. Ojala, S ., Salakka, A., Adlercreutz, H . 1996 . Isotope
dilution gas chromatographic-mass spectrometric method for the determination of
isoflavonoids, coumestrol, and lignans in food samples . Analytical biochemistry
233 :169-180 .
Meagher, LP. . and Beecher, UR. 2000. Assessment of Data on the Lignan Content of
Foods . Journal of Food Composition and Analysis. 13 :935-947 .
0
Metzler, M., Kulling, S.E ., Pfeiffer, E ., and Jacobs, E. 1998 . Genotoxicity of Estrogens.
Z . Lebensm .-Unters.-Forsch A 206,367-373 .
Mueller, S .O ., Simon, S ., Chae, K., Metzler, M. and Korach, K.S . 2004 . Phytoestrogens
and their human metabolites show distinct agonistic and antangonistic properties
on estrogen receptor a (ERa) and ER(3 in human cells. Toxicological Sciences 80,
14-25.
Muir, A.TJ. and Westcott, N.D ., 2000 . "Quantitation of the lignan secoisolariciresinol
diglucoside in baked goods containing flax seed or flax meal", J Agric Food
C'hem. 2000, 48, 4048-4052 .
Neimeyer, H.B., Honig, D ., Lange-Bohern, A., Jacobs, E., Kulling, S.E ., and Metzler, M.
2000. Oxidative metobolites of the mammalian enterolactone and enterodiol in rat
bile and urine. J. Agric. Food Chem 48, 2910-2919 .
Nesbitt, PD., Lam, Y, and Thompson, L . 1999 . Human metabolism of mammalian
lignan precursors in raw and processed flaxseed . Am. J. Clin. Nutr. 69: 549-555 .
Obermeyer, W .R., Musser, S.M., Betz, .T.M., Casey, R.E., Pohland, A.E. and Page,
S .W . 1995 . Chemical Studies of Phytoestrogens and Related Compounds
in Dietary Supplements : Flax and Chaparral (43824) . P.S.E .B.M. 208 :6-11
40
C)rcheson, J .J., Rickard, S.E ., Seidl, M.M. and Thompson . L .U. 1998. Flaxseed and its
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in rats . Cancer Letters 125, 69-76 .
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Prasad, K. 1999 . Reduction of Serum Cholestrol and Hypercholesterolemic
Atherosclerosis in Rabbits by Secoisolariciresinol Diglucoside Isolated from
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metabolites, secoisolariciresinol, enterodiol, and enterolactone. Int'1 Journal of
Angiobiology, 9: 220-225 .
Prasad, K. 2000b. Flaxseed : A Source of Hypocholesterolemic and Anti-atherogenic
Agents. Drug News Perspect 13(2):99-104 .
Prasad, K. 2005 . Hypocholesterolemic and antiatherosclerotic effect of flax lignan
complex isolated from flaxseed . Atherosclerosis 179:269-275 .
Ratnayake, M.W.N., Behrens, W .A ., Fisher, P .W.E., L'Abbe, M.R., Mongeau, R. and
Beare-Rogers, J.L. 1992 . Chemical and nutritional studies of flaxseed (variety
I.inott) in rats . J. Nutr. Biochem. 3:232 .
Rickard. S .E., Orcheson, L.J., Seidl, M .M ., Luyengi, L ., Fong, H .H ., and Thompson, L.U.
1996. Dose-dependent production of mammalian lignans in rats and in vitro from
the purified precursor secoisolarisciresinol diglucoside for flaxseed. J. Nutr . 126,
2,012-2019 .
Rickard S .E. and Thompson L .U . 1998 . Chronic exposure to secoisolariciresinol
diglycoside alters lignan disposition in rats . J Nutr 128 : 615-623 .
Rickard., S .E. and Thompson L.U . 2000 . Urinary composition and postprandial blood
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eds) pp . 82-89, AOCS Press, Champaign, Illinois .
Stuglin, C. and Prasad, K. 2005 . Effect of flaxseed consumption on blood pressure,
serum lipids, hemopoietic system and lever and kidney enzymes in healthy
humans. J. Cardiovasc . Pharmacol . Therapeut. 10(l):23-27 .
'ran, KP, Chen, J, Ward, WE, and Thompson LU. 2004 . Mammary gland morphogenesis
is enhanced by exposure to flaxseed or its major lignan during suckling in rats.
Exp Biol Med 229 : 147-157.
Thompson, L.U., 2003 . Analysis and bioavailability of lignans . Hapter 4. In Flaxseed in
Human Nutrition . Editors : Cunnane, S.S ., and Thompson, L.U ., eds) pp . 92-116,
AOCS Press, Champaign, Illinois .
"
Thompson, LU., Rickard, SE ., Cheung, F., Kenaschuk, EO., and Obermeyer, WR. 1997
Variability in Anticancer Lignan Levels in Flaxseed. Nutrition and Cancer
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7Chompson, L.U ., Li., T ., Chen, J. and Goss, P .E. 2000 . Biological Effects of
Dietary Flaxseed in Patients with Breast Cancer. Breast Cancer Res Treat. 64,50
(abstract) .
Thompson, LU and Ward WE. 2002 Chapter 22. Flaxseed Lignans : Health Benefits,
Bioavailability and Safety . In Phytoestrogens and Health . Editors: Gilani, G . S.
and Anderson, J.J.B . AOCS Press, Champaign, Illinois, pp 405-426.
Thompson LU. 2003 . Analysis and bioavailability of lignans . In: Flaxseed in Human
Nutrition, eds Thompson LU and Cwmane SC, 2nd ed, AOCS Press, Champaign,
IL, pp . 92-116.
Tou, J.C ., Chen, J. and Thompson, L.U . 1998 Flaxseed and Its Lignan Precursor,
Secoisolariciresinol Diglucoside, Affect Pregnancy Outcome and Reproductive
Development in Rats, J. Nutr. 128,1861-1868 .
'l['ou, J.C ., Chen, J. and Thompson, L.U. 1999. Dose, Timing, and Duration of Flaxseed
Exposure Affect Reproductive Indices and Sex Hormone Levels in Rats . J.
Toxicol. Environ. Health 56,555-570 .
"
Ward, W.E ., Chen, J ., and Thompson, L .U . 2001 . Exposure of flaxseed or its purified
lignan SDG during suckling only or continuously does not alter reproductive
indices in male and female offspring rats . J. of Tox and Environ . Health,
Fart A 64 : 567-577 .
`Vestcott, ND . and Muir, AD., 2000 . Overview of flax lignans . Inform 11 :118-121 .
Xie LH, Ahn EM, Akao T, Abdel-Hafez AAM, Nakamura N, and Hattari M. 2003 .
Transformation of arctin to estrogenic and antiestrogenic substances by human
intestinal bacteria. Chem Pharm Bull 51(4) : 378-384 .
Wang, L,.Q . 2002 . Mammalian phytoestrogens : enterodiol and enterolactone . J. of
Chromatography B, 777, 289-309 .
Zhang, W . 2005a. Effects of dietary flaxseed lignans on plasma lipids . (personal
communication) .
Zhang, \7V . 2045b . Effect of dietary flaxseed lignans on benign prostatic hyperplasia
(BPH). (personal communication) .
0
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7 .0
Appendices
Appendix I:
Metabolic pathway of SDG conversion to enterolactone and enterodiol.
Appendix II:
Online search of FDA website on flaxseeds and flaxseed lignans.
Appendix III: MEDLINE and CAPLUS literature search on flaxseed lignans safety and
toxicity.
Appendix IV: Summary of literature review, on animal and human studies using
flaxseeds or flax lignans.
Appendix V:
Independent report on "The potential estrogenicity of SDG flax lignan
extract" .
"
Appendix VI : Selected key articles cited in this NDI dossier
1.
Mazza, G. and Oomah, B .D., 1995 Flaxseed, dietary fiber, and
cyanogens . Chapter 4. In "Flaxseed in Human Nutrition ." Editors :
Cunnane, S . and Thompson, L.U. Published by AOCS Press .
2 . Jenkins, D.J.A . 1995 . Incorporation of flaxseed of flaxseed
components into cereal foods. Chapter 10 . In "Flaxseed in Human
Nutrition." Editors : Cunnane, S . and Thompson, L.U. Published by
AOCS Press.
3.
Thompson L.U. 2003 . Thompson LU . 2003 . Analysis and
bioavailability of lignans . Chapter 4 . In: Flaxseed in Human Nutrition,
Editors : Thompson L.U. and Cunnane SC, 2nd Edition, AOCS Press
4 . Thompson, L.U . and Ward, W.E. 2002 Chapter 22 . Flaxseed Lignans:
Health Benefits, Bioavailability and Safety . In Phytoestrogens and
Health . Editors : Gilani, G .S. and Anderson, J .J.B . AOCS Press .
5 . Wang, L .Q . 2002 . Mammalian phytoestrogens : enterodiol and
enterolactone. J. of Chromatography B, 777, 289-309.
"
6 . Kuijsten, A ., Arts, I.C .W ., Vree, T.B . and Hollman, P .C .H . 2005 .
Pharmacokinetics of enterolignans in healthy men and women
consuming a singe dose of secoisolariciresinol diglucoside . J. Nutr.
135 : 795-801 .
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