(cid:38)(cid:68)(cid:83)(cid:86)(cid:88)(cid:74)(cid:72)(cid:79)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:20)(cid:19)(cid:19)(cid:24)
`
`Page 1 of 34
`
`

`

`WW.
`.
`‘t
`
`f {( DEPARTMENTOFHEALTH&HUMANSERVICES
`PublicHealthService
`a,“ C ————————~————-———m
`
`
`
`Food and Drug Administration
`Washington. DC 20204
`
`AUG 2 4 [999
`
`John C. Young
`Director, Regulatory Affairs — Nutritionals
`McNeil Consumer Healthcare
`
`7050 Camp Hill Road
`Fort Washington, Pennsylvania 19034—2299
`
`Dear Mr. Young:
`
`This is to notify you that your submission pursuant to section 413(a)(2) of the Federal Food,
`Drug, and Cosmetic Act (the Act) dated August 19, 1999, concerning the marketing of a
`substance that you assert is a new dietary ingredient (i.e., plant stanol esters) was received by
`the Food and Drug Administration (FDA) on August 20, 1999. Your submission will be kept
`confidential for 90 days from the date of receipt, and after November 2, 1999, your
`submission will be placed on public display at Dockets Management Branch (Docket No.
`953-0316). Commercial and confidential information in the notification will not be made
`available to the public.
`'
`
`Please contact us if you have questions concerning this matter.
`
`Sincerely,
`
`WWbert J. Moore, Ph.D.
`
`Senior Regulatory Scientist
`Division of Programs and Enforcement Policy
`Office of Special Nutritionals
`
`Page 2 of 34
`
`Page 2 of 34
`
`

`

`
`
`Mt'Nt’H Consumer Ht’trfihr‘m‘t'. .7050 Camp Hm R Had. For! litti'i’irrligi‘nrr‘ PA {9034—3399 (2 .15) 273-7000
`
`0930 '99 SEP-? A9229
`
`Office of Special Nutritionals {HFS-450]
`Center for Food Safety and Applied Nutrition
`
`”F l 9 1993
`
`Food and Drug Administration
`200 C Street, SW
`
`Washington, DC 20204
`
`RE:
`
`New Dietary Ingredient Notification
`
`Dear Sir or Madam:
`
`
`
`McNeil Consumer Healthcare l"McNeil”l submits the attached information to the
`
`Food and Drug Administration, pursuant to the provisions of Section 413(a} of
`Federal Food. Drug and Cosmetic Act,
`in anticipation of its marketing of a dietary
`supplement form which contains the new dietary ingredient plant stanol esters.
`McNeil
`intends to incorporate the ingredient plant stanol esters into a dietary
`supplement form by encapsulating it into a gelatin capsule.
`
`in a format provided in
`On February 18, 1999, McNeil submitted to the Agency,
`proposed regulation 21 CFR 170.36 [62 FR 18938, Substances Generally
`Recognized as Safe {GRASiL a summary of plant stanol ester information for use
`as an ingredient
`in food. That submission, now included in Food Master File
`000626, informed the Agency of McNeil’s conclusion that plant stanol esters are
`generally recognized as safe {GRAS} for use in food at a level of 1.79 of plant
`stanol esters per serving of food.
`
`The Food and Drug Administration responded to the summary on May 17, 1999
`that, at that time and based upon their evaluation of the submission and other
`available data, there were no questions regarding McNeil's conclusion that plant
`stanol esters are GRAS under the intended conditions of use. That finding, together
`with the scientific information relied upon and cited in that submission, forms the
`scientific basis on which McNeil has concluded that
`the stanol esters dietary
`
`supplement is safe. This conclusion meets and exceeds the statutory requirement
`established under section 413iall2l of the Federal Food, Drug and Cosmetic Act
`that the dietary supplement will "...reasonably be expected to be safe.”
`
`Page 3 of 34
`
`Page 3 of 34
`
`

`

`(F‘s
`
`McNeil Consumer Healthcare
`
`Dietary Ingredient Notification
`
`Page 2
`
`This submission is made under section 413 of the Federal Food, Drug and Cosmetic
`Act; therefore, we request that it be accorded the 90 day confidentiality provisions
`relating to public notice. McNeil
`further considers
`some of
`the information
`
`contained in this notification relating unpublished studies to be trade secret or
`
`protected from public
`therefore,
`and,
`information
`commercial
`confidential
`disclosure. Such information has been stamped "CONFIDENTIAL."
`
`If you have any questions. please do not hesitate to call me at 215/273-7695.
`
`Sincerely
`MCNEIL CONSUMER HEALTHCARE
`
`a5?
`
`Joh C. Young
`ir ctor, Regulatory Affairs — Nutritionals
`
`attach.
`
`Page 4 of 34
`
`Page 4 of 34
`
`

`

`LNOILOQS
`
`_h_.__.__._.__+-—————--
`
`Page 5 of 34
`
`Page 5 of 34
`
`

`

`SECTION 1
`
`The name and complete address of the manufacturer or distributor of the dietary
`supplement that contains the dietary ingredient. or the dietary ingredient.
`
`The distributor of the dietary supplement will be:
`
`McNeil Consumer Healthcare
`
`7050 Camp Hill Road
`
`Fort Washington, Pennsylvania 19034
`
`Page 6 of 34
`
`Page 6 of 34
`
`

`

`ZNOILOES
`
`”\
`
`Page 7 of 34
`
`Page 7 of 34
`
`

`

`SECTION 2
`
`The name of the dietary ingredient.
`
`The dietary ingredient is plant stanol esters (”plant stanol fatty acid esters," ”stanol
`esters," “phytostanol fatty acid esters,” or “phytostanol esters”).
`
`Plant stanol esters are made from a variety of plant sterol sources, including wood-
`
`derived oils and vegetable oils. The principal plant stanol esters are mixed fatty acid
`esters of
`the Soc-phytostanols,
`sitostanol and campestanol. Sitostanol” (24-
`
`ethylcholestan-SB—ol, CAS No. 19486-47-8) is formed by the hydrogenation of the
`A5-mono-unsaturated plant sterol, sitosterol l24-ethylcholestan-S-en-3B—ol, CAS No.
`83-46-51 and also by the complete hydrogenation of the As'zz—di-unsaturated plant
`sterol. sigmasterol l24—ethylcholest-5,22-dien-3B—ol, CAS No. 83-483}, hence the
`
`alternative name “sigmastanoi.” Campestanol (24-methycholestan-SB-oll is formed
`by the hydrogenation of the A5-mono-unsaturated plant sterol, campesterol
`{24—
`
`methychoiest-5-en-36—ol, CAS No. 474-62-4}. Sitostanol and campestanol,
`
`in the
`
`free form and as their fatty acid esters, also occur naturally in cereal grains such as
`
`wheat, rye, corn and other foods that have for many years been part of the human
`diet in the United States.
`
`are
`After the hydrogenation process has been completed, the mixed plant sterols
`converted to the corresponding fully saturated plant
`stanols
`lsitosterol and
`sigmasterol
`to sitostanol, campesterol
`to campestanol). The plant stanols are
`thereafter converted to their fatty acid esters by an interesterification process using
`
`food grade esters from vegetabie oils.
`
`” Synonyms for sitostanoi are B-sitostantol, 5,6-dihydro-fl-sitosterol, 24~u-ethylcholestanol,
`dihydrositosterin, fucostanol, spinastanol, stigmastanoi. Sitosteroi is often referred to in the
`scientific literature as B-sitostertol.
`
`Page 8 of 34
`
`Page 8 of 34
`
`

`

`Page 9 of 34
`
`Page 9 of 34
`
`

`

`SECTION 3
`
`Description of the dietary supplement or dietary supplements that contain the
`dietary ingredient
`including {ii the level of the dietary ingredient
`in the dietary
`supplement, and iii} the conditions of use recommended or suggested in the
`labeling of the dietary supplement, or if no conditions of use are recommended or
`
`suggested in the labeling of the dietary supplement. the ordinary conditions of use
`of the supplement.
`
`The dietary supplement containing the plant stanol esters dietary ingredient will be
`in an encapsulated gelatin form. This plant stanol esters softgel product form will
`be clearly labeled and promoted as a dietary supplement intended for use to reduce
`the absorption of cholesterol from the gastrointestinal tract. The number of gelatin
`capsules per serving size will be described on the label and each serving of the
`dietary supplement will contain 1.79 of plant stanol esters. Label directions will
`suggest or recommend consumption of up to 3 servings per day,
`resulting in
`maximum daily consumption of up to 59 of plant stanol esters. That
`level of
`consumption is within the level of dietary exposure considered as safe for use in
`food.
`
`T)
`
`Page 10 of 34
`
`Page 10 of 34
`
`

`

`VNOLLOES
`
`Page 11 of 34
`
`Page 11 of 34
`
`

`

`SECTION 4
`
`the dietary
`The history of use or other evidence of safety establishing that
`ingredient. when used under the conditions recommended or suggested in the
`labeling of the dietary supplement, will
`reasonably be expected to be safe,
`including any citation to published articles or other evidence that is the basis on
`
`which the distributor or manufacturer has concluded that the dietary supplement
`will reasonably be expected to be safe.
`
`On February 18, 1999, McNeil submitted a summary of plant stanol esters
`information for use as an ingredient in food. This information formed the basis for
`McNeil‘s conclusion that plant stanol esters are safe lGRAS] for use in food when
`
`intended for use to reduce the absorption of cholesterol from the gastrointestinal
`tract.
`
`The Agency responded on May 17, 1999 that, after evaluating the materials, there
`were no further questions regarding McNeil‘s conclusion that stanol esters are
`
`GRAS for use in food at a level of 1.79 of plant stanol esters per serving of food.
`
`The materials and information submitted in support of the GRAS issue, which have
`
`been updated to include information that has become available since the February
`18, 1999 submission, together with the response from FDA, form the basis for the
`
`opinion that plant stanol esters meet land exceed} the statutory requirement under
`section 413(ali2} that they are “..reasonably expected to be safe...” for use as a
`dietary supplement.
`
`The information provided in support of McNeil's conclusion of safety are:
`
`.
`
`.
`
`.
`
`Attachment 1 — The Agency's May 17, 1999 response to McNeil's GRAS
`submission.
`
`Attachment 2 - The updated list of scientific articles which form the basis
`
`for the opinion of safety. The references listed in bold have become
`
`available since the February 18, 1999 submission, or have been updated
`
`with their current publication status.
`
`Copies of the listed references are attached and, where appropriate, are
`stamped ”CONFIDENTIAL."
`
`Page 12 of 34
`
`Page 12 of 34
`
`

`

`Page 13 of 34
`
`Page 13 of 34
`
`

`

`Public Health Service
`DEPARTMENT OF HEALTH 8: HUMAN SERVICES
`
`
`Food and Drug Administration
`Washington. DC 20204
`
`M.M.B.
`
`"Av 2 ~ m
`
`May [7, 1999
`
`Vivian A. Chester
`Edward B. Nelson, MD, PhD.
`McNeil Consumer Healthcare
`
`T050 Camp Hill Road
`Fort Washington, PA 19034-2299
`
`Re: Food Master File 000626
`
`Dear Ms. Chester and Dr. Nelson:
`
`The Food and Drug Administration (FDA) is responding to the summary of information, dated
`February 18, 1999, that you submitted to FDA. FDA received this summary ofinforrnation on
`February 19, 1999, and designated it as Food Master File 000626.
`
`The subject of year submission is plant stanol esters. Your submission informs FDA of McNeil’s
`view that plant stanol esters are generally recognized as safe (GRAB) for use as a nutrient in
`spread at a level of 1.7 grams of plant stariol esters per serving of spread. According to your
`submission, plant stanol esters are intended for use as nutrients in food to reduce the absorption of
`cholesterol from the gastrointestinal tract. The basis for McNeii’s view that this use of plant stanol
`esters is GRAS is through scientific procedures (21 CFR 170.30(b)). The submission states that
`the determination that plant stanoi esters are GRAS has been made through the deliberations of a
`panel ofindividuals (Raisio’s GRAS panel) who were convened by Raisio Benecol Ltd. McNeil
`considers the members of Raisio’s GRAS panel to be qualified by scientific training and
`experience to evaluate the safety of substances added to food.
`
`McNeil’s submission describes the manufacturing process for plant stanol esters and proposes
`food grade specifications. According to McNeil, sitostanol and campestanol are the main stanol
`components of plant sranol esters. These stanols are prepared by the hydrogenation of
`commercially available plant sterol blends, which are obtained as distillates from vegetable oils
`and as byproducts of the krafi paper pulping industry. These stanols are transesterified with fatty
`acid esters that are obtained from food-grade refined, bleached and deodorized vegetable oils, fats,
`or their blends (e.g., canola oil, sunflower oil, safflower oil, or corn oil). The transesterification of
`plant stanols improves their solubility in fat and allows them to be properly distributed in the fat
`phase in the gut prior to digestion.
`
`Page 14 of 34
`
`Page 14 of 34
`
`

`

`Page 2 - Ms. Chester and Dr. Nelson
`
`Based on the use of plant stanol esters in regular and reduced fat spreads at a level of 1.? gram per
`8 gram spread (packaged in single-serving units) or at a level of l .7 gram per 15 gram spread
`(packaged in a tub), and the consumption of three servings per day, McNeil estimates that
`consumer exposure to plant stanol esters would be approximately 5.] g/persom‘day, which
`corresponds to an estimated dietary exposure to plant stanols of approximately 3 g/personlday (i.e.
`approximately 43 mg’kg body weight/’day for a 70 kg adult). McNeil estimates that the current
`dietary exposure to plant stanols from naturally occurring sources is in the range of 20 to 30
`mgfpersonfday.
`
`McNeil describes published and unpublished absorption, distribution, metabolism, and excretion
`studies in animals and humans. Based on these studies, which show that 97% or more of stanol
`esters that are administered to humans is excreted quantitatively and unchanged in feces, McNeil
`concludes that plant stanol esters are hydrolyzed to free stanols in the gastrointestinal tract, that
`there is no evidence of further metabolism ofthe plant stanols that are absorbed, and that plant
`stanols from the blood and liver are excreted in the bile and eliminated in the feces intact.
`
`McNeil describes published and unpublished human studies that were conducted in support ofthe
`safety and efficacy of plant stanols or plant stanol esters in reducing serum cholesterol levels. The
`populations described in these studies include adults with elevated serum cholesterol levels, adults
`with normal cholesterol levels, adults with coronary heart disease, adults consuming cholesterol
`lowering drugs, adults with non-insulin dependent diabetes mellitus, children with elevated
`cholesterol, and children with normal cholesterol. According to McNeil, approximately 2000
`people have consumed plant stanol or plant stanol ester-containing products for periods of up to
`one year in human studies at ingestion rates that range from 1.2 to 17 grams of plant stanol esters
`per day, with most studies using an ingestion rate in the range of 3.4 to 5.] grams of plant stanol
`esters per day.
`
`McNeil states that no serious adverse events have been reported in either the published or the
`unpublished human studies and that stanol ester containing products have been well tolerated by
`the study populations. According to McNeil, extensive clinical laboratory mouitoring in subjects
`fed stanol ester spreads demonstrated no systemic abnormalities related to glycernic control, liver
`enzymes, or kidney function. McNeil conducted an in-depth follow-up with the clinical
`investigators to determine the nature and extent of safety data collections and to corroborate the
`safety conclusions reported in the publications. In addition, McNeil reports that a survey
`conducted by the government of Finland provides information that almost 140,000 adults in
`Finland consume commercially available plant stanol ester—containing spread on a daily basis.
`According to McNeil, the Finnish survey does not identify any association between consumption
`of plant stanol esters and any health conditions.
`
`The minimal absorption of plant stanol esters, coupled with their lipophilic nature, raises the
`question of the potential effect of plant stanol esters on the uptake of fat-soluble vitamins
`(Vitamins A, D, E, and K). McNeil’s submission separately addresses the potential effect of plant
`stanol esters on each ofthese vitamins. For Vitamins A, D, and E, McNeil describes (l) the
`results of published and unpublished human studies that included measurements or observations
`bearing on the potential effect of plant stanol esters on vitamin status; and (2) scientific symposia
`and other scientific meetings where the results of these human studies were discussed by the
`scientific community. For Vitamin K, McNeil (1) describes the results of human studies, which
`
`Page 15 of 34
`
`Page 15 of 34
`
`

`

`Page 3 - Ms. Chester and Dr. Nelson
`
`have been discussed at scientific symposia and other scientific meetings, that included
`measurements or observations bearing on the potential effect of plant stanol esters on Vitamin K
`status; and (2) reasons that any serious impairment of Vitamin K function would result in readily
`observable side effects, such as bruising or bleeding, that would have been noticed during studies
`of the quality and duration of the published human studies. For each of the fat-solubie vitamins,
`McNeil notes that widespread use of plant stanol esters in Finland for more than three years, with
`follow-up in the form of a public health survey conducted by the Finnish government, revealed no
`issues related to vitamin deficiency. Finally, for each of the fat-soluble vitamins, McNeil states
`that Raisio’s GRAS panel assessed the available published and unpublished data and concluded
`that ingestion of plant stanol esters does not affect vitamin status. McNeil concludes that ingestion
`of plant stanol esters has not been accompanied by clinically significant changes in fat soluble
`nutrient status.
`
`McNeil describes a series of recently published animal toxicity tests, including tests for oral
`toxicity, genotoxicty, developmental toxicity, reproductive toxicity, and potential for estrogenic
`effects. According to McNeil, the test articles used in these studies included wood-derived
`mixtures of plant stanol esters and vegetable oil-derived mixtures of plant stanol esters that cover
`the range of composition of the commercial product. Based on these studies, McNeil draws the
`following conclusions: (1) Based on a 13-week oral toxicity study in the rat, the no-observed-
`adverse~effect-level (NOAEL) for plant stanol esters derived either from wood or from vegetable
`oil corresponds to a daily intake of about 370 mg plant stanol esters per kg body weight in the rat
`(or approximately 61 grams per day for a 70 kg human); (2) plant stanol esters are not genotoxic;
`{3) plant stanol esters produced no indication of embryotoxic or teratogenic effects, and had no
`adverse effects on reproductive performance, at levels corresponding to a daily intake of about
`4500 mg plant stanol esters per kg body weight in the rat (or approximately 320 grams per day for
`a T0 kg human); and (4) plant stanol esters demonstrated no estrogenic effects in a uterotrophic
`assay in the rat. McNeil also concludes that a carcinogenicity study is not needed for plant stanol
`esters because of their low absorption, their lack of systemic toxicity, their lack of genotoxicity,
`and the absence of structural features that are predictive of carcinogenic activity.
`
`FDA has evaluated the information in McNeil’s submission as well as other available data and
`
`information, inctuding the Cyrea’lin file that is available at FDA’s Center for Drug Evaluation and
`Research.
`In addition, FDA went to the office of ENVIRON Corporation and evaluated certain
`data and information that were reviewed by Raisio's GRAS panel. Based on its evaluation, the
`agency has no questions at this time regarding McNeil‘s conclusion that plant stanol esters are
`GRAS under the intended conditions of use. Furthermore, FDA is not aware of any scientific
`evidence that plant stanol esters would be harmful. The agency has not, however, made its own
`determination regarding the GRAS status of the subject use of plant stanol esters. As always, it is
`McNeil’s continuing responsibility to ensure that food ingredients that the firm markets are safe,
`and are otherwise in compliance with all applicable legal and regulatory requirements.
`
`Page 16 of 34
`
`Page 16 of 34
`
`

`

`Page 4 - Ms. Chester and Dr. Nelson
`
`An evaluation that a use ofa food ingredient is safe is a time-dependentjudgment that is based
`on general scientific knowledge as well specific data and information about the ingredient. The
`intended use of plant stanol esters to reduce the absorption of cholesterol from the gastrointestinal
`tract exemplifies a recent trend in the food industry to develop food ingredients that have a
`nontraditional function. The evolving scientific knowledge about such ingredients in the context
`of changing dietary patterns, including long~term nutritional implications, amplifies the time-
`dependent nature of any safety evaluation. Accordingly, the agency believes that it would be both
`prudent and responsible for McNeil to continue to monitor, through scientific studies or otherwise,
`c0nsumers’ dietary exposure to plant stanol esters and the long-term nutritional implications for
`individuals in all age-groups who routinely consume the ingredient.
`In this regard, we were
`pleased to receive McNeil’s letter dated May 12, 1999, which (1) describes McNeil’s intent to
`continue its clinical evaluation of plant stanol esters; (2) describes initiatives to ensure that plant
`stanol esters are well understood by consumers and healthcare professionals and to evaluate
`consumer use and understanding regarding plant stanol esters; and (3) states McNeil's
`commitment to provide FDA with updates on the outcome of these activities, including summaries
`of safety findings from McNeil‘s clinical program.
`
`Finally, we have been advised by the Office of Food Labeling (OFL) in the Center for Food Safety
`and Applied Nutrition that the proposed claim, “Helps promote healthy cholesterol levels,” falls
`within the purview of structureffunction claims. However, as McNeil discussed with OFL on
`May 2, 1999, the label of Benecol® must include the percentage and type of fat, e. g., "_%
`vegetable oil" as part of the term "spread" where that term appears on the label, and the agency
`expects you to bring this aspect of your label into compliance with the applicable regulations.
`OFL will be sending you a separate letter discussing this issue. OFL has no other objection to
`your label in light of your letter dated May 3, 1999, and the commitments made therein.
`
`Sincerely yours,
`
`AlaJ’l/LM
`
`Alan M. Rulis, Ph.D.
`Director
`
`Office of Premarket Approval
`Center for Food Safety
`and Applied Nutrition
`
`Page 17 of 34
`
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`
`

`

`>44)OIZ.MZ._.M
`
`__/_
`
`Page 18 of 34
`
`Page 18 of 34
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`

`

`SAFETY OF PLANT STANOL ESTERS
`
`REFERENCES {Updated}
`
`Agricultural Research Service IARS). Continuing Survey of Food Intakes by
`Individuals 1989-1992. U.S. Department of Agriculture. Computer tapes.
`1994.
`
`3--
`
`Ansari, G.A.S.; Walker, R.D.; Smart, V.B.; Smith, LL. Further investigations
`of mutagenic cholesterol preparations. Food Chem. Toxic. 1982, 20, 35-41.
`
`Barnes, P.J.
`
`Non-saponifiable lipids
`
`in cereals.
`
`In Lipids
`
`in Ceres!
`
`TechnologY: Academic: London, 1983; pp 33-55.
`
`Becker, M.: Staab, 0.; von Bergmann, K.
`
`Treatment of severe familial
`
`hypercholesterolemia in childhood with sitosterol and sitostanol.
`1993. 1'22, 292-296.
`
`J. Pediatr.
`
`Blair, 8.: et al. A randomized trial comparing the efficacy and safety of a
`
`combination of HMG Co-A reductase inhibitor and spread containing plant
`stanol esters versus HMG-CoA reductase inhibitor and placebo spread to help
`reduce LDL and total-cholesterol
`levels. McNeii Protocoi 97-035.
`Fort
`
`Washington, PA 19034. Unpublished. CONFIDENTIAL
`
`I.;
`Blomqvist, S.M.; Jauhiainen, M.; van Tol, A.; Hyvonen, M.; Torstila,
`Vanhanen, H.T.: Miettinen, T.A.: Ehnholm, C. Effect of sitostanol ester on
`
`composition and size distribution of low- and high-density lipoprotein. Nutr.
`Metab. Cardiovasc. Dis. 1993, 3, 158-164.
`
`Booth, S.L.; Suttie, J.W. Dietary intake and adequacy of Vitamin K. J. Nutr.
`1998, 728, 785-788.
`
`Borzelleca, J.F. Macronutrient substitutes: safety evaluation. Regui. Toxicoi.
`Pharmacoi. 1992, 16, 253-264.
`
`In Oiive Oilr Chemistry and Technology:
`Boskou, D. Olive oil composition.
`Boskou, 0., Ed.: AOCS: Champaign, Illinois, 1996: p. 52-83.
`'
`
`Brown, E.E.; Fudge,
`
`J.F.; Richardson, LR.
`
`Diet of mother and brain
`
`hemorrhages in infant rats. J. Nutr. 1947, 34, 141-151.
`
`Burck, P.J.; Thakkar, A.L.; Zimmermann, R.E. Antifertility action of a sterol
`
`sutphate in the rabbit. J. Reprod. Fen. 1982, 66, 109-112.
`
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`
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`
`Page 19 of 34
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`Cater N.B.; Grundy, S.M. Lowering serum cholesterol with plant sterols and
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`Developments in the Dietary Management of High Cholesterol, Nguyen, TT,
`Ed.,' McGraw-Hill: Minneapolis, Minnesota, November 1998; pp 6-14.
`
`Lycopene: Chemistry, biology, and implications for human
`Clinton, S.K.
`health and diseases. Nutr. Rev. 1999, 56(2), 35-51.
`
`and
`Lipoproteins
`Cullen, P.; Funke, H.: Schulte, H.: Assmann, G.
`cardiovascular risk -from genetics to CH0 prevention. Eur. Heart J. 1998, 79
`Supp. C, C5-11.
`
`Curran, G.L.: Costello, R.L. Effect of dihydrocholesterol and soybean sterols
`
`on cholesterol metabolism in rabbit and rat. Proc. Soc. Exp. Biol. Med. 1956,
`91', 52-56.
`
`Customs Laboratory. Test Report 1999 0118 003. February 2, 1999.
`
`Czubayko, F.; Beumers, B.: Lammsfuss, 8.; Lutjohann, D.; van Bergmann, K.
`A simplified micro-method for quantification of fecal excretion of neutral and
`
`acidic sterols for outpatient studies in humans. J. Lipid Res. 1991, 32, 1861-
`1867.
`
`Dale, L.C. A clinical use extension study of a spread containing plant stanol
`esters to help reduce cholesterol. McNeii Protocoi 98-043. Unpublished.
`CONFIDENTIAL
`
`Dutta, P.C.; Appelqvist, L.-A.. Saturated sterols [stanoisi in unhydrogenated
`and hydrogenated edible vegetable oils and in cereal
`lipids.
`J. Sci. Food
`Agric. 1996, 71'. 383-391.
`
`Dutta, P.C. Phytosterol oxides in some samples of pure phytosterols mixture
`and in a few tablet supplement preparations in Finland. Second international
`Conference on Natural Antioxidants and Anticarcinogens in Nutrition, Health
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