[Federal Register Volume 62, Number 108 (Thursday, June 5, 1997)]
[Rules and Regulations]
[Pages 30751-30757]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-14683]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 184
[Docket No. 86G-0289]
Substances Affirmed as Generally Recognized as Safe: Menhaden Oil
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is affirming that
menhaden oil is generally recognized as safe (GRAS) as a direct human
food ingredient with specific limitations. The agency is also affirming
that partially hydrogenated menhaden oil with an iodine number between
86 and 119 is GRAS as a direct human food ingredient with no limitation
other than current good manufacturing practice. These actions complete
the agency's response to a petition filed by the National Fish Meal and
Oil Association.
DATES: Effective June 5, 1997. The Director of the Office of the
Federal Register approves the incorporation by reference, in accordance
with 5 U.S.C. 552(a) and 1 CFR part 51, of certain publications in 21
CFR 184.1472(a)(2), effective June 5, 1997.
FOR FURTHER INFORMATION CONTACT: Lawrence J. Lin, Center for Food
Safety and Applied Nutrition (HFS-206), 200 C St. SW., Washington, DC
20204, 202-418-3103.
SUPPLEMENTARY INFORMATION: In accordance with 21 CFR 170.35, the
National Fish Meal and Oil Association, 2000 M St. NW., suite 580,
Washington, DC 20036 (current address: 1525 Wilson Blvd., suite 500,
Arlington, VA 22209), submitted a petition (GRASP 6G0316) seeking
affirmation that menhaden oil and partially hydrogenated menhaden oil
are GRAS for use as direct human food ingredients. The petition
included information about the identity of, and manufacturing processes
for, menhaden oil and partially hydrogenated menhaden oil; final
reports and published articles of long-term animal feeding studies with
partially hydrogenated menhaden oil; information about the history of
human food use of partially hydrogenated menhaden oil; and the results
of an extensive search of the published scientific literature
(encompassing over 2,600 articles) with respect to the safety of fish
oils in general.
FDA published a notice of filing of this petition in the Federal
Register of July 31, 1986 (51 FR 27461), and gave interested persons an
opportunity to submit comments to FDA's Dockets Management Branch. FDA
received three comments, two from manufacturers and one from a
government agency. All of the comments supported the affirmation of
GRAS status for use of the oils in food.
FDA affirmed that partially hydrogenated menhaden oil (with an
iodine number not more than 85) and fully hydrogenated menhaden oil are
GRAS in the Federal Register of September 15, 1989 (54 FR 38219). These
oils were affirmed as GRAS based on the chemical similarity between
these oils and partially hydrogenated common edible vegetable oils, and
on the established history of use in Europe
[[Page 30752]]
of these oils in margarine and shortening (54 FR 38219 at 38222).
Pending further evaluation, the agency deferred its decision on
menhaden oil that has not been hydrogenated, because this oil contains
high levels of the omega-3 polyunsaturated fatty acids eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA), which are known to have
physiologic effects, for example, effects on blood clotting (54 FR
38219). The agency's evaluation is now complete.
I. Basis for GRAS Status
Under section 201(s) of the act (21 U.S.C. 321(s)) and Sec. 170.30
(21 CFR 170.30), general recognition of safety may be based only on the
views of experts qualified by scientific training and experience to
evaluate the safety of substances added to food. The basis of such
views may be either: (1) Scientific procedures or, (2) in the case of a
substance used in food prior to January 1, 1958, experience based on
common use in food. General recognition of safety based upon scientific
procedures requires the same quantity and quality of scientific
evidence as is required to obtain approval of a food additive and
ordinarily is to be based upon published studies, which may be
corroborated by unpublished studies and other data and information
(Sec. 170.30(b)). The petitioner relies upon scientific procedures to
establish that menhaden oil is GRAS, because the oil has no history of
common use as a food ingredient prior to 1958.
II. Identity
Menhaden oil is a refined marine oil that is derived from menhaden
fish (Brevoortia species). It consists primarily of triglycerides, with
small amounts of monoglycerides and diglycerides. The triglycerides are
esters of glycerol and fatty acids with chains of 14 to 22 carbon
atoms. Menhaden oil differs from edible vegetable oils and animal fats
in its high proportion of polyunsaturated fatty acids with 4, 5 and 6
double bonds (about 25 percent). The mean percentages for these
polyunsaturated fatty acids in menhaden oil are C18:4 (2.3 percent),
C20:4 (2.0 percent), C20:5 (13.1 percent), C22:5 (2.5 percent) and
C22:6 (6.7 percent).\1\ C20:5 and C22:6 are EPA and DHA, respectively,
and are the major source of omega-3 fatty acids from fish oil. (Omega-3
fatty acids refer to fatty acids with the first double bond occurring
at the third carbon from the methyl (or omega) end of the fatty acid.)
Menhaden oil also contains about 33 percent saturated fatty acids and
about 31 percent monounsaturated fatty acids.
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\1\ The first number refers to the total number of carbon atoms
in the fatty acid; the second number refers to the total number of
double bonds.
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III. Manufacturing Process
Menhaden, a plankton-feeding fish, is harvested commercially from
the Gulf of Mexico and northward along the Atlantic coast of the United
States. The fish is less than 12 inches long and less than a pound in
weight. To produce menhaden oil, the fish is cooked whole at about 96
deg.C for 8 to 10 minutes to coagulate the protein and rupture the fat
cells. The cooked fish is then pressed and the liquid is centrifuged to
separate the oil and aqueous phases. Crude oil is then shipped to food
companies for further processing, which may include storage
(winterization), degumming, neutralization, bleaching, deodorization,
and hydrogenation.
IV. Previous Evaluations
Data in the petition indicate that ingestion of EPA and DHA from
fish oils can have a significant effect on bleeding time (the time
taken for bleeding from a standardized skin wound to cease) and other
physiological effects, as discussed below. Because of the potential
safety concerns raised by these effects, and because there are no food
oils in the food supply containing significant amounts of EPA and DHA,
the agency contracted with the Mitre Corp. to perform an independent
analysis of the scientific literature on the safety of menhaden oil.
The Mitre Corp. issued, in April 1989, a report entitled, ``Health
Effects of Refined Menhaden Oil.'' (Copies are available from the
National Technical Information Service, Order No. PB89-182398, price
code A08.)
The report stated that:
[a]n increase in bleeding time is the only prominent health
effect observed in humans that has been firmly established as a
consequence of fish oil ingestion. This effect has been reported
anecdotally in the Eskimo population and consistently observed in
studies of healthy human subjects with a daily intake of 3 g [grams]
of omega-3 fatty acids. The magnitude of the effect at this low dose
is not a cause for alarm, but a lack of systematic dose-response
data precludes prediction of the severity of the effect at higher
daily intakes.
(Pages 7-1 and 7-2 of the report.)
In addition, the Nutrition Labeling and Education Act of 1990
required FDA to evaluate health claims for 10 nutrient-disease
relationships, including the relationship of omega-3 fatty acids and
heart disease. The agency evaluated the claim that consumption of
omega-3 fatty acids is associated with a decreased risk of coronary
heart disease under the standard set forth in section 403(r)(3) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 343(r)(3)): Whether,
based on the totality of publicly available scientific evidence, there
is significant scientific agreement, among experts qualified by
scientific training and experience, that the claim for the diet-disease
relationship is supported by the evidence. In the Federal Register of
January 6, 1993 (58 FR 2682), FDA issued a final rule announcing its
decision not to authorize a health claim relating to an association
between omega-3 fatty acids and a decreased risk of coronary heart
disease because it had concluded that there was not significant
scientific agreement among experts that the totality of the scientific
evidence supported the claim. Because the focus of that evaluation was
a review of evidence concerning a possible beneficial effect of omega-3
fatty acids on the heart, a comprehensive review of the safety of
omega-3 fatty acids from fish oils or other sources was not conducted.
However, in the health claim final rule the agency did discuss, in
addition to the potential health benefit, concerns over possible
adverse effects of fish oils on bleeding time, glycemic control, and
low-density lipoprotein (LDL) cholesterol. These issues are discussed
below.
V. Safety Information
A. Bleeding Time
Increased bleeding time has been reported in many studies with
humans whose diets were supplemented with fish oils. FDA stated in the
health claim final rule that the importance of the increase in bleeding
time reported in many studies with supplemental fish oils or with
increased fish consumption is not clear (58 FR 2682 at 2699). Further,
increases in bleeding time do not correlate with clinically significant
bleeding, and there are debates regarding the clinical significance of
the increase in bleeding time (Ref. 1). However, FDA considers
excessive bleeding to be a safety concern, and has examined the
scientific literature for evidence that consumption of fish oils may
contribute to excessive bleeding.
There are more than 50 reports in the scientific literature on fish
oils that include data on bleeding time. Several reports described the
absence of changes in bleeding time, but did not provide data. A few
studies involving substantial numbers of healthy human subjects
indicated that there was no statistically significant increase in
bleeding time after supplemental intakes of EPA and DHA from fish oils
[[Page 30753]]
in daily amounts of 3.0 g or less (Refs. 3 through 6). Other studies
with fewer human subjects, but in which the total diet was carefully
controlled, also revealed that daily intakes of 3.0 g or less of EPA
and DHA in fish oils did not increase bleeding time (Refs. 7 and 8).
However, two studies described increases in bleeding time that were
reported to be statistically significant. Subjects in the studies
consumed about 3.0 g per person per day (/p/d) EPA and DHA from fish
oils. Mortensen et al. (Ref. 9), in a crossover, double-blind, placebo-
controlled study among 20 normal, healthy males, showed that
consumption of slightly more than 3.0 g/d of EPA and DHA in fish oil
capsules for 4 weeks produced a small but statistically significant
increase (16 percent) in median bleeding time; however, both the mean
and 75th percentile bleeding times were well within the normal range.
Harris and Windsor (Ref. 10) reported that consumption of fish oil
containing 2.2 g/d of EPA and DHA also produced a small (15 percent)
but statistically significant increase in bleeding time, but this
increase was also within the normal range.
Studies in which greater daily amounts (higher than 3.0 g/p/d) of
fish oils were fed often reported statistically significant increases
in bleeding time (Refs. 11 through 22). In some of those studies, use
of fish oils resulted in substantial prolongation of bleeding time
outside the normal range, as indicated by the standard deviations
reported (Refs. 8, 12, 18, 21, and 22). However, the pre-treatment
bleeding times in those studies were also beyond the normal range,
making it difficult to evaluate the effect of fish oils on bleeding
time. In other studies, the increase in bleeding time after daily
intakes of more than 3.0 g of EPA and DHA is difficult to interpret
meaningfully because of the small number of subjects tested (Refs. 23
through 27).
Studies have also been carried out with subjects who had evidence
of coronary heart disease or risk factors for coronary heart disease.
After intake of 3.2-6.0 g/p/d of EPA and DHA in fish oils, many of
these subjects showed increased bleeding time (Refs. 20, and 28 through
33). However, none of the studies reported evidence that the prolonged
bleeding time was clinically significant. In those cases where the
effect of fish oils in angioplasty or bypass surgery patients (a total
of 520 patients fed supplemental fish oil) was studied, excessive
bleeding was not reported even though acetylsalicylic acid (aspirin),
which itself greatly prolongs bleeding time, was used concurrently
(Refs. 34 through 40). One large study that used a dose of 6 g/p/d EPA
and DHA in fish oils did report four cases of increased bleeding in the
fish oil group (of 124 treated) versus none in the placebo group, but
the difference in rates of occurrences between the two groups was not
statistically significant (Ref. 40).
In summary, the totality of the scientific evidence demonstrates
that when consumption of fish oils is limited to 3 g/p/d or less of EPA
and DHA, there is no significant risk for increased bleeding time
beyond the normal range. A report from an industry-sponsored roundtable
discussion on the topic of fish oils and bleeding time (Ref. 2) also
supports the conclusion that EPA and DHA are safe at intake levels at
or below 3 g/p/d. On the other hand, amounts of fish oils providing
more than 3 g/d of EPA and DHA have generally been found to produce
increases in bleeding time that are statistically significant. At this
time, there are insufficient data to evaluate the clinical significance
of this finding. Because of the lack of data and because of the
potential risk of excessive bleeding in some individuals with intakes
at higher levels, FDA concludes that the safety of menhaden oil is
generally recognized only at levels that limit intake of EPA and DHA to
3 g/p/d.
B. Glycemic Control
Some studies on non-insulin-dependent diabetics have reported
increased glucose levels when large amounts of fish oils (4.5 to 8.0 g/
p/d) were used in the diet. In the health claim final rule, FDA
discussed the possible adverse effects of fish oil consumption on
glycemic control among diabetics and stated that such effects were a
safety concern (58 FR 2682 at 2704 through 2705). FDA concluded in that
document that the effects of fish oils on blood glucose appear to
depend on the amount of fish oils fed, based on review of a number of
studies (58 FR 2682 at 2705). One study found no change in fasting
blood glucose levels among type-II [non-insulin-dependent] diabetics
treated with 3.0 g/d EPA plus DHA for 2 weeks (Ref. 41). Two other
studies that used 3 g/d EPA plus DHA for 6 weeks (Ref. 42) and 2.7 g/d
EPA plus DHA for 8 weeks (Ref. 43) found only transient increases in
blood glucose halfway through their respective supplementation periods.
Another study (Ref. 44) that used 3.0 g/d EPA plus DHA for 3 weeks
found comparable increases in fasting blood glucose when either fish
oil or safflower oil was fed, so the increase cannot be attributed
specifically to omega-3 fatty acids. A study that compared the effects
of fish oil and olive oil (Ref. 45) fed 3 g/d of EPA plus DHA and did
not find a difference in fasting glucose or glycosylated hemoglobin
after fish oil supplementation compared to baseline; they did find a
significant difference compared to the olive oil treatment, which
produced changes in the opposite direction from fish oil. Studies on
type II diabetics that reported increased glucose used higher amounts
(4.5 to 8 g/d) of omega-3 fatty acids (Refs. 46 through 49).
Based on the available information, FDA concludes that consumption
of EPA and DHA in fish oils at 3 g/p/d by diabetics has no clinically
significant effect on glycemic control, although higher amounts of EPA
and DHA (4.5 g/p/d and above) remain of concern. Therefore, FDA
concludes that 3 g/p/d of EPA and DHA is a safe level with respect to
glycemic control.
C. LDL Cholesterol
In the health claim final rule, FDA noted that many studies on
hypertriglyceridemic or hypercholesterolemic subjects, and some studies
on normal subjects, reported an increase in LDL cholesterol or apo B
(apolipoprotein B, a principal component of LDL) following fish oil
supplementation (58 FR 2682 at 2705). Because increases in LDL
cholesterol predict increased risk of coronary heart disease, FDA
recently reevaluated those studies, as well as newer studies published
since the health claim final rule, to address the question of whether 3
g/p/d of EPA and DHA derived from menhaden oil is generally recognized
as a safe level with respect to its effect on LDL cholesterol. The
agency considered the reported effects of fish oil on LDL cholesterol
levels in healthy persons with normal cholesterol levels, as well as in
persons with diabetes mellitus, hypertension, abnormal blood lipid
levels, and cardiovascular disease.
As a result of its reevaluation, FDA found that although reported
study results are variable, there appears to be a trend toward
increased LDL cholesterol values with increased fish oil consumption in
all population subgroups, with the magnitude of the increase appearing
greater and more consistent in populations with abnormal blood lipid
levels, hypertension, diabetes, and cardiovascular disease.
In the health claims final rule, FDA noted that because most
reports of increased LDL were in studies where large amounts of fish
oils were given (i.e., 5 g or more per day of EPA plus DHA), any safety
concern relating to
[[Page 30754]]
changes in LDL cholesterol might be suitably addressed by restricting
the intake of DHA and EPA (58 FR 2682 at 2705). As discussed below, the
petitioner has suggested maximum use levels of menhaden oil for each
food category in which menhaden oil can be used. Based on these levels,
FDA has determined that the mean intake of menhaden oil, if menhaden
oil were to be used at the maximum allowable level in all permitted
food categories, would be less than 3 g of DHA and EPA per day.
Further, menhaden oil would substitute for other dietary fats, some of
which have similar effects on LDL cholesterol. Based on its evaluation,
the agency concludes that the petitioned levels of menhaden oil are
safe with respect to the effect on LDL cholesterol.
VI. Consumer Exposure
In September 1993, the petitioner amended the petition to include
maximum use levels for menhaden oil in various food categories. Based
on these levels, FDA estimated that the mean exposure to EPA and DHA
from the use of menhaden oil in all food categories would be 2.8 g/p/d
(Ref. 50). Although the petition originally included all potential food
uses of menhaden oil, the petitioner subsequently requested that the
use of menhaden oil in infant formula be withdrawn from consideration.
Therefore, the exposure estimate does not include this potential use of
menhaden oil.
VII. Iodine Numbers of Oils from Menhaden
When FDA affirmed hydrogenated and partially hydrogenated menhaden
oils as GRAS based on their pre-1958 history of safe use in food, the
agency included in the regulation a specification that the iodine
number for partially hydrogenated menhaden oil be no more than 85.
(Iodine number is a measure of the unsaturation of fats and oils,
expressed in terms of centigrams of iodine absorbed per gram of
sample.) The iodine number limit of 85 was chosen then because menhaden
oil with an iodine number greater than 85 is not considered hardened,
and only hardened oil had a documented history of common use in food
before 1958 (54 FR 38219 at 38222). Moreover, corroborative
toxicological studies submitted in the petition used oil with an iodine
number no more than 85 (54 FR 38219 at 38222). The iodine number limit
of 85 also ensured that the partially hydrogenated menhaden oil
affirmed as GRAS at that time would contain no more than traces of EPA
and DHA, and thus would not significantly increase the dietary intake
of these substances, pending completion of the agency's evaluation of
the safety of DHA and EPA as part of its review of the GRAS status of
menhaden oil. By specifying this upper limit, the agency deferred its
decision on the GRAS status of partially hydrogenated menhaden oil with
an iodine number above 85.
The agency now concludes (as stated below), based on scientific
procedures, that menhaden oil is GRAS, provided that daily intakes of
EPA and DHA from menhaden oil do not exceed 3 g/p/d. The petitioner has
provided information demonstrating that partially hydrogenated menhaden
oil may have an iodine number up to 119. The agency finds that the use
of partially hydrogenated menhaden oil with an iodine number up to 119
under conditions specified in current 21 CFR 184.1472 will not cause
the total exposure to EPA and DHA from all types of menhaden oil to
exceed 3 g/p/d (Ref. 50). Therefore, FDA concludes that partially
hydrogenated menhaden oil with an iodine number between 86 and 119 is
GRAS based on scientific procedures, and is raising the iodine number
limit in the regulation for partially hydrogenated menhaden oil to 119.
With this change, the iodine number range for partially hydrogenated
menhaden oil will be 11 through 119 instead of 11 through 85.
The effect of the change in the iodine number range for partially
hydrogenated menhaden oil will be to affirm as GRAS a substance that
was not previously affirmed as GRAS (i.e., partially hydrogenated
menhaden oil with an iodine number between 86 and 119), rather than to
amend the specifications for a substance already affirmed as GRAS. Even
if the change in the iodine number range is characterized as an
amendment, however, the Administrative Procedure Act (5 U.S.C.
553(b)(3)(B)) permits an agency to amend a regulation without notice
and comment procedures when the agency for good cause finds that such
procedures are impracticable, unnecessary, or contrary to the public
interest. Because notice of the filing of a petition seeking GRAS
affirmation of menhaden oil and partially hydrogenated menhaden oil was
given (51 FR 27461), and an opportunity for public comment on all
issues relating to the petition, including iodine number ranges, was
provided at that time, FDA finds that separate, additional notice and
comment procedures on the specific issue of the iodine number range for
partially hydrogenated menhaden oil are unnecessary. Therefore, the
agency finds that there is good cause to proceed to final action
without an opportunity for additional public comment on this issue.
VIII. Conclusions
FDA has evaluated the information in the petition and many
published articles in scientific journals, along with other relevant
information. Based on this evaluation, the agency finds that the use of
menhaden oil as a direct food ingredient is safe, provided that daily
intakes of EPA and DHA from menhaden oil do not exceed 3 g/p/d. As
noted in section VI of this document, the petitioned uses of menhaden
oil incorporate maximum use levels for menhaden oil in specific food
categories to ensure that daily intakes of EPA and DHA from menhaden
oil do not exceed 3 g/p/d. FDA has further determined that the many
pertinent published human clinical studies provide an adequate basis to
conclude that the safety of the petitioned uses of menhaden oil is
generally recognized among the community of experts qualified by
scientific training and experience to evaluate the safety of food
ingredients. Therefore, the agency is affirming that the use of
menhaden oil as a direct human food ingredient is GRAS with specific
limitations (21 CFR 184.1(b)(2)). This GRAS affirmation is based on
scientific procedures (21 CFR 170.30(b)). To ensure that only food-
grade menhaden oil is used in food, FDA is including appropriate
specifications in the regulation.
FDA further concludes, based on scientific procedures, that
partially hydrogenated menhaden oil with an iodine number between 86
and 119 is GRAS with no limitation other than current good
manufacturing practice. Therefore, the agency is increasing the iodine
number limit for partially hydrogenated menhaden oil to 119.
IX. Environmental Impact
The agency is affirming that menhaden oil is generally recognized
as safe (GRAS) as a direct human food ingredient with specific
limitations. The agency is also affirming that partially hydrogenated
menhaden oil with an iodine number between 86 and 119 is GRAS as a
direct human food ingredient with no limitation other than current good
manufacturing practice.
The agency has carefully considered the potential environmental
effects of these actions. FDA has concluded that these actions will not
have a significant impact on the human environment, and that an
environmental impact statement is not required. The agency's finding of
no significant impact and the evidence supporting that finding,
contained in an
[[Page 30755]]
environmental assessment, may be seen in the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857, between 9 a.m. and 4 p.m., Monday through Friday.
X. Analysis of Impacts
FDA has examined the economic implications of the final rule as
required by Executive Order 12866 and the Regulatory Flexibility Act (5
U.S.C. 601-612). Executive Order 12866 directs agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select the regulatory approach that
maximizes net benefits (including potential economic, environmental,
public health and safety effects; distributive impacts; and equity).
Executive Order 12866 classifies a rule as significant if it meets any
one of a number of specified conditions, including having an annual
effect on the economy of $100 million or adversely affecting in a
material way a sector of the economy, competition, or jobs, or if it
raises novel legal or policy issues. If a rule has a significant
economic impact on a substantial number of small entities, the
Regulatory Flexibility Act requires agencies to analyze regulatory
options that would minimize the economic impact of that rule on small
entities.
FDA finds that this final rule is not a significant rule as defined
by Executive Order 12866. This final rule recognizes the applicability
of a statutory exemption. The impact of the rule is to remove
uncertainty about the regulatory status of the petitioned substance.
Accordingly, under the Regulatory Flexibility Act, 5 U.S.C. 605(b), the
Commissioner of Food and Drugs certifies that this final rule will not
have a significant economic impact on a substantial number of small
entities (Ref. 51).
XI. Effective Date
As this rule recognizes an exemption from the food additive
definition in the Federal Food, Drug, and Cosmetic Act, and from the
approval requirements applicable to food additives, no delay in
effective date is required by the Administrative Procedure Act (5
U.S.C. 553(d)). The rule will therefore be effective immediately (5
U.S.C. 553(d)(1)).
XII. References
The following information has been placed on display with the
Dockets Management Branch (address above), and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Rodgers, R. P. C., and J. Levin, ``A Critical Reappraisal of
the Bleeding Time,'' Seminars in Thrombosis and Hemostasis, 16:1-20,
1990.
2. ``Proceedings and Conclusions of the Round Table Discussion
on Fish Oils and Bleeding Times,'' October 31, 1990, Chester,
England, supported by the Council for Responsible Nutrition,
Washington, DC.
3. Agren, J. J., O. Hanninen, A. Hanninen, and K. Seppanen,
``Dose Responses in Platelet Fatty Acid Composition, Aggregation,
and Prostanoid Metabolism During Moderate Freshwater Fish
Diet,''Thrombosis Research, 57:565-575, 1990.
4. Blonk, M. C., H. J. G. Bilo, J. J. P. Nauta, C. Popp-
Snijders, C. Mulder, and A. J. M. Donker, ``Dose Response Effects of
Fish Oil Supplement in Healthy Volunteers,''American Journal of
Clinical Nutrition, 52:120-127, 1990.
5. Deslypere, J. P., ``Influence of Supplementation with n-3
Fatty Acids on Different Coronary Risk Factors in Men--A Placebo
Controlled Study,'' Verh K. Acad. Geneeskd. Belg., 54:189-216, 1992.
6. Rogers, S., K. S. James, B. K. Butland, M. D. Etherington, J.
R. O'Brien, and J. G. Jones, ``Effects of Fish Oil Supplement on
Serum Lipids, Blood Pressure, Haemostasis and Rheological
Variables,'' Atherosclerosis, 67:137-143, 1987.
7. Nelson, G. J., P. C. Schmidt, and L. Corash, ``The Effect of
a Salmon Diet on Blood Clotting, Platelet Aggregation, and Fatty
Acids in Normal Adult Men,''Lipids, 26:87-96, 1991.
8. Wander, R. C., and B. D Patton, ``Comparison of Three Species
of Fish Consumed as a Part of a Western Diet: Effects on Platelet
Fatty Acids and Function, Hemostasis, and Production of
Thromboxane,''American Journal of Clinical Nutrition, 54:326-333,
1991.
9. Mortensen, J. Z., E. B. Schmidt, A. H. Nielson, and J.
Dyerberg, ``The Effect of n-6 and n-3 Polyunsaturated Fatty Acids on
Hemostasis, Blood Lipids, and Blood Pressure,'' Thrombosis and
Haemostasis, 50:543-546, 1983.
10. Harris, W. S., and S. L. Windsor, ``N-3 Fatty Acid
Supplements Reduce Chylomicron Levels in Healthy Volunteers,''
Journal of Applied Nutrition, 43:5-15, 1991.
11. Sanders, T. A. B., V. Marquerite, and A. P. Haines, ``Effect
on Blood Lipids and Haemostasis of a Supplement of Cod Liver Oil,
Rich in Eicosapentaenoic and Docosahexaenoic Acids, in Healthy Young
Men,'' Clinical Science, 61:317-324, 1981.
12. Goodnight, S. H., W. S. Harris, and W. E. Connor, ``The
Effects of Dietary -3 Fatty Acids on Platelet Composition
and Function in Man: A Prospective, Controlled Study,'' Blood,
58:880-885, 1981.
13. Fischer, S., and P. C. Weber, ``Prostaglandin I3
is Formed in vivo in Man After Dietary Eicosapentaenoic Acid,''
Nature, 307:165-168, 1984.
14. Knapp, H. R., I. A. G. Reilly, P. Alessandrini, and G. A.
FitzGerald, ``In vivo Indexes of Platelet and Vascular Function
During Fish-oil Administration in Patients with Atherosclerosis,''
New England Journal of Medicine, 314:937-942, 1986.
15. Sanders, T. A. B., and F. Roshanai, ``The Influence of
Different Types of -3 Polyunsaturated Fatty Acids on Blood
Lipids and Platelet Function in Healthy Volunteers,'' Clinical
Science, 64:91-99, 1983.
16. Schmidt, E. B., K. Varming, E. Ernst, P. Madsen, and J.
Dyerberg, ``Dose-Response Studies on the Effect of n-3
Polyunsaturated Fatty Acids on Lipids and Haemostasis,'' Thrombosis
and Haemostasis, 63:1-5, 1990.
17. Schmidt, E. B., H.-H. Lervang, K. Varming, P. Madsen, and J.
Dyerberg, `` Long-term Supplementation with n-3 Fatty Acids, I:
Effect on Blood Lipids, Haemostasis, and Blood Pressure,''
Scandinavian Journal of Clinical Laboratory Investigation, 52:221-
228, 1992.
18. Thorngren, M., S. Shafi, and G. V. R. Born, ``Delay in
Primary Haemostasis Produced by a Fish Diet without Change in Local
Thromboxane A2,'' British Journal of Haematology, 58:567-
578, 1984.
19. Wojenski, C. M., M. J. Silver, and J. Walker,
``Eicosapentaenoic Acid Ethyl Ester as an Antithrombotic Agent,
Comparison to an Extract of Fish Oil,'' Biochemica et Biophysica
Acta, 1081:33-38, 1991.
20. Zucker, M. L., D. S. Bilyeu, G. M. Helmkamp, W. S. Harris,
and C. A. Dujovne, ``Effects of Dietary Fish Oil on Platelet
Function and Plasma Lipids in Hyperlipoproteinemic and Normal
Subjects,''Atherosclerosis, 73:13-22, 1988.
21. Dehmer, G. J., J. J. Popma, E. K. Egerton, et al.,
``Reduction in the Rate of Early Restenosis After Coronary
Angioplasty by a Diet Supplemented with n-3 Fatty Acids,''New
England Journal of Medicine, 319:733-740, 1988.
22. Harris, W. S., D. W. Rothrock, A. Fanning, et al., ``Fish
Oils in Hypertriglyceridemias: A Dose Response Study,'' American
Journal of Clinical Nutrition, 51:399-406, 1990.
23. Atkinson, P. M., M. C. Wheeler, D. Mendelsohn, et al.,
``Effects of a 4-week Freshwater Fish (Trout) Diet on Platelet
Aggregation, Platelet Fatty Acids, Serum Lipids, and Coagulation
Factors,'' American Journal of Hematology, 24:143-149, 1987.
24. Harris, W. S., S. Silveria, and C. A. Dujovne, ``The
Combined Effects of n-3 Fatty Acids and Aspirin on Hemostatic
Parameters in Man,'' Thrombosis Research, 57:517-526, 1990.
25. Jensen, C. D., G. A. Spiler, V. J. Wookey, L. G. Wong, J. H.
Whitman, and J. Scala, ``Plasma Lipids on Three Levels of Fish Oil
Intake in Healthy Human Subjects,''Nutrition Reports International,
38:165-171, 1988.
26. Lorenz, R., U. Spengler, S. Fischer, et al., ``Platelet
Function, Thromboxane Formation, and Blood Pressure Control During
Supplementation of the Western Diet with Cod Liver Oil,''
Circulation, 67:504-511, 1983.
27. Owens, M. R., and W. T. Cave, ``Dietary Fish Lipids Do Not
Diminish Platelet Adhesion to Subendothelium,'' British Journal of
Haematology, 75:82-85, 1990.
28. DeCaterina, R., D. Giannessi, A. Mazzone, W. Bernini, G.
Lazzerini, S. Maffei,
[[Page 30756]]
M. Cerri, L. Salvatore, and B. Weksler, ``Vascular Prostacyclin is
Increased in Patients Ingesting -3 Polyunsaturated Fatty
Acids Before Coronary Artery Bypass Graft Surgery,'' Circulation,
82:428-438, 1990.
29. Green, D., L. Barreres, J. Borensztajn, P. Kaplan, M. N.
Reddy, R. Rovner, and H. Simon, ``A Double-Blind, Placebo-Controlled
Trial of Fish Oil Concentrate (MaxEpa) in Stroke Patients,'' Stroke,
16:706-709, 1985.
30. Smith, P., H. Arnesen, T. Opstad, K. H. Dahl, and J.
Eritsland, ``Influence of Highly Concentrated n-3 Fatty Acids on
Serum Lipids and Hemostatic Variables in Survivors of Myocardial
Infraction Receiving Either Oral Anticoagulants or Matching
Placebo,'' Thrombosis Research, 53:467-474, 1989.
31. Schmidt, E. B., E. Ernst, K. Varming, J. O. Pederson, and J.
Dyerberg, ``The Effect of n-3 Fatty Acids on Lipids and Haemostasis
in Patients with Type IIa and Type IV Hyperlipidemia, Thrombosis and
Haemostasis,'' 62:797-801, 1989.
32. Solomon, S. A., I. Cartwright, G. Pockley, M. Greaves, F. E.
Preston, L. E. Ramsay, and P. C. Walker, ``A Placebo-Controlled
Double-Blind Study of Eicosapentaenoic Acid-rich Fish Oil in
Patients with Stable Angina Pectoris,'' Current Medical Research and
Opinion, 12:1-11, 1990.
33. Harris, W. S., S. L. Windsor, and C. A. Dujovne, ``Effects
of Four Doses of n-3 Fatty Acids Given to Hyperlipidemic Patients
for Six Months,'' Journal of the American College of Nutrition,
10:220-227, 1991.
34. Nilsen, D. W. T., K. Dalaker, A. Nordoy, et al., ``Influence
of a Concentrated Ethylester Compound of n-3 Fatty Acids on Lipids,
Platelets, and Coagulation in Patients Undergoing Coronary Bypass
Surgery,'' Thrombosis and Haemostasis, 66:195-201, 1991.
35. Franzen, D., M. Schannwell, K. Oette, and H. W. Hopp, ``A
Prospective, Randomized, and Double-Blind Trial on the Effect of
Fish Oil on the Incidence of Restenosis Following PTCA,''
Catheterization and Cardiovascular Diagnosis, 28:301-310, 1993.
36. Bowles, M. H., D. Klonis, T. G. Plavac, et al., ``EPA in the
Prevention of Restenosis Post PTCA,'' Angiology, pp. 187-194, March
1991.
37. Bairati, I., L. Roy, and F. Meyer, ``Double-blind,
Randomized, Controlled Trial of Fish Oil Supplements in Prevention
of Recurrence of Stenosis after Coronary Angioplasty,'' Circulation,
85:950-956, 1992.
38. Grigg, L. E. T., W. H. Kay, P. A. Valentine, et al.,
``Determinants of Restenosis and Lack of Effect of Dietary
Supplementation with Eicosapentaenoic Acid on the Incidence of
Coronary Artery Restenosis after Angioplasty,'' Journal of the
American College of Cardiology, 13:665-672, 1989.
39. Milner, M. R., R. A. Gallino, A. Leffingwell, et al.,
``Usefulness of Fish Oil Supplements in Preventing Clinical Evidence
of Restenosis After Percutaneous Transluminal Coronary
Angioplasty,'' American Journal of Cardiology, 64:294-299, 1989.
40. Reis, G. J., T. M. Boucher, M. E. Sipperly, et al.,
``Randomized Trial of Fish Oil for Prevention of Restenosis After
Coronary Angioplasty,'' Lancet, pp. 177-181, July 1989.
41. Annuzzi, G., A. Rivellese, B. Capaldo, L. Di Marino, C.
Iovine, G. Marotta, and G. Riccardi, ``A Controlled Study on the
Effects of N-3 Fatty Acids on Lipid and Glucose Metabolism in Non-
Insulin-Dependent Diabetic Patients,'' Atherosclerosis, 87:65-73,
1991.
42. Hendra, T.J., et al., ``Effects of Fish Oil Supplements in
NIDDM Subjects: Controlled Study,'' Diabetes Care, 13:821-829, 1990.
43. Kasim, S.E., et al., ``Effect of Omega-3 Fish Oils on Lipid
Metabolism, Glycemic Control, and Blood Pressure in Type II Diabetic
Patients,'' Journal of Clinical Endocrinology and Metabolism, 67:1-
5, 1988.
44. Borkman, M., et al., ``Effects of Fish Oil Supplementation
on Glucose and Lipid Metabolism in NIDDM,'' Diabetes, 38:1314-1319,
1989.
45. Vessby, B., and M. Boberg, ``Dietary Supplementation with N-
3 Fatty Acids May Impair Glucose Homeostasis in Patients with Non-
Insulin-Dependent Diabetes Mellitus,'' Journal of Internal Medicine,
228:165-171, 1990.
46. Friday, K.E., et al., ``Elevated Plasma Glucose and Lowered
Triglyceride levels from Omega-3 Fatty Acid Supplementation in Type
II Diabetics,'' Diabetes Care, 12:276-281, 1989.
47. Glauber, H., P. Wallace, K. Griever, and G. Brechtel,
``Adverse Metabolic Effect of Omega-3 Fatty Acids in Non-Insulin-
Dependent Diabetes Mellitus,'' Annals of Internal Medicine, 108:663-
668, 1988.
48. Schectman, G., S. Kaul, A.H. Kissebah, ``Effect of Fish Oil
Concentrate on Lipoprotein Composition in NIDDM,'' Diabetes,
37:1567-1573, 1988.
49. Zambon, S., et al., ``Effect of Glyburide and -3
Fatty Acid Dietary Supplements on Glucose and Lipid Metabolism in
Patients with Non-Insulin-Dependent Diabetes Mellitus,'' American
Journal of Clinical Nutrition, 56:447-454, 1992.
50. Memorandum, October 19, 1993, Michael DiNovi, FDA,
Washington, DC to Lawrence Lin, FDA, Washington, DC.
51. Memorandum, May 16, 1997, William Hubbard, Associate
Commissioner for Policy Coordination, FDA, Rockville, MD to Lawrence
Lin, FDA, Washington, DC.
List of Subjects in 21 CFR Part 184
Food additives, Food ingredients, Incorporation by reference.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, and
redelegated to the Director, Center for Food Safety and Applied
Nutrition, 21 CFR part 184 is amended as follows:
PART 184--DIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED
AS SAFE
1. The authority citation for 21 CFR part 184 continues to read as
follows:
Authority: Secs. 201, 402, 409, 701 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).
2. Section 184.1472 is revised to read as follows:
Sec. 184.1472 Menhaden oil.
(a) Menhaden oil. (1) Menhaden oil is prepared from fish of the
genus Brevoortia, commonly known as menhaden, by cooking and pressing.
The resulting crude oil is then refined using the following steps:
Storage (winterization), degumming (optional), neutralization,
bleaching, and deodorization. Winterization may separate the oil and
produce a solid fraction.
(2) Menhaden oil meets the following specifications:
(i) Color and state. Yellow liquid to white solid.
(ii) Odor. Odorless to slightly fishy.
(iii) Saponification value. Between 180 and 200 as determined by
the American Oil Chemists' Society Official Method Cd 3-25--
``Saponification Value'' (reapproved 1989), which is incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies
of this publication are available from the Office of Premarket
Approval, Center for Food Safety and Applied Nutrition (HFS-200), Food
and Drug Administration, 200 C St. SW., Washington, DC 20204, or
available for inspection at the Center for Food Safety and Applied
Nutrition's Library, Food and Drug Administration, 200 C St. SW., rm.
3321, Washington DC, or at the Office of the Federal Register, 800
North Capitol St. NW., suite 700, Washington, DC.
(iv) Iodine number. Not less than 120 as determined by the American
Oil Chemists' Society Recommended Practice Cd 1d-92--``Iodine Value of
Fats and Oils, Cyclohexane--Acetic Acid Method,'' which is incorporated
by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. The
availability of this incorporation by reference is given in paragraph
(a) (2) (iii) of this section.
(v) Unsaponifiable matter. Not more than 1.5 percent as determined
by the American Oil Chemists' Society Official Method Ca 6b-53--
``Unsaponifiable Matter'' (reapproved 1989), which is incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. The
availability of this incorporation by reference is given in paragraph
(a) (2) (iii) of this section.
(vi) Free fatty acids. Not more than 0.1 percent as determined by
the American Oil Chemists' Society Official Method Ca 5a-40--``Free
Fatty Acids''
[[Page 30757]]
(reapproved 1989), which is incorporated by reference in accordance
with 5 U.S.C. 552(a) and 1 CFR part 51. The availability of this
incorporation by reference is given in paragraph (a) (2) (iii) of this
section.
(vii) Peroxide value. Not more than 5 milliequivalents per kilogram
of oil as determined by the American Oil Chemists' Society Official
Method Cd 8-53--``Peroxide Value, Acetic Acid--Chloroform Method''
(updated 1992) or Recommended Practice Cd 8b-90--``Peroxide Value,
Acetic Acid--Isooctane Method'' (updated 1992), which are incorporated
by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. The
availability of this incorporation by reference is given in paragraph
(a)(2)(iii) of this section.
(viii) Lead. Not more than 0.1 part per million as determined by
the American Oil Chemists' Society Official Method Ca 18c-91--
``Determination of Lead by Direct Graphite Furnace Atomic Absorption
Spectrometry'' (revised 1992), which is incorporated by reference in
accordance with 5 U.S.C. 552(a) and 1 CFR part 51. The availability of
this incorporation by reference is given in paragraph (a)(2)(iii) of
this section.
(ix) Mercury. Not more than 0.5 part per million as determined by
the method entitled ``Biomedical Test Materials Program: Analytical
Methods for the Quality Assurance of Fish Oil,'' published in the
``NOAA Technical Memorandum NMFS-SEFC-211,'' F. M. Van Dolah and S. B.
Galloway, editors, National Marine Fisheries Service, U. S. Department
of Commerce, pages 71-88, November, 1988, which is incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. The
availability of this incorporation by reference is given in paragraph
(a)(2)(iii) of this section.
(3) In accordance with Sec. 184.1(b)(2), the ingredient may be used
in food only within the following specific limitations:
------------------------------------------------------------------------
Maximum level of use in food
Category of food (as served)
------------------------------------------------------------------------
Cookies, crackers, Sec. 170.3(n)(1) of 5.0 percent
this chapter..
Breads, rolls (white & dark), Sec. 1.0 percent
170.3(n)(1) of this chapter..
Fruit pies, custard pies, Sec. 7.0 percent
170.3(n)(1) of this chapter..
Cakes, Sec. 170.3(n)(1) of this 10.0 percent
chapter..
Cereals, Sec. 170.3(n)(4) of this 4.0 percent
chapter..
Fats, oils, Sec. 170.3(n)(12) of this 20.0 percent
chapter, but not in infant formula..
Yogurt, Sec. 170.3(n)(31) of this 4.0 percent
chapter..
Cheese products, Sec. 170.3(n)(5) of 5.0 percent
this chapter..
Frozen dairy products, Sec. 5.0 percent
170.3(n)(20) of this chapter..
Meat products, Sec. 170.3(n)(29) of 10.0 percent
this chapter..
Egg products, Sec. 170.3(n)(11) of 5.0 percent
this chapter..
Fish products, Sec. 170.3(n)(13) of 20.0 percent
this chapter..
Condiments, Sec. 170.3(n)(8) of this 5.0 percent
chapter..
Soup mixes, Sec. 170.3(n)(40) of this 3.0 percent
chapter..
Snack foods, Sec. 170.3(n)(37) of this 5.0 percent
chapter..
Nut products, Sec. 170.3(n)(32) of 5.0 percent
this chapter..
Gravies, sauces, Sec. 170.3(n)(24) of 5.0 percent
this chapter..
------------------------------------------------------------------------
(b) Hydrogenated and partially hydrogenated menhaden oils. (1)
Partially hydrogenated and hydrogenated menhaden oils are prepared by
feeding hydrogen gas under pressure to a converter containing crude
menhaden oil and a nickel catalyst. The reaction is begun at 150 to 160
deg.C and after 1 hour the temperature is raised to 180 deg.C until
the desired degree of hydrogenation is reached. Hydrogenated menhaden
oil is fully hydrogenated.
(2) Partially hydrogenated and hydrogenated menhaden oils meet the
following specifications:
(i) Color. Opaque white solid.
(ii) Odor. Odorless.
(iii) Saponification value. Between 180 and 200.
(iv) Iodine number. Not more than 119 for partially hydrogenated
menhaden oil and not more than 10 for fully hydrogenated menhaden oil.
(v) Unsaponifiable matter. Not more than 1.5 percent.
(vi) Free fatty acids. Not more than 0.1 percent.
(vii) Peroxide value. Not more than 5 milliequivalents per kilogram
of oil.
(viii) Nickel. Not more than 0.5 part per million.
(ix) Mercury. Not more than 0.5 part per million.
(x) Arsenic (as As). Not more than 0.1 part per million.
(xi) Lead. Not more than 0.1 part per million.
(3) Partially hydrogenated and hydrogenated menhaden oils are used
as edible fats or oils, as defined in Sec. 170.3(n)(12) of this
chapter, in food at levels not to exceed current good manufacturing
practice.
(4) If the fat or oil is fully hydrogenated, the name to be used on
the label of a product containing it shall include the term
``hydrogenated,'' or if it is partially hydrogenated, the name shall
include the term ``partially hydrogenated,'' in accordance with
Sec. 101.4(b)(14) of this chapter.
Dated: May 22, 1997.
Fred R. Shank,
Director, Center for Food Safety and Applied Nutrition.
[FR Doc. 97-14683 Filed 6-4-97; 8:45 am]
BILLING CODE 4160-01-F