[Federal Register Volume 62, Number 108 (Thursday, June 5, 1997)]
[Rules and Regulations]
[Pages 30751-30757]
From the Federal Register Online via the Government Printing 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