Substances Affirmed as Generally Recognized as Safe: Menhaden Oil

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