[Federal Register Volume 61, Number 170 (Friday, August 30, 1996)]
[Rules and Regulations]
[Pages 45886-45889]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-22246]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 184

[Docket No. 85G-0335]


Direct Food Substances Affirmed as Generally Recognized as Safe; 
Enzyme-Modified Lecithin

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations to affirm that the use of enzyme-modified lecithin as a 
direct human food ingredient is generally recognized as safe (GRAS). 
This action is in response to a petition filed by Kyowa Hakko Kogyo 
Co., Ltd.

DATES: Effective August 30, 1996. 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 two publications listed in 
new Sec. 184.1063, effective August 30, 1996.

FOR FURTHER INFORMATION CONTACT: Aydin Orstan, Center for Food Safety 
and Applied Nutrition (HFS-217), Food and Drug Administration, 200 C 
St. SW., Washington, DC 20204, 202-418-3076.

SUPPLEMENTARY INFORMATION:

I. Background

    In accordance with the procedures described in Sec. 170.35 (21 CFR 
170.35),

[[Page 45887]]

Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan, submitted a petition (GRASP 
5G0301) proposing that enzyme-modified lecithin be affirmed as GRAS as 
a direct human food ingredient.
    FDA published a notice of filing of this petition in the Federal 
Register of August 27, 1985 (50 FR 34758), and gave interested parties 
an opportunity to submit comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. FDA received two comments in response to that 
notice. One of the comments stated that the specifications proposed by 
the petitioner for enzyme-modified lecithin did not agree with the 
specifications for lecithin in the Food Chemicals Codex, 3d ed. (1981) 
and argued that because of the differences in the specifications, 
enzyme-modified lecithin should be the subject of a food additive 
petition rather than a GRAS affirmation petition. FDA finds that the 
specifications of enzyme-modified lecithin need not agree with those of 
lecithin, because the two substances are chemically different. The 
agency further concludes that the differences between the 
specifications should not affect the classification of this petition. 
The second comment endorsed the petitioned use of enzyme-modified 
lecithin. Subsequently, the same commenter requested that FDA regulate 
enzyme-modified lecithin under the existing GRAS affirmation regulation 
for lecithin (Sec. 184.1400) (21 CFR 184.1400)). The agency concludes 
that because the chemical composition of enzyme-modified lecithin is 
different than that of lecithin, enzyme-modified lecithin should be 
regulated separately.

II. Standards for GRAS Affirmation

    Under 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 (Sec. 170.30(a)). 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)). In its petition, Kyowa 
Hakko Kogyo Co., Ltd., relies on scientific procedures, primarily 
published scientific papers and books, corroborated by unpublished 
information, to demonstrate that enzyme-modified lecithin is GRAS.

III. Identity, Production, and Technical Effect

    Lecithin is a complex mixture primarily composed of phospholipids, 
triglycerides, fatty acids, and carbohydrates (Refs. 1 and 2). The 
removal of most of the triglycerides and fatty acids of lecithin 
produces an ``oil-free'' or ``deoiled'' lecithin with a 90 percent or 
more phospholipid content. The enzyme phospholipase A2, identified 
with the Enzyme Commission (EC) number EC 3.1.1.4, converts the 
principal phospholipids of lecithin to their corresponding 
lysophospholipids. This reaction produces enzyme-modified lecithin 
(Refs. 3 through 6).
    Enzyme-modified lecithin is prepared from various types of crude or 
deoiled lecithin, using either purified phospholipase A2 or 
pancreatin, an enzyme preparation from porcine pancreas that contains 
phospholipase A2. Added calcium chloride supplies calcium ions 
required for the activation of phospholipase A2. The process is 
carried out at pH 6 to 10 and within the temperature range of 30 to 
70 deg.C. At completion, phospholipase A2 is inactivated by 
raising the temperature to 90 to 100 deg.C.
    The resulting enzyme-modified lecithin contains lysophospholipids 
and fatty acids produced by the enzymic reaction, as well as other 
components of lecithin (e.g., phospholipids, carbohydrates). 
Inactivated phospholipase A2 and calcium chloride are also present 
in enzyme-modified lecithin. The exact composition of enzyme-modified 
lecithin varies depending on the type and the composition of lecithin 
used and on the degree of modification of lecithin achieved during the 
production of enzyme-modified lecithin (Ref. 7).
    The petitioner intends to use enzyme-modified lecithin as an 
emulsifier in various foods, including bakery products, pasta products, 
margarine, mayonnaise, and salad dressings. The petition contains a 
published report and several patents demonstrating the effectiveness of 
enzyme-modified lecithin as an emulsifier in foods (Refs. 4, 5, 6, 8, 
and 9).

IV. Safety Evaluation

    In evaluating the safety of enzyme-modified lecithin, the agency 
considered the following issues: (1) The safety of lecithin and 
phospholipase A2, (2) the safety of enzyme-modified lecithin, (3) 
exposure to levels of the ingredient in food, and (4) specifications.

A. The Safety of Lecithin and Phospholipase A2

    FDA has affirmed lecithin as GRAS (Sec. 184.1400). Therefore, the 
agency has no safety concerns about the use of lecithin for the 
manufacture of enzyme-modified lecithin.
    Phospholipase A2 is one of the digestive enzymes present in 
the pancreatic juice of mammals, including humans (Refs. 10 through 
12). Phospholipase A2 is irreversibly inactivated by heat at the 
end of the manufacture of enzyme-modified lecithin. Active and inactive 
enzymes are constituents of many foods normally consumed by humans. 
Therefore, FDA concludes that inactive phospholipase A2 in enzyme-
modified lecithin will be digested like any other protein present in 
food. The agency also notes that calcium chloride, which is used to 
activate phospholipase A2 during the production of enzyme-modified 
lecithin, has been affirmed as GRAS (21 CFR 184.1193).

B. The Safety of Enzyme-Modified Lecithin

    The end products of the modification of lecithin by phospholipase 
A2 are lysophospholipids and fatty acids. Fatty acids are normal 
constituents of lecithin. They also occur naturally in many foods and 
form in the human body during normal cellular metabolism (Refs. 11 and 
12). FDA has approved the use of salts of fatty acids as binders, 
emulsifiers and anticaking agents in food (21 CFR 172.863). Therefore, 
the agency has no safety concerns about the presence of fatty acids in 
enzyme-modified lecithin.
    Numerous published reports establish that the lysophospholipids 
produced during the manufacture of enzyme-modified lecithin also occur 
naturally in a variety of foods, especially in cereal grains and eggs 
(Refs. 13 through 19). Furthermore, these lysophospholipids form in the 
human body from the action of pancreatic phospholipase A2 on 
dietary lecithin (Refs. 11 and 12).
    FDA reviewed several published studies suggesting that under 
certain pathologic conditions the intestinal fluid containing 
lysophospholipids may regurgitate into the stomach and damage the 
stomach mucosal tissue (Refs. 12 and 20 through 23). The agency 
evaluated these studies in light of the possible adverse effects of 
enzyme-modified lecithin ingested in food. FDA concludes that the 
results of the studies suggesting that regurgitated lysophospholipids 
may damage the

[[Page 45888]]

stomach mucosal tissue are not relevant to the food ingredient uses of 
enzyme-modified lecithin, because the lysophospholipids present in 
enzyme-modified lecithin will be emulsified within a large excess of 
undigested food, which would provide a physical barrier to direct 
interaction of the lysophospholipids with the mucosal lining.
    Moreover, in 1979, the Select Committee on GRAS Substances reviewed 
the available information on the metabolism of lecithin, including its 
breakdown to lysophospholipids in the human body, and concluded that 
there was no evidence of a hazard to the public from the use of 
lecithin in food at existing levels or levels that might reasonably be 
expected in the future (Ref. 24).
    FDA also reviewed one published animal feeding study included in 
the petition (Ref. 6). During this study two groups of rats were fed 
for 3 and 13 weeks, respectively, diets containing various doses of 
enzyme-modified lecithin. The results of this study did not reveal any 
significant adverse effects in rats attributable to enzyme-modified 
lecithin.
    Furthermore, the petitioner provided one unpublished corroborative 
feeding study. During this study enzyme-modified lecithin was 
administered to rats at a dose of 2,000 milligrams per kilogram body 
weight per day (mg/kg bw/d) for 30 days, followed by 6 days per week 
for 60 days, for a total of 90 days. The results of this study did not 
reveal any adverse effects on the gastric mucosa of the rats or any 
other significant adverse effects attributable to enzyme-modified 
lecithin.

C. Estimated Exposure Levels

    Based on the petitioner's intended use of enzyme-modified lecithin 
in a manner similar to lecithin, and using information on consumption 
of various food categories containing lecithin (Ref. 25), the agency 
calculated the estimated daily intake (EDI) of enzyme-modified lecithin 
as 326 mg/person/d.
    Moreover, the data obtained in the published 13-week rat feeding 
study (Ref. 6) showed no adverse effects at a level of 20 grams enzyme-
modified lecithin/kg bw/d. Application of a 1,000-fold safety factor to 
this value produces, for a 60 kg person, an acceptable daily intake of 
1,200 mg enzyme-modified lecithin/person/d, which exceeds the EDI 
reported above (326 mg/person/d).

D. Specifications

    FDA reviewed the specifications for enzyme-modified lecithin 
suggested in the petition. The agency notes that the petitioner 
originally suggested a lead limit of not more than 10 parts per 
million. However, after discussions with FDA about the agency's desire 
to limit human exposure to lead to the lowest level possible in food 
(see 59 FR 5363, February 4, 1994), the petitioner amended the petition 
to suggest a lead limit of not more than 1.0 part per million. FDA 
agrees that this lower limit should be adopted. Also, the agency notes 
that in a notice published in the Federal Register of March 14, 1994 
(59 FR 11789), the National Academy of Sciences/Institute of Medicine 
Committee on Food Chemicals Codex (the Committee) announced its new 
policy that inclusion of arsenic limits in Food Chemicals Codex 
monographs should no longer be routine, but should be considered on an 
``as-needed'' basis. To implement this new policy, the Committee 
proposed to delete the arsenic specification for various Food Chemicals 
Codex substances, including lecithin. The proposal became final when 
the fourth edition of the Food Chemicals Codex was published in 1996. 
FDA agrees that a specification for arsenic in enzyme-modified lecithin 
is not necessary. Therefore, no such specification is being adopted in 
this final rule. FDA concludes that the other specifications suggested 
in the petition should be adopted.

V. Conclusion

    FDA has evaluated the published information in the petition, along 
with other corroborative information, and finds that the use of enzyme-
modified lecithin as an emulsifier in foods is GRAS.
    Furthermore, these data show no potential risk from any foreseeable 
use of enzyme-modified lecithin. Therefore, in accordance with 21 CFR 
184.1(b)(1), the agency is affirming that the use of enzyme-modified 
lecithin in foods is GRAS with no limits other than current good 
manufacturing practice.

VI. Environmental Impact

    The agency has carefully considered the potential environmental 
effects of this action. FDA has concluded that the action 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 environmental impact analysis report submitted under 
previous 21 CFR part 25, may be seen in the Dockets Management Branch 
(address above) between 9 a.m. and 4 p.m., Monday through Friday.

VII. Analysis of Impacts

    FDA has examined the economic implications of this final rule 
affirming the GRAS status of the use of enzyme-modified lecithin in 
foods under Executive Order 12866. Executive Order 12866 directs 
agencies to assess all costs and benefits of available regulatory 
alternatives and, when regulation is necessary, to select regulatory 
approaches that maximize net benefits (including potential economic, 
environmental, public health, and safety issues; distributive impacts; 
and equity). The agency believes that this final rule is consistent 
with the regulatory philosophy and principles identified in the 
Executive Order. In addition, the final rule is not a significant 
regulatory action as defined by the Executive Order and so is not 
subject to review under the Executive Order.
    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 significant economic 
impact of the rule on small entities. This final rule recognizes the 
applicability of a statutory exemption. The impact of the rule is to 
remove uncertainty about the regulatory status of enzyme-modified 
lecithin for use in foods. Therefore, pursuant to the Regulatory 
Flexibility Act, 5 U.S.C. 605(b), the Commissioner certifies that this 
rule will not have a significant economic impact on a substantial 
number of small entities.

VIII. 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)).

IX. References

    The following references have been placed on display in 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. Scholfield, C. R., ``Composition of Soybean Lecithin,'' 
Journal of American Oil Chemists' Society, 58:889-892, 1981.
    2. Rydhag, L., ``The Importance of the Phase Behaviour of 
Phospholipids for Emulsion Stability,'' Fette Seifen Anstrichmittel, 
81:168-173, 1979.
    3. Van Nieuwenhuyzen, W., ``The Industrial Uses of Special 
Lecithins: A Review,'' Journal of American Oil Chemists' Society, 
58:886-888, 1981.

[[Page 45889]]

    4. Lincklaen, H. W., and J. H. M. Rek, ``Pourable Emulsion,'' 
U.S. Patent 3,796,815, March 12, 1974.
    5. Van Dam, A. F., ``Emulsions,'' U.S. Patent 4,034,124, July 5, 
1977.
    6. Dutilh, C. E., and W. Groger, ``Improvement of Product 
Attributes of Mayonnaise by Enzymic Hydrolysis of Egg Yolk with 
Phospholipase A2,'' Journal of Science of Food and Agriculture, 
32:451-458, 1981.
    7. Pardun, H., ``Advances in the Extraction and Processing of 
Phytolecithins,'' Fette Seifen Anstrichmittel, 84:1-29, 1982.
    8. Pardun, H., ``Phosphatide Emulsifiers,'' U.S. Patent 
3,661,795, May 9, 1972.
    9. Van Dam, A. F., ``Oil-in-Water Emulsion and Process for the 
Preparation Thereof,'' U.S. Patent 4,119,564, October 10, 1978.
    10. De Haas, G. H., N. M. Postema, W. Nieuwenhuizen, and L. L. 
M. Van Deenen, ``Purification and Properties of Phospholipase A from 
Porcine Pancreas,'' Biochimica et Biophysica Acta, 159:103-117, 
1968.
    11. Rossiter, R. J., ``Metabolism of Phosphatides,'' in 
``Metabolic Pathways,'' edited by D. M. Greenberg, vol. II, pp. 69-
115, Academic Press, New York, 1968.
    12. Johnson, A. G., and S. J. McDermott, ``Lysolecithin: A 
Factor in the Pathogenesis of Gastric Ulceration?'' Gut, 15:710-713, 
1974.
    13. Acker, L., and G. Becker, ``On the Subject of the Grain 
Starch Lipids,'' Gordian, 72:275-278, 1972.
    14. Hargin, K. D., and W. R. Morrison, ``The Distribution of 
Acyl Lipids in the Germ, Aleurone, Starch and Non-starch Endosperm 
of Four Wheat Varieties,'' Journal of Science of Food and 
Agriculture, 31:877-888, 1980.
    15. Morrison, W. R., D. L. Mann, W. Soon, and A. M. Coventry, 
``Selective Extraction and Quantitative Analysis of Non-starch and 
Starch Lipids from Wheat Flour,'' Journal of Science of Food and 
Agriculture, 26:507-521, 1975.
    16. Clayton, T. A., and W. R. Morrison, ``Changes in Flour 
Lipids During the Storage of Wheat Flour,'' Journal of Science of 
Food and Agriculture, 23:721-736, 1972.
    17. Mano, Y., and Y. Fujino, ``Combined Lipid in Rice Starch,'' 
Denpun Kagaku, 22:1-5, 1975.
    18. Tan, S. L., and W. R. Morrison, ``The Distribution of Lipids 
in the Germ, Endosperm, Pericarp and Tip Cap of Amylomaize, LG-11 
Hybrid Maize and Waxy Maize,'' Journal of American Oil Chemists' 
Society, 56:531-535, 1979.
    19. Weihrauch, J. L., and Y. Son, ``The Phospholipid Content of 
Foods,'' Journal of American Oil Chemists' Society, 60:1971-1978, 
1983.
    20. Davenport, H. W., ``Effect of Lysolecithin, Digitonin, and 
Phospholipase A upon the Dog's Gastric Mucosal Barrier,'' 
Gastroenterology, 59:505-509, 1970.
    21. Bolin, T., L. Franzen, R. Sjodahl, and C. Tagesson, 
``Passage of Molecules Through the Wall of the Gastrointestinal 
Tract,'' Scandinavian Journal of Gastroenterology, 21:441-448, 1986.
    22. Salo, J. A., H. Myllarniemi, and E. Kivilaakso, ``Morphology 
of Lysolecithin-Induced Damage on Esophageal Mucosa,'' Journal of 
Surgical Research, 42:290-297, 1987.
    23. Ritchie, W. P., ``Other Causes of GI Mucosal Injury: Upper 
Intestinal Content,'' Clinical and Investigative Medicine, 10:264-
269, 1987.
    24. Select Committee on GRAS Substances, ``Evaluation of the 
Health Aspects of Lecithin as a Food Ingredient,'' Report No. 106, 
Life Sciences Research Office, Federation of American Societies for 
Experimental Biology, Bethesda, Maryland, 1979.
    25. Memorandum from the Food Additive Chemistry Evaluation 
Branch to the GRAS Review Branch, June 3, 1985.

List of Subjects in 21 CFR Part 184

    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. New Sec. 184.1063 is added to subpart B to read as follows:


Sec. 184.1063  Enzyme-modified lecithin.

    (a) Enzyme-modified lecithin is prepared by treating lecithin with 
either phospholipase A2 (EC 3.1.1.4) or pancreatin.
    (b) The ingredient meets the specifications in paragraphs (b)(1) 
through (b)(8) of this section. Unless otherwise noted, compliance with 
the specifications listed below is determined according to the methods 
set forth for lecithin in the Food Chemicals Codex, 4th ed. (1996), pp. 
220-221, which are incorporated by reference in accordance with 5 
U.S.C. 552(a) and 1 CFR part 51. Copies are available from the National 
Academy Press, 2101 Constitution Ave. NW., Washington DC 20418, or may 
be examined at the Center for Food Safety and Applied Nutrition's 
Library, 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.
    (1) Acetone-insoluble matter (phosphatides), not less than 50.0 
percent.
    (2) Acid value, not more than 40.
    (3) Lead, not more than 1.0 part per million, as determined by 
atomic absorption spectroscopy.
    (4) Heavy metals (as Pb), not more than 20 parts per million.
    (5) Hexane-insoluble matter, not more than 0.3 percent.
    (6) Peroxide value, not more than 20.
    (7) Water, not more than 4.0 percent.
    (8) Lysolecithin, 50 to 80 mole percent of total phosphatides as 
determined by ``Determination of Lysolecithin Content of Enzyme-
Modified Lecithin: Method I,'' dated 1985, which is incorporated by 
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies 
are available from the
Division of Petition Control, Center for Food Safety and Applied 
Nutrition (HFS-215), Food and Drug Administration, 200 C St. SW., 
Washington, DC 20204, or may be examined at the Center for Food Safety 
and Applied Nutrition's Library, 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.
    (c) In accordance with Sec. 184.1(b)(1), the ingredient is used in 
food with no limitation other than current good manufacturing practice. 
The affirmation of this ingredient as generally recognized as safe as a 
direct human food ingredient is based upon the following current good 
manufacturing practice conditions of use:
    (1) The ingredient is used as an emulsifier as defined in 
Sec. 170.3(o)(8) of this chapter.
    (2) The ingredient is used at levels not to exceed current good 
manufacturing practice.

    Dated: July 31, 1996.
Fred R. Shank,
Director, Center for Food Safety and Applied Nutrition.
[FR Doc. 96-22246 Filed 8-29-96; 8:45 am]
BILLING CODE 4160-01-F