Chapter 2
Regulatory Status of Maillard Reaction Flavors Lawrence J. Lin Center for Food Safety and Applied Nutrition, Food and Drug Administration, 200 C Street, SW, Washington, DC 20204
Maillard reaction flavors have been introduced into the food supply based on manufacturers' conclusions that the scientific community has considered them to be GRAS. At the present time, FDA does not have enough information to disagree with such conclusions. An analytical method is being developed to determine the amounts and identities of heterocyclic amines which may be present in those flavors. This information is needed to clarify the GRAS status of Maillard reaction flavors. W h e n a food ingredient (new or old) i s u s e d as a component of food, a regulatory b u r d e n i s associated w i t h i t s use. T h e first question i s whether the ingredient i s a food additive u n d e r the definition provided i n the Federal Food, D r u g , a n d Cosmetic A c t (referred to hereafter as the statute). If it i s a food additive, it m u s t obtain premarket approval from the Food a n d D r u g A d m i n i s t r a t i o n (FDA) before it c a n be marketed for u s e i n food. O n the other h a n d , i f u s e of the ingredient i s generally recognized a s safe (GRAS) or h a s been sanctioned b y F D A or the U . S . Department of A g r i c u l t u r e (USDA) before 1958, the ingredient i s not a food additive. T h e latter two categories of substances, G R A S a n d prior-sanctioned, are exempt from the pre-market approval required of a food additive. M a i l l a r d reaction flavors are referred to here a s processed flavors. They are produced from complex m i x t u r e s that are converted to flavors (e.g., meat o r c h i c k e n flavor) b y a heating
This chapter not subject to U.S. copyright Published 1994 American Chemical Society
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THERMALLY GENERATED FLAVORS
process (1-3). The recipes for the precursor ingredients vary from c o m p a n y to c o m p a n y but invariably i n c l u d e , as essential ingredients, specific a m i n o acids, r e d u c i n g sugars, a n d a n i m a l or vegetable fats or oils. O p t i o n a l ingredients m a y i n c l u d e hydrolyzed vegetable protein, o n i o n extract, thiamine, inositol monophosphate, meat extract, a n d other substances (4). A l l of these p r e c u r s o r materials are c o m m o n food a n d flavoring ingredients. However, the safety of processed flavors centers a r o u n d the heating process w h i c h allows these ingredients to develop a desirable flavor i n the reaction mixture. B e c a u s e of this reaction, the review of the safety of processed flavors m u s t be focused on the reaction p r o d u c t s rather t h a n s i m p l y on the precursor materials. There is no question that processed flavors so produced are flavoring ingredients a n d t h u s their use m u s t be i n compliance w i t h the statute. The first question we w i l l a s k about processed flavors is: Is s u c h a flavor G R A S , priorsanctioned, or a food additive?
Regulations Pertaining to Processed Flavors Before we try to determine the categories to w h i c h processed flavors may belong, let u s d i s c u s s the legal definitions for food additives, G R A S substances, a n d prior-sanctioned substances, as w e l l as some h i s t o r i c a l b a c k g r o u n d related to the F D A ' s a p p l i c a t i o n s of the G R A S concept. A c c o r d i n g to section 201(s) of the statute, food additives include a n y substance, the intended use of w h i c h results, or m a y reasonably be expected to result, directly or indirectly, i n its becoming a component of, or otherwise affecting the characteristics of, a n y food. Food additives m u s t be approved by F D A , based o n a fair evaluation of the entire record available to the agency i n accordance w i t h section 4 0 9 of the statute. Food additives are deemed to be safe w h e n there is a reasonable certainty that the additive is not h a r m f u l u n d e r the intended c o n d i t i o n s of use. Section 201(s) also gives a brief definition of G R A S substances. G R A S substances i n c l u d e a n y substance, w h i c h is generally recognized a m o n g experts qualified by scientific t r a i n i n g a n d experience to evaluate its safety, as h a v i n g been adequately s h o w n t h r o u g h experience based o n c o m m o n use i n food before J a n u a r y 1, 1958, to be safe u n d e r the conditions of its intended use. G R A S substances also i n c l u d e a n y substance, w h i c h is generally recognized by the same experts as h a v i n g been adequately s h o w n t h r o u g h scientific procedures to be safe u n d e r the c o n d i t i o n s of its intended use. The statute d i d not appoint F D A as the sole authority to determine w h i c h substances are G R A S a n d w h i c h are not. The statute, i n fact, explicitly recognizes the scientific
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Regulatory Status of Maillard Reaction Flavors
c o m m u n i t y ' s expert opinions o n safety of food s u b s t a n c e s as a b a s i s for determining whether they are G R A S . Because of t h i s statutory definition r e q u i r i n g general recognition, it is quite obvious that a n y substance that is secret or not w e l l - k n o w n to the scientific c o m m u n i t y cannot be G R A S . Prior-sanctioned substances i n c l u d e those approved by F D A u n d e r the statute or by U S D A u n d e r the Federal Meat Inspection Act or the Federal Poultry Products Inspection A c t before September 6, 1958, as described i n section 201(s)(4) of the statute. The purpose of the exemption was to m a k e it u n n e c e s s a r y to seek approval of those substances that h a d been sanctioned by these two government agencies before the effective date of the 1958 Food Additives A m e n d m e n t . G R A S substances are a n open group of s u b s t a n c e s tied to the current state of scientific information a n d expert o p i n i o n s . In contrast, prior-sanctioned substances are a closed group of s u b s t a n c e s determined by pre-1958 F D A or U S D A decisions. The concept of " G R A S " is unique; no c o u n t r y other t h a n the U . S . h a s s u c h a category for food ingredients. The creation of the G R A S concept i n 1958 by Congress was p r a c t i c a l . The l a w m a k e r s at that time recognized that to subject a large n u m b e r of G R A S s u b s t a n c e s to safety testing w o u l d not only d i s r u p t the food supply, b u t w o u l d also place a n unnecessary financial b u r d e n o n i n d u s t r y . However, there w a s considerable debate over the usefulness of the G R A S concept d u r i n g the hearings h e l d i n Congress before it w a s finally adopted. M a n y people expressed c o n c e r n that the term " G R A S " was imprecise a n d vague, a n d d i d not specify how general the recognition of safety m u s t be i n order for a s u b s t a n c e to be G R A S . Others envisioned that the G R A S provision m a y present a p r o b l e m to food manufacturers w h o m u s t decide i f a new food ingredient w o u l d be G R A S . Nevertheless, Congress adopted the G R A S concept w i t h the support of F D A officials, w h o c l a i m e d that the G R A S provision h a d been w o r k i n g well w i t h new d r u g s a n d w i t h pesticide chemicals. There w a s little activity u p to 1971 o n the part of F D A to define what " G R A S " meant. F r o m 1959 to 1971, 21 C F R 121.3, w h i c h described G R A S criteria, stated t h a t " . . . a n y s u b s t a n c e added to food w h i c h h a s no history of c o m m o n use as a food ingredient s h o u l d be regarded as a substance that is not generally recognized as safe...unless it has been scientifically tested a n d s h o w n to be safe." O n J u n e 2 5 , 1971, 21 C F R 121.3 (based o n a proposal of December 8, 1970) was revised to be more specific about " G R A S . " The revised version declared that any substance of n a t u r a l biological origin (including those modified by conventional processing)
9
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THERMALLY GENERATED FLAVORS
c o n s u m e d p r i m a r i l y for n u t r i e n t properties before J a n u a r y 1, 1958, w i t h o u t detrimental effect, w o u l d be considered G R A S a n d there w a s no need for a p r o m u l g a t i o n i n the Federal Register for t h i s type of substance. It also listed five categories of substances w h i c h were considered eligible for G R A S classification, provided that c o n v i n c i n g evidence of their safety (including c o m m e n t s from qualified experts) w a s obtained by the agency. (1) S u b s t a n c e s defined i n s u b p a r a g r a p h (l)(i) of this paragraph that have been modified by processes proposed for i n t r o d u c t i o n into c o m m e r c i a l use after J a n u a r y 1, 1958, where s u c h processes m a y reasonably be expected to significantly alter the c o m p o s i t i o n of the substance. (2) S u b s t a n c e s that have h a d significant alteration of composition by breeding or selection a n d the change may reasonably be expected to alter to a significant degree the nutritive value or the concentration of toxic constituents therein. (3) Distillates, isolates, extracts, concentrates of extracts, or reaction products of substances considered as G R A S . (4) S u b s t a n c e s not of n a t u r a l biological origin i n c l u d i n g those for w h i c h evidence is offered that they are identical w i t h a G R A S counterpart of n a t u r a l biological origin. (5) S u b s t a n c e s of n a t u r a l biological origin intended for c o n s u m p t i o n for other t h a n their n u t r i e n t properties. F o u r of these five categories were substances of n a t u r a l biological origin a n d the r e m a i n i n g one w a s substances not of n a t u r a l biological origin b u t identical to their n a t u r a l counterparts that were G R A S . 21 C F R 121.3 also stated that substances that were neither of n a t u r a l biological origin n o r identical to G R A S substances of n a t u r a l biological origin w o u l d not be eligible for G R A S status if they h a d no history of food use. The 1971 version of 21 C F R 121.3 m a r k e d the agency's first attempt to define a b o u n d a r y for eligible G R A S substances. A more significant change i n the F D A ' s interpretation of the G R A S concept occurred w h e n the agency proposed to further revise 21 C F R 121.3 o n September 2 3 , 1974. The proposal, w h i c h w a s
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Regulatory Status of Maillard Reaction Flavors
11
finalized w i t h little change o n December 7, 1976, represented a refined a n d restricted view of what the G R A S criteria were supposed to be from the agency's point of view. The new 21 C F R 121.3 (recodified i n 1977 as 21 C F R 170.30) defined " G R A S " as: (1) G e n e r a l recognition of safety t h r o u g h scientific procedures m u s t ordinarily be based o n p u b l i s h e d literature, a n d requires the same quality a n d quantity of scientific evidence that w o u l d be required for approval of a food additive regulation. (2) G e n e r a l recognition of safety based o n history of c o m m o n use i n food does not require the same quality a n d quantity of scientific evidence required of a food additive, but s h a l l o r d i n a r i l y be based o n generally available d a t a a n d information. T h i s change was p a r t i c u l a r l y significant. It declared that a n y G R A S substance, based on scientific procedures, s h o u l d be required to p a s s the same rigid safety standards set for approval of a food additive, i.e., the same quality a n d quantity of scientific evidence.
Current Regulatory Status of Processed Flavors Are processed flavors G R A S , prior-sanctioned, or food additives? We k n o w that processed flavors have not been regulated by F D A as food additives, a n d we are also certain that processed flavors were not sanctioned by U S D A or F D A before September 6, 1958. Therefore, processed flavors m u s t have been m a r k e t e d for use i n food o n the basis of their manufacturers' determination that s u c h flavors are G R A S . A s stated earlier, the statute authorizes the scientific c o m m u n i t y , not F D A , to be the arbiter i n deciding w h i c h substances are G R A S a n d w h i c h are not. T h u s , a m a n u f a c t u r e r m a y consider that a p a r t i c u l a r food ingredient is G R A S , based o n its j u d g m e n t that the scientific c o m m u n i t y h a s considered that p a r t i c u l a r ingredient to be G R A S . T h i s type of determination i s often referred to as a n independent G R A S determination made by i n d i v i d u a l s outside F D A . However, s u c h a u n i l a t e r a l determination is subject to the r i s k that F D A may object to it a n d m a y challenge its use i n food o n the g r o u n d that the ingredient is a n u n a p p r o v e d food additive. A n example is the recent court cases o n evening primrose o i l , i n w h i c h F D A challenged independent GRAS determinations made for the oil by its promoters (5,6). Once F D A
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a n d the companies contest the G R A S s t a t u s of a s u b s t a n c e i n court, the ultimate decision as to whether the substance i s t r u l y G R A S lies w i t h the presiding judge. Processed flavors m a y be considered G R A S for the following reasons: (1) The m a n u f a c t u r i n g of processed flavors m i m i c s h i g h temperature c o o k i n g s u c h as barbecuing. The major difference between the flavors i n cooked meat a n d processed flavors i s that the latter are a mixture of selected food ingredients rather t h a n a raw a g r i c u l t u r a l commodity. A l s o , most processed flavors are produced at temperatures below 1 5 0 ° C (4), m u c h milder t h a n those u s e d i n barbecuing. (2) W h e n preparing a gravy, a chef m i x e s selected food ingredients a n d cooks at a certain temperature for a specified period of time. S u c h a gravy is i n fact s i m i l a r to a processed flavor, although the temperature used for the gravy is lower. (3) The use level of processed flavors is low, as is true w i t h other flavoring ingredients.
Safety of Processed Flavors To date, we are not aware of any significant adverse effects associated w i t h processed flavors u s e d as food ingredients. However, m a n y studies reported that meats cooked at h i g h temperatures c o n t a i n heterocyclic amines (7-11). Some processed flavors m a y also contain s m a l l a m o u n t s of heterocyclic a m i n e s , w h i c h are present as by-products or i m p u r i t i e s . The following nine s u c h heterocyclic amines have been isolated from cooked meat or fish. (1)
2-amino-3-methylimidazo[4,5-f]quinoline (IQ),
(2)
2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MelQ),
(3)
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx),
(4)
2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMelQx),
(5)
2-amino- l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP),
(6)
3-amino-l,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1),
(7)
3-amino-l-methyl-5H-pyrido[4,3-b]indole (Trp-P-2),
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Regulatory Status of Maillard Reaction Flavors ,
(8)
2-amino-6-methyldipyrido[l,2-a:3',2 -d]imidazole ( G l u P-l),
(9)
2-aminodipyrido[l,2-a:3 ,2'-d]imidazole (Glu-P-2).
,
These c o m p o u n d s were found to be mutagenic by the A m e s test. Moreover, dietary exposure to a l l of these c o m p o u n d s , except D i M e l Q x , increased the incidence of t u m o r s i n mice a n d rats (Carrington, C . D . , F D A , personal c o m m u n i c a t i o n , 1992). The p r i n c i p a l site for t u m o r i n d u c t i o n w a s the liver. M a l i g n a n t lesions following exposure to these c o m p o u n d s were also noted i n the forestomach, intestine, blood vessels, a n d the z y m b a l a n d clitoral glands of rats. Furthermore, i n a n ongoing study c o n d u c t e d by the N a t i o n a l C a n c e r Institute, IQ caused liver t u m o r s i n m o n k e y s . After 5 years, 8 out of 20 m o n k e y s w i t h a n intake of 10 m g I Q / d a y a n d 16 out of 2 0 m o n k e y s receiving 2 0 m g I Q / d a y developed liver t u m o r s , beginning from 21 m o n t h s to 40 m o n t h s . Studies i n m o n k e y s , sponsored by National C a n c e r Institute, w i t h M e l Q x a n d PhIP, are also u n d e r way. After 3.5 years, no t u m o r s have been observed i n the study w i t h M e l Q x . The same is true w i t h the study u s i n g PhIP, w h i c h has been ongoing for 2 years. A t this time, most of the information o n heterocyclic a m i n e s i n foods relates to cooked meat products. We do not have comparable information o n processed flavors. Therefore, new information m u s t be generated to show whether processed flavors c o n t a i n heterocyclic a m i n e s i n a m o u n t s sufficient to affect their safe use i n food. A n analytical method w o r k i n g group, started by F D A a n d the Flavor a n d Extract Manufacturers' Association (FEMA) i n 1990, involving government a n d i n d u s t r y laboratories is developing a protocol for quantification of heterocyclic a m i n e s i n processed flavors. F E M A h a s also conducted a survey of the i n d u s t r y to estimate the types a n d a m o u n t s of processed flavors made by the i n d u s t r y (4). The analytical method developed w i l l then be u s e d to determine the a m o u n t s a n d identities of heterocyclic a m i n e s present i n r a n d o m l y selected processed flavors. We hope that this information w i l l m a k e it possible to see the patterns i n w h i c h heterocyclic a m i n e s are formed i n the m a n u f a c t u r i n g of processed flavors. If so, manufacturers w i l l be able to control their m a n u f a c t u r i n g conditions to minimize the presence of heterocyclic a m i n e s i n processed flavors. Reliable information o n the identities a n d a m o u n t s of heterocyclic a m i n e s i n processed flavors w i l l also m a k e it possible to use r i s k assessment procedures to estimate the u p p e r - b o u n d limit
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of risk presented by any of these compounds present in processed flavors. By using risk assessment procedures, the scientific community will be in a better position to render a more informed judgment on the safe use of processed flavors. Summary 1.
The industry basis for considering processed flavors to be GRAS is presumably due to the similarity in processing conditions of these flavors to some home-cooking operations, e.g., barbecue sauce and gravy preparations.
2.
Safety of processed flavors should be based on reaction products and not on initial ingredients.
3.
The FDA does not have any data to challenge the industry's assertion that processed flavors are safe.
4.
More needs to be known about the composition of reaction flavor products, particularly the heterocyclic amine content.
5.
Some heterocyclic amines are toxic. Using the information from point 4, risk assessment can be performed.
Literature Cited 1.
2.
3. 4. 5.
6. 7.
Bailey, M. E. In The Maillard Reaction in Foods and Nutrition; Waller, G. R.; Feather, M. S., Eds.; ACS Symposium Series No. 215; American Chemical Society: Washington, DC, 1983; pp 169-184. Danehy, J . P. In Advances in Food Research; Chichester, C. O.; Mrak, E. M.; Schweigert, B. S., Eds.; Academic Press: New York, 1986; Vol. 30, pp 77-138. Hurrell, R. F. In Food Flavours; Morton, I. D.; Macleod, P. J . , Eds.; Elsevier: Amsterdam, 1982; pp 399-437. Easterday, O.; Manley, C.H. A Report to the Toxicology Forum; 1992, Aspen, CO. United States v. 45/194 kg Drums..."Pure Vegetable Oil..", Case No. CV 89-73 (Central District of California, Nov. 27, 1989). United Statesv.21 Approximately 180 kg Bulk Metal Drums..., Civil No. 88-0101-P (District of Maine, April 9, 1991). Felton, J . S.; Knize, M. G.; Shen, N. H.; Anderson, B.D.; Bjeldanes, L. F.; Hatch, F. T. Environ. Health Perspect. 1986, 67, 17-24.
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10. 11.
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Gross, G. A.; Philippossian, G.; Aeschbacher, H. U. Carcinogenesis 1989, 10, 1175-1182. Felton, J. S.; Knize, M. S. In Chemical Carcinogenesis and Mutagenesis. I. Handbook of Experimental Pharmacology; Cooper, C. S.; Grover, P. L., Eds.; Springer-Verlag: Berlin-Heidelberg, 1990; Vol. 94, pp 471-502. Gross, G. A. Carcinogenesis 1990, 11, 1597-1603. Miller, A. J. In Protein Quality and the Effects of Processing; Phillips, R. D.; Finley, J. W., Eds.; Marcel Dekker, Inc: New York, 1989; pp 145-188.
RECEIVED
June 17, 1993
