WHAT IS MEANT WHEN SOMETHING IS SAID TO BE “SAFE”?

In the definitions section of the Federal Food, Drug and Cosmetic Act (FFDCA) safety is defined; that is, “The term ‘safe’…has reference to the health of man or animal.”[1] The presumptive interpretation of this succinct statement is that “safe” is binary i.e., either something is safe, or it is not. However, on reflection, there is a need for more context: for example:

· Safe for whom?

· If “safe” is binary, does the difference in safety standards for one category of substances vs another, indicate different degrees of assurance of that safety?

· Who determines what is safe?

· What should be considered in determining safe use?

· Finally, is something safe by default if there is no data showing it is unsafe?

None of these questions are rhetorical questions or an argumentum ad absurdum in the faculty lounge but bear directly on the very real proposition of the assurance of no harm to the consumer.

Safe for whom?

In the famous US v Lexington Mill & Elevator Co.[2] the Court answers this question by describing the person who should not be harmed by the use of an ingredient (in this case, flour); that is “It [the substance] may be consumed … by the strong and the weak, the old and the young, the well and the sick, and it is intended that, if any [substance]…may possibly injure the health of any of these, it shall come within the ban of the statute.” However, because this definition is so broad, safety determinations were later re-calibrated toward the average (healthy) person.

As medical science progressed, it became obvious that certain consumers could not be included in the “average” person category, as described in the regulation “Foods for Special Dietary Use”[3], which was implemented to accommodate: “… a special dietary need that exists by reason of a physical, physiological, pathological or other condition including but not limited to the condition of disease, convalescence, pregnancy, lactation, infancy, allergic hypersensitivity to food, underweight, overweight, or the need to control the intake of sodium…[or] artificial sweetener…for use in the diets of diabetics…”[4]

From the Special Dietary Use regulation, sprouted the regulations for infant formula and medical foods, the former of which addressed infants whose vulnerability resided in the fact they have only a single source of nutrition and therefore require a complete diet in each serving. The latter (medical foods) protected those individuals that could not be included in the category of an “average healthy person”[5] but those with a particular inborn error of metabolism,[6] whose needs cannot not be met by a simple modification of a diet. Later, the Food Allergen Labeling and Consumer Protection Act of 2004 immortalized the concept that some ingredients were, in fact, dangerous for some consumers and required a label warning that the product contained common allergens such as milk, eggs, crustaceans, tree nuts, peanuts, soy, etc.

Even some food additives, while approved for use under “normal” conditions of intake, must include language on their label suggesting that over-consumption could have adverse consequences. Included in this group are maltitol (21CFR§180.25(e)) … "Excess consumption may have a laxative effect" and polydextrose (21CFR§172.841(e))… "Sensitive individuals may experience a laxative effect from excessive consumption of this product".

In sum, the safe use of a substance must recognize that there is a difference between individuals, such that an ingredient may be safe for use by some consumers, but not safe for other consumers, based on the health and circumstances of each individual. Plus the fact that consumers may occasionally use safe food ingredients in an unsafe manner.

Safety is a binary proposition, but there are degrees to the assurance of safety

The concept of degrees of assurance of safety can be demonstrated by the different degrees found between food ingredients and for dietary supplements. For food additives (21CFR§170.3(i)) and GRAS substances, “Safe or safety means that there is a reasonable certainty [emphasis added] in the minds of competent scientists that the substance is not harmful under the conditions of its intended use.” So then, the standard is “a reasonable certainty” but the regulation also goes on to state: “It is impossible in the present state of scientific knowledge to establish with complete certainty [emphasis added] the absolute harmlessness of the use of any substance. Thus, the boundaries of the degree of assurance of safety for food ingredients are drawn i.e., reasonable certainty vs. complete certainty (the latter sometimes referred to as “safety per se”), which as we have seen earlier was abandoned in US v Lexington Mill & Elevator Co. ruling.

The standard for dietary supplements is described in FFDCA §402 wherein adulterated foods[7] are defined and provides that if an (old[8]) dietary supplement or a product containing a dietary ingredient that “presents a significant or unreasonable risk of illness or injury…”[9] it should not enter into commerce. Likewise, “…a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury”[10] should not enter into commerce.

A new dietary ingredient that does not present an unreasonable risk is more popularly expressed as “…reasonably be expected to be safe”[11] [emphasis added] or as having a “reasonable expectation of safety”.

Therefore, although safety is a binary proposition, the assurance of that safety is a graded one in which food additives and GRAS substances must meet the standard of a “reasonable certainty” vs the dietary supplement standard of “reasonable expectation or assurance” and “does not present an unreasonable risk of injury”.

Who determines what is safe?

The credentials of anyone passing judgment on the safety of a substance (or of anything, for that matter), should be considered. If the person making the call on what is safe or not safe is not qualified to make that judgment, it really does not matter which safety standard the person wishes to employ.

Again, two examples come to mind, both enshrined in the FFDCA. First, for food ingredients, the FFDCA calls for “…experts qualified by scientific training and experience to evaluate its safety…”.[12] The statute is unmistakable in its insistence on “experts”[13] [emphasis added] and further, how the criteria by which experts can be determined: “qualified by scientific training and experience to evaluate its safety”.[14] The FDA has also offered suggestions on who might be included in a GRAS panel of experts.[15] In contrast, for a dietary supplement, “…the manufacturer or distributor (note this is singular) of the dietary ingredient or dietary supplement [shall provide] the Secretary with information…on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.”[16] There is no mention of the level or type of qualifications for a judgment of safety for the manufacturer, nor is there a requirement for a consensus among individuals.

What should be considered in determining safe use?

As important as who is making a safety judgement is the criteria on which the decision is made. Various criteria have been put into place by, among others, the FDA, to assist in characterizing the safety of ingredients or food products. The FFDCA §409I(1)(A) indicates conditions under which an additive may be used, including specifications, foods or classes of foods into which the substance is added, the maximum amount used, etc. One regulation (21CFR§170.20) refers a food additive petitioner to consult principles and procedures for establishing the safety of food additives described in current publications of the National Academy of Sciences-National Research Council. Some criteria are laid out in greater detail in several regulations such as 21CFR§170.230[17] (which suggests including, but not limited to chemical name, CAS number or an Enzyme Commission number, empirical formula, structural

formula, quantitative composition, characteristic properties, method of manufacture, specifications, and relevant safety data). Other sources, available online at FDA include the Red Book, Priority-Based Assessment of Food Additives, Principles and Methods for the Risk Assessment of Chemicals in Food, Initiation, and Conduct of All “Major” risk Assessments within a Risk Analysis Framework, as well as numerous guidance documents and FAQs.

In contrast, for dietary supplements (the political stepchild forced on FDA and a statute originally designed to minimize FDA oversight), the regulation offers little in the way of detail, but very granular detail is provided in the guidance and FAQs, all supposedly pursuant to making the submitter’s (i.e., the manufacturer) life easier.

At the end of the day, it appears that more or less generic instruction was laid out for a food additive petition or GRAS conclusion so as to let the criteria for a safety determination evolve in a more organic manner, incorporating the ideas of many into finalized guidelines.[18],[19] In contrast, because the statute allowed for laymen (manufacturers) to submit New Dietary Ingredient Notifications, no specific touchstones are enumerated in the CFR; however, very exacting descriptions were laid out in “informal” guidelines and FAQs.[20]

Collaborating to find the best way to determine safety evolved with the cooperation of both government and private sector scientists, with occasional aid from the judiciary, resulting in a documented process for making safety determinations of new categories of products, such as dietary supplements. Challenges ahead include safety assessment of such things as products of nanotechnology.

Is something safe if there is no data showing it is unsafe?

The fact that there must be dispositive evidence of safety is well established in case law.[21],[22] The classic reference for establishing safety relates to a beverage company which attempted to ship beverage concentrate from Puerto Rico to New York that contained potassium nitrate (added for producing a desirable flavor and color), but for which the purpose (which includes intended use level) had never been approved, even though potassium nitrate was used under prior sanction for the preservation of meat.[23] FDA maintained that potassium nitrate was not generally recognized as safe for use in beverages, that there was some question about the safety of infants who might consume the potassium nitrate-containing beverage and that there was no scientific literature showing potassium nitrate was safe for use in beverages. A company representative countered that nitrates and nitrites are not food additives because they are prior sanctioned and, although some animal studies have cast suspicion on nitrates and nitrites as possible carcinogens, the representative was not aware of any conclusive scientific evidence that the use of potassium nitrate in beverages is unsafe and that the representative knew of no

difference in health effects between potassium nitrate as used in meat and as used in beverages. In sum, nitrate was in use, albeit for other purposes and was therefore generally recognized as safe and there was no data indicating it was unsafe for use in beverages.

The court concluded otherwise, citing precedent that a lack of any studies concerning effects of intended use cannot establish general recognition of safety, that potassium nitrate was not in common use, but used only in meat and the prior sanction was explicit for use in meat, and despite the fact the company had used potassium nitrate for 50 years without any complaint of ill effects did not constitute “common use” because use in one manufacturer’s product does not constitute “common use” in food.

Thus, the absence of negative data does not demonstrate safe use, but that there must be a dispositive finding of safety for GRAS or food additive status.

Conclusion

Nothing can be said to be “safe” in the absence of context; thus, the term “safety-in-use” is applied when referring to food and dietary supplement ingredients, as well as cosmetics, drugs, pesticides, and other chemicals. Further, nothing can be said to be absolutely safe at any dose, for we know that even water, although essential for life, can be fatal if ingested in sufficient amounts resulting in hyponatremia.[24]

Essential to a rigorous determination of safety are “experts” competent in the evaluation of the effects of substances on the body and critical to their examination, and the data provided for the examination. The result of their examination may be a conditional determination of safety with limits on use and consumption, changes to the manufacturing process, and sometimes even warning labels on substances that have potential for abuse or misuse.

At Burdock Group, we strive to provide safety and regulatory assessments that our clients know they can rely upon. We have the sound infrastructure of a 30+ year old company that includes comprehensive literature searches, library resources, proprietary consumption assessment software, and scientists incorporating a diverse range of knowledge. The fact that the majority of our clients have been with us for many years with successive projects is testimony to our ability.

Reference Footer

[1] FFDCA §201(u)

[2] 232 U.S. 399 (1914). But most widely known for its decision that an adulterant must be of sufficient quantity in the article of food to render the article of food injurious to the consumer before an article may condemned as adulterated.

[3] 21CFR§105.3

[4] Federal Register 42(50):14328, March 15, 1977.

[5] Such as an individual with phenylketonuria, whose consumption of the common amino acid phenylalanine could result in severe mental defect.

[6] Such as an individual with phenylketonuria, whose consumption of the common amino acid phenylalanine could result in severe mental defect.

[7] Dietary supplements are considered to be foods, as stated in 21CFR§1.227(2) “Examples of food include: Fruits, vegetables, fish, dairy products, eggs, raw agricultural commodities for use as food or as components of food, animal feed (including pet food), food and feed ingredients, food and feed additives, dietary supplements and dietary ingredients, infant formula, beverages (including alcoholic beverages and bottled water), live food animals, bakery goods, snack foods, candy, and canned foods.”

[8] An “old” dietary supplement is a dietary supplement in use prior to 1994

[9] FFDCA §402(f)(1)(A)

[10] FFDCA §402(f)(1)(B)

[18] Guidance for Industry: Recommendations for Submission of Chemical and Technological Data for Direct Food Additive Petitions March 2009 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-recommendations-submission-chemical-and-technological-data-direct-food-additive) (site accessed 17Aug2022).

[19] Substances Generally Recognized as Safe – the GRAS Final rule (81FR54960, August 17, 2016). (https://www.federalregister.gov/documents/2016/08/17/2016-19164/substances-generally-recognized-as-safe) (site accessed 17Aug2022).

[20] Including but not limited to: Draft Guidance for Industry: New Dietary Ingredient Notifications and Related Issues October, 2016 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/draft-guidance-industry-new-dietary-ingredient-notifications-and-related-issues) (site accessed 17Aug2022).

[21] United States of America, Plaintiff, Appellee, v. an Article of Food, Etc., et al., Defendants, Appellees. Coco Rico, Inc., Claimant, Appellant, 752 F.2d 11 (1st Cir. 1985)

[22] United States v. Articles of Food & Drug, 518 F.2d 743 (5th Cir. 1975)

[23] 21CFR§181.33, §181.34

[24] Farrell DJ and Bower L (2003). Fatal water intoxication. Journal of Clinical Pathology 56:803-804.