Overview
Suitable purity suits all of us.
In our recent StepLadder article on FDA's General Safety Clause and Good Manufacturing Practice (GMP) Requirements, we discussed Section 402(a) of the Federal Food, Drug, and Cosmetic Act, which states that food shall not be introduced into interstate commerce if it is adulterated. Adulteration is a legal term of art, and occurs when food "bears or contains any poisonous or deleterious substance that may render the food injurious to health." These requirements are further implemented by the food additive regulations under 21 C.F.R. § 174.5 ("General provisions applicable to indirect food additives”), which states that food-contact materials must be of a "purity suitable for [their] intended use."
Addressing the Presence of Constituents in Food Contact Substances
Substances used in food-contact applications range from simple commodity chemicals to complex polymeric reaction products. Regardless of the chemical nature of the food-contact substance (FCS), companies throughout the supply chain – and particularly those that introduce the finished material or article onto the market – share an obligation to ensure that the FCS is suitably pure for the intended use.
To ensure suitable purity, and among other requirements, one must consider and evaluate the potential migration of – and resulting dietary exposure to – residual monomers (in the case of polymeric FCSs), impurities, catalysts and other byproducts that may remain in the finished FCS following the manufacturing process. These substances are collectively referred to as "constituents."
In the case of polymeric FCSs, for example, the monomer(s) used to produce the finished polymer (i.e., the reactants or "building blocks") are sometimes potential carcinogens. This is not uncommon given the chemical nature of the structure and corresponding reactivity of the monomers; indeed, it is this very reactivity that allows for the monomers to polymerize (often in the presence of one or more catalysts or polymer production aids) – and is both a necessary and purposeful feature of the chemistry. Importantly, however, the finished polymer does not contain the same reactive sites once the polymerization process is brought to completion, and for this reason, the polymer itself is not considered a carcinogen.
Nevertheless, the potential remains for small amounts of residual monomer to remain in the finished polymer following the reaction process, either as a result of incomplete polymerization, or resulting from variations in the manufacturing process. As part of meeting its suitable purity obligations, companies are required to assess the potential presence of these residual substances (and other impurities and byproducts that may remain in the finished FCS) in the diet, prior to introduction into the market. While this suitable purity obligation applies to the assessment all constituents, we focus on the specific case where the constituent may be a carcinogen (C), mutagen (M), or a substance potentially toxic to reproduction (R), or "CMR."
As a threshold matter, the "Delaney Clause" of the Federal Food, Drug, and Cosmetic Act states that no food additive shall be deemed to be safe by FDA if the additive is found to induce cancer in man or animal.1 Therefore, the intentional addition of carcinogenic substances to food (or food packaging) is not permitted. FDA has acknowledged, however, that all chemical substances contain "residual reactants, intermediates, manufacturing aids, and products of side reactions and degradation." Since constituents are not considered "food additives," as that term is defined by the Act, it is permissible for a food additive to contain low levels of residual carcinogenic constituents, provided that: (1) the food additive itself is not carcinogenic; and (2) the constituents are present at sufficiently low levels such that “there is a reasonable certainty that no harm will result from the proposed use of the additive." To make such a determination, the level of the constituent that may be present in the diet as a result of the use of the FCS is evaluated for safety on a case-by-case basis.
‘Reasonable Certainty of No Harm' Standard
The "reasonable certainty of no harm" standard is evaluated based on three primary factors:2
- The probable consumption of the substance and of any substance formed in or on food because of its use;
- The cumulative effect of the substance in the diet, taking into account any chemically or pharmacologically related substance or substances in such diet; and
- Safety factors which, in the opinion of experts qualified by scientific training and experience to evaluate the safety of food and food ingredients, are generally recognized as appropriate.
In practice, this often means a comparison of dietary exposure to the evaluation of quantitative scientific risk assessment procedures, including toxicological assessments based on oral carcinogenicity studies conducted on animals.3 The results of these studies may be further extrapolated, where appropriate, to estimate the potential corresponding carcinogenic risk in humans where comparable amounts of the constituent are consumed as part of the daily diet.
Calculating Risk
For those substances where a threshold for carcinogenicity has not been conclusively established, the risk is considered negligible where the upper-bound calculated Lifetime Cancer Risk (LCR) of carcinogenicity from all sources of exposure to the constituent is sufficiently small (i.e., a risk of potential carcinogenicity of less than one in one million (10-6)). To account for the fact that the same constituents may be present in the diet from the multiple sources, we generally consider the contribution from any one source to be acceptable if the LCR contributes no more than one-tenth of the acceptable risk from the intended use (i.e., a risk of potential carcinogenicity of one in ten million (10-7)). For certain substances, FDA has independently developed a Unit Cancer Risk (UCR) value.4 These substances include (but are not limited to): ethylene oxide, propylene oxide, 1,4-dioxane, cumene, styrene, vinyl acetate, acetaldehyde, and diethanolamine. For other substances, a UCR value can be determined by evaluating toxicology studies – typically via the oral route of exposure – to derive an appropriate reference value.
The LCR is calculated by multiplying the Estimated Daily Intake (EDI) (e.g., the amount that could potentially be present in the diet) by the UCR, as follows:
LCR = EDI × UCR
Provided that the LCR is less than 1×10-6(i.e., one-in-one million risk of cancer due to exposure), or 1×10-7 (i.e., one-in-ten million risk of cancer due to exposure) to account for multiple sources of exposure in the diet, a company may properly conclude that there is a reasonable certainty that no harm will result from the presence of the potentially carcinogenic impurity or byproduct resulting from the intended use of the FCS.
For substances presumed or shown to be mutagenic or toxic to reproduction via the oral route of exposure, one similarly should reference available toxicity information in relevant databases and literature, and their associated endpoints (such as No Observed Adverse Effect Levels (NOAELs)), in combination with appropriate safety factors to account for interspecies, intraspecies, and animal-to-human variation to develop a value for which a reasonable certainty of no harm can be established. Similarly, one can reference assessments and conclusions developed by competent regulatory authorities to establish an appropriate threshold for safety. One pertinent example includes a list of the Maximum Allowable Dose Levels (MADLs) published by the State of California under The Safe Drinking Water and Toxic Enforcement Act of 1986 ("Proposition 65").5 More generally, companies should evaluate published and unpublished toxicology data and provide appropriate weight to study conclusions consistent with FDA’s Toxicology Guidance6and the Toxicological Principles for the Safety Assessment of Food Ingredients Guidance Document (“Redbook”).7
Companies have an ongoing obligation to monitor and update their risk assessments and safety determinations over time, and to consider both positive and negative toxicity data that comes to light following an initial evaluation. Therefore, a suitable purity determination is an ongoing responsibility that should be revisited periodically to ensure that the underlying safety assessment reflects the most accurate and up-to-date information.
1 See Section 409(c)(1)(A) of the Act.
2 See 21 C.F.R. § 170.3.
3 Id. at 21 C.F.R. § 170.3(i). Safe or safety means "that there is a reasonable certainty in the minds of competent scientists that the substance is not harmful under the conditions of its intended use." FDA acknowledges that "[i]t is impossible in the present state of scientific knowledge to establish with complete certainty the absolute harmlessness of the use of any substance. Safety may be determined by scientific procedures or by general recognition of safety.”
4 FDA defines the UCR as “the slope of a straight line drawn from the lowest apparent effect dose to zero." See FDA, "Preparation of Food Contact Substance Notifications (Toxicology Recommendations): Guidance for Industry" (October 2021), available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-preparation-food-contact-substance-notifications-toxicology-recommendations.
5 See California Office of Environmental Health Hazard Assessment (OEHHA), "The Proposition 65 List," available at: https://oehha.ca.gov/proposition-65/proposition-65-list.
6 See footnote 4.
7 See FDA, "Guidance for Industry and Other Stakeholders: Redbook 2000 – Toxicological Principles for the Safety Assessment of Food Ingredients" (July 2007), available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-and-other-stakeholders-redbook-2000.
* * *
About the Steptoe StepLadder Series
Steptoe & Johnson LLP is pleased to publish the Stepladder series of articles for our clients, prospective clients, and interested companies as a way of educating attorneys and non-attorneys alike about legal and regulatory principles related to food packaging in meaningful ways. While there are many sources of information available online, the StepLadder series is intended to be accessible to, and understandable by all, to help support business decisions related to food packaging compliance.
This information is provided for educational purposes only, is not legal advice, and does not establish an attorney-client relationship with Steptoe. Our lawyers made us write that. If you have legal questions, please consult an attorney. Preferably from a team well-versed in food packaging regulation – and definitely from a group of attorneys that have a good sense of humor. Because you are what you eat… unless your food packaging isn’t a 'food additive,' in which case you’re not food packaging.
