February 29, 2000

Mr. Curtis Coleman
Safe Foods Corporation
1505 Rebsamem Park Road
Little Rock, AR 72202

Re: GRAS Notice No. GRN 000038

Dear Mr. Coleman:

The Food and Drug Administration (FDA) is responding to the notice, dated January 14, 2000, that you submitted in accordance with the agency's proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received this notice on January 19, 2000 and designated it as GRAS Notice No. GRN 000038.

In a previous submission dated September 15, 1999 (GRAS Notice No. GRN 000031), you informed FDA of the view of Safe Foods Corporation (Safe Foods) that cetylpyridinium chloride (CPC) is GRAS, through scientific procedures, for use as an antimicrobial treatment in various types of raw and fully cooked food products that may include poultry, red meat, fish and shellfish, eggs, fruits, vegetables, cereal grains, nutmeats, and dairy products at a level not to exceed 1 percent in any food category. In a letter dated January 10, 2000, Safe Foods withdrew GRN 000031 from consideration under proposed 21 CFR 170.36.

The subject of GRN 000038 is also CPC. The notice informs FDA of the view of Safe Foods that CPC is GRAS, through scientific procedures, for use as an antimicrobial in raw and fully cooked food products, including meat and poultry products at a level not to exceed 1 percent. Although the conditions of use that you describe under proposed 21 CFR 170.36(c)(1) include the use of CPC in fish and shellfish, in a telephone conversation with representatives of the Center for Food Safety and Applied Nutrition on February 17, 2000, you clarified that your intended use of CPC under GRN 000038 does not include use on fish or shellfish.

In the GRAS proposal, FDA proposed to establish a procedure whereby any person may notify FDA of a determination that a particular use of a substance is GRAS. Such notice to FDA is a voluntary mechanism for communication between a person who determines that a use of a substance is not subject to the statutory premarket approval requirements and FDA, the federal agency responsible for implementing those statutory provisions. A threshold question for such a notice is whether the particular use of a substance satisfies the GRAS criteria, which are described in 21 CFR 170.30. Under 21 CFR 170.30(b), a scientific procedures GRAS determination requires the same quantity and quality of scientific evidence as is required to approve the use of a substance as a food additive. As discussed more fully below, your notice does not describe such evidence. In addition, under 21 CFR 170.30(a), general recognition of safety requires common knowledge about the substance throughout the scientific community knowledgeable about the safety of substances directly or indirectly added to food. Given that your notice does not describe scientific evidence relevant to the safety of CPC, it follows that your notice does not provide a basis to conclude that such scientific evidence is common knowledge throughout the scientific community of qualified experts. For these reasons, your notice does not provide a sufficient basis for a determination that the intended use of CPC is GRAS.

Data and information that you present to support the GRAS determination

We summarize below the data and information that you present to support your GRAS determination.

• Your notice provides information regarding the identity of CPC and its method of manufacture.
• Your notice states that the patented formulation of CPC that would be used to treat food products includes propylene glycol as a non-ionic surfactant.
• Your notice cites a recently issued patent regarding the prevention of absorption of CPC into wet tissues by adding any of "a whole list of nonionic surfactants."
• Your notice cites a recently issued patent in which "adding cationic surfactants and/or amphoteric surfactants to aqueous compounds containing the microbiocide" ... "prevents excess use of the microbiocide.
• Your notice describes published residue data from studies in which poultry or catfish were treated with a 0.1 percent or 0.4 percent solution of CPC that did not contain propylene glycol.
• Your notice notes that CPC is a component of currently marketed mouthwashes and throat lozenges.
• Your notice estimates that persons who use mouthwash on a daily basis would consume 900 mg of CPC per year (i.e., a chronic exposure of approximately 2.5 mg per day) and that persons who use 100 throat lozenges per year (i.e., as an acute, rather than chronic, exposure) would consume 150 to 250 mg of CPC per year.
• Your notice states that the U.S. population currently consumes approximately 230 pounds of "total meat," on an annual basis, or 192 pounds of total meat on a boneless, trimmed-weight equivalent basis. Based on this information, and assuming a 10 percent treatment absorption rate, your notice estimates that persons who consume meat and poultry treated with CPC would consume no more than 1460 mg of CPC per year from consumption of these food products (i.e., a chronic exposure of no more than 4 mg per day).
• Your notice asserts that your assumption of a 10 percent treatment absorption rate provides a great margin of safety because the addition of the propylene glycol would be expected to prevent absorption.

FDA's evaluation of the data and information regarding your GRAS determination

FDA has evaluated the information that you describe in your notice, as well as other data and information that are available to the agency. FDA's recommendations regarding the quantity and quality of scientific information that would support the safety of the use of a food substance depend on its potential for toxicity. In general, the potential for toxicity of a substance depends on its estimated dietary exposure and on its structure or biological activity.

1. Estimating dietary exposure through analysis of relevant residue data

The customary mechanism to address the estimated dietary exposure for a substance that would be used in the way that you intend to use CPC is to analyze residue data to determine how much of the applied substance remains in or on treated food products. Your notice cites published residue data for the use of CPC on poultry and catfish. Importantly, these data were obtained from studies that were conducted under conditions of use that are quite different from the intended conditions of use of CPC. For example, the cited studies were conducted with a CPC solution that contained CPC at a level that would be 2.5- to 10-fold lower than your intended level of use of CPC. In addition, the cited studies were conducted with a CPC solution that did not contain propylene glycol. Further, the cited studies do not address your intended use in meat products. Given these differences, we do not consider the cited data to be directly relevant to your intended use of CPC.

Your notice asserts that the addition of the propylene glycol would be expected to prevent absorption.⁽¹⁾ Although your notice states that your patented formulation contains propylene glycol as a non-ionic surfactant, and describes a patent in which the absorption of CPC into wet tissues was prevented by adding "any of a whole list of nonionic surfactants," you make no direct statement about whether this patent describes studies that investigated the absorption of CPC into the intended food products in the presence of propylene glycol. Likewise, although you cite another patent regarding the impact of a cationic or amphoteric surfactant on residual activity of a "microbicide," and interpret this patent as evidence that any CPC that would be absorbed would nonetheless exhibit no residual antimicrobial activity, you make no direct statement about whether this patent describes studies that investigated the residual antimicrobial activity of CPC in the presence of propylene glycol. Given these facts, we do not consider the cited patents to be directly relevant to your intended use of CPC.

Although your notice does not provide data that could be used to estimate dietary exposure in a meaningful way, it nonetheless hypothesizes that the intended use of CPC would result in the consumption of no more than 4 mg of CPC per person per day. We acknowledge that this estimate may be high; however, your notice provides no relevant data that would enable us, or qualified experts outside FDA, to calculate a realistic estimate of dietary exposure.

2. Toxicity data

Given your hypothesis that the intended use of CPC would result in the consumption of up to 4 mg of CPC per person per day, we would expect your notice to include a discussion of the results of extensive animal testing to support safety - e.g., chronic feeding studies in more than one species of laboratory animal (Ref. 1). In general, such animal tests are used to establish a "No Observed Adverse Effect Level" (NOAEL), which is used to estimate the maximum "acceptable daily intake" (ADI) that would be safe for human consumption.

Your notice neither provides information about a NOAEL established in any oral toxicological study nor provides reference to an ADI that has been established through such a study. Rather, your notice relies solely on the current use of CPC as an ingredient in mouthwashes and throat lozenges as evidence that the intended use of CPC would be safe. Although it is possible that studies that were conducted to support the safe use of CPC as an ingredient in mouthwash and throat lozenges demonstrate a NOAEL in a toxicological study that is adequate to establish an ADI for your intended use of CPC, your notice neither describes such a toxicological study nor directs us to such a toxicological study in the generally available scientific literature. Absent information about the ADI for CPC, we find no merit in your argument that the consumption of CPC as an ingredient in mouthwashes and throat lozenges would establish the safety of CPC for its intended use in meat or poultry products.

3. Conditions of Use

Your notice provides virtually no information about the procedures for use of CPC on cooked products. We do not understand why it would be used on cooked products, because cooking should destroy surface microorganisms.

Your notice provides minimal information about the procedures for use of CPC on raw products (e.g., whether a potable water rinse would follow CPC treatment). For your information, we would consider such procedures to be part of the conditions of use of CPC. For example, to be relevant, residue data should be collected in a manner that is consistent with procedures that would be incorporated into the processing of raw meat or poultry products.

4. Submission dated February 22, 2000

On February 24, 2000, we received your submission dated February 22, 2000. In the February 22 submission, you reduce the scope of your GRAS determination to the intended use of CPC in poultry, lower the maximal level of use of CPC from 1.0 per cent to 0.4 per cent, describe research studies regarding the effects of certain conditions of use on the residues of CPC in poultry, and provide the LD₅₀ from various acute oral toxicity studies. We have not conducted a formal evaluation of your February 22 submission because, as discussed in the GRAS proposal, under the notification procedure FDA bases its response primarily on the notifier's initial submission (62 FR 18958). However, for your information, your February 22 submission does not appear to adequately address all of the issues discussed above.

Conclusions

FDA has evaluated the information in GRAS Notice No. GRN 000038, as well as other available data and information. Your notice does not provide a sufficient basis for a determination that CPC is GRAS under the conditions of its intended use.

This letter explains why we concluded that the information in your notice does not provide the quantity and quality of scientific evidence that could establish the safety of CPC under its intended conditions of use. This letter also provides a brief description of the type of data and information that ordinarily would be evaluated to reach a conclusion that the intended use of a substance such as CPC is safe. This letter cannot, however, provide all relevant information or details about how to evaluate the safety of a food substance. We would be willing to meet with you to direct you to relevant resource materials.

Prior to such a meeting, we recommend that you review the agency's discussion, in the GRAS proposal, of the scientific, legal, and regulatory underpinnings of the GRAS notification program. In particular, we recommend that you review the agency's discussion of the differences between a food additive and a GRAS substance. As discussed in that proposal (62 FR 18940), a determination that a particular use of a substance is GRAS requires technical evidence of safety and a basis to conclude that this technical evidence of safety is generally known and accepted by qualified experts. In contrast, authorization of a particular use of a substance as a food additive requires technical evidence of safety and review and approval by FDA. For this reason, we also recommend that you review the information on the Office of Premarket Approval's home page regarding the food additive petition process (Ref. 2).

In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter, as well as a copy of the information in your notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the Office of Premarket Approval's homepage on the World Wide Web.

References

1. Toxicological Testing of Food Additives, which is available at http://vm.cfsan.fda.gov/~dms/opa-tg1.html

2. A series of guidance documents are available at http://vm.cfsan.fda.gov/~lrd/foodadd.html

⁽¹⁾FDA has affirmed the GRAS status of propylene glycol for use as a surface-active agent (21 CFR 184.1666). For your information, under that regulation propylene glycol is used in foods as a surface- active agent at a maximum level of 2.0 percent.

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