### 36582 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 5, 25, 170, 171, and 174 (Docket Nos.77P-0122 and 92N-0181]

Food Additives;Threshold of Regulation forSubstances Used in Food-Contact Articles

AGENCY: Food and 

### Drug Administration, HHS. ACTION: Final rule.

SUMMARY: The Food and Drug 

### Administration (FDA)is amending its food additive regulations to establish a process for determining when the likelihood or extent ofmigration to food ofa substance used in a food-contact article is so trivial as not to require regulation ofthe substance as a food additive. Although still a "food additive," a substance exempted from regulation under this process will notbe required tobe the subject ofa food additive listingregulation. Under this process, information about the proposed

use ofthe substance will undergo an abbreviated review by FDA, asopposed to the extensive review normally required forfood additives. This final rule also lists the criteria that FDA will

use in its revieq in deciding whether it isnecessary to regulate the use ofa substance as a food additive and identifieg the types ofdata that it will need tomake this determination. EFFECTIVE DATE: August 16, 1995.
FOR FURTHER INFORMATION CONTACT: 

### Edward J.Machuga, Center forFood Safetyand Applied Nutrition (HFS216), Food and Drug Administration, 200 C St. SW., Washington, DC 20204, 202-418-3085.

SUPPLEMENTARY INFORMATION:


### I.Background

In the Federal Register ofOctober 12, 1993 (58 FR 52719), the agency 

### proposed to establish a process for determining when the likelihood or extentof migration to food ofa substance used in afood-contact article is sotrivial as notto require regulation ofthe substance asa food additive. The proposal was inresponse to a number ofcomments from representatives ofthe food packaging and processing industries suggesting that FDA establish

a threshold ofregulation policy whereby 

### those substances used in food-contact articles that resultin minimal migration into food would beexempt from regulation as food additives.

The proposal also responded to a citizen petition (DocketNo. 77P-0122) submitted by the Society ofthe Plastics Industry, Inc., requesting that FDA modify 

### § 170.3(e) (21 CFR 170.3(e)), the 

### regulation that defines "food additive,"

to provide that the use ofa substance 

### that does not result in detectable levels of migration into food-simulating solvents (using validated analytical methods sensitive to at least 50 parts per billion (ppb)) would be exempt from regulation as a food additive unless there-is scientific evidence that the substance presents a significant risk of harm to human health.

Traditionally, FDA had been reluctant
to adopt any ofthese suggestions in the absence of data thatclearly show that substances present in the daily diet at concentrations at or below the proposed threshold level would not pose safety

concerns. However, data on the toxic effects ofa large number of representative compounds have become available overthe last 5 to 10 years that have made it possible for FDA to evaluate the feasibility ofestablishing a threshold ofregulation for food-contact articles. These data show that noncarcinogenic and carcinogenic toxic effects usually occur within predictable
ranges of dietary exposure. They make it possible to identify a specific level of dietary exposure that is well below the
range of dietary exposures that typically induce toxic effects and, therefore, that
poses only negligible safety concerns. This level can function asthe "threshold ofregulation" for components offood-contact articles.

A Federal courthas addressed the issue ofwhether the use ofa foodcontact material that results in migration into food atinsignificant levels can be exempted from regulation

as a food additive. InMonsantov. Kennedy,613 F.2d 947 (D.C. Cir. 1979). the Monsanto Co. contended that no detectable migration ofacrylonitrile copolymer resulted from the use oftheir beverage bottles that contained the substance, and that, therefore, the copolymer did not haveto be regulated

as a food additive. In its decision, the
court stated that the Commissioner of Food and Drugs (the Commissioner)
may determine that the level of migration into food ofa particular substance is so negligible as to present

no public health or safety concerns and, in such cases,-maydecline to define the substance as a food additive even though it comes within the strictly literal terms ofthe statutory definition ofa food additive (613 F.2d at 956). The
court also stated thatthe Commissioner has the discretion not to exercise this exemption authority (id.).

Based on available toxicological data showing that it is feasible to establish a 

### threshold level below which dietary exposures to substances used in foodcontact articles are so negligible as to poseno public health or safety
concerns, the discretionary authority of theCommissioner to exempt those substances that present no public health

concerns from regulation as food additives, and the agency's consideration ofthe comments that it received on the October 12, 1993, proposal, FDA is amending the food additive regulations to establish a process for determining when the likelihood or extent ofmigration to food ofa substance used in a food-contact article is so trivial as not to require that the substance be regulated as a food additive.

As part ofthis process, the agency is establishing two types ofthresholds for the regulation ofsubstances used in food-contact articles. The first type of threshold will exempt from regulation those substances whose use in foodcontact articles results ina dietary concentration ofthe substance of 0.5 ppb orless. The second type of threshold will exempt regulated direct food additives from regulation when used in food-contact articles at levels that result in adietary exposure of1 percent or less ofthe acceptable daily intake (ADI) for the additive.
I. Comments on the Proposed Rule

The agency provided 60 days for comment onthe proposed rule.It received two requests from industry for

an extension ofthe comment period. The agency granted a 60-day extension ofthe comment period to February 11, 1994, ina notice published inthe Federal Register ofDecember 13, 1993 (58FR 65139).

FDA received 20 comments from the food packaging industry and trade associations that represent the plastics and paper industries. One ofthese comments concerned the economic impact ofthe proposed action. This comment is discussed in section IV of this document. The other issues raised inthe comments, and the agency's response to them, are set forth below.

A. TheExemption Appropriateness ofthe 0.5 PPB Threshold Level for Components of Food-Contact Articles

1.Eightcomments expressed the opinionthat the 0.5 ppb threshold is

more conservative and restrictive than is necessary to adequately protect the publichealth. In general, these comments expressed the view that current scientific data support the

### Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

establishment of adietary concentration higher than 0.5 ppb as thethreshold.

The agency does not agree that a 0.5 ppb threshold is unduly conservative, especially in light ofthe factthat a substance being considered for an exemption may nothave been the subject ofany toxicological testing.As discussed in the proposed rule, carcinogenic toxic effects in testanimals typically occur at lower dietary concentrations than the levels at which noncarcinogenic toxic effects occur. Therefore, FDA's goal has been to establish athreshold that is low enough to ensure that even ifan unstudied compound that is exempted from regulation is later shownto be a carcinogen, its usewould not have represented anymore than a negligible risk to the public,health.

Although eight comments were received that expressed the opinion that the 0.5 ppb threshold is more conservative and restrictive thanis necessary to adequately protect the public health, no data were provided in any ofthese comments to show that a threshold significantly higher than 0.5 ppbis adequate to ensure that substances present inthe dietat or below the threshold would pose only negligible safety concerns. Therefore, as proposed, thisfinal rule establishes 0.5 ppbas the threshold ofregulatory

concern for substances used in foodcontact articles. We willreconsider this thresholdifwereceive new data that justify a higher level.

2.One comment objected tothe agency's apparent use ofa 200-fold safety factorwhen applying tohumans the results ofstudies showing the noncarcinogenic toxic effects observed inanimals subjected to chronic chemical exposure. The comment stated that FDA guidelinesemploy only a 100- fold safety factor. The comment argued that the use ofthe 100-fold safety factor would allow FDAto establish a threshold ofregulatory concern higher than 0.5 ppb.



### The agency emphasizes that it didnot base its propo'sed threshold on noncarcinogenic toxic endpoints, and that, therefore, it did not employ the safety factor approach typically used when applyingto humans the results of studies showing the noncarcinogenic toxic effects observed in animals subjected to chronic chemical exposure. Because carcinogenic effects typically

occur intest animals atlower dietary concentrations than those at which noncarcinogenic toxic effects occur, as stated above, FDA's goal was to establish athreshold that is low enough
to ensure that substances that are exempted from regulation under it will pose only negligible safety concerns
even if theyare ultimately shown to have carcinogenic effects.

Based on its analysis ofthe carcinogenic potencies of477 chemicals, and using the assumptions that the distribution ofcarcinogenic potencies ofthe 477 chemicals studied

are representative ofall known and unknown carcinogens, andthat it is very unlikely that an unstudied compound wouldboth: (1)Be a carcinogen and (2) 

### have an intrinsic carcinogenic potency far greater than the typical potency observed forthe studied compounds, FDA has determined that, ifan exempted substance present inthe diet at 0.5 ppb

were later found tobe a carcinogen, the upper-bound lifetime riskresulting from the use ofthe substance is likelytobe below one in a million. This level ofrisk is generally regarded as very low (i.e.,

one that poses only negligible safety concerns). Because carcinogenic effects typically occur at lower dietary concentrations than those at which noncarcinogenic toxic effects occur, an 0.5 ppbthreshold would ensure that substances thatpass under it pose negligible safety concerns from noncarcinogenic toxic effects as well. However, the factthat a 0.5 ppb threshold level happens tobe 200, rather than a 100,times lower than the chronic exposure level at which potent pesticides induce noncarcinogenic toxic effects is merely coincidental and does not reflectthe agency's reasoning.

3.One comment expressed the opinion that the threshold should have been based on the mean TD 502 value of 

### the 477 known carcinogens that were the subject ofFDA analysis as opposed
to the most probable TD5 0

### value. This
comment stated that the use ofamean TDs0

### would allow FDA to establish a threshold significantly higher than 0.5 ppb.

FDA does not agree that it is appropriate to establish athreshold level based on the mean TD 50

### value of the 477 known carcinogens that were the subject ofFDA's analysis because this approach would give inappropriate weight to carcinogens with high TDso

IThe agency typically uses a 100-fold safety factor when applying to humans the resultsof animal data obtained from long term exposure to a chemical (i.e., 2-year chronic feeding studies). Short
term toxicological testing (i.e., 90-day subchronic feeding studies) may notalways be long enough to show all ofthe toxic effects that may be induced by long term exposure to achemical, and, therefore, in suchcases, FDA often uses higher safety factors (lO00-fold to2000-fold).

2The TDse, forthepurposes ofthis regulation, is the feeding dose that causes cancer in 50 percent ofthe test animals when corrected for tumors found in control animals. 

### values. Because the carcinogenic potency of asubstance is inversely related to its TD 50

### value, this approach would give too much emphasis to carcinogens with low potencies. Amore meaningful approach to estimating the likelihood that a substance willpose a potential health hazard at agiven dietary concentration is to use the potency that it is most likelytohave if it were later foundto be a carcinogen. Because such anapproach would be based onthe frequency distribution of the potencies ofa large number of ' carcinogens (i.e., a distribution showing the number ofcarcinogens whose potencies occur within particular dietary-concentration ranges) and would notbebased on the magnitude ofthe potencies themselves, thisapproach would notgive undue weight to carcinogens with low potencies (i.e., high TDso values).

In arriving at athreshold of regulation, FDA's analysis ofthe potencies of477 animal carcinogens consisted in part ofgrouping them by dietary concentration ranges (Ref. 1). The agency plotted the potencies as a probability distribution on a semilogarithmic scale and found that they formed a bell-shaped distribution

curve. Using thisprobability distribution for carcinogenic potencies, FDA determined that most known carcinogens pose less than one in a million upper-bound lifetime risk if present in the daily dietat 0.5 ppb or less.

4. One comment expressed the view that it was unlikely that agiven packaging material wouldbe present in the daily diet over the course ofa lifetime. It asserted that,therefore, FDA shouldnot have based its threshold on potential lifetime carcinogenic risks.

Because ofthe changing technology associated with the food-packaging industry,FDA agrees that is notalways possible topredict whether a given type ofpackaging material is likely to be presentin the daily dietover the course ofa lifetime. However, because many of the substances considered for an exemption from regulation will not have been the subject ofany toxicological testing, it is imperative, in establishing

athreshold level, to use an approach that is not likelyto underestimate the risk associated with the use ofsuch additives. Therefore, the agency used an approach that assumed that a given packaging material wouldbe present in the daily diet for an entire lifetime.

Lifetime upper-bound risks have traditionally been used by FDA to assess the overall safety ofpackaging materials containing small amounts of carcinogenic impurities, and the agency 36583

### 36584 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

believes that it is appropriate touse a similar approach in assessing the likelihood ofpotential carcinogenic effects associated with substances exempted from regulation. Based on its analysis of the potencies of477 known carcinogens and the lifetime upperbound risks that theywould pose if present in the daily dietover a lifetime, FDA has determined thata substance present inthe daily diet for a lifetime at 0.5 ppb would pose only negligible risk

even ifit were later shown tobe a carcinogen. Because ofthe conservatisms used by the agency in its approach to determining a threshold level, FDA is confident that an exempted substance present inthe daily diet for a lifetime at 0.5 ppb would pose
no regulatory concern. 5.Four ofthe comments recommended that FDA establish a higher threshold for substances that have been shown to be nonmutagenic or to have relatively high LD5 03 values. For 

### example, one comment recommended that for substances that have been shown to be nonmutagenic andto have LDso values greater than 2,000 milligrams perkilogram (mg/kg), the threshold shouldbe raised to 5ppb.

FDA agrees withthese comments that it may bepossible to establish separate thresholds forcompounds that have been the subject oftoxicological tests that show that they are nonmutagenic,

or thatthey have high LDso values. However, a direct correlation will need
tobe firmly established showing that such compounds, ifcarcinogenic, are likely to beless potent than those that have been shown to be mutagenic or to have lower LDso values. Such a correlation would provide confirmation thata substance that hasbeen shown to benonmutagenic orto have a high LDso value poses a significantly lower risk from potential carcinogenic effects when present inthe daily diet at the

same level than onethat has been shown to be mutagenic or to have a low LD5

### ovalue.

The correlation between mutagenicity

or acute toxicity and carcinogenic potency is the subject ofongoing FDA analysis. Ifthe results ofFDA's analysis confirm that the likelihood that a substance posesa significant risk from potential carcinogenic effects is significantly lower when that substance has been shown to be nonmutagenic or to have ahigh LD5

### ovalue, it may be possible to establish a threshold for such substances that is higher than 0.5 ppbbut that stillensures that their use

3The LD 5ois the dose in acute feeding studies thatcauses lethality in 50 percent ofthetest animals. 

### infood-contact articles will pose only negligible health concerns.

6. 

### Three comments suggested that FDA establish ahigher threshold for 

### compounds that do notpossess structural concerns (i.e., that do not possess structural similarities to known carcinogens).

In general, the principle behind the

use ofquantitative structure activity relationships is that the analysis ofthe toxicity ofa large number ofcompounds ofknown structure enables one to predict therelative toxicity ofunstudied compounds based on the degree of similarity in chemical structure to studied compounds. While FDA may

use structure activity relationships to ascertain whether there is abasis to suspect that a substance is a carcinogen, knowledge about such relationships is
not reliable enough at this time tojustify reliance on an analysis ofthem to establish ahigher threshold of regulation for some compounds. The
comments did not submit any evidence
to support a contrary conclusion.

7. Three comments recommended that the threshold be raised for compounds that have been shown to be noncarcinogenic. For example, one comment recommended that the threshold be raised to 100 ppb for substances that have been shown to be negative in 2-yearbioassays.

FDA agrees that it may bepossible in the future to establish a threshold higher than 0.5 ppb for substances thathave been shown to be noncarcinogenic based on results obtained from appropriate 2-year bioassays. As discussed above, carcinogenic effects in
test animals typically occur at lower dietary concentrations than do noncarcinogenic toxic effects. Therefore, FDA proposed to establish 0.5 ppb as the dietary concentration threshold because this level is low enough to preclude the likelihood ofall but negligible risk even ifan unstudied compound is later shown to be a carcinogen. In the case of noncarcinogens, however, the threshold ofregulation could bebased solely on the level at, and below which, noncarcinogenic toxic effects are unlikely to occur.

As stated in the proposed rule (58 FR 52719 at 52722), FDA's analysis ofthe data on 18,000 acute oral feeding studies in rats and mice found that all ofthe acute toxic effects occurred above 1,000 ppb. The results of 2-year chronic oral feeding studies on 220 compounds have shown that only 5 ofthe 220 chemicals exhibited toxic effects below 1,000 ppb, and that all 5 ofthese chemicals were pesticides, compounds that are expected to be more toxic than 

### most substances. Even for these five pesticides, none exhibited toxic effects
at dietary concentrations below 100 ppb. These results suggest that it may be feasible to establish a separate threshold for substances thathave been appropriately tested and found nottobe carcinogens. Such athreshold would likelybe well below the level at which noncarcinogenic toxic effects are likely
to occurbut higher than the 0.5 ppb threshold that FDA is establishing to minimize the risk from potential carcinogens. FDA is not establishing a separate threshold fornoncarcinogenic substances at thistime, however, because thenumber ofchemicals, particularly pesticides, that have been' analyzed is not sufficient to ensure that the results ofthis analysis are representative of substances used in the manufacture offood-contact articles. An analysis ofthe dietary concentrations at which alarge number and a wide variety ofpotent toxicants, such as pesticides, exhibit noncarcinogenic toxic effects is needed before FDA can determine whether establishment ofa threshold significantly higherthan 0.5 ppb for noncarcinogenic substances is justified. 

### Appropriateness ofthe 1-Percent ADI Threshold for Regulated Direct Additives

8. One comment recommended that

once the final rulehas been established, and the policy hasbeen put into practice for atime, FDA should reassess the 1percent ofthe ADI threshold for regulated direct food additives used in food-contact articles to see whether this threshold can be raised.

As stated inthe proposal, a 1-percent ADI threshold forregulated direct food additives used infood-contact articles is appropriate because thislevel ofdietary exposure will contribute only a small fraction ofthe ADI ofa substance and, therefore, will be well withinthe margin ofsafety for those direct food additives with small cumulative dietary
exposures. For substances with high cumulative dietary exposures resulting from regulated direct food additive uses,

a level ofexposure thatis 1percent of the ADI would bewithin the margin of

error forthe estimated dailyintake. It would, therefore, not significantly affect the cumulative dietary exposure, even in the event that a particular substance is granted exemptions for several different types ofuses infood-contact articles.

The agency would like to emphasize that no comments werereceived that expressed any safety concern about the 1percent ofthe ADI threshold. As for raising this threshold above the 1-

### Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

percent ADI level, FDA's main concern is with those cases in which a particular substance may be granted exemptions for anumber ofdifferent types ofnew
uses, each ofwhich results in a dietary
exposure at ornear the threshold level. In such cases, the dietary exposure resulting from all of theexempted uses could represent a significant increase in the cumulative dietary exposure for the substance and, in cases where the estimated dietary intake from currently regulated uses is close to the ADI, may notbe supported by existing safety data. It is possible, however, that oncethe threshold ofregulation process is put into practice, other factors will surface that mitigate the agency's concerns on this issue. Ifthe latter situation proves to be the case, the agency may find it appropriate to reassess the 1 percent of the ADI threshold for regulated direct food additives used in food-contact articles.

9. Onecomment recommended that FDA publish or otherwise make available the ADI's for currently regulated direct food additives. In cases where such ADI's are not readily available, FDA should consider other

sources (e.g., the European Union's Scientific Committee for Foods) or provide guidelines for the calculation of appropriate ADI's.

FDA agrees that the ADI's for currently regulated direct food additives should bemade more readily available. Therefore, FDA plans to incorporate this information into its priority based
assessment offood additives (PAFA) data base and make this data base accessible to the public (Ref. 2). In the meantime, requestors can obtain this type ofinformation on a specific substance by submitting awritten request to FDA's Office ofPremarket Approval (HFS-200, 200 C St. SW., Washington, DC 20204). In some cases, especially for those uses ofdirect additives that result in low dietary
exposures such as flavoring agents, FDA
may not have an ADI in its files. Therefore, in those relatively few cases where FDA does not have an appropriate ADI for aregulated direct food additive, the agency would consider the use ofanADI value from another appropriate source, such as the Joint World Health Organization/Food and Agriculture Organization (WHO/ FAO), Expert Committee on Food Additives, or theEuropean Union's Scientific Committee for Foods, assuming that the data or other information on which that ADI value is based are also available. FDA is revising proposed § 170.39(a)(2)(ii) to state that FDA may use other appropriate sources for ADI values. 

### FDA disagrees with the comment's suggestion that the agency provide guidelines forthe calculation of appropriate ADI's forreview under the process specified in thisfinal rule. Regulated direct food additives for which an appropriate ADI does not exist

are not suitable candidates for an abbreviated review under thethreshold ofregulation process. This process is not appropriate forreviewing submissions containing detailed toxicity studies on asubstance for the purpose ofcalculating an ADI value or for verifying an ADI value calculated by the requestor. Suchextensive reviews are better handled by the food additive petition process.

10. One commentrecommended that FDA expand the proposed threshold of regulation process forregulated direct food additives to include exemptions for direct uses in food, provided the dietary exposures from such uses donot exceed 1percent ofthe ADI.The proposed rule limited such exemptions to only those

uses thatmay result in their indirectly becoming components offood (i.e., resulting from theiruse infood-contact articles).

FDA does not agree that the final rule shouldbe expanded inthis manner. There is a fundamental difference in regulatory significance between substances that are deliberately added directlyto food to accomplish a technical effect inthe food and substances that areused infood-contact articles ina manner such that they may reasonablybe expected to become components offood indirectly and to have notechnical effect inthat food. The purpose ofthe food additive provisions ofthe act is to ensure that substances added to food are safe and will have theirintended technical effect inthe food that isto beconsumed (S. Rept. 2422, 85th Cong., August 18, 1958). Thus, given this purpose, there simply would notbe circumstances in which a dirbct additive would be of such little regulatory concern asto justify application to it ofthe de minimis 4

### doctrine thatunderlies the threshold ofregulation concept (see Monsantov.Kennedy, supra).For 

### indirect food additives, in contrast, the substance isbeing used for its technical effect in a food-contact article, notin an article thatwill itselfbe consumed.

Moreover, on occasion, it is foreseeable that, while the exact amount ofan indirect additive that will get into food is unclear, itwill not exceed an extremely small amount. It is in the

4This doctrine is expressed inLatin as de minimis non curatlex (the law does not concern itselfwith trifles). 

### latter circumstances that it is fair to say that, given the purposes ofthe Federal Food, Drug, and Cosmetic Act (the act), the use ofthe substance is ofno significant regulatory concern, and thus the use can be exempted from regulation under the food additive provisions of the act. In light ofthe purposes ofthe food additive provisions, however, FDA concludes that it is not appropriate to extend the threshold ofregulation concept to substances intended for direct use in food.

11. One comment expressed the opinion that the proposed regulation is unduly restrictive for the use of regulated direct food additives in foodcontact articles whenthe direct additive does not have any specific use level restrictions. An example ofthetype of situation raised by the comment would be flavoring agents where the level of their use in food would be selflimiting (i.e., use athigh levels would make the food unpalatable, and, therefore, FDA did not find it necessary to impose, specific maximum use levels as part of the regulations authorizing the use of such substances). The comment emphasized that, because ofthe time required to obtain FDA approval (as a result ofFDA's current backlog ofwork), the consumer's access to new packaging technologies is often delayed. Not requiring premarket approval of such substances would save FDA resources, reduce the backlog ofwork, and enable the consumer to have quicker access to

new packaging formulations.

The comment argued that, based on the extremely small levels ofdietary
exposure that would result from the use ofdirect additives in food-contact articles, particularly in comparison to the levels of exposure that result from the direct uses ofthese substances, and based on the fact that direct food additives have been the subject of extensive safety testing, FDA should modify §.174,5(d) (21 CFR 174.5(d)) to allow those direct food additives that

are regulated without specific use level limitations to be used as components of food-contact articles. The comment asserted, however, that four restrictions

on suchuse were appropriate: (1) The

use ofthe substance in a food-contact article must notresult in a dietary
exposure that exceeds 1 percent ofthe ADI for that substance; (2) the use level
must not exceed good manufacturing practice (GMP) orthat necessary to accomplish theintended technical effect; (3) the substance mustbe of a purity suitable for the intended use; and (4) the technical effect for such additives must be as a formulation aid

or some other technical effect for which the substance hasbeen listed as a direct 

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### 36586 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

food.additive (e.g., a substance approved foruse as a stabilizer and thickener in food would be allowed to be used as a stabilizer and thickener in the manufacture offood-contact articles). The comment cited FDA's approach to handling generally recognized as safe (GRAS) substances as
a precedent for this approach. Under 21 CFR 186.1(a), ingredients affirmed as GRAS for direct use in part 184 (21 CFR part 184) are also affirmed as GRAS for

useas indirect human food ingredients in accordance with §184.1(a).

The agency notes that theissue raised by this comment is outside the scope of the proposed threshold ofregulation process. The comment is about whether the usesin question shouldbe approved

as food additive uses, not about whether they should be exempted from regulation under the food additive provisions ofthe act.

Although outside the scope ofthis rulemaking, FDA would like to comment on the merits ofthe approach recommended inthis comment because the agency is always interested in evaluating waysthat may help it to

more effectively implement the food additive provisions ofthe act. FDA's mainconcern with the recommended approach is that those direct food additives that are regulated without specific use level limitations, and which meet the other restrictions specified in this comment, could be used as components offood-contact articles without any further safety review by FDA. Although it is true thatthe dietary exposure resulting from theuse ofa substance added directly to food is usually much higher than that resulting from the use ofthat substance as a component ofa food-contact article, the existing safety data inFDA files used to support the direct additive usemay not always be adequate to support even a modest increase in the dietary exposure resulting from its use as an indirect food additive.

Some direct food additives have been regulated foruses in which only a
narrow margin exists between the cumulative estimated dietary exposure and the acceptable dietary exposure. Many other direct additives have been regulated foruses for which, initially, the margin between the estimated daily intake and theADI wasreasonably broad, but asthe substance hasbeen subsequently regulated for other uses, the margin has become quite narrow. Because existing safety data may notbe adequate to support theuse ofdirect additives as components offood-contact articles in all cases, such uses mustbe evaluated on a case by casebasis, either

as the subject ofa food additive petition (ifthe dietary exposure is likelyto be greater than 1percent ofthe ADI) oras

a request for an exemption from regulation (ifthe dietary exposure is likelyto be below the 1-percent ADI threshold ofregulatory concern).

. Another agency concern with the recommended approach is that some of the direct food additives may also have been regulated at a time when FDA did not conduct reviews on the possible environmental effects resulting from such uses. (FDAregulations for considering the environmental effect of its actions in accordance with the National Environmental Policy Act (NEPA) were established onMarch 15, 1973.) It may be possible thatthe manufacture, use, and disposal offoodcontact articles containing regulated direct food additives may have an adverse impact on the environment. Therefore, the potential environmental effectsresulting from the intendeduse ofadirect food additive in a foodcontact article need to be evaluated by FDA either aspart ofa review ofa petition or as part ofa review ofan exemption from regulation request. Further discussion ofthisissue is found later inthis final rule inthe agency's response to comments 28 and 29.

For the reasons listed above, FDA has concluded that the use ofaregulated direct food additive in a food-contact article should eitherbe the subject of a specific food additive regulation authorizing such use orbe exempted from regulation as a food additiveby FDA under the procedures specified in thisfinal rule.Application ofthe Food Additive Definition

12. Two comments expressed the opinion that the Monsantodecision gives FDA the flexibility to consider those substances migrating out offoodcontact articles in trivial amounts notto be food additives. These comments went on to say that the Delaney Clause (section 409(c)(3)(A) ofthe act (21 U.S.C. 348(c)(3)(A)), which prohibits the

use ofknown carcinogens as food additives, would therefore not apply.

FDA disagrees with the comments. It is true that Monsantostated that the Commissionerhas discretion to implement the statutory scheme established by the Food Additives Amendment, and that this discretion includes the option ofdeclining to define a substance as a food additive (613 F.2d at 956). However, the court also saidthat the Commissioner's discretion is limited (id.). The Commissioner's exercise ofdiscretion mustbeconsistent with the statutory scheme. He cannot exercise his discretion to vitiate thatscheme. Under the FoodAdditives Amendment, a carcinogenic additive is deemed tobe unsafe, no matter how low the exposure to the additive orhow low the risk from the additive (seePublicCitizenv. Young, 831 F.2d 1W8, 1122 (D.C. Cir. 

### 1987), cert. denied, 485 U.S. 1006 (1988)). Given these facts, FDA has formulated the threshold ofregulation regime to exempt substances from regulation as food additivesbased on the level ofdietary exposure but has conditioned that exemption on such substances nothaving been shown to be carcinogens. No other approach would be consistent with the act. 13.Three comments recommended that FDA clarify whether companies can make their own threshold ofregulation determinations. The comments stated that, inthose cases where the use ofthe substance meets the definition ofa "food additive" in section 201(s) ofthe
act (21 U.S.C. 321(s)), individual manufacturers should be ableto make their own determination as to whether the use ofa substance in a food-contact article meets the criteria for an exemption from regulation. One ofthe comments requested that theagency's position on this issue be explicitly stated inthe finalregulations.

According to Monsanto,only the Commissioner has the statutory authority to exempt a substance from regulation as afood additive. A substance that meets the definition ofa food additive in section 201(s) ofthe act must, therefore, either be thesubject of

a regulation authorizing its use orbe exempted from regulation by FDA under the process specified in new § 170.39, unless the use ofthe substance conforms to an exemption for investigational use issued under section 409(i) ofthe act.

From apolicy standpoint, the procedure outlined inthis finalrule, whereby FDA makes all exemption decisions, offers a number ofadvantages

over an approach that allows individual manufacturers tomake their own threshold ofregulation decisions. One advantage isthat the agency's determination asto whether a substance used in a food-contact article meets the criteria for an exemption from regulation as a food additive willbe binding on the agency. Thus, manufacturers offood-contact articles will be able to rely onthese determinations andmarket their products without fear ofregulatory action.

This approach also will result in more consistent decisions. Qualified experts may disagree on what specific assumptions are appropriate for estimating the dietary concentrations resulting from the use ofsubstances in

### Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

food-contact articles. Thus, allowing individual manufacturers to make their

own determinations would increase the likelihood ofinconsistent decisions.

For example, in cases where there is

no detectable migration into food or food simulants, or when noresidual level of a substance is detected in the food-contact article by a suitable analytical method, the validated detection limit ofthe method used to analyze for the substance would need to be considered in order to estimate the dietary concentration from the intended

use. Qualified experts may disagree not only on the specific numeric value for this detection limit but also on what percentage ofthe detection limit should be used in such situations to estimate actual migration (e.g., 100 percent

versus 50 percent). Qualified experts
may also disagree on the appropriate consumption factor to use in estimating dietary concentrations. Different conclusions on the environmental effects resulting from the use ofa foodcontact article may also arise from such independent determinations. The
agency believes thathaving all such exemption decisions made by areview
team consisting ofa small number of
agency personnel will help lessen the likelihood ofinconsistent decisions on these matters.

Having such determinations made by FDA will also mean that the agency will have more complete information on what materials industry is actually using in food-contact articles. As a result, FDA will be able to make more informed decisions in the event that data become available that raise significant concerns about whether the continued use ofa component ofa foodcontact article is safe.

Although only the Commissioner of FDA has the statutory authority to exempt a substance from regulation as a food additive in those cases where the

use ofthe substance meets the "food additive" definition in section 201(s) of the act, FDA emphasizes that nothing in this final rule limits the use ofa substance exempted by FDA from regulation to only the manufacturer who submitted the request for an exemption. Other manufacturers may use exempted substances in food-contact articles as long asthe conditions ofuse (e.g., use levels, temperature, type offood contacted, etc.) are those for which the exemption was issued.

Consistent with this fact, FDA plans
to give general notice by means ofthe' Federal Register, should it ever decide
to revoke an exemption. The notice will

state that continued use ofsuch a substance would constitute the use ofan unapproved food additive, unless a petition is filed, and the substance is listed foruse in FDA's regulations. It will also set out the reasons for FDA's decision to revoke the exemption, thereby providing manufacturers with the opportunity to submit relevant data
to the agency and to request that the exemption be reinstated.

FDA does not believe, however, that it would bepractical to routinely provide notice in theFederal Register of its intent to revoke an exemption. Such

a process would only unduly delay and burden the revocation process. It would be inconsistent with the intent ofthe threshold ofregulation process to minimize theuse ofagency and industry resources for those substances whose use in food-contact articles poses only negligible safety concerns. Accordingly, FDA is revising § 170.39(g)
to make clear thatthe agency plans to provide notice inthe Federal Register after it has decided to revoke an exemption issued for a specific use ofa substance in a foodcontact article.

FDA has decided, however, not to include in § 170.39 a statement that only the Commissioner can make threshold ofregulation determinations. It is not the agency's usual practice to enumerate in its regulations those regulatory decisions that are reserved to the
agency. Therefore, the agency is not doing so here. Scope ofthe Exemption

14. Two comments recommended that FDA expand its proposed threshold of regulation to enable the agency to exempt entire classes ofcompounds. Under the scheme suggested by these comments, FDA would review one or

more compounds within a given class, and, ifit determined that these individual chemicals qualified for an exemption, the agency would exempt all ofthe chemicals within the class. One ofthese comments expressed the yiew that many manufacturers do not use their proprietary chemicals for foodcontact applications because ofFDA's requirement that theybe regulated based on their chemical identity, and that the use of such an approach would

remove impediments that stifle innovation in the food industry.

FDA disagrees with this approach for

a number ofreasons. Because the level ofmigration, and resulting dietary concentration, ofthe chemical depend

on both its molecular weight and chemical properties, it would be impossible to predict whether the use of all compounds within a class would result in dietary concentrations below the threshold based on the migration properties ofjust one ortwo sample chemicals. For example, polymeric 

### materials manufactured from the same
monomer buthaving significantly different molecular weights would belong to thesame class ofchemicals but would beexpected to have different migration properties. Similarly, the intrinsic toxic potencies forchemicals within acertain class may vary significantly. For example, the polychlorinated dibenzo-p-dioxins are a class of75 congeners that exhibits a wide range oftoxicity depending on the degree ofchlorination and the location ofthe chlorine atoms within the chemical structure. As aresult, the likelihood that asubstance poses a health hazard isnot necessarily determinable based on the information about the toxicity ofother chemicals that are inthe same class. In addition, it would be difficult to predict the environmental impactthat would result from the manufacture, use, and disposal ofall substances within aclass based on the impact ofone ortwo chemicals. Therefore, FDA does notbelieve that it ispossible,based on the review ofone

ormore compounds within a given class, tojustify an exemption for all other chemicals belonging tothe same class.



### Forthe foregoing reasons and because the dietary concentration ofa specific chemical is dependent on the conditions ofits use (e.g., type ofuse, temperature, food type, and contact time), FDA concludes that to adequately safeguard the public health, it is necessary to limitexemptions under §170.39 to those conditions ofuse ofa chemical that it has evaluated.

15. One comment recommended that rather than require a submission for each chemical and each proposed use, FDA should publish guidelines based

on categories ofuses that would provide performance standards that could be used by manufacturers to guide
customers on how to stay below the threshold exposure.

As discussed earlier, the dietary concentration resulting from the use of

a substance in a food-contact article may vary considerably depending on the type ofuse and the conditions ofuse. Therefore, it would notbe feasible to establish guidelines foruse with respect to all possible food-contact articles under all possible conditions. Interpretation of such complicated guidelines by individual manufacturers and customers would inevitably lead to confusion and inconsistencies.

The process specified inthis final rule, as part ofwhich a small team of agency personnel willreview each request foran exemption, will result in

more consistent decisions. Having all such determinations made byFDA 36587

### 36588 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

using the process specified inthe final rule should also result in the agency havingmore complete information on what substances are being used in foodcontact articles. This information will permit the agency to take action inthe event that data become available that raise significant questions as to whether the continued use ofa substance in a food-contact article is safe.

16. Onecomment stated that the 0.5 ppb threshold wastoo low forthe use ofpigments in food-contact articles because such pigments are less toxic than other chemicals. Because these pigments are relatively insoluble, they would also have lower bioavailability.

FDA does not believe that it is feasible
to establish specific thresholds of regulation for each ofthe many types of chemicals used in food-contact articles. Such an approach, with many different thresholds, would becumbersome. Moreover, as discussed in a previous comment, the toxicological properties of chemicals within aclass can vary greatly. Therefore, it would be extremely difficult to establish a single threshold for all the chemicals within a given class. Because ofthis difficulty, FDA is not taking any action inresponse to thiscomment.

The agency believes that it may be feasible inthe future to establish a higher threshold based on a substance's toxicological properties rather than based on itstype or on the class of chemicals to which itbelongs. For example, as discussed in a previous comment, it may be possible inthe future to establish separate thresholds for substances thateither have been shown tobe noncarcinogenic by appropriate 2-yearbioassays or,based

on the results ofshort-term toxicity testing (e.g., mutagenicity and acute oral feeding studies), are likely to have a low carcinogenic potency ifthey are, in fact, carcinogenic.

17. One comment requested that FDA specifically address whether biocides

. would be eligible for consideration under thethreshold ofregulation regime. Because such substances must be registered with the Environmental Protection Agency (EPA) in accordance with the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) (7U.S.C. 136 et al), and must undergo an extensive review for safety and efficacy, the comment stated thatbiocides are well suited for an abbreviated review under FDA's threshold ofregulation
process.

As long as thecriteria specified in this final rule are met,FDA will grant exemptions from regulation as food additives for biocides that become components offood-contact articles. 18. Two comments requested that FDA clarify how the presence ofa "barrier" (one that would limit the migration ofa packaging substance into food) would be factored into threshold ofregulation decisions. In particular, the comment asked whether, in cases where there is a functional barrier, and

no migration can be detected, FDA would still consider the validated detection limit ofthe method used to analyze for the substance in its dietary
exposure estimate.

The key factor in FDA's decision to grant an exemption from regulation for

a substance used in a food-contact article is whether the dietary concentration of the substance resulting from its use isbelow the threshold. Thus, ifthe presence ofa functional barrier limits themigration ofthe substance into food such that the resulting dietary concentration is below the threshold, FDA will grant an exemption for the intended use ofthat substance, provided thatthe other criteria specified in this final rule are met.

In mostcases, the effectiveness ofa material to act as a barrier to migration will depend not only on the physical and chemical properties ofthe barrier material and the potential migrant but also on the thickness ofthe barrier layer and the conditions ofuse (e.g., temperature, food type, contact time). Therefore, it is usually not possible to draw any conclusions regarding the effectiveness ofa barrier material in the absence of migration data. In such cases, requests for exemptions from the food additive regulations would need to contain data showing that the barrier material precludes all but minimal migration ofthe substance into food (i.e., the resulting dietary concentration is at orbelow thethreshold). FDA will consider thevalidated detection limit of the method used to analyze forthe substance in arriving at its dietary
exposure estimate.

There are a number of specific situations, however, where FDA would
not require data to show that a barrier material precludes all butminimal migration ofthe substance into food. For example, some packaging materials such

as aluminum foil, when used as the inner layer oflaminates, have been generally recognized asbeing able to provide an effective barrier to migration ofthe outer layer components into food under a variety ofconditions. In such

cases, it would not be necessary for the requestor to carry out and submit extraction studies designed to show the effectiveness ofthe barrier layer. Another example involves those cases in which FDA has reviewed the barrier 

### material and has established specific conditions under which the material would indeed function as a barrier. In these cases, the agency will be able to make decisions on similar constructions in the absence ofany additional extraction studies, as long as the conditions ofuse do not differ significantly fromthose the agency reviewed.

19. One comment inquired asto whether the final rule establishing a threshold ofregulation for substances used infood-contact articles willbe applicable to regulated direct animal feed additives that are intended to be used as components ofarticles that may contact animal feed (i.e., indirect animal feed additives).

This finalrule will allow those substances exempted under §170.39 to be used in articles contacting animal feed as longas the intended conditions ofuse ofthe substance are those for which the exemption was issued. This result follows from §§ 174.6 and §570.14 (21 CFR 570.14) ofFDA's regulations. Under §174.6 Thresholdof regulation forsubstancesusedinfoodcontactarticles,FDA will exempt substances fromregulation as food additives whose use ii food-contact articles meet the criteria in §170.39. Authority to,use substances exempted under § 174.6 in articles contacting animal feed is set out in §570.14 Indirect foodadditivesresulting from packaging materials foranimal feed and pet food,which states thatthe regulations providing for the use of food-packaging materials inparts 174 through 179 (21 CFRparts 174 through 179) are applicable to packaging materials used in animal feed and pet food.

Moreover, in cases where the exemption request concerns the use of

a substance in an article that is used only in contact with animal feed, the criteria used by FDA to determine whether an exemption from regulation is warranted willbe those specified in

new §170.39. Because § 570.14 contains

a cross-reference that includes § 174.6, in accordance with thatprovision, FDA

can review a request for exemption ofa substance used only in contact with animal feed under § 170.39.

Sections 170.39, 174.6, and 570.14, 

### however, will notprovide forthe use in articles contacting animal feed, ata level that is 1percent or less oftheir ADI, ofsubstances that are currently regulated for direct use in animal feed in part 573 (21 CFR part 573). To provide forsuch areview, FDA will have to adopt a regulation similarto § 170.39 that applies to direct animal feed additives that have notbeen

### Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

regulated for direct addition to human food. However, such a regulation is outside the scope ofthisrulemaking and would require a separate proceeding. Application ofthe Exemption
20. One comment inquired whether exempted substances may be used in
contact with alltypes of food.

Because the dietary concentration resulting from theuse ofa substance in

a food-contact article is dependent on the type offood with which it comes in contact, theuse ofa substance in an article contacting one type of foodmay result in adietary concentration below the threshold, while the use ofthe same material in contact with another type of food may not.Therefore, FDA will limit exemptions to those conditions ofuse warranted by the available data.

B. The Regulation

21. One comment recommended that FDA revise the language in § 170.39(a)(1) tomake clear whether the phrase "there is noreason, based onthe chemical structure ofthe substance, to suspect that thesubstance is a carcinogen" refers toimpurities within the substance orthe substance itself.

FDA agrees with thiscomment and is revising proposed § 170.39(a)(1) tomake it clearthat the phrase "there is no reason,based on the chemical structure ofthe substance, to suspect that the substance is a carcinogen" refers only to the substance itself.

22. One comment recommended that FDA revisethe language inproposed § 170.39(c)(1) to make clearthat the description ofthechemical composition ofthe substance for which therequest is made should include, whenever possible, thename ofthe chemical in accordance with current chemical abstracts service (CAS) nomenclature guidelines and a CASregistry number if available.

FDA agrees with this comment and has revised proposed § 170.39(c)(1) accordingly.

23. One comment recommended that the word "substance" inproposed § 170.39(c)(4)(ii) and (c)(4)(iii) should refer to the singular case for consistency..

FDA agrees and has made the changes that respond tothis comment inthis finalrule.

24. Onecomment recommended that the regulation define in detail thetypes ofinformation required by FDA in submissionsrequesting exemptions from the food additive regulations.

FDA agrees that a detailed description ofthe information that needs tobe included in a request for an exemption shouldbe readily available to interested parties. However, FDA does not believe that it is necessary orappropriate to include this information in the Code of Federal Regulations (CFR). The agency considers it appropriate to make this information available in a manner similar to that which FDA uses with respect to the contents of food additive petitions. For food additive petitions, FDA generally describes the information that must be submitted in part 171 (21 CFR part 171) of its regulations and maintains more detailed guidelines that

are available from the agency upon request. While FDA publishes modifications in the CFR only annually, it can modify guidelines whenever
necessary, thereby providing requestors with up-to-date guidance. This flexibility in modifying detailed guidelines is needed to take into
account ongoing advances in the development offood-contact articles and in themethodologies used to quantify migration ofcomponents of such aticles into food.

Therefore, FDA is adding § 170.39(h), which states that guidelines to assist requestors in the preparation of submissions seeking exemptions from the food additive regulations are available from FDA's Office of Premarket Approval (HFS-200), 200 C St. SW., Washington, DC 20204.

Because it is notpractical to provide guidelines thatwould cover all ofthe possible topics associated with these types ofsubmissions, thisfinal rule
encourages interested parties to obtain specific guidance from FDA on the protocols to use in obtaining extraction data, on the validation of theanalytical methods used to quantify migration levels, on the procedures to useto relate migration data to dietary exposures, and

on any other issuenot specifically covered in FDA's guidelines.

FDA formerly proposed to announce the availability of guidelines in § 170.39(c)(4)(v) because the guidelines

were meant to focus on questions associated with the dietary concentration resulting from the intended use ofa substance in a foodcontact article. However, the agency believes it is more appropriate to include such language as part of § 170.39(h) to emphasize that interested parties may seek guidance on any issue involving exemption requests. Therefore, FDA is revising § 170.39 to include this provision and has deleted proposed § 170.39(c)(4)(v).

C.Procedural Issues Obtaining an Exemption

25. One comment commended FDA forits statement in the preamble that 

### manufacturers may make their own determination asto whether theuse of

a substance in afood-contact article meetsthe "food additive" definition in section 201(s) ofthe act and recommended that FDA explicitly state this fact inthe finalregulation.

Inresponse to this comment, FDA would like to reaffirm itsposition that nothing inthe regulatory scheme presented inthis rule would prevent a company frommaking its own determination that a particular use ofa substance does notmeet the definition of a "food additive" in section 201(s) of the act. However, as noted in the proposal, companies make such determinations at their own risk. Ifthe agency learns ofthe use ofa substance from, for example, a competitor and reaches a different conclusion than the company, the agency may take regulatory action against the substance

asan unsafe food additive oragainst the company that makesthe substance for introducing an adulterated food injo interstate commerce. Therefore, incases where it is not clear whether the use of

a food-contact article meets the "food additive" definition, FDA recommends that manufacturers seek a determination under the procedures specified in this ruleto avoid the possibility of regulatory action.

FDA doesnotbelieve, however, that it is appropriate to address this issue in the regulation. The issue raised by the comment applies generally to FDA's application ofthe "food additive" definition in section 201(s) ofthe act. This rulemaking concerns only the threshold ofregulation process. Therefore, the question ofwhether, and how, to incorporate into FDA's regulations the statement that the comment seeks is outside the scope of this rulemaking.

26. Seven comments recommended that the agency establish atime limit for reviewing and responding to requests forexemptions from regulation as food additives to ensuretimely responses. Two ofthe comments suggested specific time limits of60 and 90 days.

The agency agrees that such reviews shouldbe carried outin atimely

manner. Timely review will meanthat manufacturers and suppliers of substances that are exempted from regulation as food additives will be able to market their products much more quickly than has been the case.Timely review will also mean that manufacturers and suppliers of substances that arenot exempted will receive promptnotice ofthe need to file

a food additive petition.

A pilot study carried outbyFDA showed that such reviews can usually 36589

### 36590 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

be completed within 3 to 4 months as compared to the 1to 2 years typically required forindirect food additive petitions. The agency is concerned, however,that establishing aformal time limit for completion ofsuch reviews will unduly restrict its ability to allocate its limited resources to projects that may be more critical. Therefore, the agency has decided not to establish atime limit forreviewing and responding to requests for exemptions from regulation

as food additives atthis time. Asthe agency gains experience with its threshold ofregulation policy, it will consider establishing an appropriate time limit.In the interim, however, the agency is committed toreviewing exemption requests asexpeditiously as
resources allow.

27. One comment recommended that there bea phase-in process that would allow companies to carefully evaluate products that are on the market and to obtain exemption determinations where, and if,required.

As discussed previously"iftheuse of

asubstance results in, or isreasonably expected to result in, migration into food, even atlow levels,and is not specifically excluded from the definition ofa "food additive" in section 201(s) ofthe act, then thesubstance is a food additive that must eitherbe the subject ofa regulation authorizing its use orbe exempted from regulation by FDA under the process specified in thisrule. However,ifthe

use ofa substance in a food-contact article currently on the market involves low levels of migration into food (i.e., results in a dietary concentration at or below the threshold ofregulatory concern), and is the subject ofa request for an exemption under the process specified by this final rule, it is unlikely that FDA would takeregulatory action during thetime needed by the agency to complete its review. Therefore, the agency does not believe it is necessary to establish a phase-in program to allow companies to evaluate food-contact articles currently on the market.

28. One comment recommended that §170.39 berevised to include an abbreviated review (i.e., one that does not require areview ofenvironmental impact data and toxicological feeding study data) for those exemption requests that deal only with new uses of regulated indirect food additives that involve the same manufacturing process but a different technical effect (e.g., a substance currently regulated as a defoamer in the manufacture ofpaper and paperboard under § 176.170 that is the subject ofan exemption request for its use as a deposit control agent in the manufacture ofpaperand paperboard). The agency is currently reevaluating its environmental regulations under NEPA, and is committed to expanding the list ofcategorical exclusions found in §25.24 (21 CFR 25.24). However, as indicated earlier, a key factor in FDA's decision to grant an exemption from regulation is whether the substance has

a significant impact on the environment. A new use ofaregulated indirect food additive that involves the same manufacturing process but a different technical effect may have, as a result of its use or subsequent disposal, a significantly different environmental
exposure than anypreviously regulated

use ofthe substance. Therefore, an abbreviated review (i.e., one that does
notinclude a review ofenvironmental impact data) is notjustified for all such substances. Although these types ofuses do not currently qualify for a categorical exclusion, somemay qualify in the future (thecategorical exclusion list is currently under consideration for expansion).

In regard to reducing the requirements for the submission oftoxicological feeding studies, FDA emphasizes that § 170.39 requires only that submissions contain the results ofan analysis of existing toxicological information on the substance and its impurities. This information is needed to show whether

an animal carcinogen bioassay hasbeen carried out, or whether there is some other basis for suspecting that the substance is a carcinogen or potent toxin. FDA also requires this type of information to enable it to determine whether any oftheimpurities present in the substance-have been shown to be carcinogenic, and, ifcarcinogenic, whether their TD50 value is greater than 6.25 mg/kgbodyweight per day (see § 170.39(a)(1)). To clarify this issue, FDA is revising the language in § 170.39(c)(5) to state that the only toxicological information that mustbe included in a submission for an exemption from the food additive regulations is an analysis ofexisting toxicological information on the substance and its impurities.

29. Two comments stated that exempted substances should notbe subjected to the environmental impact reviews typically required for food additives. The comments asserted that, instead, exempted substances should

come under anewly created "categorical exclusion" that would exclude such actions from the requirement that an environmental
assessment be prepared.

An FDA decision to exempt a substance from regulation as a food additive is an agency action under the National Environmental Policy Act (NEPA) (42 U.S.C. 4321). Under NEPA,

an agency action must include a consideration ofthe environmental effects resulting from the intended use, unless it is the subject ofone ofthe categorical exclusions listed in 21 CFR 25.24. Actions are made subject to an exclusion either because, as a class, they will not result in the production or distribution ofany substance and, therefore, will not result inthe introduction ofany substance into the environment, or because they meet specific criteria that are intended to

ensure they will not cause significant environmental effects. As stated above, the agency is actively examining its categorical exclusion regulations. However, neither ofthe subject
comments provided information to show that as a class, substances used in food-contact articles would notbe introduced into the environment or to support the establishment ofa new categorical exclusion. The agency welcomes the submission ofdata and information that would support the establishment ofa categorical exclusion forthese substances. At this time, however, all requests for threshold of regulation exemptions must include an abbreviated environmental assessment. Availability ofthe Information Submitted

30. Six comments were submitted on the general subject ofwhat types of information contained in submissions under § 170.39 should be made publicly available (i.e., on display at the Dockets Management Branch or released in
response to requests submitted under the Freedom ofInformation Act (FOIA) (5 U.S.C. 552)). Three ofthese
comments were quite general, recommending that FDA handle the confidential information contained in such submissions in the same manner that it has traditionally treated other documents submitted. A more specific
comment recommended that the information released under FOIA should be consistent with that released from food additive petitions. One
comment expressed the opposite viewpoint, stating that exempted substances should not be considered food additives, and that, therefore, the rules governing therelease of information submitted on food additives should not apply. This comment also requested that the final regulation include a statement recognizing the possible trade secret status of information submitted in support ofan exemption request. Another comment stated that the names ofcompanies receiving exemption letters are trade
secret.

### Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

As a general matter, the FOIA requires that agencies make the fullest possible disclosure of recordsto the public. The procedures that FDA uses to handle the release ofpublic information in accordance with FOIA are described in part 20 (21 CFRpart 20). Under these procedures, information submitted to FDA, including that submitted on the

use of food additives, is made publicly available to thegreatest extent possible.

As for substances that become components offood below the threshold that FDA is establishing, they will be exempt from the requirement that their

use be the subject of afood additive listing regulation. This exemption, like

a listing regulation, allows these substances to be used in food contact articles. Given the similarity in effect between a food additive listing and the grant ofan exemption, FDA concludes that it is appropriate for it to make publicly available under § 170.39(e) the

same type of information that is releasable on regulated food additives. This information includes the name of the company that sought and received authorization to use the substance.

Inresponse to the request that the final regulation include a statement recognizing the possible trade secret status ofinformation submitted in support ofan exemption request, FDA is revising § 170.39(e) to state that the
agency will respond to all FOIA requests for information subnmtted under § 170.39 in accordance with part 20. Thus, data and information that are trade secret or confidential commercial

or financial information are not available for public disclosure in accordance with § 20.61(c).

31. One comment stated that information contained in submissions under § 170.39 should not be released in
response to FOIA requests.

FDA does not agree with this
comment. As discussed in the previous comment, FOIA requires that agencies make the fullest possible disclosure of records to the public. The agency, however, recognizes that it has an obligation to protect trade secret and confidential commercial or financial information as defined in §20.61(a) and (b). Therefore, FDA will not disclose this type ofinformation.

32. Two comments stated that the chemical identities ofexempted substances should not be publicly disclosed. One ofthese comments stated that such information is trade secret and considered by economists as "circumstantially relevant business information." The comment stated that, ifthe company requesting an exemption regards this information astrade secret, keeping such information confidential is 

### consistent with controlling case law interpretation ofthe confidentiality standard that is applied to FDA under Critical MassEnergyProjectv.NRC,975 F. 2d 871 (D.C. Cir. 1992). This
comment also stated that, because these substances are exempt from regulation

as food additives, FDA is not under any obligation to disclose their chemical identities. The comment stated that release ofproprietary information could force companies to make their own determinations as to whether a food additive regulation is needed. This
comment suggested that FDA adopt a system whereby the chemical would be identified only by the general class of chemicals to which -itbelongs. This
comment also pointed out thatEPA has used this type ofsystem in PreManufacture Notifications submitted under the Toxic Substances Control Act (40 CFR 720.85). One of these comments raised the possibility that exempted substances could be referred to only by their trade names.

FDA disagrees with the suggestion that exempted substances be referred to only by trade names or by reference to the general class ofchemicals to which they belong. Two factors underlie FDA's disagreement. First, the provisions of the act added by the 1958 Food Additives Amendment permit any manufacturer to use any regulated food additive as long as the substance meets all applicable specifications, including those associated with the identity ofthe additive. Second, as previously discussed,FOIA requires that agencies make the fullest possible disclosure of records to the public. Under the procedures usedby FDA to determine the releasability ofinformation under FOIA, the agency has traditionally considered the chemical identity offood additives to be disclosable information, and thus, the regulations implementing the 1958 Food Additives Amendment referto food additives by their chemical

names. Because FDA's approach to exempted substances derives from the food additive provisions ofthe act, and,

as stated above, FDA is acquiescing in the use ofthe substance, FDA concludes that the.chemical identities ofexempted substances are disclosable under FOIA.

Critical Massis not to the contrary. While a company has an alternative to making a submission to FDA under § 170.39 (i.e., filing a food additive petition), and thus, the submission is in

a sense voluntary, the key question under CriticalMassis whether the information is ofa kind thatwould customarily not be released to.the public by the person from whom it was obtained (975 F.2d at 879). As stated above, information about the chemical 

### identity offood additives forwhich listing is sought is routinely disclosed to the public in the Federal Register, pursuant to section409 ofthe act. Submitters are well aware ofthis fact. Thus, FDA finds no meritto the suggestion by the comment that the identity ofsubstances subject to §170.39 mustbe kept confidential. To provide differently forsubstances subjectto §170.39 would beto create a special exemption. Clearly, Critical Massdoesnot require such a result.

From a practical standpoint, chemical nomenclature has typically been used to characterize food additives because chemical names are universally recognized and are not subject to change

as tradenames often are. Moreover, trade names are often used to refer to formulations in which the chemical composition isheld confidential. In such cases, referring to regulated food additives by trade names would make it impossible for other manufacturers to determine whether their chemical substances meet applicable regulations. A similar situation would occur ifthe list ofexempted substances made publicly available didnot include the, chemical identities ofsuch substances.

Making available the chemical identities ofsubstances exempted from regulation will permit other manufacturers to use these substances

as long asthe conditions ofuse are no
more likelyto result inmigration to food than those for which the exemption was originally issued. It will also allow interested persons to determine what substances havebeen exempted by FDA under the process established by this final rule.FDA believes that, in the interest ofopen government, it is essential that decisions made under this policy be available to the public. Therefore, for the reasons specified above, FDA will make publicly available the chemical identities ofexempted substances.

33. One comment stated thatthe technical effect orfunction ofthe substance should notbe made publicly available.

Underthe procedures used by FDA to implement FOIA, the agency hasnot considered information on the technical effect or functionality ofa food additive
to be trade secret as defined in §20.61(a)

orconfidential commercial or financial information as defined in §20.61(b). Because the dietary exposure resulting from the use ofa substance in a foodcontact article may vary considerably depending on thetechnical effect ofthat additive, it is often necessary to include such information in the regulation authorizing a specific type ofuse ofthe food additive in ordertorestrict the 36591

### 36592 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

dietary exposure to levels that can be supported by existing safety data. For example, substances regulated in 21 CFR 178.3400 are restricted to use as emulsifiers and/or surface active agents in the manufacture ofarticles or as. components ofarticles contacting food. Moreover, theprovisions ofthe act added by the 1958 Food Additives Amendment permit any manufacturer to

use any regulated food additive as long

as the use ofthe substance meets all applicable specifications and limitations. Such limitations include those that restrict the use ofthe additive
to a specific technical effect. Therefore, it is often necessary to include this information as part ofthe conditions of

use set forth in the regulation authorizing theuse ofthe additive so that other manufacturers may use the

same substance under only those conditions that are safe. In addition to being made available as part ofa regulation, the agency has routinely made technical effect information

. contained in food additive petitions available to thepublic in response to FOIA requests in accordance with § 171.1(h)(1)(i). Consistent withthe explanation above, FDA sees no reason to change this policy with regard to food additives exempted from regulation.

Treatment ofthe List ofExempted Uses of Substances

34. One comment recommended that in addition to making available a list of exemptions atthe Dockets Management Branch, FDA should publish this list in the Federal Register.

The public should have ready access to an up-to-date list of those uses of substances thathave been exempted from regulation as food additives by FDA. However, maintaining such a list, updated on a regular basis, on display
at the Dockets Management Branch, is the most efficient way ofachieving this result. FDA anticipates being able to respond to exemption requests within 3
to 4 months. Thus, the list ofexempted substances would be continually changing. Monthly updates in the Federal Register would be expensive and yearly updates oflittle value. Therefore, FDA has no plans to publish this list in the Federal Register.

However, toensure that interested
persons are aware thatFDA is maintaining such a list at its Dockets Management Branch, the agency plans
to publish annually a briefnotice in the Federal Register on the availability of this list. An updated list ofexempted substances can also be obtained by contacting FDA's Office ofPremarket Approval (address above). FDA is revising § 170.39(e) to reflect this fact. Revocation

35. One comment recommended that FDA establish timeframes forthe revocation process. The comment suggested that the requestor would have 60 days to respond to FDA's tentative decision to revoke an exemption. Once the response is submitted, FDA would have 60 days to reach its final decision.

FDA agrees that in cases in which

new information becomes available showing that continued exemption ofa substance in a food-contact article from regulation under the food additive provisions cannot be supported in light ofexisting safety data, the requestor's
response to FDA's tentative decision to revoke an exemption, and FDA's subsequent decision, should occur in a timely manner. However, because the complexity ofsuch reviews may vary greatly and require varying amounts of time to complete, FDA does not consider it to be appropriate to establish specific timeframes for such reviews.

III. Other Actions

FDA is revising § 170.39(c) to state that three copies ofarequest for an exemption from regulation are to be submitted. The agency is requiring three copies to help expedite its review of such requests. To further expedite such reviews, the agency is revising § 170.39(c) to state that ifpart ofthe submitted material is in a foreign language, it must be accompanied by an English translation verified to be complete and accurate in accordance with § 10.20(c)(2) (21 CFR 10.20(c)(2)).

IV. Analysis ofImpacts

FDAhas examined the impacts ofthis final rule under Executive Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). Executive Order 12866 directs agencies to assess all costs and benefits ofavailable regulatory alternatives and, when regulation is necessary, to selectregulatory approaches that maximize net benefits. (including potential economic, environmental, public health and safety effects; distributive impacts; and equity). Under Executive Order.12866, a regulatory action is economically significant ifit meets any one ofa number ofspecified conditions, including having an annual effect on the
economy of$100 million or adversely affecting in a material way a sector of the economy, competition, or jobs. A regulation is otherwise considered significant under Executive Order 12866 ifit raises novel legal or policy issues. The Regulatory Flexibility Act requires analyzing options for regulatory relief for small businesses. FDA finds that this final rule is not a significant regulatory action as defined by Executive Order 12866. In compliance with the Regulatory Flexibility Act, the agency certifies that this final rule will nothave

a significant impact on a substantial number ofsmall businesses.

38. One comment suggested that the proposed threshold ofregulation
process would have an adverse impact

on small businesses. FDA disagrees. The regulation that FDA is adopting does not prohibit orrestrict any present activity and, therefore, does not generate compliance costs for either large or small firms. In addition, FDA has received no information that the benefits ofthe proposed action will

accrue differentially to large firms. In fact, this approach should minimize the burden on all businesses by providing a procedure that is less burdensome than the food additive petition process. Without this threshold ofregulation
process, those components offoodcontact materials whose use results in low levels ofmigration into food would require premarket approval through the food additive petition process.

Based on information provided to FDA by representatives ofthe food packaging and processing industries, the collection ofinformation and preparation ofan exemption request for review under the process established by this final rule is estimated to cost anywheit from $1,400 to $25,000 depending on the complexity ofthe project. Ifanalytical studies are required
to be carried out to show that the dietary
exposure resulting from the proposed

use is below the threshold ofregulation, FDA estimates that the additional cost would vary from $10,000 to $50,000 depending on the complexity ofthe project (e.g., the number ofsubstances

or food simulating solvents involved, and the method ofanalysis). Thus, the
agency estimates that the total cost to submit exemption from regulation requests may vary from $1,400 to $75,000.

The time required to prepare such requests would also vary with the type ofdata needed to estimate the dietary
exposure associated with the intended

use. A simple request (i.e., onethat does
not contain any analytical work) would typically contain: (1) Identity and use information; (2) a literature search ofthe existing toxicological data on the substance and its impurities; and (3) information on the environmental impact resulting from the proposed use ofthe substance. Based on information provided to FDAby representatives of the food packaging and processing industries, the average time to prepare such requests is estimated to be 68

### Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

*hours. The average time to prepare

requests that include analytical work (e.g., extraction studies carried out using food-simulating solvents, analytical studies to determine the residual level ofthe substance in the food-contact article) is estimated tobe 108 hours.

Although the preparation ofrequests for exemptions from regulation may cost anywhere from $1,400 to $75,000 and require on average 68 hours to complete (108 hours for submissions requiring' analytical data), these estimates demonstrate that there will be a significant decrease in the overall burden to businesses for those components offood-contact articles that

are exempted from regulation by this expedited process but that previously would have required premarket approval via the food additive petition
process. (Petitions on these types of issues can require on average 2,600 hours to prepare and cost anywhere from $85,000 to $100,000.) Whenever possible, FDA will provide assistance to requestors to minimize the likelihood that unnecessary work will be performed. Based on the preceding considerations, FDA finds that the proposed action will nothave an adverse impact on small businesses.

In summary, the comments do not provide a basis on which to change the conclusions ofthe economic analysis prepared forthe proposed rule or to establish that another option would provide higher net benefits.

V. Environmental Impact Considerations

The agency has previously reviewed the environmental effects ofthisrule as announced in the proposal (see 58 FR 52719, October 12, 1993). The agency determined under 21 CFR 25.24(a)(8) that neither an environmental
assessment nor an environment impact
statement is required. No new information or comments have been received that would affect the agency's previous determination.

The agency is required to consider the environmental impact ofeach action to exempt a component ofa food-contact article from regulation as a food additive. The final rule sets out the type ofinformation that FDA needs to determine the impact on the environment resulting from the. intended use. The agency's finding ofno significant impact, and the evidence supporting that finding, contained in an environmental assessment, will be made available forpublic inspection at the Dockets Management Branch (address above) for those substances whose use in food-contact articles has been exempted from regulation by the
process established by this rule.

VI. Paperwork Reduction Act

Section 170.39 ofthis final rule contains information collection requirements that were submitted for review and approval to the Office of Mafhagement and Budget (OMB), as required by section 3504(h) ofthe Paperwork Reduction Act of1980. The requirements were approved and assigned OMB control number 0910- 0298.

VII. Conclusions

Although a number of comments expressed the opinion that the 0.5 ppb threshold is more conservative and restrictive than is necessary to adequately protect the public health, no data were submitted that would justify FDA establishing a threshold of, regulatory concern at a dietary concentration level higher than 0.5 ppb. Based on its analysis ofthe available evidence, FDA concludes that this evidence does not support a threshold significantly higher than 0.5 ppb, especially where the substancebeing considered for an exemption has not been the subject ofany toxicological testing. Therefore, this final rule establishes 0.5 ppb as the threshold of regulatory concern for substances intended for use in food-contact articles. This final rule also establishes the threshold ofregulatory concern for regulated direct food additivesused in food-contact articles asthat dietary exposure that is at orbelow 1 percent ofthe ADI forthat substance.

Listedbelow are the revisions that are being incorporated into this final rule based on comments received in
response to the proposal:

(1) FDA is revising § 170.39(a)(1) to make it clear that the'phrase "there is

no reason, based on the chemical
structure ofthe substance, to suspect that the substance is a carcinogen" refers only to the substance itself(see
comment 21 ofthis document).

(2) FDA is revising § 170.39(a)(2)(ii) to
state that, for requests seeking an exemption on the basis that the substance is a regulated direct food additive whose use in a food-contact article will result in a dietary exposure at orbelow 1 percent ofthe ADI for that substance, FDA's review will not necessarily be restricted to ADI values based on data inFDA files. In particular, in cases where FDA has not calculated

an ADI value for aregulated direct food additive, the agency will consider ADI values from other appropriate sources (see comment 9 of this document). (3) FDA is adding paragraph (h)to § 170.39 to state that guidelines to assist requestors in the-preparation of submissions seeking exemptions from the food additive regulations are available from FDA's Office of Premarket Approval (HFS-200, 200 C St. SW., Washington, DC 20204). Because it isnot practical to provide guidelines that would cover all ofthe possible topics associated with these types ofsubmissions, §170.39(h)
encourages interested parties to obtain specific guidance from FDA on the appropriate protocols to beused for obtaining extraction data, on the validation ofthe analytical methods used to quantify migration levels, on the procedures used to relate migration data to dietary exposures, and on any other issue not specifically covered inFDA's guidelines (see comment 24 ofthis document).

(4) FDA is revising § 170.39(c)(1) to state thatthe description ofthe chemical composition ofthe substance for which the request is made should include, whenever possible, the name of the chemical in accordance with current CAS nomenclature guidelines and a CAS registry number, if available (see
comment 22 ofthis document).

(5) For consistency, FDA is revising § 170.39(c)(4)(ii) and (c)(4)(iii) so that the word "substance" refers to the singular case (seecomment 23 ofthis document).

(6) FDA is revising the language in § 170.39(c)(5) to state that the only toxicological information that must be included in a submission for an exemption from the food additive regulations is an analysis ofexisting toxicological data on the substance and, its impurities. Thisinformation is needed to show whether an animal carcinogen bioassay hasbeen carried out,or whether there is some other basis for suspecting that the substance is a carcinogen orpotent toxin. This type of information on the impurities is needed
to show whether any of them are carcinogenic and, ifcarcinogenic, whether their TD 50 value is greater than 6.25 mg/kg bodyweight per day in accordance with § 170.39(a)(1) (see
comment 28 ofthis document).

(7) FDA is revising § 170.39(e) to state that interested persons may obtain a list ofexempted substances by contacting FDA's Office ofPremarket Approval 

### (HFS-200), 200 C St. SW., Washington, DC 20204 (see comment 34 ofthis document).

(8)FDA is also revising § 170.39(e) to state that FDA will handle requests for. copies ofreleasable information contained in submissions requesfing exemptions from the food additive 

### 36593

### 36594 Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

*regulations in accordance with FDA's

FOIA procedures as described in part 20. In particular, data and information that fall within the definitions ofa trade
secret or confidential commercial or financial information are not available forpublic disclosure in accordance with 21 CFR 20.61(c) (see comment 30 ofthis document).

(9)FDA is revising the language in § 170.39(g) to state that the agency plans
to notify manufacturers by means of a notice published inthe Federal Register ofits decision to revoke'an exemption issued for a specific use ofa substance in a food-contact article (seecomment 13 ofthis document).

(10) FDA is revising § 170.39(c) to state that three copies of arequest for an exemption from regulation are to be submitted. Ifpart ofthe submitted material is in a foreign language, it must be accompanied by an English translation verified to becomplete and
accurate in accordance with § 10.20(c)(2) (see Section III. ofthis document: Other Actions). In addition
to these changes, FDA is clarifying its definition ofTDso in § 170.39(a)(1). This minor change from the October 12, 1993, proposal ensures the scientific soundness ofthis definition.

VIII. References

The following references have been placed on display in the Dockets Management Branch (addressabove) and may be seen by interested persons between 9 a.m. and 4 p.m., Monday through Friday.

1.Rulis, A., "Threshold ofRegulation: Options forHandling Minimal Risk Situations," in FoodSafetyAssessment, edited by Finley, J.W., S. F. Robinson, and D.J.Armstrong, American Chemical Society Symposium Series 484, pp. 132-139, 1992.

2. Rulis, A. M., D. G. Hattan, and V. M. Morgenroth II, "FDA's Priority Based Assessment ofFood Additives," Regulatory ToxicologyandPharmacology, vol. 4, pp. 37-56,1984.

List ofSubjects

21 CFR Part 5
Authority delegations (Government agencies), Imports, Organization and functions (Government agencies).

21 CFRPart 25

Environmental impact statements, Foreign relations, Reporting and recordkeeping requirements.

21 CFRPart170

Administrative practice and procedure, Food additives, Reporting and recordkeeping requirements. 21 CFRPart171

Administrative practice and procedure, Food additives.

21 CFRPart174

Food additives, Food packaging. Therefore, under the Federal Food, Drug, and Cosmetic Act and under

. authority delegated to the Commissioner ofFood and Drugs, 21 CFR parts 5, 25, 170, 171, and 174 are amended as follows:

PART5-DELEGATIONS OF AUTHORITY AND ORGANIZATION

1. The authority citation for21 CFR part 5 continues to read as follows:

Authority: 5 U.S.C. 504, 552, App. 2; 7 U.S.C. 138a, 2271; 15 U.S.C. 638, 1261-1282, 3701-3711a; secs. 2-12 ofthe Fair Packaging and Labeling Act (15 U.S.C. 1451-1461); 21 U.S.C. 41-50, 61-63, 141-149,467f, 679(b),- 801-886, 1031-1309; secs. 201-903 of the .Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321-394); 35 U.S.C. 156; secs. 301, 302,303,307, 310,311,351,352,354,361, 362, 1701-1706, 2101, 2125, 2127, 2128 of the Public Health Service Act (42 U.S.C. 241, 242, 242a, 2421, 242n, 243, 262, 263, 263b, 264, 265, 300u-300u-5, 300aa-1, 300aa-25, 300aa-27, 300aa-28); 42 U.S.C. 1395y, 3246b, 4332, 4831(a), 10007-10008; E.O. 11490, 11921, and 12591; secs. 312, 313, 314 ofthe National ChildhoodVaccine Injury Act of 1986, Pub. L. 99-660 (42 U.S.C. 300aa-1 note).

2. Section 5.61 is amended by adding

new paragraph (h)to read as follows:
§5.61 Food standards, food additives, generally recognized assafe (GRAS) substances,coloradditives, nutrient content claims, and health claims.

(h) The following officials are authorized to issue letters concerning substances determined to be below the "threshold ofregulation" under § 170.39 ofthis chapter:

(1)The Director and Deputy Directors, Center for Food Safety and Applied Nutrition (CFSAN). (2) The Director, Office ofPolicy, Planning and Strategic Initiatives, CFSAN.

(3) The Director, Office ofPremarket Approval, CFSAN.

(4) The Directors ofthe Divisions of Petition Control and Product Policy, Office ofPremarket Approval, CFSAN.

PART25--ENVIRONMENTAL IMPACT CONSIDERATIONS

3. The authority citation for 21 CFR part 25 continues to read as follows:

Authority: Secs. 201-903 ofthe Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321-393); secs. 351, 354-361 ofthe Public Health Service Act (42 U.S.C. 262, 263b264); 42 U.S.C. 4321, 4332; 40 CFR parts 1500-1508; E.O. 11514 as amended by E.O. 11991; E.O. 12114.

4. Section 25.22 is amended by revising paragraph (a)(10) to read as follows:

§25.22 Actions requiring preparation otan environmental assessment.

(a) * * * (10) Approval offood and color additive petitions, approval ofrequests for exemptions for investigational use of food additives, and granting ofrequests for exemption from regulation as a food additive.

* * * * *

5. Section 25.31a is amended by revising the introductory text of paragraphs (a), (b)(1), and (b)(2)to read

as follows:
§25.31a Environmental assessment for proposed approvals of FDA-regulated products-Format 1

(a) For proposed actions to approve food or color additives, drugs, biological products, animal drugs, and class III medical devices, for proposed actions to affirm food substances as generally recognized as safe (GRAS), and for proposed actions to grant requests for exemption from regulation as a food' additive, the applicant orpetitioner shall prepare an environmental
assessment in the following format:

* * * * *

(b)(1) For actions (eitherto approve food additive petitions orto grant requests for exemption from regulation

as a food additive) concerning components of food-contact articles present in the finished food-packaging -materialat a level not greater than 5- percent-by-weight, the following information is required for the format items specified:

*
, *¢ * * *

(b)(2) For actions (either to approve food additive petitions or to grant requests for exemption from regulation

as a food additive) concerning components offood-contact articles to be used in surfaces ofpermanent or semipermanent equipment orofother food-contact articles intended for repeated use, the f6llowing information is required for the items specified:

• * * * *

PART 170-FOOD ADDITIVES

6. The authority citation for 21 CFR part 170 continues to read as follows:

Authority: Secs. 201, 401, 402,408,409, 701 ofthe Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 346a, 348, 371).

7. Section 170.3 is.amended by redesignating paragraph (e) as (e)(1) and

### Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules and Regulations

by addingnew paragraph (e)(2) to read

as follows: 

### §170.3 Definitions.

(e)(2) Usesof foodadditivesnot requiringalistingregulation. Substances used in food-contact articles (e.g., food-packaging and foodprocessing equipment) that migrate, or maybe expected tomigrate, into food at such negligible levels that they have been exempted from regulation as food additives under § 170.39.



### 8. New § 170.39 is added to subpart B toread as follows: §170.39 Threshold of regulationfor substances used In food-contactarticles. (a)A substance used in afood-contact article (e.g., food-packaging or foodprocessing equipment) that migrates, or that may be expected to migrate, into food willbe exempted from regulation

as a food additive because itbecomes a component of food atlevels that are below the threshold ofregulation if: (1)The substance has notbeen shown
tobe a carcinogen in humans or animals, and there is noreason, based

onthe chemical structure of the substance, to suspect that the substance is a carcinogen. The substance must also
notcontain a carcinogenic impurity or, ifitdoes, must not contain a carcinogenic impurity with aTDs0

### value based on chronic feeding studies reported iiithe scientific literature or otherwise available to the Food and Drug Administration ofless than 6.25 milligrams perkilogram bodyweight per day (TheTD 5

### o,forthe purposes ofth*s section, is the feeding dose thatcauses
cancer in 50 percent ofthe test animals when corrected for tumors found in control animals. Ifmore than one TD5 0 

### value hasbeen reported in the scientific literature fora substance, the Food and Drug Administration will use the lowest appropriate TD50 value in its review.); (2) The substance presents noother health or safety concerns because:

(i)The use in question hasbeen shown toresult in ormay be expected
to result in dietary concentrations ator below 0.5 parts per billion, corresponding to dietary exposure levels
at orbelow 1.5 micrograms/person/day (based on a dietof 1,500grams ofsolid food and 1,500 grams ofliquid food per person perday); or

(ii)The substance is currently regulated for direct addition into food, andthe dietary exposure tothe substance resulting from the proposed

use is at orbelow 1percent ofthe acceptable daily intake as determined by safety data in the Food and Drug Administration's files or from other appropriatesources; 3) The substance has no technical effect in or on the food to which it migrates; and

(4) The substance use has no significant adverse impact on the environment.

(b) Notwithstanding paragraph (a) of this section, the Food and Drug Administration reserves the right to decline to grant an exemption in those

cases in which available information establishes thatthe proposed use may pose a public health risk.The reasons for the agency's decision to decline to grant an exemption will be explained in the Food and Drug Administration's
response to the requestor. (c)A request for the Food and Drug Administration to exempt a use ofa substance from regulation as a food additive shall include three copies of the following information (Ifpart ofthe submitted material is in a foreign language, it must be accompanied by an English translation verified to be complete and accurate in accordance with § 10.20(c)(2) ofthis chapter):

(1) The chemical composition ofthe substance for which the request ismade, including, whenever possible, the name ofthe chemical in accordance with
current Chemical Abstract Service (CAS) nomenclature guidelines and a CAS registry number, ifavailable;

(2) Detailed information on the conditions ofuse ofthe substance (e.g., temperature, type offood with which the substance will come into contact, the duration ofthe contact, and whether the food-contact article will be for repeated or single use applications);

(3) A clear statement as to whether the request for exemption from regulation as

a food additive is based on the fact that the use ofthe substance in the foodcontact article results in a dietary concentration at orbelow 0.5 parts per billion, or on the fact that it involves the

use ofa regulated direct food additive for which the dietary exposure is at or below 1 percent ofthe acceptable dietary intake (ADI);

(4) Data that will enable the Food and Drug Administration to estimate the daily dietary Concentration resulting from the proposed use ofthe substance. These data shouldbe in the form of:

(i) Validated migration data obtained under worst-case (time/temperature) intended use conditions utilizing appropriate food simulating solvents;

(ii) Information on the amount ofthe substance used in themanufacture of the food-contact article; or

(iii) Information on the residual level ofthe substance in the food-contact article. For repeat-use articles, an 

### estimate ofthe amount of food that contacts a specific unit ofsurface area
over the lifetime ofthe article should also be provided. (In cases where data

are provided only inthe form of manufacturing use levels orresidual levels ofthe substance presentin the food-contact article,the Food and Drug Administration will calculate a worstcase dietary concentration level assuming 100 percent migration.) A detailed description ofthe analytical method used to quantify the substance should also be submitted along with data used to validate the detection limit.

(iv)In cases where there is no detectable migration into food or food simulants, or when no residual level of

a substance is detected inthe foodcontact article by a suitable analytical method, the Food and Drug Administration will, forthe purposes of estimating the dietary concentration, consider the validated detection limit of the method used to analyze for the substance.

(5)The results ofan analysis of existing toxicological information on the substance and its impurities. This information on the substance is needed
to show whether an animal carcinogen bioassay has been carried out, or whether there is some other basis for suspectingthat the substance is a carcinogen orpotent toxin. This type of information onthe impurities is needed
to show whether any ofthem are carcinogenic, and, ifcarcinogenic, whether their TD50 values are greater than 6.25 milligrams perkilogram bodyweight per day inaccordance with paragraph (a)(1) ofthis section.

(6)Information on the environmental impact that would result from the proposed use ofthe substance. Depending onthe type ofuse, this information should be in the form ofan abbreviated environmental assessment

as specified in § 25.31a(b)(1) or (b)(2) of thischapter.

(d)Data tobereviewed under this section shall be submitted to the Food and Drug Administration's Office of Premarket Approval (HFS-200), 200 C St. SW., Washington, DC 20204.

(e) The Food and Drug Administration will inform the requester by letter whether the specific food-contact application is exempt from regulation as
a food additive ornot. Although a substance that migrates to food at a level that results in a dietary concentration at

orbelow the threshold ofregulation will
notbe the subject ofa regulation published in the Federal Register and will not appear inthe CodeofFederal Regulations, the Food and Drug Administration will maintain a list of substances exempted from regulation as 36595

### Federal Register / Vol. 60, No. 136 /,Monday, July 17, 1995 / Rules and Regulations

food additives under this section on display at theDockets Management Branch. This list will include the name ofthe company that made the request, the chemical name ofthe substance, the specific use for which it has received an exemption from regulation as a food additive, and any appropriate limitations on its use. The list will not include any tradenames. This list will enable interested persons to see the types ofuses offood-contact materials being exempted under the regulation. Interested persons may also obtain a copy ofthe list ofexempted substances bycontacting the Food and Drug Administration's Office ofPremarket Approval (HFS-200), 200 C St. SW., 

### Washington, DC20204. The agency's finding ofno significant impact and the evidence supporting that finding, contained in an environmental assessment, also willbe available for public inspection atthe Dockets Management Branch in accordance with §25.41(b)(2) ofthis chapter. Requests forcopies ofreleasable information contained in submissions requesting exemptions from the food additive regulations will behandled in accordance with the Foodand Drug Administration's,Freedom of Information Act procedures, as described inpart 20 ofthis chapter. In particular, data and information that fall within the definitions of atrade secret

or confidential commercial orfinancial information are not available forpublic disclosure in accordance with §20.61(c) ofthis chapter.

(f) Ifthe request for an exemption from regulation as a food additive is not granted, the requestor may submit a petition to the Foodand Drug Administration forreconsideration of the decision in accordance with the provisions of§10.33 ofthis chapter.

(g)Ifthe Food and Drug Administration receives significant new information thatraises questions about the dietary concentration orthe safety of

a substance that the agency has exempted from regulation, the Food and Drug Administration may reevaluate the substance. Ifthe Food and Drug Administration tentatively concludes that the information that is available about the substance no longer supports an exemption forthe use ofthe foodcontact material from the food additive regulations, the agency will notify any persons that'requested an exemption for the substance ofits tentative decision. The requestors will begiven an opportunity to show why the use ofthe substance shouldnot be regulated under the food additive provisions ofthe act. Ifthe requestors fail to adequately respond to the new evidence, the agency willnotify them that further use ofthe substance in question for theparticular

use willrequire a food additive regulation. This notification willbe placed on public display atthe Dockets Management Branch as part ofthe file ofuses ofsubstances exempted from 'regulation as food additives. The Food and DrugAdministration recognizes that manufacturers other than those that actually made a request for exemption may also be using exempted substances infood-contact articles under conditions ofuse (e.g., use levels, temperature, type offood contacted, etc.) that are similarto those for which the exemption was issued. Because only requestors willbe notified aspart ofthe revocation process described inthis section, the Food and Drug Administration plans to notify other manufacturers by means ofanotice published in the Federal Register ofits decision to revoke an exemption issued for a specific use ofa substance in a food contact article.

(h)Guidelines to assist requestors in the preparation ofsubmissions seeking exemptions from the food additive regulations are available from theFood and Drug Administration's Office of Premarket Approval (HFS-200), 200 C St. SW., Washington, DC 20204. Interested persons are encouraged to obtain specific guidance from the Food and Drug Administration on the appropriate protocols to be used for obtaining migration data, on the * validation ofthe analytical methods used.to quantify migration levels, on the procedures used to relate migration data
to dietary exposures, and on any other issue not specifically covered inthe Food and Drug Administration's guidelines. PART 171-FOOD ADDITIVE PETITIONS

9. The authority citation for 21 CFR part 171 continues to read as follows:

Authority: Secs. 201,402,409, 701 ofthe Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).

10. New §171.8 is added to subpart A

to read as follows:

§171.8 Threshold of regulation for substhnces used Infood-contact articles.

Substances used in food-contact articles (e.g., food-packaging or foodprocessing equipment) that migrate or that may be expected to migrate into food at negligible levels may be reviewed under § 170.39 ofthis chapter. The Food and DrugAdministration will exempt substances whose uses it determines meet the criteria in § 170.39 of this chapter from regulation as food additives and, therefore, a food additive petition will not be required for the exempted use.

PART 174-INDIRECT FOOD ADDITIVES: GENERAL

11. The authority citation for 21 CFR part 174 continues to read as follows:

Authority: Secs. 201, 402, 409, 701 ofthe Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).

12. New § 174.6 is added to read as follows: 

### §174.6 Threshold of regulation for substances used Infood-contactarticles.

Substances used in food-contact articles (e.g., food-packaging or foodprocessing equipment) that migrate, or that may be expected to migrate, into food atnegligible levels may be reviewed under § 170.39 ofthis chapter. The Food and Drug Administration will exempt substances whose uses it determines meet the criteria in § 170.39 ofthis chapter from regulation as food additives and, therefore, a food additive petition will not be required for the exempted use.

Dated: July 11, 1995. William B.Schultz, DeputyCommissioner forPolicy. [FR Doc. 95-17435 Filed 7-14-95; 8:45 am]

BILUNG CODE 4160-01-P 

### I 36596