[Federal Register Volume 60, Number 136 (Monday, July 17, 1995)]
[Rules and Regulations]
[Pages 36582-36596]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-17435]
[[Page 36581]]
_______________________________________________________________________
Part VII
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 5, et al.
Food Additives: Threshold of Regulation for Substances Used in Food-
Contact Articles; Final Rule
Federal Register / Vol. 60, No. 136 / Monday, July 17, 1995 / Rules
and Regulations
[[Page 36582]]
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 for Substances Used in
Food-Contact Articles
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its food
additive regulations to establish a process for determining when the
likelihood or extent of migration to food of a substance used in a
food-contact article is so trivial as not to require regulation of the
substance as a food additive. Although still a ``food additive,'' a
substance exempted from regulation under this process will not be
required to be the subject of a food additive listing regulation. Under
this process, information about the proposed use of the substance will
undergo an abbreviated review by FDA, as opposed to the extensive
review normally required for food additives. This final rule also lists
the criteria that FDA will use in its review in deciding whether it is
necessary to regulate the use of a substance as a food additive and
identifies the types of data that it will need to make this
determination.
EFFECTIVE DATE: August 16, 1995.
FOR FURTHER INFORMATION CONTACT: Edward J. Machuga, Center for Food
Safety and Applied Nutrition (HFS-216), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-418-3085.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of October 12, 1993 (58 FR 52719), the
agency proposed to establish a process for determining when the
likelihood or extent of migration to food of a substance used in a
food-contact article is so trivial as not to require regulation of the
substance as a food additive. The proposal was in response to a number
of comments from representatives of the food packaging and processing
industries suggesting that FDA establish a threshold of regulation
policy whereby those substances used in food-contact articles that
result in minimal migration into food would be exempt from regulation
as food additives.
The proposal also responded to a citizen petition (Docket No. 77P-
0122) submitted by the Society of the Plastics Industry, Inc.,
requesting that FDA modify Sec. 170.3(e) (21 CFR 170.3(e)), the
regulation that defines ``food additive,'' to provide that the use of a
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 of these
suggestions in the absence of data that clearly 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 of a large number of representative compounds have become
available over the last 5 to 10 years that have made it possible for
FDA to evaluate the feasibility of establishing a threshold of
regulation 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 as the ``threshold of regulation'' for components of food-
contact articles.
A Federal court has addressed the issue of whether the use of a
food-contact material that results in migration into food at
insignificant levels can be exempted from regulation as a food
additive. In Monsanto v. Kennedy, 613 F.2d 947 (D.C. Cir. 1979), the
Monsanto Co. contended that no detectable migration of acrylonitrile
copolymer resulted from the use of their beverage bottles that
contained the substance, and that, therefore, the copolymer did not
have to 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 of a particular
substance is so negligible as to present no public health or safety
concerns and, in such cases, may decline to define the substance as a
food additive even though it comes within the strictly literal terms of
the statutory definition of a food additive (613 F.2d at 956). The
court also stated that the 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 food-contact articles are so negligible as to pose
no public health or safety concerns, the discretionary authority of the
Commissioner to exempt those substances that present no public health
concerns from regulation as food additives, and the agency's
consideration of the 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 of migration to
food of a 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 of this process, the agency is establishing two types of
thresholds for the regulation of substances used in food-contact
articles. The first type of threshold will exempt from regulation those
substances whose use in food-contact articles results in a dietary
concentration of the substance of 0.5 ppb or less. The second type of
threshold will exempt regulated direct food additives from regulation
when used in food-contact articles at levels that result in a dietary
exposure of 1 percent or less of the acceptable daily intake (ADI) for
the additive.
II. Comments on the Proposed Rule
The agency provided 60 days for comment on the proposed rule. It
received two requests from industry for an extension of the comment
period. The agency granted a 60-day extension of the comment period to
February 11, 1994, in a notice published in the Federal Register of
December 13, 1993 (58 FR 65139).
FDA received 20 comments from the food packaging industry and trade
associations that represent the plastics and paper industries. One of
these comments concerned the economic impact of the proposed action.
This comment is discussed in section IV of this document. The other
issues raised in the comments, and the agency's response to them, are
set forth below.
A. The Exemption
Appropriateness of the 0.5 PPB Threshold Level for Components of Food-
Contact Articles
1. Eight comments expressed the opinion that the 0.5 ppb threshold
is more conservative and restrictive than is necessary to adequately
protect the public health. In general, these comments expressed the
view that current scientific data support the
[[Page 36583]]
establishment of a dietary concentration higher than 0.5 ppb as the
threshold.
The agency does not agree that a 0.5 ppb threshold is unduly
conservative, especially in light of the fact that a substance being
considered for an exemption may not have been the subject of any
toxicological testing. As discussed in the proposed rule, carcinogenic
toxic effects in test animals typically occur at lower dietary
concentrations than the levels at which noncarcinogenic toxic effects
occur. Therefore, FDA's goal has been to establish a threshold that is
low enough to ensure that even if an unstudied compound that is
exempted from regulation is later shown to be a carcinogen, its use
would not have represented any more 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 than is
necessary to adequately protect the public health, no data were
provided in any of these comments to show that a threshold
significantly higher than 0.5 ppb is adequate to ensure that substances
present in the diet at or below the threshold would pose only
negligible safety concerns. Therefore, as proposed, this final rule
establishes 0.5 ppb as the threshold of regulatory concern for
substances used in food-contact articles. We will reconsider this
threshold if we receive new data that justify a higher level.
2. One comment objected to the agency's apparent use of a 200-fold
safety factor when applying to humans the results of studies showing
the noncarcinogenic toxic effects observed in animals subjected to
chronic chemical exposure. The comment stated that FDA guidelines
employ only a 100-fold safety factor. The comment argued that the use
of the 100-fold safety factor would allow FDA to establish a threshold
of regulatory concern higher than 0.5 ppb.
The agency emphasizes that it did not base its proposed threshold
on noncarcinogenic toxic endpoints, and that, therefore, it did not
employ the safety factor approach typically used when applying to
humans the results of studies showing the noncarcinogenic toxic effects
observed in animals subjected to chronic chemical exposure. Because
carcinogenic effects typically occur in test animals at lower dietary
concentrations than those at which noncarcinogenic toxic effects occur,
as stated above, FDA's goal was to establish a threshold that is low
enough to ensure that substances that are exempted from regulation
under it will pose only negligible safety concerns even if they are
ultimately shown to have carcinogenic effects.
Based on its analysis of the carcinogenic potencies of 477
chemicals, and using the assumptions that the distribution of
carcinogenic potencies of the 477 chemicals studied are representative
of all known and unknown carcinogens, and that it is very unlikely that
an unstudied compound would both: (1) Be a carcinogen and (2) have an
intrinsic carcinogenic potency far greater than the typical potency
observed for the studied compounds, FDA has determined that, if an
exempted substance present in the diet at 0.5 ppb were later found to
be a carcinogen, the upper-bound lifetime risk resulting from the use
of the substance is likely to be below one in a million. This level of
risk 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 ppb threshold would ensure
that substances that pass under it pose negligible safety concerns from
noncarcinogenic toxic effects as well. However, the fact that a 0.5 ppb
threshold level happens to be 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
reflect the agency's reasoning.1
\1\ The agency typically uses a 100-fold safety factor when
applying to humans the results of 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 not always be long enough to show all of the toxic
effects that may be induced by long term exposure to a chemical,
and, therefore, in such cases, FDA often uses higher safety factors
(1000-fold to 2000-fold).
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3. One comment expressed the opinion that the threshold should have
been based on the mean TD502 value of the 477 known
carcinogens that were the subject of FDA analysis as opposed to the
most probable TD50 value. This comment stated that the use of a
mean TD50 would allow FDA to establish a threshold significantly
higher than 0.5 ppb.
\2\ The TD50, for the purposes of this regulation, is the
feeding dose that causes cancer in 50 percent of the test animals
when corrected for tumors found in control animals.
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FDA does not agree that it is appropriate to establish a threshold
level based on the mean TD50 value of the 477 known carcinogens
that were the subject of FDA's analysis because this approach would
give inappropriate weight to carcinogens with high TD50 values.
Because the carcinogenic potency of a substance is inversely related to
its TD50 value, this approach would give too much emphasis to
carcinogens with low potencies. A more meaningful approach to
estimating the likelihood that a substance will pose a potential health
hazard at a given dietary concentration is to use the potency that it
is most likely to have if it were later found to be a carcinogen.
Because such an approach would be based on the frequency distribution
of the potencies of a large number of carcinogens (i.e., a distribution
showing the number of carcinogens whose potencies occur within
particular dietary concentration ranges) and would not be based on the
magnitude of the potencies themselves, this approach would not give
undue weight to carcinogens with low potencies (i.e., high TD50
values).
In arriving at a threshold of regulation, FDA's analysis of the
potencies of 477 animal carcinogens consisted in part of grouping 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 this
probability 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 diet at 0.5 ppb or less.
4. One comment expressed the view that it was unlikely that a given
packaging material would be present in the daily diet over the course
of a lifetime. It asserted that, therefore, FDA should not have based
its threshold on potential lifetime carcinogenic risks.
Because of the changing technology associated with the food-
packaging industry, FDA agrees that is not always possible to predict
whether a given type of packaging material is likely to be present in
the daily diet over the course of a lifetime. However, because many of
the substances considered for an exemption from regulation will not
have been the subject of any toxicological testing, it is imperative,
in establishing a threshold level, to use an approach that is not
likely to underestimate the risk associated with the use of such
additives. Therefore, the agency used an approach that assumed that a
given packaging material would be present in the daily diet for an
entire lifetime.
Lifetime upper-bound risks have traditionally been used by FDA to
assess the overall safety of packaging materials containing small
amounts of carcinogenic impurities, and the agency
[[Page 36584]]
believes that it is appropriate to use a similar approach in assessing
the likelihood of potential carcinogenic effects associated with
substances exempted from regulation. Based on its analysis of the
potencies of 477 known carcinogens and the lifetime upper-bound risks
that they would pose if present in the daily diet over a lifetime, FDA
has determined that a substance present in the daily diet for a
lifetime at 0.5 ppb would pose only negligible risk even if it were
later shown to be a carcinogen. Because of the conservatisms used by
the agency in its approach to determining a threshold level, FDA is
confident that an exempted substance present in the daily diet for a
lifetime at 0.5 ppb would pose no regulatory concern.
5. Four of the comments recommended that FDA establish a higher
threshold for substances that have been shown to be nonmutagenic or to
have relatively high LD503 values. For example, one comment
recommended that for substances that have been shown to be nonmutagenic
and to have LD50 values greater than 2,000 milligrams per kilogram
(mg/kg), the threshold should be raised to 5 ppb.
\3\ The LD50 is the dose in acute feeding studies that
causes lethality in 50 percent of the test animals.
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FDA agrees with these comments that it may be possible to establish
separate thresholds for compounds that have been the subject of
toxicological tests that show that they are nonmutagenic, or that they
have high LD50 values. However, a direct correlation will need to
be firmly established showing that such compounds, if carcinogenic, are
likely to be less potent than those that have been shown to be
mutagenic or to have lower LD50 values. Such a correlation would
provide confirmation that a substance that has been shown to be
nonmutagenic or to have a high LD50 value poses a significantly
lower risk from potential carcinogenic effects when present in the
daily diet at the same level than one that has been shown to be
mutagenic or to have a low LD50 value.
The correlation between mutagenicity or acute toxicity and
carcinogenic potency is the subject of ongoing FDA analysis. If the
results of FDA's analysis confirm that the likelihood that a substance
poses a significant risk from potential carcinogenic effects is
significantly lower when that substance has been shown to be
nonmutagenic or to have a high LD50 value, it may be possible to
establish a threshold for such substances that is higher than 0.5 ppb
but that still ensures that their use in food-contact articles will
pose only negligible health concerns.
6. Three comments suggested that FDA establish a higher threshold
for compounds that do not possess structural concerns (i.e., that do
not possess structural similarities to known carcinogens).
In general, the principle behind the use of quantitative structure
activity relationships is that the analysis of the toxicity of a large
number of compounds of known structure enables one to predict the
relative toxicity of unstudied 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 a
basis to suspect that a substance is a carcinogen, knowledge about such
relationships is not reliable enough at this time to justify reliance
on an analysis of them to establish a higher 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-year bioassays.
FDA agrees that it may be possible in the future to establish a
threshold higher than 0.5 ppb for substances that have 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 of all but negligible risk even if an unstudied
compound is later shown to be a carcinogen. In the case of
noncarcinogens, however, the threshold of regulation could be based
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 of the data on 18,000 acute oral feeding studies in rats and
mice found that all of the 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 of the 220 chemicals exhibited toxic
effects below 1,000 ppb, and that all 5 of these 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 that have been appropriately tested and found not to be
carcinogens. Such a threshold would likely be well below the level at
which noncarcinogenic toxic effects are likely to occur but 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 for noncarcinogenic substances at this time, however, because
the number of chemicals, particularly pesticides, that have been
analyzed is not sufficient to ensure that the results of this analysis
are representative of substances used in the manufacture of food-
contact articles. An analysis of the dietary concentrations at which a
large number and a wide variety of potent toxicants, such as
pesticides, exhibit noncarcinogenic toxic effects is needed before FDA
can determine whether establishment of a threshold significantly higher
than 0.5 ppb for noncarcinogenic substances is justified.
Appropriateness of the 1-Percent ADI Threshold for Regulated Direct
Additives
8. One comment recommended that once the final rule has been
established, and the policy has been put into practice for a time, FDA
should reassess the 1 percent of the ADI threshold for regulated direct
food additives used in food-contact articles to see whether this
threshold can be raised.
As stated in the proposal, a 1-percent ADI threshold for regulated
direct food additives used in food-contact articles is appropriate
because this level of dietary exposure will contribute only a small
fraction of the ADI of a substance and, therefore, will be well within
the margin of safety 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 of exposure that is 1 percent of the ADI would be within the
margin of error for the estimated daily intake. 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 of uses in food-contact articles.
The agency would like to emphasize that no comments were received
that expressed any safety concern about the 1 percent of the ADI
threshold. As for raising this threshold above the 1-
[[Page 36585]]
percent ADI level, FDA's main concern is with those cases in which a
particular substance may be granted exemptions for a number of
different types of new uses, each of which results in a dietary
exposure at or near the threshold level. In such cases, the dietary
exposure resulting from all of the exempted 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 not be supported by
existing safety data. It is possible, however, that once the threshold
of regulation process is put into practice, other factors will surface
that mitigate the agency's concerns on this issue. If the 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. One comment 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 be made more readily available. Therefore, FDA plans
to incorporate this information into its priority based assessment of
food additives (PAFA) data base and make this data base accessible to
the public (Ref. 2). In the meantime, requestors can obtain this type
of information on a specific substance by submitting a written request
to FDA's Office of Premarket Approval (HFS-200, 200 C St. SW.,
Washington, DC 20204). In some cases, especially for those uses of
direct 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 a
regulated direct food additive, the agency would consider the use of an
ADI value from another appropriate source, such as the Joint World
Health Organization/Food and Agriculture Organization (WHO/FAO), Expert
Committee on Food Additives, or the European 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 Sec. 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 for the calculation of appropriate ADI's for review under
the process specified in this final rule. Regulated direct food
additives for which an appropriate ADI does not exist are not suitable
candidates for an abbreviated review under the threshold of regulation
process. This process is not appropriate for reviewing submissions
containing detailed toxicity studies on a substance for the purpose of
calculating an ADI value or for verifying an ADI value calculated by
the requestor. Such extensive reviews are better handled by the food
additive petition process.
10. One comment recommended that FDA expand the proposed threshold
of regulation process for regulated direct food additives to include
exemptions for direct uses in food, provided the dietary exposures from
such uses do not exceed 1 percent of the ADI. The proposed rule limited
such exemptions to only those uses that may result in their indirectly
becoming components of food (i.e., resulting from their use in food-
contact articles).
FDA does not agree that the final rule should be expanded in this
manner. There is a fundamental difference in regulatory significance
between substances that are deliberately added directly to food to
accomplish a technical effect in the food and substances that are used
in food-contact articles in a manner such that they may reasonably be
expected to become components of food indirectly and to have no
technical effect in that food. The purpose of the food additive
provisions of the act is to ensure that substances added to food are
safe and will have their intended technical effect in the food that is
to be consumed (S. Rept. 2422, 85th Cong., August 18, 1958). Thus,
given this purpose, there simply would not be circumstances in which a
direct additive would be of such little regulatory concern as to
justify application to it of the de minimis 4 doctrine that
underlies the threshold of regulation concept (see Monsanto v. Kennedy,
supra). For indirect food additives, in contrast, the substance is
being used for its technical effect in a food-contact article, not in
an article that will itself be consumed.
\4\ This doctrine is expressed in Latin as de minimis non curat
lex (the law does not concern itself with trifles).
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Moreover, on occasion, it is foreseeable that, while the exact
amount of an indirect additive that will get into food is unclear, it
will not exceed an extremely small amount. It is in the latter
circumstances that it is fair to say that, given the purposes of the
Federal Food, Drug, and Cosmetic Act (the act), the use of the
substance is of no significant regulatory concern, and thus the use can
be exempted from regulation under the food additive provisions of the
act. In light of the purposes of the food additive provisions, however,
FDA concludes that it is not appropriate to extend the threshold of
regulation 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
food-contact articles when the direct additive does not have any
specific use level restrictions. An example of the type of situation
raised by the comment would be flavoring agents where the level of
their use in food would be self limiting (i.e., use at high 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 of the time required to obtain FDA approval
(as a result of FDA's current backlog of work), 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 of work, and enable the consumer to have quicker access to new
packaging formulations.
The comment argued that, based on the extremely small levels of
dietary exposure that would result from the use of direct additives in
food-contact articles, particularly in comparison to the levels of
exposure that result from the direct uses of these substances, and
based on the fact that direct food additives have been the subject of
extensive safety testing, FDA should modify Sec. 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 such use were appropriate: (1) The use of the substance
in a food-contact article must not result in a dietary exposure that
exceeds 1 percent of the ADI for that substance; (2) the use level must
not exceed good manufacturing practice (GMP) or that necessary to
accomplish the intended technical effect; (3) the substance must be 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 has been listed as a direct
[[Page 36586]]
food additive (e.g., a substance approved for use as a stabilizer and
thickener in food would be allowed to be used as a stabilizer and
thickener in the manufacture of food-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 use as indirect human food
ingredients in accordance with Sec. 184.1(a).
The agency notes that the issue raised by this comment is outside
the scope of the proposed threshold of regulation process. The comment
is about whether the uses in question should be approved as food
additive uses, not about whether they should be exempted from
regulation under the food additive provisions of the act.
Although outside the scope of this rulemaking, FDA would like to
comment on the merits of the approach recommended in this comment
because the agency is always interested in evaluating ways that may
help it to more effectively implement the food additive provisions of
the act. FDA's main concern 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 of food-contact articles without
any further safety review by FDA. Although it is true that the dietary
exposure resulting from the use of a substance added directly to food
is usually much higher than that resulting from the use of that
substance as a component of a food-contact article, the existing safety
data in FDA files used to support the direct additive use may 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 for uses 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 for uses for which, initially, the margin
between the estimated daily intake and the ADI was reasonably broad,
but as the substance has been subsequently regulated for other uses,
the margin has become quite narrow. Because existing safety data may
not be adequate to support the use of direct additives as components of
food-contact articles in all cases, such uses must be evaluated on a
case by case basis, either as the subject of a food additive petition
(if the dietary exposure is likely to be greater than 1 percent of the
ADI) or as a request for an exemption from regulation (if the dietary
exposure is likely to be below the 1-percent ADI threshold of
regulatory 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. (FDA regulations for considering the
environmental effect of its actions in accordance with the National
Environmental Policy Act (NEPA) were established on March 15, 1973.) It
may be possible that the manufacture, use, and disposal of food-contact
articles containing regulated direct food additives may have an adverse
impact on the environment. Therefore, the potential environmental
effects resulting from the intended use of a direct food additive in a
food-contact article need to be evaluated by FDA either as part of a
review of a petition or as part of a review of an exemption from
regulation request. Further discussion of this issue is found later in
this final rule in the agency's response to comments 28 and 29.
For the reasons listed above, FDA has concluded that the use of a
regulated direct food additive in a food-contact article should either
be the subject of a specific food additive regulation authorizing such
use or be exempted from regulation as a food additive by FDA under the
procedures specified in this final rule. Application of the Food
Additive Definition
12. Two comments expressed the opinion that the Monsanto decision
gives FDA the flexibility to consider those substances migrating out of
food-contact articles in trivial amounts not to be food additives.
These comments went on to say that the Delaney Clause (section
409(c)(3)(A) of the act (21 U.S.C. 348(c)(3)(A)), which prohibits the
use of known carcinogens as food additives, would therefore not apply.
FDA disagrees with the comments. It is true that Monsanto stated
that the Commissioner has discretion to implement the statutory scheme
established by the Food Additives Amendment, and that this discretion
includes the option of declining to define a substance as a food
additive (613 F.2d at 956). However, the court also said that the
Commissioner's discretion is limited (id.). The Commissioner's exercise
of discretion must be consistent with the statutory scheme. He cannot
exercise his discretion to vitiate that scheme. Under the Food
Additives Amendment, a carcinogenic additive is deemed to be unsafe, no
matter how low the exposure to the additive or how low the risk from
the additive (see Public Citizen v. Young, 831 F.2d 1108, 1122 (D.C.
Cir. 1987), cert. denied, 485 U.S. 1006 (1988)). Given these facts, FDA
has formulated the threshold of regulation regime to exempt substances
from regulation as food additives based on the level of dietary
exposure but has conditioned that exemption on such substances not
having 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 of regulation determinations. The comments
stated that, in those cases where the use of the substance meets the
definition of a ``food additive'' in section 201(s) of the act (21
U.S.C. 321(s)), individual manufacturers should be able to make their
own determination as to whether the use of a substance in a food-
contact article meets the criteria for an exemption from regulation.
One of the comments requested that the agency's position on this issue
be explicitly stated in the final regulations.
According to Monsanto, only the Commissioner has the statutory
authority to exempt a substance from regulation as a food additive. A
substance that meets the definition of a food additive in section
201(s) of the act must, therefore, either be the subject of a
regulation authorizing its use or be exempted from regulation by FDA
under the process specified in new Sec. 170.39, unless the use of the
substance conforms to an exemption for investigational use issued under
section 409(i) of the act.
From a policy standpoint, the procedure outlined in this final
rule, whereby FDA makes all exemption decisions, offers a number of
advantages over an approach that allows individual manufacturers to
make their own threshold of regulation decisions. One advantage is that
the agency's determination as to whether a substance used in a food-
contact article meets the criteria for an exemption from regulation as
a food additive will be binding on the agency. Thus, manufacturers of
food-contact articles will be able to rely on these determinations and
market their products without fear of regulatory 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 of substances in
[[Page 36587]]
food-contact articles. Thus, allowing individual manufacturers to make
their own determinations would increase the likelihood of inconsistent
decisions.
For example, in cases where there is no detectable migration into
food or food simulants, or when no residual level of a substance is
detected in the food-contact article by a suitable analytical method,
the validated detection limit of the 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 of the 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 of a food-contact article may also arise from such independent
determinations. The agency believes that having all such exemption
decisions made by a review team consisting of a small number of agency
personnel will help lessen the likelihood of inconsistent 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 of a component of a food-contact 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 of the substance meets the ``food additive'' definition
in section 201(s) of the act, FDA emphasizes that nothing in this final
rule limits the use of a 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 as the conditions of use (e.g., use levels, temperature, type of
food contacted, etc.) are those for which the exemption was issued.
Consistent with this fact, FDA plans to give general notice by
means of the Federal Register, should it ever decide to revoke an
exemption. The notice will state that continued use of such a substance
would constitute the use of an unapproved food additive, unless a
petition is filed, and the substance is listed for use 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 be practical to
routinely provide notice in the Federal 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 of the
threshold of regulation process to minimize the use of agency and
industry resources for those substances whose use in food-contact
articles poses only negligible safety concerns. Accordingly, FDA is
revising Sec. 170.39(g) to make clear that the agency plans to provide
notice in the Federal Register after it has decided to revoke an
exemption issued for a specific use of a substance in a food contact
article.
FDA has decided, however, not to include in Sec. 170.39 a statement
that only the Commissioner can make threshold of regulation
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 of the Exemption
14. Two comments recommended that FDA expand its proposed threshold
of regulation to enable the agency to exempt entire classes of
compounds. Under the scheme suggested by these comments, FDA would
review one or more compounds within a given class, and, if it
determined that these individual chemicals qualified for an exemption,
the agency would exempt all of the chemicals within the class. One of
these comments expressed the view that many manufacturers do not use
their proprietary chemicals for food-contact applications because of
FDA's requirement that they be 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 of reasons. Because
the level of migration, and resulting dietary concentration, of the
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 of just one or two sample
chemicals. For example, polymeric materials manufactured from the same
monomer but having significantly different molecular weights would
belong to the same class of chemicals but would be expected to have
different migration properties. Similarly, the intrinsic toxic
potencies for chemicals within a certain class may vary significantly.
For example, the polychlorinated dibenzo-p-dioxins are a class of 75
congeners that exhibits a wide range of toxicity depending on the
degree of chlorination and the location of the chlorine atoms within
the chemical structure. As a result, the likelihood that a substance
poses a health hazard is not necessarily determinable based on the
information about the toxicity of other chemicals that are in the same
class. In addition, it would be difficult to predict the environmental
impact that would result from the manufacture, use, and disposal of all
substances within a class based on the impact of one or two chemicals.
Therefore, FDA does not believe that it is possible, based on the
review of one or more compounds within a given class, to justify an
exemption for all other chemicals belonging to the same class.
For the foregoing reasons and because the dietary concentration of
a specific chemical is dependent on the conditions of its use (e.g.,
type of use, temperature, food type, and contact time), FDA concludes
that to adequately safeguard the public health, it is necessary to
limit exemptions under Sec. 170.39 to those conditions of use of a
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 of uses 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 of use and the conditions of use. Therefore, it
would not be feasible to establish guidelines for use 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 in this final rule, as part of which a small
team of agency personnel will review each request for an exemption,
will result in more consistent decisions. Having all such
determinations made by FDA
[[Page 36588]]
using the process specified in the final rule should also result in the
agency having more complete information on what substances are being
used in food-contact articles. This information will permit the agency
to take action in the event that data become available that raise
significant questions as to whether the continued use of a substance in
a food-contact article is safe.
16. One comment stated that the 0.5 ppb threshold was too low for
the use of pigments 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 of the many types of chemicals used
in food-contact articles. Such an approach, with many different
thresholds, would be cumbersome. Moreover, as discussed in a previous
comment, the toxicological properties of chemicals within a class can
vary greatly. Therefore, it would be extremely difficult to establish a
single threshold for all the chemicals within a given class. Because of
this difficulty, FDA is not taking any action in response to this
comment.
The agency believes that it may be feasible in the future to
establish a higher threshold based on a substance's toxicological
properties rather than based on its type or on the class of chemicals
to which it belongs. For example, as discussed in a previous comment,
it may be possible in the future to establish separate thresholds for
substances that either have been shown to be noncarcinogenic by
appropriate 2-year bioassays or, based on the results of short-term
toxicity testing (e.g., mutagenicity and acute oral feeding studies),
are likely to have a low carcinogenic potency if they are, in fact,
carcinogenic.
17. One comment requested that FDA specifically address whether
biocides would be eligible for consideration under the threshold of
regulation regime. Because such substances must be registered with the
Environmental Protection Agency (EPA) in accordance with the Federal
Insecticide, Fungicide and Rodenticide Act (FIFRA) (7 U.S.C. 136 et
al.), and must undergo an extensive review for safety and efficacy, the
comment stated that biocides are well suited for an abbreviated review
under FDA's threshold of regulation process.
As long as the criteria specified in this final rule are met, FDA
will grant exemptions from regulation as food additives for biocides
that become components of food-contact articles.
18. Two comments requested that FDA clarify how the presence of a
``barrier'' (one that would limit the migration of a packaging
substance into food) would be factored into threshold of regulation
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 of the 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 is
below the threshold. Thus, if the presence of a functional barrier
limits the migration of the substance into food such that the resulting
dietary concentration is below the threshold, FDA will grant an
exemption for the intended use of that substance, provided that the
other criteria specified in this final rule are met.
In most cases, the effectiveness of a material to act as a barrier
to migration will depend not only on the physical and chemical
properties of the barrier material and the potential migrant but also
on the thickness of the barrier layer and the conditions of use (e.g.,
temperature, food type, contact time). Therefore, it is usually not
possible to draw any conclusions regarding the effectiveness of a
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 of the substance into food (i.e., the resulting
dietary concentration is at or below the threshold). FDA will consider
the validated detection limit of the method used to analyze for the
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 but
minimal migration of the substance into food. For example, some
packaging materials such as aluminum foil, when used as the inner layer
of laminates, have been generally recognized as being able to provide
an effective barrier to migration of the outer layer components into
food under a variety of conditions. In such cases, it would not be
necessary for the requestor to carry out and submit extraction studies
designed to show the effectiveness of the 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
of any additional extraction studies, as long as the conditions of use
do not differ significantly from those the agency reviewed.
19. One comment inquired as to whether the final rule establishing
a threshold of regulation for substances used in food-contact articles
will be applicable to regulated direct animal feed additives that are
intended to be used as components of articles that may contact animal
feed (i.e., indirect animal feed additives).
This final rule will allow those substances exempted under
Sec. 170.39 to be used in articles contacting animal feed as long as
the intended conditions of use of the substance are those for which the
exemption was issued. This result follows from Secs. 174.6 and
Sec. 570.14 (21 CFR 570.14) of FDA's regulations. Under Sec. 174.6
Threshold of regulation for substances used in food-contact articles,
FDA will exempt substances from regulation as food additives whose use
in food-contact articles meet the criteria in Sec. 170.39. Authority to
use substances exempted under Sec. 174.6 in articles contacting animal
feed is set out in Sec. 570.14 Indirect food additives resulting from
packaging materials for animal feed and pet food, which states that the
regulations providing for the use of food-packaging materials in parts
174 through 179 (21 CFR parts 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 will be those specified in new Sec. 170.39.
Because Sec. 570.14 contains a cross-reference that includes
Sec. 174.6, in accordance with that provision, FDA can review a request
for exemption of a substance used only in contact with animal feed
under Sec. 170.39.
Sections 170.39, 174.6, and 570.14, however, will not provide for
the use in articles contacting animal feed, at a level that is 1
percent or less of their ADI, of substances that are currently
regulated for direct use in animal feed in part 573 (21 CFR part 573).
To provide for such a review, FDA will have to adopt a regulation
similar to Sec. 170.39 that applies to direct animal feed additives
that have not been
[[Page 36589]]
regulated for direct addition to human food. However, such a regulation
is outside the scope of this rulemaking and would require a separate
proceeding.
Application of the Exemption
20. One comment inquired whether exempted substances may be used in
contact with all types of food.
Because the dietary concentration resulting from the use of a
substance in a food-contact article is dependent on the type of food
with which it comes in contact, the use of a substance in an article
contacting one type of food may result in a dietary concentration below
the threshold, while the use of the same material in contact with
another type of food may not. Therefore, FDA will limit exemptions to
those conditions of use warranted by the available data.
B. The Regulation
21. One comment recommended that FDA revise the language in
Sec. 170.39(a)(1) to make clear whether the phrase ``there is no
reason, based on the chemical structure of the substance, to suspect
that the substance is a carcinogen'' refers to impurities within the
substance or the substance itself.
FDA agrees with this comment and is revising proposed
Sec. 170.39(a)(1) to make it clear that the phrase ``there is no
reason, based on the chemical structure of the substance, to suspect
that the substance is a carcinogen'' refers only to the substance
itself.
22. One comment recommended that FDA revise the language in
proposed Sec. 170.39(c)(1) to make clear that the description of the
chemical composition of the substance for which the request is made
should include, whenever possible, the name of the chemical in
accordance with current chemical abstracts service (CAS) nomenclature
guidelines and a CAS registry number if available.
FDA agrees with this comment and has revised proposed
Sec. 170.39(c)(1) accordingly.
23. One comment recommended that the word ``substance'' in proposed
Sec. 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 to this comment in
this final rule.
24. One comment recommended that the regulation define in detail
the types of information required by FDA in submissions requesting
exemptions from the food additive regulations.
FDA agrees that a detailed description of the information that
needs to be included in a request for an exemption should be readily
available to interested parties. However, FDA does not believe that it
is necessary or appropriate 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 of food-contact articles and in the
methodologies used to quantify migration of components of such articles
into food.
Therefore, FDA is adding Sec. 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 not practical to provide guidelines that would cover
all of the possible topics associated with these types of submissions,
this final rule encourages interested parties to obtain specific
guidance from FDA on the protocols to use in obtaining extraction data,
on the validation of the analytical methods used to quantify migration
levels, on the procedures to use to relate migration data to dietary
exposures, and on any other issue not specifically covered in FDA's
guidelines.
FDA formerly proposed to announce the availability of guidelines in
Sec. 170.39(c)(4)(v) because the guidelines were meant to focus on
questions associated with the dietary concentration resulting from the
intended use of a substance in a food-contact article. However, the
agency believes it is more appropriate to include such language as part
of Sec. 170.39(h) to emphasize that interested parties may seek
guidance on any issue involving exemption requests. Therefore, FDA is
revising Sec. 170.39 to include this provision and has deleted proposed
Sec. 170.39(c)(4)(v).
C. Procedural Issues
Obtaining an Exemption
25. One comment commended FDA for its statement in the preamble
that manufacturers may make their own determination as to whether the
use of a substance in a food-contact article meets the ``food
additive'' definition in section 201(s) of the act and recommended that
FDA explicitly state this fact in the final regulation.
In response to this comment, FDA would like to reaffirm its
position that nothing in the regulatory scheme presented in this rule
would prevent a company from making its own determination that a
particular use of a substance does not meet 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. If the
agency learns of the use of a substance from, for example, a competitor
and reaches a different conclusion than the company, the agency may
take regulatory action against the substance as an unsafe food additive
or against the company that makes the substance for introducing an
adulterated food into interstate commerce. Therefore, in cases 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 rule to avoid the
possibility of regulatory action.
FDA does not believe, however, that it is appropriate to address
this issue in the regulation. The issue raised by the comment applies
generally to FDA's application of the ``food additive'' definition in
section 201(s) of the act. This rulemaking concerns only the threshold
of regulation process. Therefore, the question of whether, 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 a time
limit for reviewing and responding to requests for exemptions from
regulation as food additives to ensure timely responses. Two of the
comments suggested specific time limits of 60 and 90 days.
The agency agrees that such reviews should be carried out in a
timely manner. Timely review will mean that 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 are not exempted will receive prompt notice of the need
to file a food additive petition.
A pilot study carried out by FDA showed that such reviews can
usually
[[Page 36590]]
be completed within 3 to 4 months as compared to the 1 to 2 years
typically required for indirect food additive petitions. The agency is
concerned, however, that establishing a formal time limit for
completion of such 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 a time limit for reviewing and
responding to requests for exemptions from regulation as food additives
at this time. As the agency gains experience with its threshold of
regulation policy, it will consider establishing an appropriate time
limit. In the interim, however, the agency is committed to reviewing
exemption requests as expeditiously as resources allow.
27. One comment recommended that there be a 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, if the use of a substance results in, or
is reasonably expected to result in, migration into food, even at low
levels, and is not specifically excluded from the definition of a
``food additive'' in section 201(s) of the act, then the substance is a
food additive that must either be the subject of a regulation
authorizing its use or be exempted from regulation by FDA under the
process specified in this rule. However, if the use of a 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 of regulatory concern), and is the subject of a
request for an exemption under the process specified by this final
rule, it is unlikely that FDA would take regulatory action during the
time 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 Sec. 170.39 be revised to include
an abbreviated review (i.e., one that does not require a review of
environmental 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 of paper and paperboard under
Sec. 176.170 that is the subject of an exemption request for its use as
a deposit control agent in the manufacture of paper and paperboard).
The agency is currently reevaluating its environmental regulations
under NEPA, and is committed to expanding the list of categorical
exclusions found in Sec. 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 of a regulated 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 any previously
regulated use of the substance. Therefore, an abbreviated review (i.e.,
one that does not include a review of environmental impact data) is not
justified for all such substances. Although these types of uses do not
currently qualify for a categorical exclusion, some may qualify in the
future (the categorical exclusion list is currently under consideration
for expansion).
In regard to reducing the requirements for the submission of
toxicological feeding studies, FDA emphasizes that Sec. 170.39 requires
only that submissions contain the results of an analysis of existing
toxicological information on the substance and its impurities. This
information is needed to show whether an animal carcinogen bioassay has
been 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 of the
impurities present in the substance have been shown to be carcinogenic,
and, if carcinogenic, whether their TD50 value is greater than 6.25 mg/
kg bodyweight per day (see Sec. 170.39(a)(1)). To clarify this issue,
FDA is revising the language in Sec. 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 of
existing toxicological information on the substance and its impurities.
29. Two comments stated that exempted substances should not be
subjected to the environmental impact reviews typically required for
food additives. The comments asserted that, instead, exempted
substances should come under a newly 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 of the environmental effects resulting from the
intended use, unless it is the subject of one of the 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 of any substance and, therefore, will not
result in the introduction of any 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 of the subject comments provided information to show
that as a class, substances used in food-contact articles would not be
introduced into the environment or to support the establishment of a
new categorical exclusion. The agency welcomes the submission of data
and information that would support the establishment of a categorical
exclusion for these substances. At this time, however, all requests for
threshold of regulation exemptions must include an abbreviated
environmental assessment.
Availability of the Information Submitted
30. Six comments were submitted on the general subject of what
types of information contained in submissions under Sec. 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
of Information Act (FOIA) (5 U.S.C. 552)). Three of these 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 the release 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 of an exemption request. Another
comment stated that the names of companies receiving exemption letters
are trade secret.
[[Page 36591]]
As a general matter, the FOIA requires that agencies make the
fullest possible disclosure of records to the public. The procedures
that FDA uses to handle the release of public information in accordance
with FOIA are described in part 20 (21 CFR part 20). Under these
procedures, information submitted to FDA, including that submitted on
the use of food additives, is made publicly available to the greatest
extent possible.
As for substances that become components of food below the
threshold that FDA is establishing, they will be exempt from the
requirement that their use be the subject of a food 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 of an exemption,
FDA concludes that it is appropriate for it to make publicly available
under Sec. 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.
In response to the request that the final regulation include a
statement recognizing the possible trade secret status of information
submitted in support of an exemption request, FDA is revising
Sec. 170.39(e) to state that the agency will respond to all FOIA
requests for information submitted under Sec. 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 Sec. 20.61(c).
31. One comment stated that information contained in submissions
under Sec. 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 Sec. 20.61(a) and
(b). Therefore, FDA will not disclose this type of information.
32. Two comments stated that the chemical identities of exempted
substances should not be publicly disclosed. One of these comments
stated that such information is trade secret and considered by
economists as ``circumstantially relevant business information.'' The
comment stated that, if the company requesting an exemption regards
this information as trade secret, keeping such information confidential
is consistent with controlling case law interpretation of the
confidentiality standard that is applied to FDA under Critical Mass
Energy Project v. 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 of proprietary
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 it belongs. This comment
also pointed out that EPA has used this type of system in Pre-
Manufacture 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 of
chemicals 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 of the additive. Second,
as previously discussed, FOIA requires that agencies make the fullest
possible disclosure of records to the public. Under the procedures used
by FDA to determine the releasability of information under FOIA, the
agency has traditionally considered the chemical identity of food
additives to be disclosable information, and thus, the regulations
implementing the 1958 Food Additives Amendment refer to food additives
by their chemical names. Because FDA's approach to exempted substances
derives from the food additive provisions of the act, and, as stated
above, FDA is acquiescing in the use of the substance, FDA concludes
that the chemical identities of exempted substances are disclosable
under FOIA.
Critical Mass is not to the contrary. While a company has an
alternative to making a submission to FDA under Sec. 170.39 (i.e.,
filing a food additive petition), and thus, the submission is in a
sense voluntary, the key question under Critical Mass is whether the
information is of a kind that would 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 of food additives
for which listing is sought is routinely disclosed to the public in the
Federal Register, pursuant to section 409 of the act. Submitters are
well aware of this fact. Thus, FDA finds no merit to the suggestion by
the comment that the identity of substances subject to Sec. 170.39 must
be kept confidential. To provide differently for substances subject to
Sec. 170.39 would be to create a special exemption. Clearly, Critical
Mass does not 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 trade names
often are. Moreover, trade names are often used to refer to
formulations in which the chemical composition is held 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 if the list of exempted substances made publicly available
did not include the chemical identities of such substances.
Making available the chemical identities of substances exempted
from regulation will permit other manufacturers to use these substances
as long as the conditions of use are no more likely to result in
migration to food than those for which the exemption was originally
issued. It will also allow interested persons to determine what
substances have been exempted by FDA under the process established by
this final rule. FDA believes that, in the interest of open 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 of exempted substances.
33. One comment stated that the technical effect or function of the
substance should not be made publicly available.
Under the procedures used by FDA to implement FOIA, the agency has
not considered information on the technical effect or functionality of
a food additive to be trade secret as defined in Sec. 20.61(a) or
confidential commercial or financial information as defined in
Sec. 20.61(b). Because the dietary exposure resulting from the use of a
substance in a food-contact article may vary considerably depending on
the technical effect of that additive, it is often necessary to include
such information in the regulation authorizing a specific type of use
of the food additive in order to restrict the
[[Page 36592]]
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 of articles or as components of articles contacting food.
Moreover, 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 use of the substance meets all applicable specifications
and limitations. Such limitations include those that restrict the use
of the additive to a specific technical effect. Therefore, it is often
necessary to include this information as part of the conditions of use
set forth in the regulation authorizing the use of the 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
of a regulation, the agency has routinely made technical effect
information contained in food additive petitions available to the
public in response to FOIA requests in accordance with
Sec. 171.1(h)(1)(i). Consistent with the explanation above, FDA sees no
reason to change this policy with regard to food additives exempted
from regulation.
Treatment of the List of Exempted Uses of Substances
34. One comment recommended that in addition to making available a
list of exemptions at the 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 that have 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 of achieving this result. FDA anticipates being able to
respond to exemption requests within 3 to 4 months. Thus, the list of
exempted substances would be continually changing. Monthly updates in
the Federal Register would be expensive and yearly updates of little
value. Therefore, FDA has no plans to publish this list in the Federal
Register.
However, to ensure that interested persons are aware that FDA is
maintaining such a list at its Dockets Management Branch, the agency
plans to publish annually a brief notice in the Federal Register on the
availability of this list. An updated list of exempted substances can
also be obtained by contacting FDA's Office of Premarket Approval
(address above). FDA is revising Sec. 170.39(e) to reflect this fact.
Revocation
35. One comment recommended that FDA establish timeframes for the
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 of a substance in a food-contact
article from regulation under the food additive provisions cannot be
supported in light of existing 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 of such 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 Sec. 170.39(c) to state that three copies of a
request 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
Sec. 170.39(c) to state that if part of the submitted material is in a
foreign language, it must be accompanied by an English translation
verified to be complete and accurate in accordance with
Sec. 10.20(c)(2) (21 CFR 10.20(c)(2)).
IV. Analysis of Impacts
FDA has examined the impacts of this 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
of available regulatory alternatives and, when regulation is necessary,
to select regulatory 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 if it meets any one of a
number of specified 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 if it 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 not have a
significant impact on a substantial number of small businesses.
38. One comment suggested that the proposed threshold of regulation
process would have an adverse impact on small businesses. FDA
disagrees. The regulation that FDA is adopting does not prohibit or
restrict 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 of the 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 of regulation process, those components of food-contact
materials whose use results in low levels of migration into food would
require premarket approval through the food additive petition process.
Based on information provided to FDA by representatives of the food
packaging and processing industries, the collection of information and
preparation of an exemption request for review under the process
established by this final rule is estimated to cost anywhere from
$1,400 to $25,000 depending on the complexity of the project. If
analytical studies are required to be carried out to show that the
dietary exposure resulting from the proposed use is below the threshold
of regulation, FDA estimates that the additional cost would vary from
$10,000 to $50,000 depending on the complexity of the project (e.g.,
the number of substances or food simulating solvents involved, and the
method of analysis). 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 of data needed to estimate the dietary exposure associated with
the intended use. A simple request (i.e., one that does not contain any
analytical work) would typically contain: (1) Identity and use
information; (2) a literature search of the existing toxicological data
on the substance and its impurities; and (3) information on the
environmental impact resulting from the proposed use of the substance.
Based on information provided to FDA by representatives of the food
packaging and processing industries, the average time to prepare such
requests is estimated to be 68
[[Page 36593]]
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 of the
substance in the food-contact article) is estimated to be 108 hours.
Although the preparation of requests 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 of
food-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 not have an adverse impact on small
businesses.
In summary, the comments do not provide a basis on which to change
the conclusions of the economic analysis prepared for the 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 of
this rule 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 of each
action to exempt a component of a food-contact article from regulation
as a food additive. The final rule sets out the type of information
that FDA needs to determine the impact on the environment resulting
from the intended use. The agency's finding of no significant impact,
and the evidence supporting that finding, contained in an environmental
assessment, will be made available for public 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 of this final rule contains information collection
requirements that were submitted for review and approval to the Office
of Management and Budget (OMB), as required by section 3504(h) of the
Paperwork Reduction Act of 1980. 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 of the
available evidence, FDA concludes that this evidence does not support a
threshold significantly higher than 0.5 ppb, especially where the
substance being considered for an exemption has not been the subject of
any 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 of regulatory concern for regulated direct food additives
used in food-contact articles as that dietary exposure that is at or
below 1 percent of the ADI for that substance.
Listed below are the revisions that are being incorporated into
this final rule based on comments received in response to the proposal:
(1) FDA is revising Sec. 170.39(a)(1) to make it clear that the
phrase ``there is no reason, based on the chemical structure of the
substance, to suspect that the substance is a carcinogen'' refers only
to the substance itself (see comment 21 of this document).
(2) FDA is revising Sec. 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 or below 1 percent of the ADI for that
substance, FDA's review will not necessarily be restricted to ADI
values based on data in FDA files. In particular, in cases where FDA
has not calculated an ADI value for a regulated 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 Sec. 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 is not practical to provide
guidelines that would cover all of the possible topics associated with
these types of submissions, Sec. 170.39(h) encourages interested
parties to obtain specific guidance from FDA on the appropriate
protocols to be used for obtaining extraction data, on the validation
of the 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 in FDA's guidelines (see
comment 24 of this document).
(4) FDA is revising Sec. 170.39(c)(1) to state that the description
of the chemical composition of the 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 of this document).
(5) For consistency, FDA is revising Sec. 170.39(c)(4)(ii) and
(c)(4)(iii) so that the word ``substance'' refers to the singular case
(see comment 23 of this document).
(6) FDA is revising the language in Sec. 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 of existing toxicological data on the substance and its
impurities. This information is needed to show whether an animal
carcinogen bioassay has been carried out, or whether there is some
other basis for suspecting that the substance is a carcinogen or potent
toxin. This type of information on the impurities is needed to show
whether any of them are carcinogenic and, if carcinogenic, whether
their TD50 value is greater than 6.25 mg/kg bodyweight per day in
accordance with Sec. 170.39(a)(1) (see comment 28 of this document).
(7) FDA is revising Sec. 170.39(e) to state that interested persons
may obtain a list of exempted substances by contacting FDA's Office of
Premarket Approval (HFS-200), 200 C St. SW., Washington, DC 20204 (see
comment 34 of this document).
(8) FDA is also revising Sec. 170.39(e) to state that FDA will
handle requests for copies of releasable information contained in
submissions requesting exemptions from the food additive
[[Page 36594]]
regulations in accordance with FDA's FOIA procedures as described in
part 20. In particular, data and information that fall within the
definitions of a trade secret or confidential commercial or financial
information are not available for public disclosure in accordance with
21 CFR 20.61(c) (see comment 30 of this document).
(9) FDA is revising the language in Sec. 170.39(g) to state that
the agency plans to notify manufacturers by means of a notice published
in the Federal Register of its decision to revoke an exemption issued
for a specific use of a substance in a food-contact article (see
comment 13 of this document).
(10) FDA is revising Sec. 170.39(c) to state that three copies of a
request for an exemption from regulation are to be submitted. If part
of the submitted material is in a foreign language, it must be
accompanied by an English translation verified to be complete and
accurate in accordance with Sec. 10.20(c)(2) (see Section III. of this
document: Other Actions). In addition to these changes, FDA is
clarifying its definition of TD50 in Sec. 170.39(a)(1). This minor
change from the October 12, 1993, proposal ensures the scientific
soundness of this definition.
VIII. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Rulis, A., ``Threshold of Regulation: Options for Handling
Minimal Risk Situations,'' in Food Safety Assessment, 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 III, ``FDA's
Priority Based Assessment of Food Additives,'' Regulatory Toxicology
and Pharmacology, vol. 4, pp. 37-56, 1984.
List of Subjects
21 CFR Part 5
Authority delegations (Government agencies), Imports, Organization
and functions (Government agencies).
21 CFR Part 25
Environmental impact statements, Foreign relations, Reporting and
recordkeeping requirements.
21 CFR Part 170
Administrative practice and procedure, Food additives, Reporting
and recordkeeping requirements.
21 CFR Part 171
Administrative practice and procedure, Food additives.
21 CFR Part 174
Food additives, Food packaging.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
5, 25, 170, 171, and 174 are amended as follows:
PART 5--DELEGATIONS OF AUTHORITY AND ORGANIZATION
1. The authority citation for 21 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 of the 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, 242l, 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 of the National Childhood Vaccine 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:
Sec. 5.61 Food standards, food additives, generally recognized as safe
(GRAS) substances, color additives, nutrient content claims, and health
claims.
* * * * *
(h) The following officials are authorized to issue letters
concerning substances determined to be below the ``threshold of
regulation'' under Sec. 170.39 of this chapter:
(1) The Director and Deputy Directors, Center for Food Safety and
Applied Nutrition (CFSAN).
(2) The Director, Office of Policy, Planning and Strategic
Initiatives, CFSAN.
(3) The Director, Office of Premarket Approval, CFSAN.
(4) The Directors of the Divisions of Petition Control and Product
Policy, Office of Premarket Approval, CFSAN.
PART 25--ENVIRONMENTAL IMPACT CONSIDERATIONS
3. The authority citation for 21 CFR part 25 continues to read as
follows:
Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 321-393); secs. 351, 354-361 of the Public Health
Service Act (42 U.S.C. 262, 263b-264); 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:
Sec. 25.22 Actions requiring preparation of an environmental
assessment.
(a) * * *
(10) Approval of food and color additive petitions, approval of
requests for exemptions for investigational use of food additives, and
granting of requests 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:
Sec. 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 or petitioner shall
prepare an environmental assessment in the following format:
* * * * *
(b)(1) For actions (either to approve food additive petitions or to
grant requests for exemption from regulation as a food additive)
concerning components of food-contact articles present in the finished
food-packaging material at 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 of food-contact articles to be used in surfaces
of permanent or semipermanent equipment or of other food-contact
articles intended for repeated use, the following 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 of the 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
[[Page 36595]]
by adding new paragraph (e)(2) to read as follows:
Sec. 170.3 Definitions.
* * * * *
(e)(2) Uses of food additives not requiring a listing regulation.
Substances used in food-contact articles (e.g., food-packaging and
food-processing equipment) that migrate, or may be expected to migrate,
into food at such negligible levels that they have been exempted from
regulation as food additives under Sec. 170.39.
* * * * *
8. New Sec. 170.39 is added to subpart B to read as follows:
Sec. 170.39 Threshold of regulation for substances used in food-
contact articles.
(a) A substance used in a food-contact article (e.g., food-
packaging or food-processing equipment) that migrates, or that may be
expected to migrate, into food will be exempted from regulation as a
food additive because it becomes a component of food at levels that are
below the threshold of regulation if:
(1) The substance has not been shown to be a carcinogen in humans
or animals, and there is no reason, based on the chemical structure of
the substance, to suspect that the substance is a carcinogen. The
substance must also not contain a carcinogenic impurity or, if it does,
must not contain a carcinogenic impurity with a TD50 value based
on chronic feeding studies reported in the scientific literature or
otherwise available to the Food and Drug Administration of less than
6.25 milligrams per kilogram bodyweight per day (The TD50, for the
purposes of this section, is the feeding dose that causes cancer in 50
percent of the test animals when corrected for tumors found in control
animals. If more than one TD50 value has been reported in the
scientific literature for a substance, the Food and Drug Administration
will use the lowest appropriate TD50 value in its review.);
(2) The substance presents no other health or safety concerns
because:
(i) The use in question has been shown to result in or may be
expected to result in dietary concentrations at or below 0.5 parts per
billion, corresponding to dietary exposure levels at or below 1.5
micrograms/person/day (based on a diet of 1,500 grams of solid food and
1,500 grams of liquid food per person per day); or
(ii) The substance is currently regulated for direct addition into
food, and the dietary exposure to the substance resulting from the
proposed use is at or below 1 percent of the acceptable daily intake as
determined by safety data in the Food and Drug Administration's files
or from other appropriate sources;
(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 that the
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
of a substance from regulation as a food additive shall include three
copies of the following information (If part of the submitted material
is in a foreign language, it must be accompanied by an English
translation verified to be complete and accurate in accordance with
Sec. 10.20(c)(2) of this chapter):
(1) The chemical composition of the substance for which the request
is made, including, whenever possible, the name of the chemical in
accordance with current Chemical Abstract Service (CAS) nomenclature
guidelines and a CAS registry number, if available;
(2) Detailed information on the conditions of use of the substance
(e.g., temperature, type of food with which the substance will come
into contact, the duration of the 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 of the
substance in the food-contact article results in a dietary
concentration at or below 0.5 parts per billion, or on the fact that it
involves the use of a regulated direct food additive for which the
dietary exposure is at or below 1 percent of the 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 of the substance. These data should be 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 of the substance used in the
manufacture of the food-contact article; or
(iii) Information on the residual level of the substance in the
food-contact article. For repeat-use articles, an estimate of the
amount of food that contacts a specific unit of surface area over the
lifetime of the article should also be provided. (In cases where data
are provided only in the form of manufacturing use levels or residual
levels of the substance present in the food-contact article, the Food
and Drug Administration will calculate a worst-case dietary
concentration level assuming 100 percent migration.) A detailed
description of the 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 in
the food-contact article by a suitable analytical method, the Food and
Drug Administration will, for the purposes of estimating the dietary
concentration, consider the validated detection limit of the method
used to analyze for the substance.
(5) The results of an 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
suspecting that the substance is a carcinogen or potent toxin. This
type of information on the impurities is needed to show whether any of
them are carcinogenic, and, if carcinogenic, whether their TD50 values
are greater than 6.25 milligrams per kilogram bodyweight per day in
accordance with paragraph (a)(1) of this section.
(6) Information on the environmental impact that would result from
the proposed use of the substance. Depending on the type of use, this
information should be in the form of an abbreviated environmental
assessment as specified in Sec. 25.31a(b)(1) or (b)(2) of this chapter.
(d) Data to be reviewed 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 requestor by
letter whether the specific food-contact application is exempt from
regulation as a food additive or not. Although a substance that
migrates to food at a level that results in a dietary concentration at
or below the threshold of regulation will not be the subject of a
regulation published in the Federal Register and will not appear in the
Code of Federal Regulations, the Food and Drug Administration will
maintain a list of substances exempted from regulation as
[[Page 36596]]
food additives under this section on display at the Dockets Management
Branch. This list will include the name of the company that made the
request, the chemical name of the 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
trade names. This list will enable interested persons to see the types
of uses of food-contact materials being exempted under the regulation.
Interested persons may also obtain a copy of the list of exempted
substances by contacting the Food and Drug Administration's Office of
Premarket Approval (HFS-200), 200 C St. SW., Washington, DC 20204. The
agency's finding of no significant impact and the evidence supporting
that finding, contained in an environmental assessment, also will be
available for public inspection at the Dockets Management Branch in
accordance with Sec. 25.41(b)(2) of this chapter. Requests for copies
of releasable information contained in submissions requesting
exemptions from the food additive regulations will be handled in
accordance with the Food and Drug Administration's Freedom of
Information Act procedures, as described in part 20 of this chapter. In
particular, data and information that fall within the definitions of a
trade secret or confidential commercial or financial information are
not available for public disclosure in accordance with Sec. 20.61(c) of
this chapter.
(f) If the request for an exemption from regulation as a food
additive is not granted, the requestor may submit a petition to the
Food and Drug Administration for reconsideration of the decision in
accordance with the provisions of Sec. 10.33 of this chapter.
(g) If the Food and Drug Administration receives significant new
information that raises questions about the dietary concentration or
the safety of a substance that the agency has exempted from regulation,
the Food and Drug Administration may reevaluate the substance. If the
Food and Drug Administration tentatively concludes that the information
that is available about the substance no longer supports an exemption
for the use of the food-contact material from the food additive
regulations, the agency will notify any persons that requested an
exemption for the substance of its tentative decision. The requestors
will be given an opportunity to show why the use of the substance
should not be regulated under the food additive provisions of the act.
If the requestors fail to adequately respond to the new evidence, the
agency will notify them that further use of the substance in question
for the particular use will require a food additive regulation. This
notification will be placed on public display at the Dockets Management
Branch as part of the file of uses of substances exempted from
regulation as food additives. The Food and Drug Administration
recognizes that manufacturers other than those that actually made a
request for exemption may also be using exempted substances in food-
contact articles under conditions of use (e.g., use levels,
temperature, type of food contacted, etc.) that are similar to those
for which the exemption was issued. Because only requestors will be
notified as part of the revocation process described in this section,
the Food and Drug Administration plans to notify other manufacturers by
means of a notice published in the Federal Register of its decision to
revoke an exemption issued for a specific use of a substance in a food
contact article.
(h) Guidelines to assist requestors in the preparation of
submissions seeking exemptions from the food additive regulations are
available from the Food 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 of the 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 in the 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 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).
10. New Sec. 171.8 is added to subpart A to read as follows:
Sec. 171.8 Threshold of regulation for substances used in food-contact
articles.
Substances used in food-contact articles (e.g., food-packaging or
food-processing equipment) that migrate or that may be expected to
migrate into food at negligible levels may be reviewed under
Sec. 170.39 of this chapter. The Food and Drug Administration will
exempt substances whose uses it determines meet the criteria in
Sec. 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 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).
12. New Sec. 174.6 is added to read as follows:
Sec. 174.6 Threshold of regulation for substances used in food-contact
articles.
Substances used in food-contact articles (e.g., food-packaging or
food-processing equipment) that migrate, or that may be expected to
migrate, into food at negligible levels may be reviewed under
Sec. 170.39 of this chapter. The Food and Drug Administration will
exempt substances whose uses it determines meet the criteria in
Sec. 170.39 of this 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,
Deputy Commissioner for Policy.
[FR Doc. 95-17435 Filed 7-14-95; 8:45 am]
BILLING CODE 4160-01-P