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respect to D&C Green No. 5 in Scott v. FDA, 728 F.2d 322 (6th
Cir. 1984) (per curiam), where the court invoked the de mini
mis doctrine and noted that FDA did not abuse its discretion
in determining that a level of risk between one in 30 million
and one in 300 million "created no reasonable risk of harm to
individuals exposed to the color additive."
The saccharin proposal is consistent with this
history. Petitioners contend that FDA's proposal to ban the
artificial sweetener saccharin is inconsistent with the
agency's de minimis policy (Pet. Br. 13).
the two are completely reconcilable.
proposal, FDA expressly found that "saccharin poses a
significant risk of cancer for humans.
By contrast, FDA has concluded that the color
additives pose at most a "trivial" risk of cancer for humans.
The differences are highlighted by FDA's risk
assessment calculations. Based on quantitative risk assessment, FDA determined that use of saccharin posed as high as a 4 in 10,000 lifetime risk of cancer. 42 Fed. Reg. at 20001
This level is 400 times higher than the one in one
million benchmark used by FDA for its de minimis policy, and almost 8 million times higher than the upper-bound level of
risk for D&C Orange No. 17.
policy); 47 Fed. Reg. 14138 (1982) (D&C Green No. 6); 47 Fed. Reg. 24278 (1982) (D&C Green No. 5); 47 Fed. Reg. 57681 (1982) (D&C Red Nos. 6 & 7); 48 Fed. Reg. 37617 (1983) (water-soluble thermosetting resins): 50 Fed. Reg. 35774 (1985) (FD&C Yellow No. 5); 51 Fed. Reg. 29460 (1986) (tris (triethylene glycol) phosphate); 51 Fed. Reg. 31760 (1986) (alpha-sulfo-omega(dodecyloxy) poly(oxyethylene) ammonium salt).
Moreover, the risks from saccharin were sufficiently great that FDA proposed to ban its use under the general safety clause as well as under the Delaney Clause. 42 Fed. Reg. at 20002. The agency also recognized that these provisions had consistently been interpreted congruently (id.), as already discussed. For all these reasons, the saccharin
proposal is not inconsistent with the de minimis policy.
3. The clarification of FDA'S De Minimis
Policy Is Consistent with the Position
Expressed in the CTFA Comments, in the
Final Rules, and in: Prior FDA Regulatory Decisions
In FDA's recent Federal Register notice clarifying
the basis for permanently listing the two color additives, the agency also grounds its application of the de minimis policy in part on an interpretation of the term "induce cancer" in
the Delaney Clause (Gov't Br. Addendum A).
to applying the de minimis principle to the Delaney Clause as a whole, as it did in the final rules, the agency has now made it clear that this principle also applies directly to whether
a substance "induces cancer in man or animal."
The two foundations for the FDA de minimis policy are, in reality, the same. The de minimis doctrine is founded
on the agency's inherent authority, not on express statutory
language (see pages 19-22, supra).
requirement that application of the principle rest on an interpretation of the entire statute or of particular words in
the statute. At the same time, basing the policy on particular words of the statute provides additional (if redundant)
support for the agency's exercise of discretion in adopting
doctrine is equally applicable.
Moreover, the two foundations for the policy are functionally equivalent in their application to the color additives in issue here. Both are based directly on quantita
tive risk assessment and on FDA's ability, using that estab
lished scientific method, to determine whether a substance
poses a significant risk of cancer under actual conditions of
Where it is an incontrovertible fact that, as here, a de
minimis risk is presented under those conditions, the sub
stance can be said both not to "induce cancer" and not to be
within the intended scope of the anticancer provisions of the
In its comments to FDA supporting the permanent listing of the color additives, CTFA had discussed the rela
tionship between the de minimis principle and interpretation
of the term "induce cancer."
See J.A. 456-460, 483-489.
Because these comments were not submitted as objections,
however, FDA did not address this position until publication of its clarification. 54/
FDA's clarification is entirely consistent with
54/ In its comments to FDA, CTFA also argued that, in addition to the de minimis policy, the color additives should be permanently listed for external uses because the animal ingestion studies showing carcinogenicity are not "appropriate" or "relevant" to a safety evaluation of the additives for these uses under the provision of the Delaney Clause applicable to externally applied color additives. See J.A. 490-491 & n.216. In approving the carcinogenic color additive lead acetate, for example, FDA stated that this noningestion provision "does not make an animal ingestion study demonstrating carcinogenicity an absolute bar to the approval of a petition for a noningested color additive.". 45 Fed. Reg. 72112, 72115 (Oct. 31, 1980). FDA's rejection of CTFA's argument in the final rules (J.A. 356, 373) takes an unduly narrow view of the statute and of the lead acetate decision.
other circumstances in which it has exercised its scientific
judgment to interpret the Delaney Clause not to apply to
substances that have been found, as a purely factual matter,
to cause cancer in animals under certain laboratory test conditions. In these cases, where there is a de minimis risk to humans, the agency has determined that causation in animals
is insufficient to conclude that a substance "induces cancer"
within the meaning of the Delaney Clause.
For example, FDA has distinguished between primary (direct) carcinogens, which initiate carcinogenesis by interacting directly with cellular genetic material, and secondary (indirect) carcinogens, which cause a physiologic change that in turn results in cancer but do not directly induce cancer. Pursuant to this distinction, FDA has stated
the Delaney Clause does not apply to secondary carcinogens. Thus, FDA approved the use of selenium as an additive to the
food of food-producing animals, even though administration of
the substance was shown in feeding studies to be associated
with a statistical increase in cancer in laboratory animals.
FDA concluded that the lesions were a consequence of liver
cirrhosis produced by toxic doses of selenium and were not
induced by selenium itself.
Where it is possible to determine
a "no effect" level for the toxic effect, FDA is able to
approve secondary carcinogens for use at a level in humans
that will not present a risk of cancer resulting from that
See 38 Fed. Reg. 10458, 10459-10460 (1973): 39 Fed. Reg.
FDA also has concluded that food additives do not
"induce cancer" within the meaning of the Delaney Clause even if feeding studies directly result in cancer in laboratory animals, where there are relevant metabolic and physiological
differences between animals and humans.
stances the animal tests are not relevant to human risk and
thus the Delaney Clause is inapplicable. For example, FDA "has required non-rodent animal models for carcinogenic testing of steroid contraceptives because the rodent was felt to be physiologically too divergent from the human to be a reliable test animal." 567 Similarly, FDA refused to take action against butylated hydroxyanisole (BHA), a widely used food preservative, on the basis of a study showing that the substance produces cancer in rat forestomachs, since humans do not have forestomachs and tests in other animals showed that BHA did not cause cancer in "analogous regions." 57/ The agency also has refused to ban calcium, an essential human
nutrient, which causes cancer in bulls but in no other animal
1355 (1974). The agency has on this basis also permitted continued use of beverage alcohol, even though it too is associated with a higher incidence of liver cirrhosis and, in turn, cancer. Id. See also The Regulation by the Department of Health and Human Services of Carcinogenic Color Additives: Hearing Before a Subcomm. of the House Comm. on Government Operations, 98th Cong., 2d Sess. 379 (1984) (statement of Richard Ronk) ("if a secondary mechanism is obtainable, then some specification can be written for the color that would preclude a carcinogenic result when ingested by man").
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tions, as to the maximum quantity or quantities which may be used or permitted to remain in or on the article or articles in or on which it is used; specifications as to the manner in which such additive may be added to or used in or on such article or articles; and directions or other labeling or packaging requirements for such additive).
(4) The Secretary shall not list a color additive under this section for a proposed use unless the data before him establish that such use, under the conditions of use specified in the regulations, will be safe: Provided, however, That a color additive shall be deemed to be suitable and safe for the purpose of listing under this subsection for use generally in or on food, while there is in effect a published finding of the Secretary declaring such substance exempt from the term "food additive" because of its being generally recognized by qualified experts as safe for its intended use, as provided in section 201(s).
(5)(A) In determining, for the purposes of this section, whether a proposed use of a color additive is safe, the Secretary shall consider, among other relevant factors
(i) the probable consumption of, or other relevant exposure from, the additive and of any substance formed in or on food, drugs, devices, or cosmetics because of the use of the additive;
(ii) the cumulative effect, if any, of such additive in the diet of man or animals, taking into account the same or any chemically or pharmacologically related substance or substances in such diec.
(iii) safety factors which, in the opinion of experts qualified by scientific training and experience to evaluate the safety of color ad. ditives for the use or uses for which the additive is proposed to be listed, are generally recognized as appropriate for the use of animal experimentation data; and
(iv) the availability of any needed practicable methods of analysis for determining the identity and quantity of (1) the pure dye and all intermediates and other impurities contained in such color additive. (II) such additive in or on any article of food, drug, device, or cosmetic, and (III) any substance formed in or on such article
because of the use of such additive. (B) A color additive (i) shall be deemed unsafe, and shall not be listed. for any use which will or may result in ingestion of all or part of such ad. ditive, if the additive is found by the Secretary to induce cancer when ingested by man or animal, or if it is found by the Secretary, after tests which are appropriate for the evaluation of the safety of additives for use in food, to induce cancer in man or animal, and (ii) shall be deemed unsafe, and shall not be listed, for any use which will not result in ingestion of any part of such additive, if, after tests which are appropriate for the evaluation of the safety of additives for such use, or after other relevant exposure of man or animal to such additive, it is found by the Secretary to induce cancer in man or animal: Provided, That clause (i) of this subparagraph (B) shall not apply with respect to the use of a color additive as an ingredient of feed for animals which are raised for food produc
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(2) any color additive which was commercially used or sold prior to the enactment date for any use or uses in or on any food, drug, device, or cosmetic, and which either (A), on the day preceding the enactment date, was not a material within the purview of any of the provisions of the basic Act enumerated in paragraph (1) of this subsection, or (B) is the color additive known as synthetic beta
carotene, shall, beginning on the enactment date, be deemed to be provisionally listed under this section as a color additive for such use or uses.
(c) Upon request of any person, the Secretary, by regulations issued under subsection (d), shall without delay, if on the basis of the data before him he deems such action consistent with the protection of the public health, provisionally list a material as a color additive for any use for which it was listed, and for which a batch or batches of such material had been certified, under section 106(b), 504, or 604 of the basic Act prior to the enactment date, although such color was no longer listed and certifiable for such use under such sections on the day preceding the enactment date. Such provisional listing shall take effect on the date of publication.
(d)(1) The Secretary shall, by regulations issued or amended from time to time under this section
(A) insofar as practicable promulgate and keep current a list or lists of the color additives, and of the particular uses thereof, which he finds are deemed provisionally listed under subsection (b), and che presence of a color additive on such a list with respect to a particular use shall, in any proceeding under the basic Act, be conclusive evidence that such provisional listing is in effect;
(B) provide for the provisional listing of the color additives and particular uses thereof specified in subsection (c);
(C) provide with respect to particular uses for which color additives are or are deemed to be provisionally listed, such temporary tolerance limitations (including such limitations at zero level) and other conditions of use and labeling or packaging requirements, it any, as in his judgment are necessary to protect the public health pending listing under section 706 of the basic Act;
(D) provide for the certification of batches of such color additives (with or without diluents) for the uses for which they are so lisced or deemed to be listed under this section, excepe chat such an additive which is a color additive deemed provisionally listed under subsec. cion (b)(2) of this section shall be deemed exempt from the require. ment of such certification while not subject to a tolerance limitation; and
(E) provide for the termination of a provisional listing (or deemed provisional listing) of a color additive or particular use thereot forthwith whenever in his judgment such action is necessary to protect the public health.
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(2)(A) Except as provided in subparagraph (C) of this paragraph, regulations under this section shall, from time to time, be issued, amended, or repealed by the Secretary without regard to the requirements of the basic Act, but for the purposes of the application of section 706(e) of the basic Act (relating to fees) and of determining the availability of appropriations of fees (and of advance deposits to cover fees), proceedings, regulations, and certifications under this section shall be deemed to be proceedings, regulations, and certifications under such section 706. Regulations providing for fees (and advance deposits to cover fees), which on the day preceding the enactment date were in effect pursuant to section 706 of the basic Act, shall be deemed to be regula. tions under such section 706 as in effect prior to the enactment date shall be available for the purposes specified in such section 706 as so amended. (B) If the Secretary, by regulation
(i) has terminated a provisional listing (or deemed provisional listing) of a color additive or particular use thereof pursuant to paragraph (1)(E) of this subsection; or
(ii) has, pursuant to paragraph (1)(C) or paragraph (3) of this subsection, initially established or rendered more restrictive a tolerance limitation or other restriction or requirement with respect to a provisional listing (or deemed provisional listing) which listing
had become effective prior to such action, any person adversely affected by such action may, prior to the expiration of the period specified in clause (A) of subsection (a)(2) of this section, file with the Secretary a petition for amendment of such regulation so as
a to revoke or modify such action of the Secretary, but the filing of such petition shall not operate to stay or suspend the effectiveness of such action. Such petition shall, in accordance with regulations, set forth the proposed amendment and shall contain data (or refer to data which are before the Secretary or of which he will take official notice), which show that the revocation or modification proposed is consistent with the protection of the public health. The Secretary shall, after publishing such proposal and affording all interested persons an opportunity to present their views thereon orally or in writing, act upon such proposal by published order.
(C) Any person adversely affected by an order entered under subparagraph (B) of this paragraph may, within thiny days after its publication, file objections thereto with the Secretary, specifying with particularity the provisions of the order deemed objectionable, stating reasonable grounds for such objections, and requesting a public hear. ing upon such objections. The Secretary shall hold a public hearing on such objections and shall, on the basis of the evidence adduced at such hearing, act on such objections by published order. Such order may reinstate a terminated provisional listing, or increase or dispense with a previously established temporary tolerance limitation, or make less restrictive any other limitation established by him under paragraph (1) or (3) of this subsection, only if in his judgment the evidence so adduced 706(d)(2)(C)
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3. Apparently, what has happened here is that the De partment rushed to judgment that these color additives have been shown to induce cancer in experimental animals without the required rigorous analysis of available data, cutting off the possibility of tolerating their use in externally applied cosmetics that are absorbed through the skin. Then, realizing the lack of "reason" for barring the colors, in terms of any practical hazard to man/woman's health, the De partment seeks to rationalize the listing of the colors for limited use by characterizing the provisions of the Delaney clause as "terms of art" and by resorting to an exercise in risk assessment and application of the "de minimis" rule. In doing this it confuses the issue of cancer causation and the establishment of a safe tolerance for a proven carcinogen.
There would be little problem here if the "rule of reason" had been applied in the first place. The Department should have regarded the tumor development in experimental animals dosed at the level of maximum tolerated dose as insufficient to prove that the additive induces cancer when ingested. The observation of tumors, even malignant ones, at this extreme boundary of the experiment should have been regarded only as a part of the total scientific evidence about carcinogenicity of the color additive, and a rule of reason judgment should have been reached that the colors do not fall within the ban of the Delaney Clause, I do not believe that FDA has ever had a policy of basing a judgment on the issue of cancer causation upon the results of a study in only one strain, gender, and species, at one dose in one ex periment. Indeed, that is what Secretary Flemming warned against. The application of the rule of reason may be what FDA has in mind in calling the terms of the Delaney Clause "terms of art" and in dismissing the observations at maximum tolerated doses as "de minimis" evidence of cancer causation.
5.
If, however, the totality of the scientific data lead to a firm conclusion that the colors are indeed carcinogenic, that finding cannot be dismissed under the rubric of "de minimis" or upon the basis of the considerations listed in the Federal Register.
6.
I am aware of no basis for calling the statutory language "terms of art", the words "induce cancer" are words of science.
SIT William W. Goodrich, Esq.
NOV 12 1987 1
Y 4.G 74/7:F 73/10
C.1 FDA's regulation of Ca
Stanford University Libraries
STANFORD UNIVERSITY LIBRARIES STANFORD, CALIFORNIA 94305-6004
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3. Apparently, what has happened here is that the De partment rushed to judgment that these color additives have been shown to induce cancer in experimental animals without the required rigorous analysis of available data, cutting off the possibility of tolerating their use in externally applied cosmetics that are absorbed through the skin. Then, realizing the lack of "reason" for barring the colors, in terms of any practical hazard to man/woman's health, the De partment seeks to rationalize the listing of the colors for limited use by characterizing the provisions of the Delaney clause as "terms of art" and by resorting to an exercise in risk assessment and application of the "de minimis" rule. In doing this it confuses the issue of cancer causation and the establishment of a safe tolerance for a proven carcinogen.
There would be little problem here if the "rule of reason" had been applied in the first place. The Department should have regarded the tumor development in experimental animals dosed at the level of maximum tolerated dose as insufficient to prove that the additive induces cancer when ingested. The observation of tumors, even malignant ones, at this extreme boundary of the experiment should have been regarded only as a part of the total scientific evidence about carcinogenicity of the color additive, and a rule of reason judgment should have been reached that the colors do not fall within the ban of the Delaney Clause, I do not believe that FDA has ever had a policy of basing a judgment on the issue of cancer causation upon the results of a study in only one strain, gender, and species, at one dose in one ex periment. Indeed, that is what Secretary Flemming warned against. The application of the rule of reason may be what FDA has in mind in calling the terms of the Delaney Clause "terms of art" and in dismissing the observations at maximum tolerated doses as "de minimis" evidence of cancer causation.
5.
If, however, the totality of the scientific data lead to a firm conclusion that the colors are indeed carcinogenic, that finding cannot be dismissed under the rubric of "de minimis" or upon the basis of the considerations listed in the Federal Register.
6.
I am aware of no basis for calling the statutory language "terms of art", the words "induce cancer" are words of science.
SIT William W. Goodrich, Esq.
NOV 12 1987 1
Y 4.G 74/7:F 73/10
C.1 FDA's regulation of Ca
Stanford University Libraries
STANFORD UNIVERSITY LIBRARIES STANFORD, CALIFORNIA 94305-6004