[Federal Register: December 8, 2005 (Volume 70, Number 235)]
[Rules and Regulations]
[Page 72906-72908]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08de05-7]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 172
[Docket No. 1994F-0153] (formerly Docket No. 94F-0153)
Food Additives Permitted for Direct Addition to Food for Human
Consumption; Synthetic Fatty Alcohols
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the food
additive regulations to provide for the safe use of n-octanol (n-octyl
alcohol) produced by a new manufacturing process, the hydrodimerization
of 1,3-butadiene. This action is in response to a petition filed by
Kuraray International Corp.
DATES: This rule is effective December 8, 2005. Submit written or
electronic objections and requests for a hearing by January 9, 2006.
See section VI of this document for information on the filing of
objections. The Director of the Office of the Federal Register approves
the incorporation by reference in accordance with 5 U.S.C. 552(a) and 1
CFR part 51 of certain publications in new Sec. 172.864(a)(3) (21 CFR
172.864(a)(3)) as of December 8, 2005.
ADDRESSES: You may submit written or electronic objections and requests
for a hearing, identified by Docket No. 1994F-0153, by any of the
following methods:
Electronic Submissions
Submit electronic submissions in the following ways:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier (for paper, disk, or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of submissions, FDA is no longer
accepting submissions sent to the agency by e-mail. FDA encourages you
to continue to send electronic submissions by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this section of this document.
Instructions: All submissions received must include the agency name
and docket number and regulatory information number (RIN) (if a RIN
number has been assigned) for this rulemaking. All objections received
may be posted without change to http://www.fda.gov/ohrms/dockets/default.htm
, including any personal information provided. For detailed
instructions on submitting objections, see the ``Objections'' heading
of the SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number, found in brackets in the heading of this
document, into the ``Search'' box and follow the prompts and/or go to
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Raphael A. Davy, Center for Food
Safety and Applied Nutrition (HFS-265), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1272.
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal Register of May 26, 1994 (59
FR 27281), FDA announced that a food additive petition (FAP 4A4419) had
been filed by Kuraray International Corp., c/o 1001 G St. NW.,
Washington, DC 20001. The petition proposed to amend the food additive
regulations in Sec. 172.864 Synthetic fatty alcohols (21 CFR 172.864)
to provide for the safe use of n-octanol produced by a new
manufacturing process, the hydrodimerization of 1,3-butadiene.
Subsequently, Kuraray America, Inc., notified the agency of the merging
of Kuraray International Corp., into Kuraray America, Inc., and the
transfer of ownership of the petition (FAP 4A4419) to Kuraray America,
Inc.
n-Octanol (n-octyl alcohol) synthesized by the proposed
manufacturing process is intended for use in the same manner as n-
octanol prepared by other manufacturing processes under Sec. 172.864.
In evaluating the safety of n-octanol synthesized by the proposed
manufacturing process, FDA has reviewed the safety of the additive and
the chemical impurities that may be present in it resulting from its
manufacturing process. Although n-octanol has not been shown to cause
cancer, it may contain minute amounts of residual precursor as an
impurity resulting from its method of production. In particular, n-
octanol may contain traces of the precursor, 1,3-butadiene, which has
been shown to cause cancer in test animals. Residual amounts of
reactants and their impurities are commonly found as contaminants of
chemical products, including food additives.
II. Determination of Safety
Under the general safety standard in section 409 of the Federal
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 348), a food additive
cannot be approved for a particular use unless a fair evaluation of the
data available to FDA establishes that the additive is safe for that
use. FDA's food additive regulations (21 CFR 170.3(i)) define safe as a
``reasonable certainty in the minds of competent scientists that the
substance is not harmful under the intended conditions of use.''
The food additives anticancer, or Delaney, clause of the act
(section 409(c)(3)(A)) provides that no food additive shall be deemed
safe if it is found to induce cancer when ingested by man or animal, or
if it is found, after tests which are appropriate for the evaluation of
the safety of food additives, to induce cancer in man or animal.
Importantly, however, the Delaney clause applies to the additive itself
and not to impurities in the additive. That is, where an additive
itself has not been shown to cause
[[Page 72907]]
cancer, but contains a carcinogenic impurity, the additive is evaluated
properly under the general safety standard using risk assessment
procedures to determine whether there is reasonable certainty that no
harm will result from the intended use of the additive (Scottv. FDA,
728 F.2d 322 (6th Cir. 1984)).
In evaluating the safety of a food additive, FDA customarily
reviews the available data on each relevant chemical impurity to
determine whether the chemical induces tumors in animals or humans. If
FDA concludes that the chemical impurity causes cancer in animals or
humans, the agency calculates the unit cancer risk for the chemical and
the upper-bound limit of lifetime human cancer risk from the chemical's
presence in the additive.
In some instances, the available data and information may not allow
the agency to determine whether a particular chemical impurity in a
food additive is a carcinogen via ingestion. However, the available
data may suggest, but not establish definitively, that the impurity
poses a human cancer risk via this route. In such circumstances, the
agency may perform a risk assessment based upon the available data and
the assumption that the impurity is carcinogenic via ingestion. This
approach permits the agency to determine whether there is a reasonable
certainty that no harm will result from the petitioned use of the food
additive, even though the carcinogenic status of the impurity is not
clearly established. FDA followed this approach to determine whether
there is a reasonable certainty that no harm will result from the food
additive use of n-octanol synthesized by hydrodimerization of 1,3-
butadiene. In doing so, FDA assumed that 1,3-butadiene, an impurity in
the additive, would also be carcinogenic when administered by
ingestion.
A. Evaluation of the Petitioned Use of the Additive Produced by the New
Manufacturing Process
n-Octanol produced by the proposed manufacturing process, the
hydrodimerization of 1,3-butadiene, is intended to be used in the same
manner as currently permitted synthetic and naturally derived n-
octanol. Therefore, FDA concludes that the proposed amendment to the
regulation providing for the petitioned manufacturing process for n-
octanol will not result in a change in the daily intake of the additive
n-octanol because no new uses are proposed. Thus, the only new issue is
human exposure to 1,3-butadiene from food containing n-octanol produced
by the new manufacturing process.
FDA has evaluated the safety of n-octanol produced by the new
manufacturing process, under the general safety standard, and concludes
that the use of the resulting additive is safe. In reaching this
conclusion, FDA reviewed relevant toxicological data on 1,3-butadiene
and used risk assessment procedures to estimate the upper-bound limit
of lifetime human risk presented by levels that may be present in the
petitioned additive.
The risk evaluation of 1,3-butadiene has two aspects: (1)
Assessment of exposure to 1,3-butadiene from the petitioned use of n-
octanol produced by the new manufacturing process and (2) extrapolation
of the risk observed in the animal bioassays to the conditions of
exposure to humans.
B. 1,3-Butadiene
In one long-term inhalation study in mice, 1,3-butadiene has been
reported to induce a variety of tumors, including in the hematopoietic
system, heart, lung, forestomach, liver, Harderian gland, brain, and
kidney in both sexes and tumors of the ovaries and mammary gland in
female mice (Ref. 1). 1,3-Butadiene also has been reported to induce
tumors of the pancreas and testis in male rats and tumors of the
uterus, mammary gland, and thyroid in female rats in another long-term
inhalation study (Refs. 2 and 3). FDA does not believe, however, that
these inhalation studies are necessarily determinative of the
carcinogenic potential of 1,3-butadiene when administered orally, the
route of human exposure to food additives.
No long-term studies are available in which 1,3-butadiene was
administered to test animals orally. Therefore, the agency has
performed a carcinogenicity risk assessment for 1,3-butadiene based on
the assumption that 1,3-butadiene would induce tumors in animals and
humans if administered orally and that its potency by the oral route of
exposure would be no greater than its potency by the inhalation route
of exposure (the predominant route of exposure). In this risk
assessment the agency utilized data on female mice from an inhalation
study of 1,3-butadiene to calculate a unit cancer risk of 1.4
(milligrams per kilograms (kg) body weight per day)-1 for
1,3-butadiene (Ref. 4).
1,3-Butadiene was not detected in the product. However, based on
the limit of detection, FDA has estimated the exposure to 1,3-butadiene
from the petitioned use of the subject additive would not exceed 0.63
parts per trillion in the daily diet (3 kg), or 1.9 nanograms per
person per day (Refs. 5 and 6). Based on this estimate and the
assumption that 1,3-butadiene would induce tumors with the same potency
in an oral study as it did in the mouse inhalation study, FDA estimates
that the upper-bound limit of lifetime human risk from butadiene
exposure as a result of the petitioned used of the subject additive
would be 4.4 x 10-8 (Ref. 4). Because of the numerous
conservative assumptions used in calculating the exposure estimate, the
actual lifetime-averaged individual exposure to 1,3-butadiene is likely
to be substantially less than the estimated exposure, and therefore,
the probable lifetime human risk would be less than the upper-bound
limit of lifetime human risk. Thus, the agency concludes that there is
reasonable certainty that no harm from exposure to 1,3-butadiene would
result from the petitioned use of the additive.
C. Need for Specifications
The agency also has considered whether specifications are necessary
to control the amount of 1,3-butadiene present as an impurity in the
food additive. The agency finds that specifications are not necessary
for the following reasons: (1) The agency would not expect 1,3-
butadiene to become a component of food at other than extremely low
levels because of its volatility and the low levels at which 1,3-
butadiene (below detection limit) may be expected to remain as an
impurity following production and purification of the additive and (2)
the upper-bound limit of lifetime human risk from exposure to 1,3-
butadiene is very low, 4.4 x 10-8.
III. Conclusion
FDA has evaluated data in the petition and other relevant material.
Based on this information, the agency concludes that the proposed use
of the additive produced by the new manufacturing process is safe, and,
therefore, the regulations in Sec. 172.864 should be amended as set
forth in this document.
In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), the petition
and the documents that FDA considered and relied upon in reaching its
decision to approve the petition are available for inspection at the
Center for Food Safety and Applied Nutrition by appointment with the
information contact person (see FOR FURTHER INFORMATION CONTACT). As
provided in Sec. 171.1(h), the agency will delete from the documents
any materials that are not available for public disclosure before
making the documents available for inspection.
[[Page 72908]]
IV. Environmental Impact
The agency has carefully considered the potential environmental
effects of this final rule. FDA has concluded that the action will not
have a significant impact on the human environment, and that an
environmental impact statement is not required. The agency's finding of
no significant impact and the evidence supporting that finding,
contained in an environmental assessment, may be seen in the Division
of Dockets Management (see ADDRESSES) between 9 a.m. and 4 p.m., Monday
through Friday.
V. Paperwork Reduction Act of 1995
This final rule contains no collection of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
VI. Objections
Any person who will be adversely affected by this regulation may
file with the Division of Dockets Management (see ADDRESSES) written or
electronic objections. Each objection shall be separately numbered, and
each numbered objection shall specify with particularity the provisions
of the regulation to which objection is made and the grounds for the
objection. Each numbered objection on which a hearing is requested
shall specifically so state. Failure to request a hearing for any
particular objection shall constitute a waiver of the right to a
hearing on that objection. Each numbered objection for which a hearing
is requested shall include a detailed description and analysis of the
specific factual information intended to be presented in support of the
objection in the event that a hearing is held. Failure to include such
a description and analysis for any particular objection shall
constitute a waiver of the right to a hearing on the objection. Three
copies of all documents are to be submitted and are to be identified
with the docket number found in brackets in the heading of this
document. Any objections received in response to the regulation may be
seen in the Division of Dockets Management between 9 a.m. and 4 p.m.,
Monday through Friday.
VII. References
The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. ``Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS
No. 106-99-0) in B6C3F1 Mice (Inhalation Studies),'' National
Toxicology Program, Technical Report Series, No. 434.
2. Owen, P.E. et al., ``Inhalation Toxicity Studies with 1,3-
Butadiene. 3 Two Year Toxicity/Carcinogenicity Studies in Rats,''
American Industrial Hygiene Association Journal, 48: 407-413, 1987.
3. Owen, P.E. and J.R. Glaister, ``Inhalation Toxicity and
Carcinogenicity Study of 1,3-Butadiene in Sprague-Dawley Rats,''
Environmental Health Perspectives, 86: 19-25, 1990.
4. Memorandum dated February 23, 2001, from the Division of
Product Policy, Scientific Support Branch to the Division of Product
Policy, Regulatory Policy Branch, ``Food Additive Petition 4A4419--
Kuraray America Inc. (formerly Kuraray International Corporation)/
Keller & Heckman. n-Octanol, a currently cleared synthetic fatty
alcohol produced by a new manufacturing process, for use as an
ingredient in food. Submissions dated 4-7-1994 and 4-12-1994.''
5. Memorandum dated May 3, 1994, from the Chemistry Review
Branch to the Indirect Additives Branch, ``FAP 4A4419 (MATS
763, M2.1.1)--Kuraray International Corporation. Submission
dated 4-7-94. Request of 4-20-94 from Indirect Additives Branch:
Estimated exposure to 1,3-butadiene from the use of synthetic n-
octanol.''
6. Memorandum dated July 26, 1994, from the Chemistry Review
Branch to the Indirect Additives Branch, ``FAP 4A4419 (MATS
763, M2.1)--Kuraray International Corporation/Keller &
Heckman. Submissions dated 4-7-94 and 4-12-94. n-Octanol via a new
manufacturing process.''
List of Subjects in 21 CFR Part 172
Food additives, Incorporation by reference, Reporting and
recordkeeping requirements.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
172 is amended as follows:
PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR
HUMAN CONSUMPTION
0
1. The authority citation for 21 CFR part 172 continues to read as
follows:
Authority: 21 U.S.C. 321, 341, 342, 348, 371, 379e.
0
2. Section 172.864 is amended by adding paragraph (a)(3) to read as
follows:
Sec. 172.864 Synthetic fatty alcohols.
* * * * *
(a) * * *
(3) n-Octyl; manufactured by the hydrodimerization of 1,3-
butadiene, followed by catalytic hydrogenation of the resulting dienol,
and distillation to produce n-octyl alcohol with a minimum purity of 99
percent. The analytical method for n-octyl alcohol entitled ``Test
Method [Normal-octanol]'' dated October 2003, and printed by Kuraray
Co., Ltd., is incorporated by reference. The Director of the Office of
the Federal Register approves this incorporation by reference in
accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a
copy from the Office of Food Additive Safety, 5100 Paint Branch Pkwy.,
College Park, MD 20740, or you may examine a copy at the Center for
Food Safety and Applied Nutrition's Library, Food and Drug
Administration, 5100 Paint Branch Pkwy., College Park, MD 20740, or at
the National Archives and Records Administration (NARA). For
information on the availability of this material at NARA, call 202-741-
6030, or go to http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html
.
* * * * *
Dated: November 29, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-23745 Filed 12-7-05; 8:45 am]
BILLING CODE 4160-01-S