[Federal Register Volume 70, Number 235 (Thursday, December 8, 2005)]
[Rules and Regulations]
[Pages 72906-72908]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-23745]


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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