[Federal Register Volume 83, Number 110 (Thursday, June 7, 2018)]
[Rules and Regulations]
[Pages 26356-26359]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-12218]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 74

[Docket No. FDA-2017-C-0935]


Listing of Color Additives Subject to Certification; D&C Black 
No. 4

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or we) is amending the 
color additive regulations to provide for the safe use of D&C Black No. 
4 for coloring ultra-high molecular weight polyethylene (UHMWPE) non-
absorbable sutures for use in general surgery. This action is in 
response to a color additive petition (CAP) submitted by DSM 
Biomedical.

DATES: This rule is effective July 10, 2018. See section VIII for 
further information on the filing of objections. Submit either 
electronic or written objections and requests for a hearing on the 
final rule by July 9, 2018.

ADDRESSES: You may submit objections and requests for a hearing as 
follows. Please note that late, untimely filed objections will not be 
considered. Electronic objections must be submitted on or before July 
9, 2018. The https://www.regulations.gov electronic filing system will 
accept comments until midnight Eastern Time at the end of July 9, 2018. 
Objections received by mail/hand delivery/courier (for written/paper 
submissions) will be considered timely if they are postmarked or the 
delivery service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic objections in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Objections submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your objection will be 
made public, you are solely responsible for ensuring that your 
objection does not include any confidential information that you or a 
third party may not wish to be posted, such as medical information, 
your or anyone else's Social Security number, or confidential business 
information, such as a manufacturing process. Please note that if you 
include your name, contact information, or other information that 
identifies you in the body of your objection, that information will be 
posted on https://www.regulations.gov.
     If you want to submit an objection with confidential 
information that you do not wish to be made available to the public, 
submit the objection as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper objections submitted to the Dockets 
Management Staff, FDA will post your objection, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2017-C-0935 for ``Listing of Color Additives Subject to 
Certification; D&C Black No. 4.'' Received objections, those filed in a 
timely manner (see ADDRESSES), will be placed in the docket and, except 
for those submitted as ``Confidential Submissions,'' publicly viewable 
at https://www.regulations.gov or at the Dockets Management Staff 
between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit an objection with 
confidential information that you do not wish to be made publicly 
available, submit your objections only as a written/paper submission. 
You should submit two copies total. One copy will include the 
information you claim to be confidential with a heading or cover note 
that states ``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' We 
will review this copy, including the claimed confidential information, 
in our consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov 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 Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Joseph M. Thomas, Center for Food 
Safety and Applied Nutrition (HFS-265), Food and Drug Administration, 
5001 Campus Dr., College Park, MD 20740-3835, 301-796-9465.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In the Federal Register on March 6, 2017 (82 FR 12531), we 
announced that we filed a color additive petition (CAP 7C0310) 
submitted by DSM Biomedical (petitioner), 735 Pennsylvania Dr., Exton, 
PA 19341. The petition proposed to amend the color additive regulations 
in part 73 (21 CFR part 73), Listing of Color Additives Exempt from 
Certification, to provide for the safe use of high-purity carbon black 
for coloring UHMWPE non-absorbable sutures for use in general 
surgery.\1\ After the petition was filed and during our review, we 
determined that the color additive will require batch certification by 
FDA. We intend to give each certified batch of the subject color 
additive the name D&C Black No. 4. Therefore, this color additive will 
be identified as D&C Black No. 4 and will be listed in part 74 (21 CFR 
part 74), Listing of Color Additives Subject to Certification.
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    \1\ The original petition did not specify that the color 
additive is to be used in sutures that are non-absorbable. 
Therefore, our March 6, 2017, notice of filing did not specify that 
the color additive is intended for use in non-absorbable sutures. 
However, petitioner's subsequent submissions to FDA indicated that 
the intended use of the additive is for sutures that are non-
absorbable.
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II. Identity and Specifications

    D&C Black No. 4 is a high-purity carbon black prepared by the oil 
furnace process. It is manufactured by injecting

[[Page 26357]]

a heated aromatic petroleum feedstock into the combustion zone of a 
natural gas-fired furnace to produce carbon black. The reaction is 
quenched with water and the carbon particles are further cooled and 
separated by a filter. The recovered high-purity carbon black is dried 
and pelletized to produce the final D&C Black No. 4 commercial product, 
consisting of aggregated particles with a surface area ranging from 50 
to 260 meters squared per gram (m\2\/g). D&C Black No. 4 is 
mechanically mixed at a maximum level of 1 percent by weight with the 
UHMWPE suture raw materials to form a homogenous suspension, absent of 
chemical reaction between components, and extruded to form black 
colored sutures.
    As explained in section III, the color additive D&C Black No. 4 may 
contain low levels of potentially carcinogenic polycyclic aromatic 
hydrocarbon (PAH) contaminants. To limit the amounts of these 
contaminants in the color additive, FDA is setting specifications for 
total PAHs, as well as for the individual PAH species benzo[a]pyrene 
(B[a]P) and dibenz[a,h]anthracene. These specifications are consistent 
with specifications for other high-purity carbon blacks approved by 
FDA, including the color additive D&C Black No. 2 (Sec.  74.2052 (21 
CFR 74.2052)), which is approved for use in certain cosmetics, 
including cosmetics for use in the area of the eye (i.e., eyeliner, 
brush-on-brow, eye shadow, mascara), and high-purity furnace black, 
which is approved for use in food-contact polymers (Sec.  178.3297 (21 
CFR 178.3297)). These specifications are also supported by the safety 
information reviewed as a part of this petition (see section III). In 
addition, to ensure compliance with these specifications, FDA is 
requiring that D&C Black No. 4 for use in UHMWPE non-absorbable sutures 
be from a batch of the color additive certified by FDA.
    The identity for D&C Black No. 4 is the same as D&C Black No. 2, 
except for the surface area. For D&C Black No. 2, we set specifications 
for arsenic, lead, and mercury, total color (as carbon), total sulfur, 
ash content, surface area, and weight loss on heating, in addition to 
the specifications for total PAHs, benzo[a]pyrene (B[a]P), and 
dibenz[a,h]anthracene. We are setting the same specifications that were 
established for D&C Black No. 2 for D&C Black No. 4 for these 
parameters with the exception of surface area specification, which is 
broader for D&C Black No. 4.

III. Safety Evaluation

A. Determination of Safety

    Under section 721(b)(4) of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) (21 U.S.C. 379e(b)(4)), a color additive cannot be listed 
for a particular use unless a fair evaluation of the data and 
information available to FDA establish that the color additive is safe 
under the intended conditions of use. Furthermore, under 21 CFR 
70.5(c), a color additive intended for use in a surgical suture must 
have a listing specifically providing for this use. FDA's color 
additive regulations in 21 CFR 70.3(i) define ``safe'' to mean that 
there is convincing evidence that establishes with reasonable certainty 
that no harm will result from the intended use of the color additive.
    Section 721(b)(5)(B)(ii) of the FD&C Act provides that for any use 
of a color additive that will not result in ingestion of any part of 
such additive, the color additive shall be deemed to be unsafe and 
shall not be listed if, after tests that 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 to 
induce cancer in man or animal. Importantly, however, section 
721(b)(5)(B) of the FD&C Act applies to the additive itself and not to 
impurities in the additive. That is, where an additive itself has not 
been shown to cause cancer, but contains a carcinogenic impurity, the 
additive is properly evaluated under the general safety standard using 
risk assessment procedures to determine whether there is a reasonable 
certainty that no harm will result from the intended use of the 
additive (Scott v. FDA, 728 F.2d 322 (6th Cir. 1984)).

B. Safety of the Petitioned Use of D&C Black No. 4

    In evaluating the safety of a color 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. To establish with reasonable certainty that 
D&C Black No. 4 intended to color UHMWPE non-absorbable sutures is not 
harmful under the intended conditions of use, we have considered the 
exposure to the color additive and its impurities, the additive's 
toxicological data, and other relevant information (such as published 
literature) available to us.
    The petitioner incorporated safety information that was previously 
submitted to FDA on behalf of Cabot Corp. in Food Additive Petition 
5B4464 by reference to support the safety of high-purity furnace black 
as a colorant for polymers in food-contact applications. D&C Black No. 
4 is manufactured in the same manner as the referenced high-purity 
furnace black.
    The petitioner also submitted data from an extraction study testing 
the migration of D&C Black No. 4 from UHMWPE sutures and provided data 
from two studies demonstrating biocompatibility of UHMWPE sutures along 
with other information. The petitioner's data from the extraction study 
indicated that D&C Black No. 4, when added to UHMWPE non-absorbable 
sutures at the maximum level of 1 percent, remains physically embedded 
in the suture matrix resulting in the color additive not being detected 
in the extracts at the limit of quantitation. This study evaluated the 
amount of non-volatile residue (NVR) and any extractables that could 
migrate from the suture. The study was performed with water, hexane, 
and ethanol at 50 [deg]C for 24 hours and demonstrated that D&C Black 
No. 4 does not migrate from the suture following exposure to solvents 
with varying polarities and exposure to heat. The study also yielded 
NVRs not able to be analyzed. To estimate potential exposure from D&C 
Black No. 4, the petitioner used data from the extraction study and the 
conservative assumption that all of the NVR that was extracted and not 
able to be analyzed was D&C Black No. 4. The petitioner derived an 
estimate for the mass amount of D&C Black No. 4 expected to migrate 
over a lifetime, expressed as the mean daily exposure, based on its 
proposed use level in surgical sutures, and using data for the maximum 
NVR extracted and the surface area of the tested sutures.
    While FDA agrees with using the conservative assumption that all 
NVR extracted was D&C Black No. 4, the petitioner's exposure estimate 
represents the scenario where D&C Black No. 4 would migrate from the 
sutures 1 day post-implantation. However, since non-absorbable sutures 
are intended to be left in the body indefinitely post-implantation, it 
is necessary to average the petitioner's exposure estimate over an 
individual's lifetime post-implantation (assumed to be 70 years) to 
estimate the lifetime average exposure to D&C Black No. 4. In this 
manner, we estimated the lifetime average exposure to D&C Black No. 4 
to

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be 15.3 nanograms per person per day (ng/p/d). However, as carbon black 
is known to be thermally stable, inert, and insoluble in water and 
common solvents, we agree with the petitioner's conclusion that D&C 
Black No. 4 is firmly embedded and does not migrate from the suture 
matrix, resulting in no potential exposure to D&C Black No. 4 from 
sutures that are in contact with the body (Ref. 1).
    As discussed in section II, D&C Black No. 4 has been shown to 
contain low levels of PAH impurities, some of which are carcinogenic. 
We have previously considered the safe use of high-purity carbon black 
as a color additive in cosmetics (D&C Black No. 2; Sec.  74.2052) and 
as a colorant in food-contact polymers (high-purity furnace black; 
Sec.  178.3297) and set limits for PAHs in these high-purity carbon 
blacks to minimize exposure. We are setting similar limits for PAHs in 
D&C Black No. 4 as those established for D&C Black No. 2: Total PAHs 
(not more than 0.5 milligrams per kilogram (mg/kg) (500 parts per 
billion)); B[a]P (not more than 0.005 mg/kg (5 parts per billion)); and 
dibenz[a,h]anthracene (not more than 0.005 mg/kg (5 parts per 
billion)).
    There were no detectable PAHs at the limit of quantitation 
resulting from the petitioner's extraction study. The petitioner stated 
that the trace levels of PAHs in the color additive, as limited by 
specifications, are strongly bound to the surface of D&C Black No. 4 
carbon particles due to the powerful adsorption capabilities of the 
color additive. FDA concurs that any PAH impurities are not expected to 
migrate under the proposed specifications and conditions of use (Ref. 
1). In calculating the lifetime average exposure to PAHs from the use 
of D&C Black No. 4 in sutures, we used the conservative assumption that 
total PAHs, B[a]P, and dibenz[a,h]anthracene are present in the color 
additive at their specification limits. These assumptions, along with 
the assumption that all NVR extracted from the sutures is D&C Black No. 
4, calculated over a 70-year lifespan, results in a conservative 
estimated lifetime average exposure of total PAHs of 7.7 x 
10-\6\ ng/p/d, B[a]P of 7.7 x 10-\8\ ng/p/d, and 
dibenz[a,h]anthracene of 7.7 x 10-\8\ ng/p/d (Ref. 1).
    Current data have shown B[a]P to be a high contributor to the total 
carcinogenic potential for the PAH family (Ref. 2). To assess the risk 
from exposure to PAHs, FDA has used a worst-case assumption that all 
PAHs are present in D&C Black No. 4 as B[a]P. We used data from a 
carcinogenesis bioassay on B[a]P, conducted by H. Brune, et al., to 
estimate the upper-bound limit of lifetime human risk from exposure to 
B[a]P equivalents resulting from the petitioned use of the color 
additive (Ref. 3). The authors reported treatment-related benign 
forestomach tumors or esophageal tumors in male rats exposed to B[a]P. 
Using a linear-at-low-dose extrapolation method and tumor incidence 
data from the H. Brune, et al. study, we estimated the unit cancer risk 
(UCR) for B[a]P to be 1.75 (milligrams per kilogram bodyweight per day 
(mg/kg bw/day))-\1\ (Ref. 4). The UCR represents the derived 
cancer risk calculated per unit dose of the additive. This same UCR was 
used to assess the risk from exposure to PAHs for D&C Black No. 2 (69 
FR 44927, July 28, 2004) and high-purity furnace black (Ref. 5). The 
lifetime cancer risk (LCR) was calculated by multiplying the UCR for 
B[a]P by the estimated lifetime average exposures. This results in LCRs 
of 2.24 x 10-\15\ and 2.24 x 10-\13\ for B[a]P 
and total PAHs, respectively. Because of the conservative assumptions 
we used to calculate the exposure estimate and the carcinogenic potency 
of PAHs in the color additive, and the fact that PAHs bind tightly to 
carbon black and are not expected to migrate, the lifetime-averaged 
individual exposure to PAHs is likely to be substantially less than our 
worst-case exposure estimate. Thus, the probable lifetime human risk 
would be less than the estimated LCR. Therefore, we conclude that there 
is reasonable certainty that no harm from exposure to PAHs will result 
from the petitioned use of the additive (Refs. 1 and 3).

IV. Conclusion

    Based on the data and information in the petition and other 
available relevant material, FDA concludes that the petitioned use of 
D&C Black No. 4 for coloring UHMWPE non-absorbable sutures for use in 
general surgery is safe. We further conclude that the additive will 
achieve its intended technical effect and is suitable for the 
petitioned uses. Based on the available information, we are amending 
the color additive regulations in part 74 as set forth in this 
document. In addition, in accordance with 21 CFR 71.20(b), we conclude 
that batch certification of D&C Black No. 4 is necessary for the 
protection of public health because of the need to limit the levels of 
PAHs, some of which have been shown to be carcinogenic. Therefore, part 
74 should be amended as set forth in this document.

V. Public Disclosure

    In accordance with Sec.  [thinsp]71.15 (21 CFR 71.15), the petition 
and the documents that we considered and relied upon in reaching our 
decision to approve the petition will be made available for public 
disclosure (see FOR FURTHER INFORMATION CONTACT). As provided in Sec.  
[thinsp]71.15, we will delete from the documents any materials that are 
not available for public disclosure.

VI. Analysis of Environmental Impact

    We previously considered the environmental effects of this rule, as 
stated in the notice of petition published in the Federal Register of 
March 6, 2017. We stated that we had determined, under 21 CFR 25.32(l), 
that this action ``is of a type that does not individually or 
cumulatively have a significant effect on the human environment'' such 
that neither an environmental assessment nor an environmental impact 
statement is required. We have not received any new information or 
comments that would affect our previous determination.

VII. 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.

VIII. Objections

    This rule is effective as shown in the DATES section, except as to 
any provisions that may be stayed by the filing of proper objections. 
If you will be adversely affected by one or more provisions of this 
regulation, you may file with the Dockets Management Staff (see 
ADDRESSES) either electronic or written objections. You must separately 
number each objection, and within each numbered objection you must 
specify with particularity the provision(s) to which you object, and 
the grounds for your objection. Within each numbered objection, you 
must specifically state whether you are requesting a hearing on the 
particular provision that you specify in that numbered objection. If 
you do not request a hearing for any particular objection, you waive 
the right to a hearing on that objection. If you request a hearing, 
your objection must include a detailed description and analysis of the 
specific factual information you intend to present in support of the 
objection in the event that a hearing is held. If you do not include 
such a description and analysis for any particular objection, you waive 
the right to a hearing on the objection.
    Any objections received in response to the regulation may be seen 
in the Dockets Management Staff between 9 a.m. and 4 p.m., Monday 
through Friday, and will be posted to the docket at https://www.regulations.gov. We will publish notice of the objections that we

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have received or lack thereof in the Federal Register.

IX. References

    The following references are on display with the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they also are 
available electronically at https://www.regulations.gov. References 
that are published articles and books are not on display.

1. Memorandum from H. Lee, Division of Petition Review, Office of 
Food Additive Safety (OFAS), CFSAN, FDA to J. Thomas, Division of 
Petition Review, OFAS, CFSAN, FDA, dated April 27, 2018.
2. Choi H, R. Harrison, H. Komulainen, et al., ``Polycyclic Aromatic 
Hydrocarbons.'' WHO Guidelines for Indoor Air Quality: Selected 
Pollutants. Geneva: World Health Organization; 2010.
3. Brune H., R. P. Deutsch-Wenzel, M. Habs, et al., ``Investigation 
of the Tumorigenic Response to Benzo(a)pyrene in Aqueous Caffeine 
Solution Applied Orally to Sprague-Dawley Rats,'' Journal of Cancer 
Research and Clinical Oncology, 102(2):153-157, 1981.
4. Memorandum from N. Anyangwe, Division of Petition Review, OFAS, 
CFSAN, FDA to J. Thomas, Division of Petition Review, OFAS, CFSAN, 
FDA, dated April 27, 2018.
5. Memorandum from the Indirect Additives Branch, FDA, to the 
Executive Secretary, Quantitative Risk Assessment Committee, FDA, 
concerning ``Estimation of the Upper-bound Lifetime Risk from 
Polynuclear Aromatic Hydrocarbons (PAH's) in High-Purity Furnace 
Black (HPFB): subject of Food Additive Petition No. 5B4464 (Cabot 
Corp.),'' dated May 9, 1996.

List of Subjects in 21 CFR Part 74

    Color additives, Cosmetics, Drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
74 is amended as follows:

PART 74--LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION

0
1. The authority citation for part 74 continues to read as follows:

    Authority: 21 U.S.C. 321, 341, 342, 343, 348, 351, 352, 355, 
361, 362, 371, 379e.


0
2. Section 74.3054 is added to subpart D to read as follows:


Sec.  74.3054  D&C Black No. 4.

    (a) Identity. The color additive D&C Black No. 4 is a high-purity 
carbon black prepared by the oil furnace process. It is manufactured by 
the combustion of aromatic petroleum oil feedstock and consists 
essentially of pure carbon, formed as aggregated fine particles with a 
surface area range of 50 to 260 meters (m)\2\/gram.
    (b) Specifications. D&C Black No. 4 must conform to the following 
specifications and must be free from impurities other than those named 
to the extent that such other impurities may be avoided by good 
manufacturing practice:
    (1) Surface area by nitrogen BET (Brunauer, Emmett, Teller) method, 
50 to 260 m\2\/gram.
    (2) Weight loss on heating at 950 [deg]C for 7 minutes (predried 
for 1 hour at 125 [deg]C), not more than 2 percent.
    (3) Ash content, not more than 0.15 percent.
    (4) Arsenic (total), not more than 3 milligrams per kilogram (mg/
kg) (3 parts per million).
    (5) Lead (total), not more than 10 mg/kg (10 parts per million).
    (6) Mercury (total), not more than 1 mg/kg (1 part per million).
    (7) Total sulfur, not more than 0.65 percent.
    (8) Total polycyclic aromatic hydrocarbons (PAHs), not more than 
0.5 mg/kg (500 parts per billion).
    (9) Benzo[a]pyrene, not more than 0.005 mg/kg (5 parts per 
billion).
    (10) Dibenz[a,h]anthracene, not more than 0.005 mg/kg (5 parts per 
billion).
    (11) Total color (as carbon), not less than 95 percent.
    (c) Uses and restrictions. (1) D&C Black No. 4 may be safely used 
at a level not to exceed 1.0 percent by weight of the suture material 
for coloring ultra-high molecular weight polyethylene non-absorbable 
sutures for general surgical use.
    (2) Authorization and compliance with this use must not be 
construed as waiving any of the requirements of sections 510(k), 515, 
and 520(g) of the Federal Food, Drug, and Cosmetic Act with respect to 
the ultra-high molecular weight polyethylene surgical sutures in which 
D&C Black No. 4 is used.
    (d) Labeling. The label of the color additive must conform to the 
requirements of Sec.  70.25 of this chapter.
    (e) Certification. All batches of D&C Black No. 4 must be certified 
in accordance with regulations in part 80 of this chapter.

    Dated: June 1, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-12218 Filed 6-6-18; 8:45 am]
BILLING CODE 4164-01-P


