[Federal Register Volume 86, Number 193 (Friday, October 8, 2021)]
[Rules and Regulations]
[Pages 56183-56195]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-21892]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 73

[Docket No. FDA-2017-C-1951]


Termination of Listing of Color Additives Exempt From 
Certification; Lead Acetate

AGENCY: Food and Drug Administration, HHS.

[[Page 56184]]


ACTION: Final rule; response to objections and denial of public hearing 
requests; removal of administrative stay.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or we) is responding to 
objections and a public hearing request that we received from Combe 
Inc., on the final rule entitled ``Termination of Listing of Color 
Additives Exempt From Certification; Lead Acetate,'' which published on 
October 31, 2018. The final rule amended the color additive regulations 
to no longer provide for the safe use of lead acetate in cosmetics 
intended for coloring hair on the scalp. After reviewing the 
objections, we have concluded that the objections do not raise issues 
of material fact that justify a hearing. Therefore, the stay of the 
effectiveness for the repeal and delisting of the color additive 
regulation is now lifted, and we are amending the color additive 
regulations to no longer provide for the safe use of lead acetate in 
cosmetics intended for coloring hair on the scalp.

DATES: This rule is effective January 6, 2022.

ADDRESSES: For access to the docket to read background documents or 
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, 
240-402-7500.

FOR FURTHER INFORMATION CONTACT: Shayla West-Barnette, Center for Food 
Safety and Applied Nutrition, Food and Drug Administration, 5001 Campus 
Dr., College Park, MD 20740-3835, 240-402-1262.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of October 31, 2018 (83 FR 54665), we 
issued a final rule repealing the color additive regulation in Sec.  
73.2396 (21 CFR 73.2396) to no longer provide for the safe use of lead 
acetate in cosmetics intended for coloring hair on the scalp because 
new data available since lead acetate was permanently listed have 
demonstrated that there is no longer a reasonable certainty that no 
harm will result from the use of this color additive. We gave 
interested persons until November 30, 2018, to file objections and 
requests for a hearing on the final rule. The preamble to the final 
rule stated that the effective date of the final rule would be on 
December 3, 2018, except as to any provisions that may be stayed by the 
filing of proper objections (83 FR 54665 at 54673). On December 3, 
2018, Sec.  73.2396 was removed from the CFR. However, we had received 
objections and requests for a hearing on the objections from Combe Inc. 
(Combe), a manufacturer of hair dyes containing lead acetate. Under 
sections 701(e)(2) and 721(d) of the FD&C Act (21 U.S.C. 371(e)(2) and 
379e(d)), the filing of objections operates to stay the effectiveness 
of our repeal until we take final action on the objections.
    To implement a stay of effectiveness as required by sections 
701(e)(2) and 721(d) of the FD&C Act, we published a final rule in the 
Federal Register of April 1, 2019 (84 FR 12081), reinstating Sec.  
73.2396 pending final FDA action on the objections to the October 31, 
2018, final rule. We also stated that this action did not reflect any 
change in our determination that new data demonstrate that there is no 
longer a reasonable certainty of no harm from the use of this color 
additive.
    FDA listed lead acetate in Sec.  73.2396 in 1980 as a color 
additive for safe use in cosmetics intended for coloring hair on the 
scalp, subject to certain restrictions and labeling requirements, at 
levels up to 0.6 percent (weight to volume; equivalent to 6,000 parts 
per million (ppm)) lead in the cosmetic product (45 FR 72112). Lead 
acetate is used in progressive hair dyes that, when applied to gray 
hair, gradually change the color with repeated applications.\1\
---------------------------------------------------------------------------

    \1\ For example, as indicated in a lead acetate-containing 
progressive hair dye product manufacturer's use direction (Ref. 10), 
after the initial application, users might apply the progressive 
hair dye daily until the desired color shade is achieved, and once 
or twice per week to maintain the hair color thereafter.
---------------------------------------------------------------------------

II. Objections and Requests for a Hearing

    Sections 701(e)(2) and 721(d) of the Federal Food, Drug, and 
Cosmetic Act (FD&C Act) collectively provide that, within 30 days after 
publication of an order relating to a color additive regulation, any 
person adversely affected by such an order may file objections, 
specifying with particularity the provisions of the order deemed 
objectionable, stating the grounds therefor, and requesting a public 
hearing upon such objections. We may deny a hearing request if the 
objections to the regulation do not raise genuine and substantial 
issues of fact that can be resolved at a hearing (Sec.  12.24(b)(1) (21 
CFR 12.24(b)(1)). (See also Community Nutrition Institute v. Young, 773 
F.2d 1356, 1364 (D.C. Cir. 1985).)
    Objections and requests for a hearing are governed by 21 CFR part 
12 of our regulations. Under 21 CFR 12.22(a), each objection must meet 
the following conditions: (1) Must be submitted on or before the 30th 
day after the date of publication of the final rule; (2) must be 
separately numbered; (3) must specify with particularity the provision 
of the regulation or proposed order objected to; (4) must specifically 
state the provision of the regulation or proposed order on which a 
hearing is requested (failure to request a hearing on an objection 
constitutes a waiver of the right to a hearing on that objection); and 
(5) must include a detailed description and analysis of the factual 
information to be presented in support of the objection if a hearing is 
requested (failure to include a description and analysis for an 
objection constitutes a waiver of the right to a hearing on that 
objection).
    Following publication of the final rule repealing the regulation in 
Sec.  73.2396 to no longer provide for the safe use of lead acetate in 
cosmetics intended for coloring hair on the scalp, we received a 
submission from Combe, a manufacturer of hair dyes containing lead 
acetate, providing 19 objections and requesting a hearing on each of 
the objections. Combe provided the following numbered objections:

    Objection 1: Combe objects to FDA's finding that there is no 
safe level of exposure for lead.
    Objection 2: Combe objects to FDA's reliance on information 
about lead exposure in children (e.g., recommendations from the 
Centers for Disease Control and Prevention (CDC)).
    Objection 3: Combe objects to FDA's reliance on sources that 
discuss blood level of lead, not exposure levels (see, e.g., 
National Toxicology Program (NTP) monograph).
    Objection 4: Combe objects to the conclusions FDA draws from the 
Joint Food and Agriculture Organization/World Health Organization 
(FAO/WHO) Expert Committee on Food Additives (JECFA) (2011).
    Objection 5: Combe objects to FDA's reliance on the 
Environmental Protection Agency's (EPA's) goals for lead in drinking 
water.
    Objection 6: Combe objects to FDA's conclusion that the 1980 
Moore et al. study (Ref. 1, the Moore study) underestimated the 
exposure of lead.
    Objection 7: Combe objects to FDA's criticisms of Moore.
    Objection 8: Combe objects to FDA's finding that the lead in the 
Moore study could have been absorbed by other parts of the body than 
the blood.
    Objection 9: Combe objects to FDA's reliance on a novel and 
unvalidated computer model.
    Objection 10: Combe objects to FDA's treating an unvalidated 
computer model as more reliable than robust human data.

[[Page 56185]]

    Objection 11: Combe objects to FDA's argument that the 
absorption percentage from the Moore study is invalid because it 
tested only a small patch of skin.
    Objection 12: Combe objects to FDA's reliance on a 
``permeability coefficient'' for lead instead of fractional 
absorption.
    Objection 13: Combe objects to FDA's use of a permeability 
coefficient for lead acetate that EPA repudiated and replaced with a 
much lower estimate.
    Objection 14: Combe objects to FDA's conclusion that lower 
median lead levels in blood since 1990 means that any lead 
contributed by lead acetate is less safe now.
    Objection 15: Combe objects to FDA's entire analysis because it 
is missing two critical links--FDA never relates exposure from lead 
acetate to any change in blood levels, and thus it never relates it 
to any predicted harm.
    Objection 16: Combe objects to FDA's whole argument as FDA never 
links exposure to lead from lead acetate to a change in steady-state 
blood levels.
    Objection 17: Combe objects to FDA's conclusion about the effect 
of lead acetate on blood lead levels.
    Objection 18: Combe objects to FDA taking a zero-tolerance 
approach for lead.
    Objection 19: Combe objects to FDA's failure to consider 
reducing the permitted lead acetate level under Sec.  73.2396 from 
0.6 percent to 0.153 percent.

    See Submission from Anthony M. Santini, Senior Vice President and 
General Counsel, Combe Inc., Peter Barton Hutt, Matthew J. Hegreness, 
and Richard F. Kingham, Covington & Burling LLP (Counsel for Combe 
Incorporated), to the Dockets Management Staff, FDA, dated November 30, 
2018, at pages 25-58, available at: https://www.regulations.gov/document/FDA-2017-C-1951-0233 (referred to as the Submission).

III. Standards for Granting a Hearing

    Specific criteria for deciding whether to grant or deny a request 
for a hearing are set out in Sec.  12.24(b). Under that regulation, a 
hearing will be granted if the material submitted by the requester 
shows, among other things, that: (1) There is a genuine and substantial 
factual issue for resolution at a hearing (a hearing will not be 
granted on issues of policy or law); (2) the factual issue can be 
resolved by available and specifically identified reliable evidence (a 
hearing will not be granted on the basis of mere allegations or denials 
or general descriptions of positions and contentions); (3) the data and 
information submitted, if established at a hearing, would be adequate 
to justify resolution of the factual issue in the way sought by the 
requester (a hearing will be denied if the data and information 
submitted are insufficient to justify the factual determination urged, 
even if accurate); (4) resolution of the factual issue in the way 
sought by the person is adequate to justify the action requested (a 
hearing will not be granted on factual issues that are not 
determinative with respect to the action requested, e.g., if the action 
would be the same even if the factual issue were resolved in the way 
sought); (5) the action requested is not inconsistent with any 
provision in the FD&C Act or any regulation particularizing statutory 
standards (the proper procedure in those circumstances is for the 
person requesting the hearing to petition for an amendment or waiver of 
the regulation involved); and (6) the requirements in other applicable 
regulations, e.g., 21 CFR 10.20, 12.21, 12.22, 314.200, 514.200, and 
601.7(a), and in the notice issuing the final regulation or the notice 
of opportunity for a hearing are met.
    A party seeking a hearing must meet a ``threshold burden of 
tendering evidence suggesting the need for a hearing'' (Costle v. 
Pacific Legal Foundation, 445 U.S. 198, 214-215 (1980), citing 
Weinberger v. Hynson, Westcott & Dunning, Inc, 412 U.S. 609, 620-621 
(1973)). An allegation that a hearing is necessary to ``sharpen the 
issues'' or to ``fully develop the facts'' does not meet this test 
(Georgia Pacific Corp. v. EPA, 671 F.2d 1235, 1241 (9th Cir. 1982)). If 
a hearing request fails to identify any factual evidence that would be 
the subject of a hearing, there is no point in holding one. In judicial 
proceedings, a court is authorized to issue summary judgment without an 
evidentiary hearing whenever it finds that there are no genuine issues 
of material fact in dispute, and a party is entitled to judgement as a 
matter of law (see Rule 56, Federal Rules of Civil Procedure). The same 
principle applies to administrative proceedings (see 21 CFR 12.28).
    A hearing request must not only contain evidence, but that evidence 
should raise a material issue of fact ``concerning which a meaningful 
hearing might be held'' (Pineapple Growers Ass'n v. FDA, 673 F.2d 1083, 
1085 (9th Cir. 1982)). Where the issues raised in the objection are, 
even if true, legally insufficient to alter the decision, an Agency 
need not grant a hearing (see Dyestuffs and Chemicals, Inc. v. 
Flemming, 271 F.2d 281, 286 (8th Cir. 1959)). A hearing is justified 
only if the objections are made in good faith and if they ``draw in 
question in a material way the underpinnings of the regulation at 
issue'' (Pactra Industries v. CPSC, 555 F.2d 677, 684 (9th Cir. 1977)). 
A hearing need not be held to resolve questions of law and policy (see 
Citizens for Allegan County, Inc. v. FPC, 414 F.2d 1125, 1128 (D.C. 
Cir. 1969); Sun Oil Co. v. FPC, 256 F.2d 233, 240 (5th Cir. 1958)).
    Even if the objections raise material issues of fact, we need not 
grant a hearing if those same issues were adequately raised and 
considered in an earlier proceeding. Once an issue has been so raised 
and considered, a party is estopped from raising that same issue in a 
later proceeding without new evidence. The various judicial doctrines 
dealing with finality, such as collateral estoppel, can be validly 
applied to the administrative process (see Pacific Seafarers, Inc. v. 
Pac. Far East Line, Inc., 404 F.2d 804, 809 (D.C. Cir. 1968), cert. 
denied, 393 U.S. 1093 (1969)). In explaining why these principles ought 
to apply to an Agency proceeding, the U.S. Court of Appeals for the 
District of Columbia Circuit wrote: ``The underlying concept is as 
simple as this: justice requires that a party have a fair chance to 
present his position. But overall interests of administration do not 
require or generally contemplate that he will be given more than a fair 
opportunity'' (Retail Clerks Union, Local 1401 v. NLRB, 463 F.2d 316, 
322 (D.C. Cir. 1972); see also Costle v. Pacific Legal Foundation, 445 
U.S. 198 at 215-17).

IV. Analysis of Objections and Response to Hearing Requests

    The submission from Combe contains 19 numbered objections, and 
Combe requests a hearing on each of them. We address each objection 
below, as well as the evidence and information filed in support of 
each, comparing each objection and the information submitted in support 
of it to the standards for granting a hearing in Sec.  12.24(b). For 
purposes of clarity, we have grouped the numbered objections into 
categories of related subjects while maintaining the objection numbers 
assigned by Combe.

A. Category A: No Known Safe Level of Lead Exposure

    Combe's numbered objections included in Category A are as follows:

    1. Combe objects to FDA's finding that there is no safe level of 
exposure for lead.
    2. Combe objects to FDA's reliance on information about lead 
exposure in children (e.g., recommendations from the CDC).
    4. Combe objects to the conclusions FDA draws from JECFA (2011).
    5. Combe objects to FDA's reliance on EPA's goals for lead in 
drinking water.
    18. Combe objects to FDA taking a zero-tolerance approach to 
lead.

    Objection 1. Combe objects to ``FDA's finding that there is no safe 
level of exposure for lead.'' The objection asserts that, ``. . . the 
weight of the scientific evidence demonstrates that low levels of

[[Page 56186]]

lead are safe, especially for the population that uses hair dye 
containing lead acetate--older men with graying hair.'' See Submission, 
page 26.
    (Response to Objection 1) Our determination that a color additive 
is safe means that there is convincing evidence that establishes with 
reasonable certainty that no harm will result from the intended use of 
the color additive (Sec.  70.3(i)). The regulation in Sec.  73.2396 
permits the use of lead acetate (calculated as lead) at levels not to 
exceed 0.6 percent (6,000 parts per million (ppm; milligrams/kilograms 
(mg/kg))) as a color additive in cosmetics intended for coloring hair 
on the scalp. Combe did not provide scientific data to support its 
objection or to demonstrate that there is a level of exposure to lead 
that could be considered safe.
    Following our full evaluation of data submitted in color additive 
petition (CAP) 7C0309 requesting repeal of Sec.  73.2396 and other 
pertinent data and information (see September 18, 2018, memorandum from 
M.K. Wyatt to M. Harry, ``the Wyatt Memorandum'' (Ref. 2)), we have 
determined that there is no known level of exposure to lead that does 
not produce adverse effects. While Combe states that ``. . . lead does 
not pose a danger to adults at low levels . . .,'' Combe failed to 
provide in this objection the specific levels at which lead does not 
pose a danger to adults and any corresponding scientific evidence to 
support this statement. See Submission, page 27.
    The objection failed to include new data or information that would 
refute our findings about the lack of a safe level of lead exposure. 
The objection merely alleges that low levels of lead are safe, without 
providing any scientific basis. A hearing will not be granted on the 
basis of mere allegations or general descriptions of positions and 
contentions (Sec.  12.24(b)(2)). The objector must, at a minimum, raise 
a genuine and substantial issue of fact for resolution at a hearing. 
Therefore, we are denying the request for a hearing on this objection.
    Objection 2. Combe objects to ``FDA's reliance on information about 
lead exposure in children (e.g., recommendations from the CDC).'' In 
this objection, ``Combe does not dispute the fact that lead exposure 
can harm a developing child,'' but states that this fact has ``no 
bearing on the use of lead acetate in a progressive hair dye for older 
men.'' See Submission, page 27. Combe also asserts that ``lead poses no 
danger at low levels to older adults.'' See Submission, page 28.
    (Response to Objection 2) We acknowledge that Combe's products 
(i.e., lead acetate-containing progressive hair dyes) are intended for 
use by adults and not by children. Our decision to repeal the 
regulation is based on the evidence of lead-related adverse health 
effects reported at low levels of lead in adults, such as adverse 
cardiovascular and kidney effects, cognitive dysfunction, and adverse 
reproductive outcomes (Ref. 3), and the lack of evidence of a safe 
level of exposure for lead. Currently, available data and information 
do not support the safe use of lead acetate intentionally added to 
cosmetics for coloring hair on the scalp of any age group or gender. 
Therefore, the use of lead acetate as a color additive no longer meets 
the safety standard of ``reasonable certainty of no harm.''
    We also note that we did not rely on the toxicity information about 
lead exposure in children; rather, in the final rule, we referred to 
the CDC statement that there is no safe blood lead level in children to 
further demonstrate the risks of lead exposure and why there is a U.S. 
Government-wide effort to limit lead exposure to the public. We 
continue to work to limit consumers' exposure to lead in all FDA-
regulated products, including cosmetics.
    Combe failed to provide scientific data and information 
demonstrating that there is a safe level of lead exposure from the 
listed use of lead acetate as a color additive. A hearing will not be 
granted on the basis of mere allegations or general descriptions of 
positions and contentions (Sec.  12.24(b)(2)). The objector must, at a 
minimum, raise a genuine and substantial issue of fact for resolution 
at a hearing. Therefore, we are denying the request for a hearing on 
this objection.
    Objection 4. Combe objects to ``the conclusions FDA draws from 
JECFA (2011).'' See Submission, page 32. In this objection, Combe cites 
JECFA's conclusion that ``it could not establish a new provisional 
tolerable weekly intake (PTWI) that would be considered health 
protective,'' and that JECFA instead established a ``negligible risk'' 
level for food. See Submission, at page 32. Combe alleges that ``FDA 
did not analyze the underlying scientific discussion in JECFA (2011).'' 
See Submission, page 32.
    (Response to Objection 4) JECFA stated that ``because the dose-
response analyses do not provide any indication of a threshold for the 
key effects of lead, the Committee therefore concluded that ``it was 
not possible to establish a new PTWI that would be considered to be 
health protective'' (Ref. 4). Notably, JECFA's statement about 
``negligible risk'' was within the context of unavoidable lead exposure 
as an impurity in food, instead of intentionally added, avoidable 
exposures to lead in a cosmetic product. We are not aware of any 
statement by a competent, national regulatory authority or an 
international risk assessment body establishing a safe level of lead 
exposure that would support a determination that there is a reasonable 
certainty of no harm from the use of lead acetate as a color additive 
in hair dye. Instead, for example, the WHO has stated that ``[t]here is 
no level of exposure to lead that is known to be without harmful 
effects.'' (Ref. 5).
    Contrary to Combe's assertion, JECFA's statement establishing a 
negligible risk level for lead as an unavoidable food impurity does not 
provide a ``safe harbor'' for any intentionally added lead in a 
cosmetic product. See Submission, page 33. Also, JECFA's negligible 
risk level for food does not support Combe's claim that the intended 
use of lead acetate in hair dye meets the safety standard of 
``reasonable certainty of no harm'' set forth at Sec.  70.3(i) (21 CFR 
70.3(i)) because as JEFCA states, currently available data do not 
provide any indication of a threshold for the reported adverse effects 
from exposure to lead (Ref. 4).
    The objection failed to include any new information or data that 
would change our findings about the lack of a safe exposure level of 
lead. The objection merely alleges that FDA did not analyze JECFA's 
conclusion and does not provide scientific information to support 
Combe's argument. A hearing will not be granted on the basis of mere 
allegations or general descriptions of positions and contentions (Sec.  
12.24(b)(2)). The objector must, at a minimum, raise a genuine and 
substantial issue of fact for resolution at a hearing. Therefore, we 
are denying the request for a hearing on this objection.
    Objection 5. Combe objects to ``FDA's reliance on EPA's goals for 
lead in drinking water.'' Combe states that the EPA goal in setting the 
maximum contaminant level for lead in drinking water at zero is based 
on the effect of lead in children. See Submission, page 33. Combe 
contends that EPA's goal for lead in drinking water ``in no way means, 
however, that lead is unsafe in a progressive hair dye for aging men 
with graying hair.'' Ibid.
    (Response to Objection 5) FDA did not rely on EPA's goal for lead 
in drinking water; we referred to it to further document the adverse 
effects resulting from lead exposure. Adverse effects to the public 
more generally

[[Page 56187]]

resulting from lead exposure are the reason why there is a government-
wide effort to limit lead exposure to the public. Our decision to 
repeal the regulation was based on the recognition that there is no 
scientific data demonstrating a safe level of exposure to lead and that 
the data currently available no longer demonstrate that there is 
reasonable certainty of no harm from the use of lead acetate as a color 
additive in hair dyes authorized under Sec.  73.2396. Combe fails to 
show that there is a genuine and substantial issue of fact for 
resolution at a hearing. A hearing will not be granted on the basis of 
mere allegations or general descriptions of positions and contentions 
(Sec.  12.24(b)(2)). Therefore, we are denying the request for a 
hearing on this objection.
    Objection 18. Combe objects to ``FDA taking a zero-tolerance 
approach to lead.'' Combe argues that ``FDA appears to draw a legal 
distinction between lead that is intentionally added and lead that is 
present as impurities. Although such a distinction can be legally drawn 
for food, FDA cannot do this for cosmetics.'' See Submission, page 54. 
Combe claims that the safety standard for cosmetics is the same, 
whether the lead is intentionally added or present as an impurity. 
Combe asserts that under section 406 of the FD&C Act (21 U.S.C. 346), 
FDA can only set tolerances for poisonous and deleterious substances 
for food, and not cosmetics. Combe further asserts that FDA is acting 
arbitrarily and capriciously by banning lead acetate in hair dyes, but 
not banning it in lipstick. See Submission, pages 55-56.
    (Response to Objection 18) We disagree that the presence of lead as 
an impurity in some cosmetic products means that FDA must find that 
there is a reasonable certainty of no harm from the use of lead acetate 
in hair dyes at levels up to 6,000 ppm (mg/kg). The intended use of 
lead acetate is as a color additive and as such we are acting under 
sections 721(d) and 601(e) (21 U.S.C. 361(e)) of the FD&C Act. See 28 
FR 13374 (December 10, 1963) (providing FDA's interpretation of 
sections 601(a) and (e) of the FD&C Act). We have concluded that 
intended use of lead acetate does not meet the safety standard of 
``reasonable certainty of no harm'' set forth at Sec.  70.3(i) for 
color additives. Combe has not demonstrated that the intended use of 
lead acetate meets this safety standard. Therefore, we are repealing 
the listing of lead acetate under section 721(d) of the FD&C Act, and 
its use adulterates a cosmetic under section 601(e) of the FD&C Act.
    Our repeal of the listing of lead acetate as a color additive in 
hair dye and our recommendation to limit lead as an unavoidable 
impurity in lipstick and other cosmetics are not arbitrary and 
capricious actions, as Combe asserts. In our ``Draft Guidance for 
Industry: Lead in Cosmetic Lip Products and Externally Applied 
Cosmetics: Recommended Maximum Level'' (2016), we recommend lead not be 
present as an impurity (not an intentionally added ingredient) in 
cosmetics at levels exceeding 10 ppm (10 mg/kg) (Ref. 6).\2\ Lead as an 
impurity may occur in any cosmetics due to its background presence in 
the environment. Lead as an impurity cannot be completely avoided, 
although we have concluded that limiting trace amounts of lead to less 
than 10 ppm (10 mg/kg) can be achieved through reasonable and practical 
approaches to control raw materials and through other good 
manufacturing practices (Ref. 7). The draft guidance does not apply to 
hair dyes that contain lead acetate as an ingredient (Ref. 6 at page 
3).
---------------------------------------------------------------------------

    \2\ The draft guidance, only when finalized, will represent the 
current thinking of the FDA on this topic. It does not establish any 
rights for any person and is not binding on FDA or the public. You 
can use an alternative approach if it satisfies the requirements of 
the applicable statutes and regulations.
---------------------------------------------------------------------------

    By contrast, lead acetate as a color additive is an intentionally 
added ingredient in hair dye and must meet the safety standard for 
color additives. We believe that the available data demonstrate that 
exposure to lead acetate from the intended use may cause adverse 
effects (Refs. 3 and 4). Therefore, the use of lead acetate in hair dye 
products that would result in lead levels up to 6,000 ppm (6,000 mg/kg) 
in the final products does not meet the safety standard for color 
additives.
    Because there is no factual issue Combe identifies in this 
objection that can be resolved by available and specifically identified 
reliable evidence, we are denying the request for a hearing on this 
objection (Sec.  12.24(b)(1)).

B. Category B: The Moore Study

    Combe's numbered objections included in Category B are as follows:

    6. Combe objects to FDA's conclusions that the Moore study 
underestimated the exposure to lead.
    7. Combe objects to FDA's criticisms of Moore.
    8. Combe objects to FDA's finding that the lead in the Moore 
study could have been absorbed by other parts of the body than the 
blood.
    11. Combe objects to FDA's argument that the absorption 
percentage from the Moore study is invalid because it tested only a 
small patch of skin.

    Objection 6. Combe objects to ``FDA's conclusions that the Moore 
study underestimated the exposure of lead.'' Combe asserts that the 
Moore study remains the best evidence of the absorption of lead from 
lead acetate, that the Moore study protocol was developed with guidance 
from FDA, and that FDA acknowledged as much because it used some of the 
figures derived from the Moore study in its own modeling. See 
Submission, pages 33-34.
    (Response to Objection 6) FDA acknowledges that the Moore study has 
some scientific merit. As discussed in our responses to Objections 9, 
12, and 13, the fractional absorption (the percentage of the total 
amount of lead applied that is absorbed through the skin) from this 
study was used to calculate EPA's permeability coefficient (Kp) value 
(the rate at which a chemical penetrates the skin), which we used in 
our assessment.\3\ Additionally, the results generated by Moore et al. 
would be reliable for a situation where the experimental conditions 
reflected the intended use conditions. However as explained below, the 
intended conditions of use of the lead acetate-containing progressive 
hair dyes are different from the experimental conditions in the Moore 
study.
---------------------------------------------------------------------------

    \3\ Objection 12 provides an additional explanation of 
fractional absorption and Kp.
---------------------------------------------------------------------------

    New scientific information and computational tools have become 
available since the Moore study protocol was developed in the 1970s to 
1980. We considered newer scientific information, including peer-
reviewed publications describing nonclinical and clinical studies that 
demonstrate that dermally applied lead acetate and other lead compounds 
penetrate human and animal skin (Ref. 2). Additionally, newer 
computational tools have shown that the surface area of the application 
site is an important factor for estimating dermal absorption of lead 
and other compounds. This includes the in silico (i.e., via computer 
simulation, as opposed to in vitro or in vivo experimental studies) 
ConsExpo dermal absorption model that we used to predict the percentage 
of dermal lead absorption. Using a surface area that is representative 
of the actual application area is also consistent with our recent 
guidance for industry, \4\ which provides recommendations for 
conducting in vivo absorption trials for topically applied active 
ingredients (Ref. 8). The

[[Page 56188]]

guidance recommends, in part, that the test article should be applied 
to the part of the body and maximal skin surface areas that are 
consistent with the final product's intended skin surface area use 
(Ref. 8, page 6).
---------------------------------------------------------------------------

    \4\ The Wyatt Memorandum (Ref. 2) refers to the draft guidance 
(Ref. 6), which has since been finalized.
---------------------------------------------------------------------------

    By contrast, the Moore study design--where the lead acetate 
formulation was applied to a small surface area on the forehead--did 
not reflect either where lead acetate hair dye is intended to be 
applied or the surface area of such application. Specifically, in the 
Moore study, the lead acetate formulation was tested on only a small 
fraction of the skin surface area (i.e., 8 to 10 square centimeters 
(cm\2\) on the forehead instead of approximately 580 cm\2\ for the full 
scalp). Additionally, the test formulation was applied to an area of 
skin without many hair follicles, which may have further underestimated 
the amount of lead absorbed. Lead absorption was measured after 12 
hours and 24 hours of exposure, and the test formulation was washed off 
after the first 12 hours. The study did not investigate the actual 
directions of use of this hair dye, which results in accumulation of 
lead on the hair and skin. \5\ Therefore, the Moore study 
underestimated exposure to lead from the use of lead acetate hair dyes. 
Based on these flaws and the additional flaws we identified in the 
Moore study, specifically, the formulation used in the study contained 
0.12 to 0.18 percent lead (instead of 0.6 percent), the ages of the 
eight male test subjects range from 20 to 35 years (instead of older 
adults), and the short duration of test article application, which were 
discussed in detail in the final rule that appeared in the Federal 
Register of October 31, 2018 (83 FR 54665 at 54668 through 54670), we 
stated that the Moore study results could no longer be relied on to 
make a safety decision for the use of lead acetate as a color additive 
in hair dye.
---------------------------------------------------------------------------

    \5\ The manufacturer's use directions state that after the 
initial application, users might apply the progressive hair dye 
daily until the desired color shade is achieved (usually takes 2-3 
weeks), and then once or twice a week to maintain the hair color.
---------------------------------------------------------------------------

    Therefore, considering the reported adverse effects at low levels 
of lead exposure (e.g., increased blood pressure, hypertension, 
decreased glomerular filtration rate) (83 FR 54665 at 54668), and the 
absence of data showing a safe level of lead exposure, we believe that 
the safety standard of reasonable certainty of no harm is no longer 
met.
    Because Combe has not provided new data that address the identified 
flaws in the Moore study, we conclude that Combe's argument on the 
Moore study is insufficient to justify a hearing (Sec.  12.24(b)(3)). 
Therefore, we are denying the request for a hearing on this objection.
    Objection 7. Combe objects to ``FDA's criticisms of Moore.'' Combe 
states that in 1981, FDA concluded that Moore's radioactive tracking 
study demonstrated a miniscule amount of lead absorption from lead 
acetate hair dyes. See Submission, page 35. Combe further states that 
the Moore study result of 0.058 percent is supported by a subsequent 
study by Bress and Bidanset (Ref. 2), which estimated absorption of 
lead acetate as 0.05 percent. See Submission, at page 37.
    (Response to Objection 7) We acknowledge that, based on the 
scientific information available 40 years ago, we considered the 1978 
radioactive tracer skin absorption study sponsored by Combe (a 
petitioner for CAP 3C0107) and conducted by Moore et al. (published in 
1980) to be the primary study supporting the approval of lead acetate 
as a color additive in 1980, and that it was applicable for studying 
human skin lead absorption at that time. However, as discussed in our 
response to Objection 6 and the October 31, 2018, final rule (83 FR 
54665 at 54668 through 54670), we have since identified several flaws 
in the Moore study design and conduct, such as applying test 
formulation with a lower lead concentration, on a smaller surface area 
of skin, and for a short period of time, when compared to the intended 
conditions of use. For example, as discussed previously, Moore et al. 
applied the lead acetate-containing formulation to an 8 to 10 cm\2\ 
surface area on the forehead without many hair follicles, which is not 
consistent with the intended condition of use for the hair dye product 
(on the full scalp with many hair follicles and a skin surface area of 
approximately 580 cm\2\), thereby underestimating the exposure to lead 
from lead acetate-containing hair dye. In addition, the result of 0.058 
percent was measured 12 hours after a single application of the hair 
dye, which was then washed off. Therefore, the result does not 
represent the accumulation of lead from daily use of the hair dye. 
Because of these identified flaws and others described in the response 
to Objection 6, the fractional absorption calculated from the Moore 
study does not accurately represent the actual dermal absorption under 
the intended conditions of use, and therefore does not support the safe 
use of lead acetate in progressive hair dyes.
    We also reviewed the study published in 1991 by Bress and Bidanset 
(Ref. 2). While the results from this study are consistent with those 
from the Moore study, Bress and Bidanset also applied the lead compound 
to a small skin surface area; thus, their study is of similar limited 
utility as the Moore study because it may also underestimate the 
exposure to lead from the use of hair dye. The objection failed to 
provide new data that address the identified flaws in the Moore study 
and the limitation of the Bress and Bidanset study for estimating skin 
absorption of lead from the use of lead acetate hair dye, and the 
information discussed in this objection is insufficient to justify a 
hearing (Sec.  12.24(b)(3)). Therefore, we are denying the request for 
a hearing on this objection.
    Objection 8. Combe objects to ``FDA's finding that the lead in the 
Moore study could have been absorbed by other parts of the body than 
the blood.'' Combe also states that the radioactive tracer skin 
absorption study conducted by Moore et al. measured whole body lead 
(including lead in the blood, other fluids, tissues, muscle, and bone) 
and that Moore et al. calculated that 40 percent of the lead absorbed 
by the whole body was absorbed into the blood. See Submission, page 38.
    (Response to Objection 8) In a March 3, 1978, final rule postponing 
the closing date for the provisional listing of lead acetate for use as 
a component of hair colors (43 FR 8790), we stated that the radioactive 
tracer skin absorption study protocol submitted to FDA would measure 
whole body counts of lead absorption, and in addition, blood and urine 
samples would be analyzed for measurable levels of lead (43 FR 8790 at 
8793). However, as further discussed in our response to Objection 12, 
the use of fractional absorption to express dermal absorption depends 
on the study design (e.g., duration of exposure, how much of the test 
material is in contact with a given surface area, the concentration of 
the substance in the matrix). Also, as stated in our response to 
Objection 6, given its fundamental flaws, the Moore study 
underestimated exposure to lead from the use of lead acetate hair dyes. 
Therefore, we can no longer rely on this study's exposure estimate to 
assure the safe use of lead acetate in hair dye. Combe does not point 
to any other studies that have evaluated lead absorption across the 
full surface area of the scalp, nor does Combe point to other studies 
demonstrating an absorption estimate after correcting the flaw in the 
Moore study that could provide evidence that the use of lead acetate in 
hair dye is safe.
    A hearing will not be granted on the basis of mere allegations or 
general descriptions of positions and contentions (Sec.  12.24(b)(2)). 
Therefore, in

[[Page 56189]]

the absence of any other evidence, studies, or new scientific 
information addressing the flaws identified in the Moore study that 
would demonstrate that the use of lead acetate in hair dye is safe, we 
are denying the request for a hearing on this objection.
    Objection 11. Combe objects to ``FDA's argument that the absorption 
percentage from Moore is invalid because it tested only a small patch 
of skin.'' See Submission, page 40. Combe acknowledges that the scalp 
has a larger surface area, but states that the use instruction for its 
hair dye product is to apply the dye to the hair while avoiding ``areas 
you want to keep gray'' and not to apply the product to the scalp. See 
Submission, page 41. Thus, Combe claims that its product ``would never 
touch the whole scalp.'' Ibid. Combe asserts that Moore's approach of 
applying the lead acetate formulations directly to skin on the forehead 
was a conservative approach that would substantially overestimate 
absorption. Combe further asserts that,

    Moore applied a small amount of hair dye to a small patch of 
skin and measured how much of that small amount was absorbed. Thus, 
Moore was able to estimate the percentage of the applied dye that 
enters the body. This fraction (0.058 percent) was then multiplied 
by the actual amount of hair dye that would reach the head, yielding 
the amount of absorption that can be expected from the whole 
application. By such multiplication, Moore took into account the 
application to more than just a small patch of skin. Moore 
considered the entire scalp.

    See Submission, pages 41-42.
    Combe also asserts that the way Moore estimated absorption 
``remains the standard way that industry and regulators do it today.'' 
See Submission, page 42. Specifically, Combe states that FDA 
``evaluated the dermal absorption of lead as a percentage of the amount 
applied to the skin'' in its 2016 draft guidance for lead as an 
impurity in cosmetic lip products and externally applied cosmetics, and 
that this approach is similar to the approach in the Moore study. Ibid.
    (Response to Objection 11) Our criticism of the Moore study is not 
limited to its testing of only a small patch of skin; however, the size 
of the skin tested is one relevant factor.
    We note that Combe asserts that lead acetate ``would never touch 
the whole scalp.'' See Submission, page 41. Yet, Combe failed to 
provide data showing how much of the scalp (by the percent area) is 
estimated to be exposed to the hair dye. Without such data, our 
assumption that the hair dye would be applied to the surface area of 
the scalp that would be expected to be treated with the hair dye 
product is consistent with the practices used in an appropriately 
designed dermal absorption study. For example, see the European 
Commission's Scientific Committee on Consumer Products' (SCCP's) 
guidance for testing and evaluating safety of cosmetic ingredients 
(Ref. 9). Page 44 of the SCCP guidance document states, ``Hence, when 
dermal absorption is expressed as a percentage, the absorbed amount 
resulting from in vitro tests has to be expressed as a percentage of 
the dose applied in real in use conditions, that can be estimated by 
the ratio of the default amount of formulation applied in real 
conditions and the respective default value of skin surface area per 
product type.''
    In addition, it is likely that some users would apply the product 
to the whole scalp. For example, Combe's Grecian[supreg] 
Formula16[supreg] liquid and cream products use instructions state that 
the user should apply the lead acetate-containing hair dye ``to cover 
gray totally, until hair feels slightly damp;'' ``[c]omb hair as 
usual;'' ``if desired apply daily until hair reaches desired shade;'' 
and ``[t]o maintain your natural look, apply once or twice a week 
thereafter'' (Ref. 10). The pictures provided in the use instructions 
appear to indicate that the dye may be applied on the area of the head 
covered by hair (Ibid.). Accordingly, we expect that some users would 
follow these instructions and apply the dye and comb the damp hair such 
that the dye would widely reach the scalp.
    Nonetheless, Combe asserts that Moore considered ``the entire 
scalp,'' by multiplying the percentage of the applied dye that enters 
the body (i.e., the fractional absorption) by the ``actual amount of 
hair dye that would reach the head.'' See Submission, page 41. 
Experimental conditions can impact fractional absorption and are not 
independent of skin loading conditions, which can have dramatic effects 
on the results (Refs. 11 and 12). The experimental conditions in the 
Moore study were drastically different from the intended conditions of 
use, thus the fractional absorption measured in this experiment is not 
representative of the real fractional absorption under the intended use 
conditions. For example, a fractional absorption obtained by applying 
0.1 milliliter (mL) of hair dye formulation containing 0.12 percent 
lead acetate to an 8 or 10 cm\2\ area of skin on the forehead without 
many hair follicles and measured after 12 hours does not accurately 
reflect the actual use conditions where 0.18 mL of formulation 
containing up to 0.6 percent lead is applied to a 580 cm\2\ area of 
scalp area with many hair follicles and is reapplied every 24 hours 
until the hair reaches the desired shade (Refs. 1 and 2). Thus, the 
relative dermal loading of the hair dye was 0.01 mL/cm\2\ (0.1 mL/10 
cm\2\) in the Moore study versus 0.00031 mL/cm\2\ (0.18 mL/580 cm\2\), 
which is a 32-fold difference that influences dermal absorption. We do 
not consider a study design, in which the test formulation (with lower 
lead acetate concentration) was applied to a small surface area on the 
forehead (instead of the full scalp) and washed off after an 
application period-to be a conservative approach as Combe asserts, nor 
do we consider it an accurate measure of lead exposure from the product 
use. Thus, we believe that the Moore study underestimated the total 
amount of lead that was absorbed.
    With regard to FDA's 2016 draft guidance, as discussed in our 
response to Objection 18, this guidance is specific to lead present in 
certain cosmetics as an impurity. It is important to note the maximum 
permitted use level of 6,000 ppm lead acetate intentionally added to a 
hair dye is 600 times greater than the maximum recommended lead level 
of 10 ppm as an impurity. For the draft guidance, FDA evaluated the 
dermal absorption of lead as a percentage of the amount applied to the 
skin in order to assess exposure more generally. The draft guidance 
incorporated usage data for three representative cosmetic product 
categories (lipstick, eye shadow, and body lotion) and estimated whole 
body exposure to lead. The draft guidance considered average daily 
usages of lipstick, eye shadow, and body lotion to make generalizations 
for lead as an impurity in all categories of cosmetics covered by this 
guidance, rather than in each specific category.
    By contrast, for our review of lead acetate, we considered 
specifically how much lead would be absorbed from a hair dye to ensure 
that this intended use of lead acetate meets the safety standard for 
color additives. Because use of lead acetate as a hair dye is 
associated with a specific usage scenario limited to only the scalp, 
the intended conditions of use, including the surface area of 
application, were important in calculating absorption. Because of study 
design limitations with the Moore study, we used a published Kp value 
(see response to Comment 12 that addresses the Kp value) in a ConsExpo 
model to estimate exposure and predict potential percentages of dermal 
lead absorption for this specific usage scenario.
    A hearing will not be granted on the basis of mere allegations or 
general descriptions of positions and

[[Page 56190]]

contentions (Sec.  12.24(b)(2)). Therefore, in the absence of any other 
evidence, studies, or new scientific information addressing the flaws 
identified in the Moore study that would demonstrate that the use of 
lead acetate in hair dye is safe, we are denying the request for a 
hearing on this objection.

C. Category C: ConsExpo In Silico [Computer] Modeling

    Combe's numbered objections included in Category C are as follows:

    9. Combe objects to FDA's reliance on a novel and unvalidated 
computer model.
    10. Combe objects to FDA's treating an unvalidated computer 
model as more reliable than robust human data.

    Objection 9. Combe objects to ``FDA's reliance on a novel and 
unvalidated computer model.'' Combe states that FDA failed to explain 
whether the model is validated and why it used this particular model. 
See Submission, page 39. Combe further claims that FDA never explained 
the details of the model, ``how the math works, or why FDA's inputs to 
the model are reasonable.'' Ibid.
    (Response to Objection 9) Contrary to Combe's contention, the 
ConsExpo dermal absorption model is not novel. The ConsExpo dermal 
absorption model is a mathematically based modeling program that 
enables general estimation of human exposure to chemicals found in 
consumer products via inhalation, skin absorption, and oral intake. The 
description of the basis of the ConsExpo dermal absorption model was 
first published in 1996 (Ref. 13). The program was developed by the 
Netherlands National Institute for Public Health and the Environment 
(RIVM) and is available to the public. The program updates are now 
released by RIVM in collaboration with other European counterpart 
institutes, including the French Agency for Food, Environmental and 
Occupational Health and Safety, the German Institute for Risk 
Assessment, the Federal Office of Public Health (Switzerland), and 
Health Canada. This model has been used by other regulators (e.g., 
Health Canada) and has been cited in various scientific publications, 
as listed in Appendix 6 of the Wyatt memorandum (Refs. 2 and 14).
    In the Wyatt memorandum (Ref. 2, Appendices 4 to 6), and in the 
October 31, 2018, final rule (83 FR 54665 at 54670), we explained our 
decision to use the in silico modeling to predict the percentage of 
dermal absorption of lead by the surface area of the full human scalp 
and all the parameters and inputs to the model. We chose to use in 
silico modeling because, as described in our response to Objection 7, 
we had identified several flaws in the Moore study design that resulted 
in the underestimation of lead exposure from this intended use.
    Using EPA's Kp value for lead acetate,\6\ we used the ConsExpo 
dermal absorption modeling software to estimate absorption based on the 
intended conditions of use (including the relevant lead concentration, 
surface area, and duration of application period). As stated in 
Appendix 4 of the Wyatt memorandum (Ref. 2), we also performed an 
internal validation by applying parameters identical to experimental 
conditions used in the Moore study into the ConsExpo dermal absorption 
model. The model successfully predicts Moore's experimental results 
using Moore's study parameters from experimental conditions, which can 
be taken as evidence of validation of the model. We believe that no 
further validation is needed for the purpose of using the model to fill 
gaps in experimental data.
---------------------------------------------------------------------------

    \6\ Kp is a chemical-specific absorption-related constant that 
is independent of the surface area, concentration, etc. (see further 
description of Kp in our response to Objection 12).
---------------------------------------------------------------------------

    The objection failed to include any new information or data that 
would refute our conclusion that the ConsExpo dermal absorption model 
was appropriate to use in the manner that we applied it. A hearing will 
not be granted on the basis of general descriptions of positions and 
contentions (Sec.  12.24(b)(2)). The objector must, at a minimum, raise 
a material issue concerning which a meaningful hearing might be held. 
Therefore, we are denying the request for a hearing on this objection.
    Objection 10. Combe objects to ``FDA's treating an unvalidated 
computer model as more reliable and robust than human experimental 
data.'' In this objection, Combe insists that the computer model is not 
needed because human data are available and that ``it is unscientific 
for a computer model to be used to trump robust human data.'' See 
Submission, page 40.
    (Response to Objection 10) FDA agrees that human studies, when 
scientifically well-designed and conducted, provide more robust and 
reliable data than computer modeling in the safety evaluations of color 
additives. As discussed in the Wyatt memorandum and in the October 31, 
2018, final rule (83 FR 54665 at 54668 through 54672), we reevaluated 
the Moore study and identified significant scientific flaws. Based on 
this reevaluation, our current thinking regarding the radioactive 
tracer skin absorption study conducted by Moore et al., is that it is 
no longer possible to rely on this human data because of these 
significant flaws. Consequently, we no longer consider it 
scientifically sound to continue the use of the experimental fractional 
absorption number derived from this study when the experimental 
conditions are not consistent with the intended conditions of use for 
the hair dye product. We believe that the flaws in the Moore study may 
have resulted in underestimating the exposure to lead from lead 
acetate-containing hair dye. We also believe that it is scientifically 
valid and appropriate to use the in silico computer model to 
extrapolate and predict the absorption to fill the data gaps created by 
the absence of data from human experimental studies designed and 
conducted to simulate the intended conditions of use for lead acetate-
containing hair dye.
    In this objection, Combe did not provide any information to address 
the significant flaws in the Moore study that we identified. This 
objection also failed to identify any other human studies that we could 
consider in lieu of the in silico computer model. Therefore, we are 
denying the request for a hearing on this objection.

D. Category D: Skin Permeability Coefficient

    Combe's numbered objections included in Category D are as follows:

    12. Combe objects to FDA's reliance on a ``permeability 
coefficient'' for lead instead of fractional absorption.
    13. Combe objects to FDA's use of a permeability coefficient for 
lead acetate that EPA repudiated and replaced with a much lower 
estimate.

    Objection 12. Combe objects to ``FDA's reliance on a `permeability 
coefficient' for lead instead of fractional absorption.'' Combe argues 
that FDA has not demonstrated that the ConsExpo dermal absorption model 
has been validated for inorganic substances such as lead, and that FDA 
does not explain how the permeability coefficient for lead acetate was 
derived and whether it is appropriate for use in the model. See 
Submission, page 44. Combe further asserts that we are relying on an 
outdated permeability coefficient from EPA. See Submission, pages 43-
44. Because this last argument is also the subject of Objection 13 (see 
Submission, page 45), we will respond to this assertion in our response 
to Objection 13 below.
    (Response to Objection 12) There are two ways to calculate skin 
absorption for exposure assessments: (1) The use of

[[Page 56191]]

the Kp and (2) the use of fractional absorption. Kp is a constant 
(i.e., the rate at which a chemical penetrates across the stratum 
corneum (the outermost layer of the skin, e.g., centimeters per hour 
(cm/h) or meters per second (m/s)). The fractional absorption is the 
percentage of the total amount of lead applied that is absorbed through 
the skin and depends on the study design (e.g., duration of exposure, 
how much of the test material is in contact with a given surface area, 
the concentration of the substance in the matrix, etc.). Thus, the 
extension of an experimental fractional absorption number is only 
scientifically valid when the experimental conditions are similar, if 
not identical, to the intended condition of use. As discussed 
previously, the experimental conditions in the Moore study are 
significantly different from the intended conditions of use for the 
lead acetate-containing hair dye. For example, as mentioned in our 
response to Objection 9, Moore's study was conducted with formulations 
containing 6 millimole per liter (mmol/L) or 9 mmol/L lead acetate 
(equivalent to 0.12 or 0.18 percent lead respectively), which are three 
to five times lower than the maximum use level (0.6 percent lead) in 
hair dyes. Second, the test formulation(s) were reportedly applied to a 
skin surface area of 8 to 10 cm\2\ on the forehead, an area of the skin 
without hair follicles, while lead acetate-containing hair dye is 
intended to be applied to the full scalp that has many hair follicles 
and a skin surface area of approximately 580 cm\2\. Third, the 12-hour 
application period in the Moore study may be too short to assess the 
full extent of percutaneous absorption of lead under the intended 
conditions of use, which in some cases could remain on the scalp for 24 
hours or longer and may accumulate due to repeated applications. 
Therefore, application to the small surface area, use of a formulation 
with a lower lead concentration, and a shorter exposure period used in 
the Moore study all resulted in an underestimation of the fractional 
absorption number of lead acetate.
    Therefore, we believe it is appropriate to use the Kp (which allows 
the incorporation of parameters, such as the surface area, 
concentration, and duration of exposure) in the modeling to determine 
dermal absorption. We note that Kp is often the preferred, more 
reliable, and commonly utilized parameter to quantify percutaneous 
absorption of chemicals from solutions (Refs. 15 and 16).\,\
    We also note that the ConsExpo dermal absorption model can be 
applied to an organic or inorganic compound because the underlying 
basis for the model is the well-known Fick's law, which describes the 
transport of mass, through diffusion, from a region of higher 
concentration to a region of lower concentration. The Fick's law-based 
equation for the ConsExpo dermal absorption model is described in the 
user manual as follows (Ref. 17):
    Aabs = Askin x (1-exp(-P x S x t/V))

Where:
Aabs = Amount of substance absorbed (kg)
Askin = Amount of substance on the skin (kg)
P = Permeability of the skin (m/s) (Equivalent to Kp in the context)
V = Volume of the substance on the skin (m\3\)
S = Exposed skin area (m\2\)
t = Exposure time (s)

As shown in the equation above, the only physicochemical property 
related to the chemical itself is the Kp; chemical composition is not a 
part of the equation. Thus, this Fick's law-based approach, which is 
not dependent on chemical composition, does not need to be specifically 
validated according to whether the substance is organic or inorganic 
because the permeability (Kp) is a set number. As discussed above in 
our response to Objection 9, we used the ConsExpo dermal absorption 
model to fill in the existing experimental data gaps (i.e., related to 
the small surface area, lower lead concentration, and shorter duration 
of exposure) in order to address the differences between the 
experimental conditions and the approved intended conditions of use.
    Because the objection failed to provide new data that would change 
our conclusion, and the information discussed in the objection is 
insufficient to justify a hearing (Sec.  12.24(b)(3)), we are denying 
the request for a hearing on this objection.
    Objection 13. Combe objects to ``FDA's use of a permeability 
coefficient for lead acetate that EPA repudiated and replaced with a 
much lower estimate.'' See Submission, page 45. Combe states that FDA 
used a permeability coefficient for lead acetate from, ``an internal 
report that EPA has since repudiated.'' Ibid. Combe further states: 
``FDA's reliance on this figure is particularly unsupportable given 
that EPA in 2004 actually published a permeability coefficient for lead 
acetate that is an order of magnitude lower than the internal interim 
1992 estimate.'' Ibid.
    (Response to Objection 13) We acknowledge that we used the 
permeability coefficient in EPA's 1992 interim report (Ref. 18) (the 
larger Kp value of 4 x 10-6 cm/hr), rather than in EPA's 
2004 final guidance (Ref. 19) (the smaller Kp value of 0.0005 x 
10-3 cm/hr, which is 5 x 10-7 cm/hr), entitled 
``Risk Assessment Guidance for Superfund Volume I: Human Health 
Evaluation Manual.'' The Kp values in EPA's 1992 and 2004 documents 
were both based on the same data set (the Moore study) and they are 
both valid. Specifically, the fractional absorption reported by the 
Moore study was in a range between 0 to 0.3 percent (Refs. 18, 19, 21, 
and 22). While the Kp value in EPA's 1992 document was based on the 
upper limit of the reported range (namely a fractional absorption of 
0.3 percent), the Kp value in EPA's 2004 document \7\ was based on the 
mean of the reported data range (minus the highest value for injured 
skin (``dry and scratch'' in the Moore study)) (namely a fractional 
absorption of 0.058 percent, instead of 0.3 percent). Using a higher Kp 
value--the upper limit of the reported range--is more conservative 
because it results in higher predictions of dermal absorption. FDA's 
use of this more conservative Kp value is consistent with ensuring 
there is a reasonable certainty of no harm from the use of this color 
additive.
---------------------------------------------------------------------------

    \7\ We disagree with Combe's characterization of EPA 
``repudiating'' the prior Kp value in the EPA 1992 document. We also 
note that in its 2004 document, FDA did not independently derive the 
Kp value of 0.0005 x 10-3 cm/hr for lead acetate and 
instead cited Hostynek et al. (1998).
---------------------------------------------------------------------------

    Had FDA used the smaller Kp value from EPA's 2004 guidance, the 
predicted fractional absorption number would have been 3.8 percent 
(acknowledged by Combe in Objection 13; see Submission, page 47). The 
3.8 percent fractional absorption is more than 10 times higher than 
what had been reported in the Moore study as the highest absorption 
value. This discrepancy in fractional absorption supports our 
conclusion that the Moore study underestimated the amount of lead 
absorbed and therefore was flawed. In addition, as stated in the Wyatt 
memorandum (Ref. 2, p. 19), FDA did not rely on the predicted levels of 
transdermal absorption from modeling to quantify the extent of lead 
acetate absorption. Rather, FDA used the predictions from modeling to 
show that the Moore study, which was relied on for the listing of lead 
acetate as an approved color additive in 1980, may have significantly 
underestimated exposure to transdermally absorbed lead from the use of 
lead acetate hair dyes (Ref. 2).
    The objection failed to provide new data that would change our 
conclusion that there is no longer reasonable certainty that no harm 
would result from the listed use of lead acetate in hair dye, and the 
information discussed in their objection is insufficient to

[[Page 56192]]

justify a hearing (Sec.  12.24(b)(3)). Therefore, we are denying the 
request for a hearing on this objection.

E. Category E: Lead Exposure and Blood Lead Levels

    Combe's numbered objections included in Category E are as follows:

    3. Combe objects to FDA's reliance on sources that discuss blood 
levels of lead and not exposure levels (see, e.g., NTP monograph).
    14. Combe objects to FDA's conclusion that lower median blood 
levels in lead since 1990 mean that any the lead contributed by lead 
acetate is less safe now.
    15. Combe objects to FDA's entire analysis because it is missing 
two critical links--FDA never relates exposure from lead acetate to 
any change in blood lead levels, and thus it never relates it to any 
predicted harm.
    16. Combe objects to FDA's whole argument as FDA never links 
exposure to lead from lead acetate to a change in steady-state blood 
lead levels.
    17. Combe objects to FDA's conclusions about the effect of lead 
acetate on blood lead levels.

    Objection 3. Combe objects to ``FDA's reliance on sources that 
discuss blood levels of lead and not exposure levels (see, e.g., NTP 
monograph).'' Combe asserts that the NTP monograph does not support 
that lead is harmful at low levels in adults. See Submission, pages 30-
32. Combe argues that the NTP showed increased risk of potential health 
effects (heart and kidney) associated with blood lead levels of 5-10 
micrograms per decaliter ([mu]g/dL), while noting that the current mean 
blood lead level in U.S. adults is 0.92 [mu]g/dL. See Submission, at 
pages 30-31. Combe asserts that there is no evidence that the use of 
lead acetate-containing hair dye can raise blood lead levels to >5 
[mu]g/dL. See Submission, page 31.
    (Response to Objection 3) With regard to the NTP monograph, the 
evaluation found sufficient evidence for an association of adverse 
effects on kidney function with blood lead levels of less than 5 [mu]g/
dL in adults (Ref. 3, page 87). A recent literature review by FDA found 
that ``the overall body of evidence . . . suggests that some adverse 
effects may occur at a blood lead level of 3 [mu]g/dL . . . in adults'' 
(Ref. 20). In addition, as discussed in our response to Objection 2, 
there is a lack of evidence of a safe level of exposure for lead. For 
example, JECFA has stated that ``because the dose-response analyses do 
not provide any indication of a threshold for the key effects of lead, 
the Committee concluded that it was not possible to establish a new 
PTWI that would be considered to be health protective'' (Ref. 4, page 
212). Furthermore, Combe fails to provide any data that shows the 
impact of the use of lead acetate-containing hair dye on blood lead 
levels.
    Combe has not provided scientific evidence to support its 
contention that the intended use of lead acetate is safe. A hearing 
will not be granted on the basis of mere allegations or general 
descriptions of positions and contentions (Sec.  12.24(b)(2)). 
Therefore, we are denying the request for a hearing on this objection.
    Objection 14. Combe objects to ``FDA's conclusion that lower median 
blood levels in lead since 1990 mean that any [of] the lead contributed 
by lead acetate is less safe now.'' Combe asserts that because blood 
lead levels in the U.S. population are lower now, any amount of lead 
contributed by lead acetate ``is safer now because of the overall lower 
levels of lead.'' See Submission, page 48.
    (Response to Objection 14) In the October 31, 2018, final rule, we 
concluded that any increase in exposure to lead resulting from use of 
lead acetate containing hair dye can no longer be considered 
insignificant in terms of public health (83 FR 54665 at 54671). Given 
that there is no known safe exposure level for lead, we disagree that 
any amount of lead contributed by lead acetate-containing hair dye is 
safer now. The decrease in blood lead levels since 1990 resulted from 
the actions taken by multiple regulatory and public health agencies to 
reduce lead exposure in order to minimize potential adverse effects. 
For example, we have taken measures to reduce exposure to lead from 
our-regulated products to the lowest level that is technically feasible 
to protect the public health. Such measures include (but are not 
limited to) prohibiting the use of tin-coated lead foil capsules for 
wine bottles (21 CFR 189.301) and prohibiting the use of lead-soldering 
in food cans (21 CFR 189.240). The decrease in blood lead levels in the 
U.S. population, resulting from these measures, does not mean that the 
use of lead acetate in hair dye is safe.
    To the contrary, as the science has evolved, more sensitive 
endpoints have been identified at lower blood lead levels than known in 
the 1970s. A growing body of evidence indicates that adults may 
experience adverse health impacts from exposure to lead levels lower 
than those previously believed to be harmful. For example, in 2012, the 
NTP provided evidence of adverse effects in adult humans (e.g., 
increased blood pressure, hypertension, decreased glomerular filtration 
rate) at blood lead levels less than 10 [mu]g/dL, based on 
epidemiological evidence (Ref. 3). Also see recent literature review by 
FDA that ``the overall body of evidence . . . suggests that some 
adverse effects may occur at a blood lead level of 3 [mu]g/dL . . . in 
adults'' (Ref. 20). We further note that any additional lead exposure 
would contribute to the occurrence of the reported adverse effects of 
lead.
    Combe has not provided data to demonstrate that the intended use of 
lead acetate-containing hair dyes would not elevate the lead level in 
blood and other tissues. A hearing will not be granted on the basis of 
mere allegations or general descriptions of positions and contentions 
(Sec.  12.24(b)(2)). Therefore, we are denying the request for a 
hearing on this objection.
    Objection 15. Combe ``objects to FDA's entire analysis because it 
is missing two critical links--FDA never relates exposure from lead 
acetate to any change in blood levels, and thus it never relates it to 
any predicted harm.'' See Submission, page 49. Combe argues that FDA, 
in its conclusion in the final rule that ``we no longer can conclude 
that exposure to lead from lead acetate-containing hair dye has no 
discernible effect on the steady-state blood lead level,'' did not link 
exposure to lead from lead acetate to any change in steady-state blood 
lead levels. See Submission, page 49.
    (Response to Objection 15) To satisfy its burden that would justify 
its request for a hearing, it is the objector's responsibility to 
provide data and scientific information that calls into question our 
conclusions. It is not enough to just make an allegation; the objection 
needs to contain scientific information to demonstrate the safety of 
the color additive under the intended conditions of use. We evaluated 
the data and information submitted in the petition (CAP 7C0309) along 
with comments submitted in response to the petition and other available 
information (including published literature) to arrive at our 
conclusion. Based on currently available data, we conclude that there 
is no known safe exposure level for lead. This view is consistent with 
conclusions by other U.S. agencies responsible for ensuring public 
health (e.g., CDC, EPA) and international bodies (e.g., JECFA).
    Combe has not provided data showing that use of lead acetate-
containing hair dyes would not increase the lead level in blood or in 
other tissues (including bones). Because a hearing will not be granted 
on the basis of mere allegations or general descriptions of positions 
and contentions (Sec.  12.24(b)(2)), we are denying the request for a 
hearing on this objection.
    Objection 16. Combe ``objects to FDA's whole argument as FDA never

[[Page 56193]]

links exposure to lead from lead acetate to a change in steady-state 
blood levels.'' See Submission, page 50.
    (Response to Objection 16) Combe's argument in Objection 16 is 
essentially the same as its argument in Objection 15. We reiterate that 
our determination is based on whether the currently available 
scientific evidence shows that there is a reasonable certainty of no 
harm from the use of lead acetate-containing hair dye.
    A hearing will not be granted on the basis of mere allegations or 
general descriptions of positions and contentions (Sec.  12.24(b)(2)). 
Therefore, we are denying the request for a hearing on this objection.
    Objection 17. Combe objects to ``FDA's conclusions about the effect 
of lead acetate on blood lead levels.'' See Submission, page 51. Combe 
argues that ``the amount of lead that lead acetate contributes to daily 
intake (e.g., 0.3 [mu]g) is less than 1 percent of the amount 
contributed daily by food, and thus the effect on steady-state blood 
lead levels would be expected to be extremely small--on the order of 
0.01 [mu]g or less.'' See Submission, page 52.
    (Response to Objection 17) We reiterate that, in lead acetate-
containing hair dyes, up to 6,000 ppm (mg/kg) lead acetate (calculated 
as lead) is intentionally added as an ingredient to achieve a coloring 
effect; as such, the lead acetate must meet the safety standard of a 
reasonable certainty of no harm. There is no lead-containing compound 
approved for use as a food additive or color additive in food. Thus, 
dietary exposure to lead results from lead that is present as an 
impurity in raw materials that manufacturers are unable to avoid 
through good manufacturing practices.
    The objection failed to provide new data that changes our 
conclusion that the scientific evidence does not support any level of 
lead intake that is safe. Therefore, the information discussed in this 
objection is insufficient to justify a hearing (Sec.  12.24(b)(3)), and 
we are denying the request for a hearing on this objection.

F. Category F: Permitted Lead Acetate Levels

    Combe's numbered objection in Category F is as follows:

    Objection 19. Combe objects to ``FDA's failure to consider 
reducing the permitted lead acetate level under 21 CFR 73.2396 from 
0.6 percent to 0.153 percent.'' Combe states, ``Since 1998, Combe's 
lead acetate hair dyes have contained only 0.153 percent lead, 
approximately a quarter of the permitted 0.6 percent under 21 CFR 
Section 73.2396.'' Submission, page 56. Combe asserts that ``the 
Agency refused to account for this fact in its Final Rule.'' Ibid.

    (Response to Objection 19) We addressed this consideration in the 
final rule in our response to Combe's comment (see 83 FR 54665 at 
54672). Combe states that it reformulated its lead acetate-containing 
products in 1998. See Submission Appendix A, page 1. Reformulating the 
hair dye product by reducing the lead content from 0.6 percent to 0.153 
percent may reduce the exposure, but it does not establish a safe level 
of exposure to lead from lead acetate when used as a color additive in 
hair dye. We reiterate that we are not aware of data demonstrating that 
any level of lead is safe. We note also JECFA's concluding statement 
that it was not possible to establish a new PTWI for lead that would be 
considered health protective.
    Moreover, a color additive regulation is not manufacturer or 
sponsor-specific and, as such, any manufacturer can use a listed color 
additive within the limitations of the regulation. Therefore, it is 
appropriate for FDA to conduct its evaluation associated with the 
repeal of Sec.  73.2396 based on the maximum permitted use level of 0.6 
percent (6,000 ppm; mg/kg) of lead acetate (calculated as lead) in hair 
dyes.
    Combe has not provided data that demonstrates with reasonable 
certainty that no harm would result from the use of 6,000 ppm (mg/kg) 
lead acetate (calculated as lead) as a color additive in cosmetics for 
coloring hair on the scalp. A hearing will not be granted on the basis 
of mere allegations or general descriptions of positions and 
contentions (Sec.  12.24(b)(2)). Therefore, we are denying the request 
for a hearing on this objection.

V. Summary and Conclusions

    Section 721 of the FD&C Act requires that a color additive be shown 
to be safe prior to marketing. Under Sec.  70.3(i), a color additive is 
safe if there is convincing evidence that establishes with reasonable 
certainty that no harm will result from the intended use of the color 
additive. When new scientific evidence comes to light that calls into 
question the safety of an approved color additive, we will evaluate the 
new evidence and determine if the color additive continues to be safe 
under the condition of use.
    In our October 31, 2018, final rule, we stated that, following a 
full evaluation of the data submitted in support of CAP 7C0309 and 
other pertinent data and information, we concluded that the data 
currently available no longer demonstrate that there is a reasonable 
certainty of no harm from the use of lead acetate as a color additive 
in hair dyes authorized under Sec.  73.2396. This conclusion was based 
on the recognition of the current consensus that there is no safe 
exposure level for lead; our reevaluation of the 1980 skin absorption 
Moore study that may have resulted in an underestimation of exposure to 
lead from its use in hair dye; and the fact that blood lead levels in 
the United States have dropped significantly since 1980, so we no 
longer could conclude that exposure to lead from lead acetate-
containing hair dyes has no discernible effect on the steady-state 
blood lead level. Therefore, we issued a final rule repealing Sec.  
73.2396.
    Our responsibility in listing a color additive for safe use in a 
regulated product is to evaluate the currently available scientific 
data and other pertinent information to determine with reasonable 
certainty that the color additive is not harmful under the intended 
conditions of use. Considering all the scientific information currently 
available, we have not changed our conclusion that the current data no 
longer support the safe use of lead acetate as a color additive in 
cosmetics intended to color hair on the scalp.
    The burden is on the objector to provide pertinent evidence that 
calls into question our conclusion. Despite all its objections, Combe 
has not provided any new scientific data or information that establish 
with reasonable certainty that there is a level of lead exposure that 
could be considered safe and health protective. Combe has also not 
provided any new data demonstrating that no harm would result from the 
use of up to 6,000 ppm of lead acetate (calculated as lead) as a color 
additive intentionally added to cosmetics for coloring hair on the 
scalp.
    Therefore, we have determined that the objections do not raise any 
genuine and substantial issue of fact that can be resolved by an 
evidentiary hearing (Sec.  12.24(b)). Accordingly, we are denying the 
requests for a hearing. Furthermore, after evaluating the objections, 
we have concluded that the objections do not provide any basis for us 
to reconsider our decision to issue the final rule amending Sec.  
73.2396 to no longer authorize the use of lead acetate as a color 
additive in cosmetics intended for coloring hair on the scalp.
    Under sections 701(e)(2) and 721(d) of the FD&C Act, the filing of 
objections operates to stay the effectiveness of our repeal of Sec.  
73.2396 until we take final action on the objections. Section 701(e)(3) 
of the FD&C Act further stipulates that, as soon as practicable, the 
Secretary shall, by order, act upon such objections and make such order

[[Page 56194]]

public. We have completed our evaluation of the objections and conclude 
that a continuation of the stay is not warranted.
    In the absence of any other objections and requests for a hearing, 
we conclude that this document constitutes final action on the 
objections received in response to the October 31, 2018, final rule as 
prescribed in section 701(e)(2) of the FD&C Act. Therefore, under 
sections 701 and 721 of the FD&C Act, notice is given that the 
objections and the requests for a hearing filed in response to the 
final rule that appeared in the Federal Register of October 31, 2018, 
do not form a basis for further stay of the effectiveness of the final 
rule. Accordingly, we are ending the stay of the final rule and we are 
repealing the listing for lead acetate in Sec.  73.2396 as a color 
additive in cosmetics intended for coloring hair on the scalp as of 
January 6, 2022.
    In the October 31, 2018, final rule, we stated our intention to 
exercise enforcement discretion for a period of 12 months from the 
effective date of the final rule regarding marketed hair dye products 
that contain the color additive lead acetate to provide an opportunity 
for industry to deplete the current stock of hair dye products with 
lead acetate and reformulate products prior to enforcing the 
requirements of the final rule. We also stated that we had taken into 
consideration the fact that bismuth citrate, which is listed in Sec.  
73.2110 for use in cosmetic hair dye products at a level up to 2.0 
percent weight/volume, was already being used as an alternative for 
lead acetate in hair dye products marketed both in the United States 
and other countries. Therefore, our intent is to exercise enforcement 
discretion for a period of 12 months from the effective date of the 
final rule for those hair dye products containing the color additive 
lead acetate that comply with the requirements of Sec.  73.2396, 
including the specifications, uses and restrictions, and labeling 
requirements.

VI. References

    The following references marked with an asterisk (*) 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 are also available electronically at https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
FDA has verified the website addresses, as of the date this document 
publishes in the Federal Register, but websites are subject to change 
over time.

1. Moore, M.R., P.A. Meredith, W.S. Watson, et al., 1980. ``The 
Percutaneous Absorption of Lead-203 in Humans from Cosmetic 
Preparations Containing Lead Acetate, as Assessed by Whole-Body 
Counting and Other Techniques.'' Food and Cosmetics Toxicology, 
18:399-405.
*2. Memorandum from M.K. Wyatt, Cosmetics Division, Office of 
Cosmetics and Colors, CFSAN, FDA to M. Harry, Division of Petition 
Review, Office of Food Additive Safety, CFSAN, FDA, September 18, 
2018.
*3. HHS, National Toxicology Program, ``NTP Monograph on Health 
Effects of Low-Level Lead,'' June 2012. https://ntp.niehs.nih.gov/ntp/ohat/lead/final/monographhealtheffectslowlevellead_newissn_508.pdf.
4. Evaluation of Certain Food Additives and Contaminants: Seventy-
Third Report of the Joint FAO/WHO Expert Committee on Food 
Additives, WHO Tech Report Series No. 960, 2011. http://apps.who.int/iris/bitstream/10665/44515/1/WHO_TRS_960_eng.pdf.
5. WHO, Fact Sheet: Lead Poisoning and Health, August 23, 2019. 
https://www.who.int/news-room/fact-sheets/detail/lead-poisoning-and-health.
*6. HHS, FDA, Center for Food Safety and Applied Nutrition. ``Lead 
in Cosmetic Lip Products and Externally Applied Cosmetics: 
Recommended Maximum Level.'' Draft Guidance, December 2016, 
available at https://www.fda.gov/media/99866/download.
*7. Supporting Document for Recommended Maximum Lead Level in 
Cosmetic Lip Products and Externally Applied Cosmetics. December 
2016, Docket No. FDA-2014-D-2275. http://wcms-internet.fda.gov/cosmetics/cosmetics-guidance-documents/supporting-document-recommended-maximum-lead-level-cosmetic-lip-products-and-externally-applied#VIII.
*8. HHS, FDA, Center for Drug Evaluation and Research. Maximal Usage 
Trials for Topical Active Ingredients being Considered for Inclusion 
in an Over-The-Counter Monograph: Study Elements and Considerations. 
Draft Guidance for Industry. Clinical Pharmacology/OTC, May 2018; 
Final Guidance: Maximal Usage Trials for Topically Applied Active 
Ingredients Being Considered for Inclusion in an Over-The-Counter 
Monograph: Study Elements and Special Considerations, May 2019. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/maximal-usage-trials-topically-applied-active-ingredients-being-considered-inclusion-over-counter.
9. European Commission. ``The SCCP'S Notes of Guidance for the 
Testing of Cosmetic Ingredients and Their Safety Evaluation.'' 6th 
Revision, 2006. https://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_03j.pdf.
*10. Easy Directions. Grecian[supreg] Formula16[supreg] LIQUID. 
Grecian[supreg] Formula16[supreg] CREAM.
11. Frasch, H.F., G.S. Dotson, and S. Wilkinson. ``Analysis of 
Finite Dose Dermal Absorption Data: Implications for Dermal Exposure 
Assessment.'' Journal of Exposure Science & Environmental 
Epidemology, 24: 65-73, 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868874/.
12. Kissel, J.C. ``The Mismeasure of Dermal Absorption.'' Journal of 
Exposure Science & Environmental Epidemiology, 21(3): 302-309, 2010. 
https://pubmed.ncbi.nlm.nih.gov/20424648/.
13. Van Veen, M.P. ``A General Model for Exposure and Uptake from 
Consumer Products.'' Risk Analysis, 16:331-338, 1996.
14. Health Canada. ``Screening Assessment Acrylates and 
Methacrylates Group. October 2018. https://www.canada.ca/en/environment-climate-change/services/evaluating-existing-substances/screening-assessment-acrylates-methacrylates-group.html.
15. Fitzpatrick D., J. Corish, and B. Hayes. ``Modelling Skin 
Permeability for Risk Assessment--The Future.'' Chemosphere, 
55:1309-1314, 2004.
16. Korinth, G., K.H. Schaller, and H. Drexler. ``Is the 
Permeability Coefficient Kp a Reliable Tool in 34 Percutaneous 
Absorption Studies?'' Archives of Toxicology, 79, 155-159, 2005.
17. National Institute for Public Health and the Environment, 
Ministry of Health, Welfare and Sport. ConsExpo Web, Consumer 
Exposure models model documentation, 2017. https://www.rivm.nl/bibliotheek/rapporten/2017-0197.pdf.
*18. EPA. Interim Report. ``Dermal Exposure Assessment: Principles 
and Applications.'' Office of Health and Environmental Assessment 
EPA/600/8-91/011B, January 1992.
*19. EPA (July 2004). ``Risk Assessment Guidance for Superfund 
Volume I: Human Health Evaluation Manual (Part E, Supplemental 
Guidance for Dermal Risk Assessment) Final.'' EPA/540/R/99/005, 
OSWER 9285.7-02EP, PB99-962212.
20. Dolan, L.C., B.M. Flannery, D. Hoffman-Pennesi, et al. ``A 
Review of the Evidence to Support Interim Reference Level for 
Dietary Lead Exposure in Adults.'' FDA, Center for Food Safety and 
Applied Nutrition, Journal of the International Society of 
Regulatory Toxicology and Pharmacology, 111. 2020.
21. Hostynek, J.J., R.S. Hinz, C.R. Lorence, and R.H. Guy. ``Human 
Skin Penetration by Metal Compounds.'' Drugs and the Pharmaceutical 
Sciences, 91:647-668, 1998.
22. M.S. Roberts and K.A. Walters, eds. ``Dermal Absorption and 
Toxicity Assessment,'' Marcel Dekker, Inc., New York.

List of Subjects in 21 CFR Part 73

    Color additives, Cosmetics, Drugs, Foods, Medical devices.


[[Page 56195]]


    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, 21 CFR 
part 73 is amended as follows:

PART 73--LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION

0
1. The authority citation for part 73 continues to read as follows:

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


Sec.  73.2396  [Removed]

0
2. Remove Sec.  73.2396.

    Dated: September 30, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-21892 Filed 10-7-21; 8:45 am]
BILLING CODE 4164-01-P


