Federal Register, Volume 81 Issue 11 (Tuesday, January 19, 2016)

[Federal Register Volume 81, Number 11 (Tuesday, January 19, 2016)]
[Proposed Rules]
[Pages 2805-2818]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-00758]

[[Page 2805]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Docket No. CDC-2015-0006]

42 CFR Part 73

RIN 0920-AA59

Possession, Use, and Transfer of Select Agents and Toxins;
Biennial Review of the List of Select Agents and Toxins and Enhanced
Biosafety Requirements

AGENCY: Centers for Disease Control and Prevention (CDC), Department of
Health and Human Services (HHS).

ACTION: Notice of Proposed Rulemaking (NPRM).

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SUMMARY: In accordance with the Public Health Security and Bioterrorism
Preparedness and Response Act of 2002 (the Bioterrorism Response Act),
the Centers for Disease Control and Prevention (CDC) in the Department
of Health and Human Services (HHS) has reviewed the list of biological
agents and toxins that have the potential to pose a severe threat to
public health and safety and proposes to amend and republish the list.
Specifically, we are proposing to remove six biological agents; add
provisions to address the inactivation of select agents; add specific
provisions to the section of the regulations addressing biosafety; and
clarify regulatory language concerning security, training, incident
response, and records.

DATES: Submit written or electronic comments by March 21, 2016.

ADDRESSES: You may submit comments, identified by Docket No. CDC-2015-
0006 or RIN 0920-AA59 by any of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Mail: Division of Select Agents and Toxins, Centers for
Disease Control and Prevention, 1600 Clifton Road NE., MS-A46, Atlanta,
Georgia 30329, Attn: Docket CDC-2015-0006.
Instructions: All submissions received must include the agency name
and docket number or Regulatory Information Number (RIN) for this
rulemaking. All relevant comments received will be posted without
change to http://regulations.gov, including any personal information
provided. For access to the docket to read background documents or
comments received, go to http://www.regulations.gov.
Comments will also be available for public inspection from Monday
through Friday, except for legal holidays, from 9 a.m. to 5 p.m.,
Eastern Time, at 1600 Clifton Road NE., Atlanta, Georgia, 30329. Please
call ahead to (404) 718-2000 and ask for a representative from the
Division of Select Agents and Toxins to schedule your visit.

FOR FURTHER INFORMATION CONTACT: Dr. Dan Sosin, Acting Director,
Division of Select Agents and Toxins, Centers for Disease Control and
Prevention, 1600 Clifton Road NE., MS-A46, Atlanta, Georgia 30329.
Telephone: (404) 718-2000.

SUPPLEMENTARY INFORMATION:
The NPRM is organized as follows:

I. Public Participation
II. Background
A. Legal Authority
B. Historical background to this rulemaking
III. Summary of Proposed Changes to 42 CFR part 73
A. Definitions
B. Proposed changes to the list of select agents
C. Inactivation of a Select Agent
D. Toxins
E. Exemptions for select agents and toxins
F. Registration
G. Responsible Official
H. Visitor Access to Select Agents and Toxins
I. Security, Biosafety, and Incident Response Plans
J. Training
K. Records
IV. Alternatives Considered
V. Required Regulatory Analyses
A. Executive Orders 12866 and 13563
B. The Regulatory Flexibility Act
C. Paperwork Reduction Act of 1995
D. EO 12988: Civil Justice Reform
E. EO 13132: Federalism
F. Plain Language Act of 2010
VI. References

I. Public Participation

Interested persons or organizations are invited to participate in
this rulemaking by submitting written views, recommendations, and data.
Comments are invited on any topic related to this rulemaking.
In addition, HHS/CDC invites comments specifically as to whether
there are biological agents or toxins that should be added or removed
from the HHS list of select agents and toxins based on the following
criteria:
(1) The effect on human health of exposure to the agent or toxin;
(2) The degree of contagiousness of the agent or toxin and the
methods by which the agent or toxin is transferred to humans;
(3) The availability and effectiveness of pharmacotherapies and
immunizations to treat and prevent any illness resulting from infection
by the agent or exposure to the toxin; and
(4) Any other criteria, including the needs of children and other
vulnerable populations that the commenter considers appropriate.
HHS/CDC also invites comments on the following questions:
(1) Are there other methods that should be required to validate the
rendering of a select agent non-viable or regulated nucleic acids that
can produce infectious forms of any select agent virus non-infectious?
(2) Should there be changes to the toxin permissible limits for
excluded toxins?
(3) Should Diacetoxyscirpenol (DAS) and T-2 be removed from the
select toxin list because they do not have the potential to pose a
severe threat to public health and safety?
(4) Does seven calendar days provide a sufficient amount of time
for the entity to destroy or transfer the select agents or toxins after
identification?
(5) Are there any specific biosafety measures that should be
required to prevent laboratory acquired infections (LAIs) or accidental
release of the select agents and toxins from an entity into the
community?
(6) What alternative regulatory requirement could be constructed
such that a registered entity would know whether it had a theft or loss
of a select agent or toxin without that registered entity first having
``an accurate, current inventory for each select agent . . . held in
long term storage''?
Comments received, including attachments and other supporting
materials, are part of the public record and subject to public
disclosure. Do not include any information in your comment or
supporting materials that you consider confidential or inappropriate
for public disclosure. HHS/CDC will carefully consider all comments
submitted in preparation of a final rule.

II. Background

A. Legal Authority

HHS/CDC is promulgating this rule under the authority of sections
201-204 and 221 of Title II of Public Law 107-188, 116 Stat 637 (42
U.S.C. 262a).

B. Historical Background to This Rulemaking

Subtitle A of the Public Health Security and Bioterrorism
Preparedness and Response Act of 2002, (42 U.S.C. 262a), requires HHS
to regulate the possession, use, and transfer of biological agents or
toxins that have the potential to pose a severe threat to public health
and safety (select agents and toxins). Subtitle B of the Public Health
Security and Bioterrorism Preparedness and Response Act of 2002

[[Page 2806]]

(which may be cited as the Agricultural Bioterrorism Protection Act of
2002), (7 U.S.C. 8401), requires the United States Department of
Agriculture (USDA) to regulate the possession, use, and transfer of
biological agents or toxins that have the potential to pose a severe
threat to animal or plant health, or animal or plant products (select
agents and toxins). Accordingly, HHS and USDA have promulgated
regulations requiring individuals or entities that possess, use, or
transfer select agents and toxins to register with the CDC or the
Animal and Plant Health Inspection Service (APHIS). See 42 CFR part 73,
7 CFR part 331, and 9 CFR part 121 (the select agent regulations). The
Federal Select Agent Program (FSAP) is the collaboration of the CDC,
Division of Select Agents and Toxins (DSAT) and the APHIS Agriculture
Select Agent Services (AgSAS) to administer the select agent
regulations in a manner that minimizes the administrative burden on
persons subject to the select agent regulations. The FSAP administers
the select agent regulations in close coordination with the Federal
Bureau of Investigation's Criminal Justice Information Services
Division (CJIS).
The Bioterrorism Response Act also requires the HHS Secretary to
establish by regulation a list of biological agents and toxins that
have the potential to pose a severe threat to public health and safety.
In determining whether to include an agent or toxin on the list, the
HHS Secretary considers criteria such as the effect on human health of
exposure to an agent or toxin; the degree of contagiousness of the
agent and the methods by which the agent or toxin is transferred to
humans; the availability and effectiveness of pharmacotherapies and
immunizations to treat and prevent illnesses resulting from an agent or
toxin; and the needs of children and other vulnerable populations. The
current list of HHS select agents and toxins can be found at 42 CFR
73.3 (HHS select agents and toxins) and 42 CFR 73.4 (Overlap select
agents and toxins). The list of HHS and Overlap select agents and
toxins is also available at: http://www.selectagents.gov/SelectAgentsandToxinsList.html.
The HHS Secretary last republished the list of HHS select agents
and toxins in the Federal Register on October 5, 2012 (77 FR 61084).
The list of HHS select agents and toxins is divided into two sections.
The select agents and toxins listed in section 73.3 (HHS select agents
and toxins) are those regulated only by HHS under the authority of the
Bioterrorism Response Act (42 U.S.C. 262a). The select agents and
toxins listed in section 73.4 (Overlap select agents and toxins) are
those regulated by HHS under the authority of the Bioterrorism Response
Act and also regulated by the U.S. Department of Agriculture under the
authority of the Agricultural Bioterrorism Protection Act of 2002 (7
U.S.C. 8401).
The Bioterrorism Response Act requires the HHS Secretary to review
and republish the list of select agents and toxins on at least a
biennial basis. Using government subject matter experts, HHS/CDC
conducts the biennial review process in consultation with the HHS/CDC
Intragovernmental Select Agents and Toxins Technical Advisory Committee
(ISATTAC). The ISATTAC is comprised of Federal government employees
from CDC, Biomedical Advanced Research and Development Authority
(BARDA) within the Office of the Assistant Secretary for Preparedness
and Response, the National Institutes of Health (NIH), the Food and
Drug Administration (FDA), the Department of Homeland Security (DHS),
the Department of Defense (DOD), the USDA/Animal and Plant Health
Inspection Service (APHIS), USDA/Agricultural Research Service (ARS),
and USDA Center for Veterinary Biologics (CVB). Based on the criteria
outlined in the Bioterrorism Response Act, the ISATTAC considered the
following criteria in their review of the HHS and Overlap lists of
select agents and toxins: The degree of pathogenicity (ability of an
organism to cause disease), communicability (ability to spread from
infected to susceptible hosts), ease of dissemination, route of
exposure, environmental stability, ease of production in the
laboratory, ability to genetically manipulate or alter, long-term
health effects, acute morbidity (illness), mortality, available
treatment, status of host immunity, vulnerability of special
populations, and the burden or impact on the health care system.
On February 27, 2015, HHS/CDC published an advance notice of
proposed rulemaking (80 FR 10656) in which we requested public comment
on (1) whether there are biological agents or toxins that should be
added or removed from the HHS list of select agents and toxins; and (2)
whether HHS/CDC should remove the following six select agents from the
HHS list of select agents and toxins: Coxiella burnetti, Rickettsia
prowazekii, Bacillus anthracis Pasteur strain, Brucella abortus,
Brucella melitensis, and Brucella suis.

III. Summary of Proposed Changes

The following changes to the list of HHS select agents and toxins
are proposed based on comments received to the advance notice of
proposed rulemaking (80 FR 10656) referenced above, recommendations
from the ISATTAC, information from the DHS Material Threat
Determinations (DHS-MTD) of biological agents and toxins (https://www.medicalcountermeasures.gov/phemce/dhs.aspx), and the expertise of
federal agencies and staff responsible for the oversight of the
possession, use, and transfer of select agents and toxins. We are also
proposing specific changes to the current regulations, as discussed
below, addressing biosafety; clarifying regulatory language concerning
security, training, incident response, and records; correcting an
omission from the technical amendment (appeal process for exclusion);
and revision of the select agent list with current taxonomic names.

A. Definitions

We are proposing to add two new terms to section 73.1 (Definitions)
of the regulations. We are proposing to define the term
``Inactivation'' as ``a method to render a select agent non-viable but
retain characteristic of interest for future use, or to render any
nucleic acids that can produce infectious forms of any select agent
virus non-infectious for future use.'' We are also proposing to define
the term ``Kill curve'' as ``the results of a dose-response experiment
where a select agent is subjected to increasing amounts of the
inactivating treatment to determine the minimum conditions required to
render it non-viable or to render any nucleic acids that can produce
infectious forms of any select agent virus as non-infectious.'' The new
definitions will help clarify proposed regulatory language in section
73.12 (Biosafety).

B. Proposed Changes to the List of Select Agents

On February 27, 2015, HHS/CDC published an advance notice of
proposed rulemaking (ANPRM) (80 FR 10656) in which we requested public
comment specifically on whether there are biological agents or toxins
that should be added or removed from the HHS list of select agents and
toxins.
In that same docket, HHS/CDC also requested public comments as to
whether biological agents specifically listed in the February 27, 2015
ANPRM should be removed or remain on the list. The listed agents were
Coxiella burnetti, Rickettsia prowazekii, Bacillus anthracis Pasteur
strain, Brucella abortus, Brucella melitensis, and Brucella suis. We
are now proposing that these agents be removed from the

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HHS list of select agents based on the twenty-two comments received in
response to the February 27, 2015 ANPRM, recommendations from the
ISATTAC, and our review of current scientific data regarding these
biological agents.
Coxiella burnetii (42 CFR 73.3)
In response to the February 27, 2015 ANPRM, we received 11 comments
concerning Coxiella burnetii. Only two commenters recommended that C.
burnetii remain on the list because ``antibiotic treatment should not
be considered for removing the agent.'' The other nine commenters
argued that C. burnetii should not be included as a select agent based
on the following assertions:
Five commenters stated it is not easily transmitted from
person to person.
Three commenters referenced that even in the absence of
antibiotic treatment, Q fever (the disease with acute and chronic
stages caused by the bacteria C. burnetii) is generally a self-limited
flu-like illness with low mortality (Ref. 1).
All commenters acknowledged that most infections are
inapparent and most seropositive individuals cannot remember an
infection consistent with Q fever.
Six commenters agreed that Coxiella is susceptible to a
number of readily available antibiotics. Preferred treatments include
tetracycline or doxycycline. Quinolones have also been used
successfully and Co-trimoxazole is recommended in specific situations
such as pregnancy.
The ISATTAC recommended the removal of C. burnetii from the HHS
list of select agents and toxins because:
It has a low mortality rate with antibiotic treatment and
most seropositive individuals cannot remember an infection consistent
with Q fever (Ref. 2); and
A whole-cell killed vaccine (Q-Vax) with nearly 100%
efficacy is licensed in Australia and has been used to vaccinate U.S.
researchers whom were at risk (Ref. 3).
We are now proposing to remove C. burnetii from the HHS list of
select agents (42 CFR 73.3). As discussed above, our proposal is
supported by comments we received in response to the February 27, 2015
ANPRM and the recommendations of the ISATTAC. Both the commenters and
the ISATTAC supported their recommendations with the scientific
references noted above. We further conclude that, based on recent
information provided by DHS-MTD, C. burnetii does not pose a severe
threat to public health and safety. We are, however, still seeking
comment from those who may believe that C. burnetii remains a severe
threat to public health and safety and accordingly should be retained
as a HHS select agent.
Rickettsia prowazekii (42 CFR 73.3)
In response to the February 27, 2015 ANPRM, we received eight
comments concerning Rickettsia prowazekii. Only one commenter
recommended to retain Rickettsia prowazekii because ``antibiotic
treatment should not be considered for removing the agent.'' The other
seven commenters supported removal based on the following reasons:
The risk of mass casualties is low because R. prowazekii
can be treated with a single dose of doxycycline when symptoms are
present;
Transmissibility from person to person is low due to the
fact that R. prowazekii is usually transmitted via blood, although it
can be spread through inhalation of louse feces;
The agent has poor environmental stability; and
The difficulty in growing and purifying substantial
quantities of these agents in vitro.
The ISATTAC recommended the removal of R. prowazekii from the HHS
list of select agents and toxins because:
It is treatable with available antibiotics (Ref. 4 and 5);
The risk of mass casualties is low because R. prowazekii
can be treated with a single dose of doxycycline when symptoms are
present (Ref. 4 and 5); and
Transmissibility from person to person is low due to the
fact that R. prowazekii is usually transmitted via blood, although it
can be spread through inhalation of louse feces (Ref. 5).
We are now proposing to remove R. prowazekii from the HHS list of
select agents (42 CFR 73.3). As discussed above, our proposal is
supported by the comments we received in response to the February 27,
2015 ANPRM and the recommendations of the ISATTAC. Both the commenters
and the ISATTAC supported their recommendations with the scientific
references noted above. We further conclude that, based on recent
information provided by DHS-MTD, R. prowazekii does not pose a severe
threat to public health and safety. We are, however, still seeking
comment from those who may believe that R. prowazekii remains a severe
threat to public health and safety and accordingly should be retained
as a HHS select agent.
Bacillus anthracis Pasteur Strain (42 CFR 73.4)
We received six comments to the February 27, 2015 ANPRM with all
commenters agreeing that Bacillus anthracis Pasteur strain should not
be included as a select agent based on B. anthracis Pasteur strain
lacks the plasmid that encodes the toxin genes causing disease. The B.
anthracis Sterne strain, which lacks the plasmid that encodes for the
capsule, was excluded from the requirements of the regulations
effective on February 27, 2003.
The ISATTAC recommended the removal of B. anthracis Pasteur strain
from the overlap list of select agents and toxins because:
B. anthracis Pasteur strain lacks the plasmid that encodes
the toxin genes causing disease (Ref. 6);
B. anthracis Sterne strain, which lacks the plasmid that
encodes for the capsule, was excluded from the requirements of the
regulations effective on February 27, 2003 (Ref. 7-8); and
Historically, the B. anthracis Pasteur strain has been
retained as a select agent to allow for continued oversight of
laboratories in which the accidental (or intentional) combination of
this strain with the Sterne strain could occur to produce de novo the
wild type phenotype B. anthracis. However, a recent study indicates
that bacterial transformation of B. subtilis with plasmid DNA is
inefficient; indicating that transformation with plasmid pXO1 into
closely related bacteria such as the Bacillus anthracis Pasteur strain
would also be inefficient (Ref. 9).
We agreed with the commenters and ISATTAC. We propose to remove B.
anthracis Pasteur strain because the transformation of a virulence
plasmid from one Bacillus strain to another is difficult.
Brucella abortus, B. melitensis, and B. suis (42 CFR 73.4)
Responses were received from 16 commenters to the February 27, 2015
ANPRM, that addressed the retention of the three Brucella species (B.
abortus, B. melitensis, and B. suis) currently on the overlap select
agent list. Only two commenters recommended to retain these species
because ``antibiotic treatment should not be considered for removing
the agent.'' The other 14 commenters supported removal based on the
rationale provided in the ANPRM.
The ISATTAC recommended the removal of B. abortus, B. melitensis,
and B. suis from the overlap list of select agents and toxins because:
B. abortus has a low human mortality rate (Ref. 10);

[[Page 2808]]

B. abortus, B. melitensis, and B. suis are treatable with
antibiotics (Ref. 10); and
Human-to-human transmission is extremely rare, and
wildlife carriers in the United States often come into contact with
humans without significant transmission (Ref. 10).
We agreed with the commenters and ISATTAC. We propose to remove B.
abortus, B. melitensis, and B. suis because although Brucella has a low
infectious dose, it is treated, mortality is low, efficacy of treatment
is good for all three Brucella strains.

C. Inactivation of a Select Agent

We are proposing to add specific requirements to the biosafety
section of the regulations (42 CFR 73.12) to address the requirements
for rendering a select agent or an nucleic acids that can produce
infectious forms of any select agent virus ``non-viable.''
Sections 73.3 (HHS select agents and toxins) and 73.4 (Overlap
select agents and toxins) both provide that a ``non-viable'' select
agent is excluded from the requirements of the select agent
regulations. We are proposing that for an agent to be ``non-viable,''
or to render a nucleic acids that can produce infectious forms of any
select agent virus non-infectious for future use, an entity must use a
validated method. A validated method means that the method must be
scientifically sound such that method will produce consistent results
each time the method is used. As outlined in our guidance for ``Non-
viable Select Agents and Nonfunctional Select Toxins and Rendering
Samples Free of Select Agents and Toxins'' (http://www.selectagents.gov/guidance-nonviable.html), an inactivation
procedure may include (1) use of the exact conditions of an accepted
method that has been validated, such as autoclaving, (2) a published
method with adherence to the exact published conditions, or (3) for in-
house methods, validation testing should include the specific
conditions used and appropriate controls.
As part of the inactivation procedure, an entity would be required
to develop a site specific kill curve to identify conditions of
inactivation for each select agent or regulated nucleic acids that can
produce infectious forms of any select agent virus. If there are
strain-to-strain variations in resistance of a select agent to the
inactivation procedure, then a specific kill curve would be required to
be developed for each strain that undergoes the inactivation procedure.
A new kill curve would also be required to be created upon any change
in procedure or inactivation equipment. In addition, a validated
sterility testing protocol to ensure that the inactivation method has
rendered a select agent non-viable or regulated nucleic acids that can
produce infectious forms of any select agent virus non-infectious would
be required to be conducted.9ij
We are also proposing that written records be kept for a select
agent or extracts that have been subjected to a procedure to render
them non-viable or regulated nucleic acids that can produce infectious
forms of any select agent virus that have been subjected to a procedure
to render them non-infectious.
We are also soliciting ideas as to whether there are other methods
that should be required to validate the rendering of a select agent
non-viable or regulated nucleic acids that can produce infectious forms
of any select agent virus non-infectious.

D. Toxins

Due Diligence
Section 73.3(d)(3) of the select agent regulations (42 CFR
73.(d)(3))specifies the select toxin amounts under the control of a
principal investigator, treating physician or veterinarian, or
commercial manufacturer or distributor that are excluded from the
requirements of the select agent regulations. However, this exclusion
applies to the transfer of select toxins ``only after the transferor
uses due diligence and documents that the recipient has a legitimate
need . . . to handle or use such toxins'' (42 CFR 73.3(d)(3)(i)). This
provision was added to the select agent regulations to address the
concern that someone might be able to covertly stockpile toxins by
receiving multiple orders below the excluded amount. The toxin ``due
diligence'' provision requires a person transferring toxins in amounts
which would otherwise be excluded from the provisions to: (1) Use due
diligence to assure that the recipient has a legitimate need to handle
or use such toxins; and (2) report to the FSAP if they detect a known
or suspected violation of Federal law or become aware of suspicious
activity related to the toxin.
``Due diligence'' is generally understood to be such a measure of
prudence, activity, or assiduity, as is properly to be expected from,
and ordinarily exercised by, a reasonable and prudent person under the
particular circumstances; not measured by any absolute standard, but
depending on the relative facts of the specific case.
We are proposing to add a more specific documentation requirement
to the toxin exclusion provision to require the transferor to document
the identity of the recipient and the legitimate need (i.e.,
prophylactic, protective, bona fide research, or other peaceful
purpose) claimed by the transferee. Information required to be
documented would also include the name of the toxin and the total
amount transferred. Identity information of the person requesting and
using the toxins would include the individual's name, institution name,
address, telephone number, and email address.
Toxin Permissible Limits
In conjunction with this biennial review, the FSAP solicited input
from biological toxin subject matter experts to review the listed
exclusion limits for select toxins in the HHS select agent regulations.
To assess the amount necessary to weaponize a biological toxin, DHS
developed toxin parameters and attack scenarios for potential
inhalation and ingestion exposures to select toxins. DHS used the
formulas described below to estimate ingestion scenarios while
employing the ``NIST CONTAM Multizone Modeling'' software (http://www.bfrl.nist.gov/IAQanalysis/) for inhalation scenarios. To estimate
the amount of toxin for each scenario, DHS analyzed a range of release
sizes (in mg) for each biological toxin in order to estimate the number
of people that would be exposed to LD-50 (lethal dose, 50% or median
lethal dose, the amount of the substance required (usually per body
weight) to kill 50% of the test population); or TD-50 (the median toxic
dose of a toxin is the dose at which toxicity occurs in 50% of cases)
levels of each toxin amount by ingestion of milk (using published TD-50
or LD-50) and/or indoor inhalation (using published LD-50). The
inhalation models analyzed toxin releases in three different indoor
public facilities that experience heavy commuter volume (population
details for these facilities are given in Table 1). One hundred
scenarios were generated for each facility using 1-10[micro]m particle
sizes. The models used 10 random locations within each facility
(potential release locations and population evenly spaced throughout
occupied area) at 10 random times. The inhalation models assumed:
No immediate symptoms, so no changes in population
movement due to attack
Respiration rate 10L/min
All people assumed to have the same mass = 70 kg (e.g.,
did not account for lower doses required for children)

[[Page 2809]]

Table 1--Summary of Facility Population and Residence Times
----------------------------------------------------------------------------------------------------------------
Simulation
2008 Annual Simulation transient
Facility passenger transient average
traffic hourly residence time
(people) population (minutes)
----------------------------------------------------------------------------------------------------------------
High throughput transportation facilities....................... 255,500,000 43,750 10
High throughput transportation facilities....................... 219,000,000 37,500 15
High throughput transportation facilities....................... 64,300,000 11,005 60
----------------------------------------------------------------------------------------------------------------

The ingestion models investigated biological toxins introduced into
a fluid (e.g., milk) that was purchased and consumed by consumers over
a two day period. Production details and specifics of how the toxins
were introduced were not considered. In particular, the largest
scenarios involve contaminating greater than ten million servings,
which was determined to be implausible in practice. The ingestion
models made the following assumptions:
Milk containing specified quantity of active toxin (1 mg
to 1 kg) reaches store shelves.
Milk is consumed over six days at a uniform rate.
Contaminated milk is consumed daily until supply is
depleted or a health advisory is issued.
Milk contamination discovered and health advisory issued a
minimum of one day, and a maximum of >1 week post attack (at which
point all contaminated milk has been consumed).
For toxins other than saxitoxin and tetrodotoxin, the
attacker chooses a toxin concentration such that a person in the 45+
years old age group will consume 1 LD-50 (or TD-50) over 6 day
consumption period.
Since saxitoxin and tetrodotoxin are largely excreted in
approximately one day after consumption, the attacker chooses a
saxitoxin or tetrodotoxin concentration such that a person in the 45+
years old age group will consume 1 LD-50 (or TD-50) over a one day
consumption period.
Total volume of milk contaminated equals the number of
grams of toxin available divided by the toxin concentration (i.e.,
total volume of milk contaminated depends on the mass of toxin assumed
to be available (which varies from 1 mg to 1 kg) and the toxin
ingestion LD-50 (or TD-50)).
If the toxin ingestion LD-50 (or TD-50) is given by a
range, the geometric mean of this range is used.
Range of total volumes of milk contaminated is less than 1
L to approximately 10\8\ L.
The amount of milk contaminated is assumed to depend on
how much toxin the attacker has available (i.e., the total volume of
milk contaminated equals the number of grams of toxin available divided
by the toxin concentration). For example, for a 1 g attack, with a
toxin that has an LD-50 of 1mg/kg, the volume of milk contaminated
would be 1000 mg/(0.056 mg/mL*1000 mL/L) = 18 L of milk.
For small attack sizes, it is assumed the attacker would
target appropriately-sized small holding tanks or containers, while for
large attack sizes, the attacker would target large holding tanks or
silos.
If the toxin is degraded due to pasteurization or storage,
the amount of toxin introduced pre-processing would have to be
correspondingly larger than these masses.
Proposed Increase of Regulatory Exclusion Limits
Based on the data generated by the models described above, we are
proposing the following exclusion limits based on the amounts estimated
to expose less than 10 people by inhalation or less than 100 people by
ingestion to the LD-50 or TD-50 levels of toxin:
Increase the regulatory exclusion limit of Botulinum
neurotoxin (BoNT) from 0.5 mg to 1 mg;
Increase the regulatory exclusion limit of Staphylococcal
enterotoxins from 5 mg to 100 mg;
Increase the regulatory exclusion limit of saxitoxin from
100 mg to 500 mg;
Increase the regulatory exclusion limit of tetrodotoxin
from 100 mg to 500 mg;
Increase the regulatory exclusion limit of abrin from 100
mg to 1,000 mg;
Increase the regulatory exclusion limit of ricin from 100
mg to 1,000 mg; and
Increase the regulatory exclusion limit of DAS from 1,000
mg to 10,000 mg.
Increase the regulatory exclusion limit of T-2 from 1,000
mg to 10,000 mg.
We are, however, still seeking comment from those who may believe
that we should retain the current exclusion limits. In addition, we are
interested in receiving comments from the public on whether DAS and T-2
have the potential to pose a severe threat to public health and safety
or whether these two toxins should be removed from the select toxin
list given the high exclusion limit for DAS and T-2.
Proposed Removal of Select Toxins
Short, Paralytic Alpha-Conotoxins
We are proposing short, paralytic alpha-conotoxins containing the
following amino acid sequence
(X1CCX2PACGX3X4X5
X6CX7) be removed as a select toxin for the
following reasons:
The DHS model reported LD-50 value for inhalation delivery
of alpha-conotoxin is 20 [micro]g/kg, which is a low toxicity compared
to other select toxins;
A regulatory exclusion limit of 10,000 mg would require
the depletion of the cone snail population to achieve this quantity.
Therefore, based on the low toxicity of short, paralytic alpha-
conotoxins and the high dosage required for inhalation exposure, we are
proposing that the alpha-conotoxin be removed from the select toxin
list (Ref. 32).
Toxins: Exclusion of Original Food Samples and Clinical Samples
Original food samples and clinical samples are those specimens that
are submitted to laboratories for diagnosis or verification purposes to
identify or verify a biological agent or toxin. For example, an
original food sample could be a container of potato salad or juice. An
original clinical sample could be serum or stool from a patient.
Laboratories that test food sample and clinical samples for the
presence of toxins generally do not know the level of toxin in a sample
and do not extract and purify a toxin as part of their studies.
Therefore, we are proposing to exclude the original food sample or
clinical sample identified to contain an HHS select toxin to be
consistent with the rationale for the current exclusion for animals
exposed to toxins (42 CFR 73.3(d)(4)). The proposed exclusion is based
upon input from biological toxin subject matter experts and our
determination that quantifying the

[[Page 2810]]

amount of toxin in these samples is problematic because (1) the amount
of toxin is highly variable, which would require large amounts of food
and clinical samples to quantify or purify, (2) laboratory procedures
to extract toxin from samples are inefficient with most extractions
producing low yields; (3) the resources that would be required to
quantify toxins in clinical samples and food samples make sample
quantification prohibitively expensive; and (4) procedures in these
laboratories, based on the requirements of their public health mission,
are designed only for toxin detection and not for purification and
quantification. Therefore, we are interested in comments regarding our
rationale that the original food sample or clinical sample identified
to contain an HHS select toxin should be excluded from the select agent
regulation.
Exclusion of Toxin Produced as a Byproduct
Laboratories that are only registered for BoNT-producing species of
Clostridium do not normally have a need to account for BoNT produced
during the culturing of Clostridium since studying the toxin is not
part of their work objective. Therefore, we propose to exclude toxins
that are produced only as a byproduct to a study of the toxin producing
host organism so long as the toxin has not been intentionally
collected, purified, or otherwise extracted, and the material
containing the toxin is inactivated and properly disposed of within 30
days of the initiation of the culture. The 30 day disposal time was
recommended by biological toxin subject matter experts based on the
time it would take to grow the organism and perform the extraction
process. This exclusion allows laboratories whose purpose does not
include purification of the toxin to more effectively conduct outbreak
investigations, food studies, and molecular characterization of agents
which produce toxin. In the case of BoNT, these laboratories would
still be regulated for the BoNT-producing species of Clostridium and in
the case of all other HHS select toxins the laboratories would be
regulated if they wished to keep the material containing toxins for
longer than 30 days from the initiation of culture of the toxin
producing host organism. If at any time an entity manipulated the
material that contains the select toxin, such as intentional
collection, purification or extraction of the toxin from culture
supernatant, such activities would void this exemption, and the entity
would be required to be registered for the select toxin and meet all
applicable select agent and toxin regulatory requirements.

E. Exemptions for Select Agents and Toxins

Informing Specimen Provider
Since a registered or certified reference laboratory typically
confirms the identification of a select agent or toxin for public
health and agriculture, clinical and diagnostic laboratories, we are
proposing to require the registered or certified reference laboratory
inform the specimen provider of the identification. This will ensure
that the reference laboratory notifies the specimen provider of the
identification of the select agent or toxin so that the specimen
provider is aware that they are in possession of the agent or toxin and
must meet the requirements outlined in 42 CFR 73.5, 73.6.
Identification of Toxin
Once a clinical or diagnostic laboratory has identified a select
toxin-positive specimen, an APHIS/CDC Form 4 (Report of the
Identification of a Select Agent or Toxin) must be submitted to the
FSAP. The select agent regulations currently require the laboratory to
transfer or destroy the material within seven days of identification
(42 CFR 73.5(a), 73.6(a)) because we determined through input from
technical experts that the seven calendar days provides a sufficient
amount of time for the entity to destroy or transfer the select agents
or toxins after identification. In the past, we have received comments
that argued that the seven day requirement for transferring or
destroying select agents or toxins used for diagnosis or testing is too
short a time limit. Therefore, we are seeking comments to determine if
seven calendar days provides a sufficient amount of time for the entity
to destroy or transfer the select agents or toxins after
identification.
In addition, we are seeking comments to extend the exemption time
period to 30 days for BoNT and Staphylococcal enterotoxin (Subtypes A-
E) to allow clinical and diagnostic laboratories sufficient time to
complete their investigations without having to transfer or destroy the
sample. Laboratories would still be required to report the
identification of BoNT immediately and Staphylococcal enterotoxin
(Subtypes A-E) within seven days. We are proposing to amend the
language in 42 CFR 73.5(a), and 42 CFR 73.6(a)to read: ``Unless
directed otherwise by the HHS Secretary, within seven calendar days
after identification of the select agent and toxin (except for
Botulinum neurotoxin and/or Staphylococcal enterotoxin (Subtypes A-E)),
or within thirty calendar days after identification of Botulinum
neurotoxin and/or Staphylococcal enterotoxin (Subtypes A-E), the select
agent or toxin is transferred in accordance with Sec. 73.16 or
destroyed on-site by a recognized sterilization or inactivation
process,''
Patient Care
To clarify how the select agent regulations apply to activities
associated with the diagnosis and care for individuals infected with a
select agent or exposure to a select toxin, we are proposing to add
provisions that HHS/CDC will not regulate material containing a select
agent or toxin when it is in a patient care setting and is not being
otherwise collected, tested or retained for non-patient care purposes.
However, once delivery of patient care for an illness associated with a
select agent or toxin has concluded these specimens would become
subject to the regulatory requirements. An entity unable to meet all of
the regulatory requirements necessary to retain the material will then
have the option of transferring the material containing the select
agent or toxin in accord with the select agent regulations or
destroying the materials within seven calendar days of the conclusion
of patient care.
We also are proposing to clarify that FSAP does not regulate waste
generated during the delivery of patient care.

F. Registration

We are codifying in regulations the current FSAP policy that an
entity is required to meet all of the regulatory requirements for those
select agents and toxins listed on the entity's registration regardless
of whether the select agent or toxin is in the actual possession of the
entity; and without regard to the actual amounts of toxins in the
possession of the entity.

G. Responsible Official (RO)

Section 73.9(a)(6) of the select agent regulations currently states
that the Responsible Official must ensure that an annual inspection is
conducted for each laboratory where select agents and toxins are stored
or used. This requirement also provides that the results of each
inspection must be documented, and any deficiencies identified during
an inspection must be corrected. We are adding a requirement that the
Responsible Official must also document the corrective actions taken by
the entity to address any identified deficiencies.

[[Page 2811]]

HHS or USDA Office of the Inspector General Hotline
In response to a recommendation in the December 2014 Federal
Experts Security Advisory Panel report, we are adding a requirement
that the Responsible Official must ensure that individuals are provided
the contact information of the HHS or USDA Office of Inspector General
Hotline so that individuals are able to anonymously report a safety or
security concern related to select agents and toxins. In its December
2014 report, the Federal Experts Security Advisory Panel recommended
adding a specific requirement to include how individuals are informed
so that they can access the HHS or USDA Office of Inspector General
Hotline to anonymously report a safety or security concern.

H. Visitor Access to Select Agents and Toxins

Section 73.10(e) of the select agent regulations currently provides
that a person with a valid approval from the HHS Secretary or APHIS
Administrator to have access to select agents and toxins may request,
through his or her Responsible Official, that the HHS Secretary or
APHIS Administrator provide their approved access status to another
registered individual or entity for a specified period of time. This
allows a scientist registered to work with a select agent at a
registered entity to work with the select agent at another registered
entity. To ensure that the Responsible Official of the entity hosting
the visitor is aware if a visiting individual loses approval for access
to select agents and toxins, we are proposing to add a requirement that
the Responsible Official at the home entity must immediately notify the
Responsible Official of the visiting entity if the person's access to
select agents or toxins has been terminated.

I. Security, Biosafety, and Incident Response Plans

The select agent regulations require a registered entity to develop
and implement a number of plans in order to ensure the safety and
security of the select agents they handle. These are:
A security plan that provides for measures sufficient to
safeguard the select agent or toxin against unauthorized access, theft,
loss, or release (42 CFR 73.11);
A biosafety plan that provides for measures sufficient to
contain the select agent or toxin (e.g., physical structure and
features of the entity, and operational and procedural safeguards) (42
CFR 73.12); and
An incident response plan that provides for measures that
the registered entity will implement in the event of theft, loss, or
release of a select agent or toxin; inventory discrepancies; security
breaches (including information systems); severe weather and other
natural disasters; workplace violence; bomb threats and suspicious
packages; and emergencies such as fire, gas leak, explosion, power
outage, etc. The response procedures must account for hazards
associated with the select agent or toxin and appropriate actions to
contain such agent or toxin. (42 CFR 73.14)
Drills or exercises must be conducted at least annually to test and
evaluate the effectiveness of the plans. The plans must be reviewed and
revised, as necessary, after any drill or exercise and after any
incident. We are proposing to require that these drills or exercises be
documented to include how the drill or exercise tested and evaluated
the plan, any problems identified and corrective actions that were
taken, and the names of the individuals who participated in the drill
or exercise. This will provide a more thorough accounting of required
activities via testing and entity-directed improvements.
Similar to the existing requirement for the security plan, we are
also proposing to add a requirement that the biosafety and incident
response plans be submitted for initial registration, renewal of
registration, or when requested by FSAP.
Biosafety
We are proposing to amend the regulatory language in section 73.12
to update the name change of the National Institutes of Health (NIH)
Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid
Molecules (Ref. 31).
Prior to the publication of the 5th edition of CDC/NIH Biosafety in
Microbiological and Biomedical Laboratories (Ref. 3), the Occupational
Safety and Health Administration (OSHA) regulations in 29 CFR 1910.1200
and 1910.1450 provided specific requirements for handling hazardous
chemicals in the laboratories. This regulation also provided
recommendations for safely working with chemical including toxins and
gave non-mandatory recommendations for prudent practices in
laboratories handling chemical hazards. As such, we included this
reference for entities to consider when developing biosafety plans for
those facilities working with toxins. Since the current edition of the
CDC/NIH Biosafety in Microbiological and Biomedical Laboratories
Appendix I provides guidelines for work with toxins of biological
origin, we have removed the reference to the OSHA regulations in 29 CFR
1910.1200 and 1910.1450. It should be noted that regulated entities
must still meet the OSHA regulatory requirements where applicable.
In addition, we want to ensure that laboratory personnel that are
working with select agents and toxins are aware of the risks associated
with these agents. As such, we are proposing to add a requirement that
a laboratory-specific biosafety manual must be accessible to
individuals. This is consistent with guidance provided by the CDC/NIH
publication, Biosafety in Microbiological and Biomedical Laboratories.
This requirement is proposed to foster an enhanced culture of
responsibility by ensuring that appropriate biosafety resources are
available to all staff with access to select agents and toxins within a
select agent laboratory.
The current regulations require that the biosafety plan be written
using performance standards. In the aftermath of recent biosafety
incidents involving select agents, we are proposing that the biosafety
plan should be designed according to a site-specific risk assessment in
accordance with the risk of a select agent, given its intended use by
adding specific provisions to the biosafety section that would require
a written risk assessment for each registered select agent or toxin;
written safety procedures to protect entity personnel, the public, and
the environment from exposure to the select agent or toxin; written
decontamination procedures; and written waste management procedures.
The FSAP would also like to solicit ideas regarding any specific
biosafety measures that should be required to prevent LAIs or
accidental or intentional release of the select agents and toxins from
an entity into the community.
Security
We are proposing to amend the requirement that the security plan
contain a description of how the entity authorizes the means of entry
into areas where select agents or toxins are stored or used, to include
a requirement that the security plan must include a description of
centralized access control management systems (e.g., keycards) and/or
key management (mechanical keys).
Paragraphs (d)(7)(i) through (d)(7)(v) of section 11 of the select
agent regulations encompass a list of events that individuals with
access approval from the APHIS Administrator or the

[[Page 2812]]

HHS Secretary must immediately report to the Responsible Official. We
are proposing to add a new requirement that the Responsible Official
must be notified of any loss of computer, hard drive, or other data
storage device containing information that could be used to gain access
to select agents or toxins. We believe that such notification will
facilitate notification of the Federal Bureau of Investigation if
deemed necessary by the Responsible Official as the loss of such
equipment may be criminal in nature.

J. Training

We are proposing to amend section 15 of the select agent
regulations which concerns the provision of training for staff and
visitors who work in or visit areas where select agents or toxins are
handled or stored. Since individuals need to understand hazards
associated with the select agents and toxins that they will be working
with in the laboratory or are in the area they will be visiting, we are
proposing to require that all individuals who have received approval to
have access to select agents and toxins have training that address the
particular needs of the individual and the risks posed by the select
agent or toxin regardless of whether they have access to the select
agents or toxins. The training would have to be completed within 12
months of that individual's anniversary of receiving access approval or
prior to his or her entry into an area where any select agents and
toxins are used or stored, whichever occurs first. This change is
necessary in order to codify our policy regarding which individuals at
registered entities are required to receive training.
We are also proposing to add a new paragraph (e) to section 15,
which would require the entity's Responsible Official to provide
contact information for the USDA or HHS Office of the Inspector General
Hotline. Details of the proposed addition may be found under the
heading ``Responsible Official.''

K. Records

Based on inspections of registered entities, we observed that
entities are maintaining records of the destruction of select agents
even though section 73.17 of the select agent regulations currently
does not include a requirement for documenting when a select agent is
destroyed. To ensure the proper tracking of a select agent from
acquisition to destruction and to incorporate into the regulations what
entities are currently doing, we are proposing to add the requirement
for records to be created and maintained for the destruction of a
select agent held in long-term storage to include the quantity (i.e.,
number of vials) of select agent destroyed, the date of such action,
and by whom.
Section 73.17 of the select agent regulations currently states that
records and databases need to be accurate. To ensure that handwritten
records are accurate, we are proposing to clarify that hand-written
record must be legible (i.e., capable of being read).
We are proposing to expand the scope of records required to be
maintained to include any records that contain information related to
the requirements of the regulations. Such records may include, but
would not limited to, biocontainment certifications, laboratory
notebooks, institutional biosafety and/or animal use committee minutes
and approved protocols, and records associated with occupational health
and suitability programs. We propose revision to the regulations will
enhance the ability of FSAP to evaluate biosafety, security, and
incident response programs and includes any record created under
sections 73.5, 73.7, 73.9, 73.11, 73.12, 73.14, 73.15, 73.16, 73.17,
and 73.19 of the select agent regulations.
Records for Long-term Storage
The FSAP continues to receive comments that are critical of that
portion of the select agent regulations that require a registered
entity to maintain ``an accurate, current inventory for each select
agent . . . held in long term storage.'' The comments typically focus
on the belief that a container based inventory requirement is not
useful to track inventory of biological agents of which small amounts
of samples from the container could be stolen without detection and
used to grow larger quantities. In the Public Health Security and
Bioterrorism Preparedness and Response Act of 2002, Congress requires
the Secretaries of Health and Human Services and Agriculture to include
in the select agent regulations a requirement for ``the prompt
notification of the Secretary, and appropriate Federal, State, and
local law enforcement agencies, of the theft or loss of listed agents
and toxins.'' HHS/CDC is soliciting ideas on any alternative regulatory
requirement that could be constructed such that a registered entity
would know whether it had a theft or loss of a select agent or toxin
without that registered entity first having ``an accurate, current
inventory for each select agent . . . held in long term storage.''

V. Required Regulatory Analyses

A. Executive Orders 12866 and 13563

Under Executive Order 12866 (EO 12866), Regulatory Planning and
Review (58 FR 51735, October 4, 1993) HHS/CDC is required to determine
whether this regulatory action would be ``significant'' and therefore
subject to review by the Office of Management and Budget (OMB) and the
requirements of the Executive Orders. This order defines ``significant
regulatory action'' as any regulatory action that is likely to result
in a rule that may:
Have an annual effect on the economy of $100 million or
more or adversely affect in a material way the economy, a sector of the
economy, productivity, competition, jobs, the environment, public
health or safety, or state, local, or tribal governments or
communities;
Create a serious inconsistency or otherwise interfere with
an action taken or planned by another agency;
Materially alter the budgetary impact of entitlements,
grants, user fees, or loan programs or the rights and obligations of
recipients; or,
Raise novel legal or policy issues arising out of legal
mandates, the President's priorities, or the principles set forth in EO
12866.
Executive Order 13563 (EO 13563), Improving Regulation and
Regulatory Review, (76 FR 3821, January 21, 2011), updates some of the
provisions of EO 12866 in order to promote more streamlined regulatory
actions. This EO charges, in part, that, while protecting ``public
health, welfare, safety, and our environment'' that regulations must
also ``promote predictability and reduce uncertainty'' in order to
promote economic growth. Further, regulations must be written in plain
language and be easy to understand.
HHS/CDC has determined that this NPRM is a significant regulatory
action as defined in EO 12866. However, the Office of Management and
Budget has waived their review of the document.

B. The Regulatory Flexibility Act (RFA), as Amended by the Small
Business Regulatory Enforcement Fairness Act (SBREFA)

We have examined the impacts of the proposed rule under the
Regulatory Flexibility Act (5 U.S.C. 601-612). Unless we certify that
the proposed rule is not expected to have a significant economic impact
on a substantial number of small entities, the Regulatory Flexibility
Act (RFA), as amended by the Small Business Regulatory Enforcement
Fairness Act (SBREFA), requires agencies to analyze regulatory

[[Page 2813]]

options that would minimize any significant economic impact of a rule
on small entities. We certify that this proposed rule will not have a
significant economic impact on a substantial number of small entities
within the meaning of the RFA.
This regulatory action is not a major rule as defined by Sec. 804
of the Small Business Regulatory Enforcement Fairness Act of 1996. This
proposed rule will not result in an annual effect on the economy of
$100,000,000 or more; a major increase in cost or prices; or
significant adverse effects on competition, employment, investment,
productivity, innovation, or on the ability of United States-based
companies to compete with foreign-based companies in domestic and
export markets.

C. Paperwork Reduction Act of 1995

In accordance with section 3507(d) of the Paperwork Reduction Act
of 1995 (44 U.S.C. 3501 et seq.), HHS/CDC has determined that the
Paperwork Reduction Act does apply to information collection and
recordkeeping requirements included in this rule. We note that the
information collection and recordkeeping requirements are already
approved by the Office of Management and Budget (OMB) under OMB Control
Number 0920-0576.

D. EO 12988: Civil Justice Reform

This rule has been reviewed under E.O. 12988, Civil Justice Reform.
Once the final rule is in effect, HHS/CDC notes that: (1) All State and
local laws and regulations that are inconsistent with this rule will be
preempted; (2) No retroactive effect will be given to this rule; and
(3) Administrative proceedings will not be required before parties may
file suit in court challenging this rule.

E. EO 13132: Federalism

HHS/CDC has reviewed this proposed rule in accordance with
Executive Order 13132 regarding Federalism, and has determined that it
does not have ``federalism implications.'' The rule does not ``have
substantial direct effects on the States, on the relationship between
the national government and the States, or on the distribution of power
and responsibilities among the various levels of government.''
In accordance with section 361(e) of the PHSA [42 U.S.C. 264(e)],
nothing in this rule would supersede any provisions of State or local
law except to the extent that such a provision conflicts with this
rule.

F. Plain Language Act of 2010

Under the Plain Language Act of 2010 (P.L. 111-274, October 13,
2010), executive Departments and Agencies are required to use plain
language in documents that explain to the public how to comply with a
requirement the Federal Government administers or enforces. HHS/CDC has
attempted to use plain language in promulgating this rule consistent
with the Federal Plain Writing Act guidelines.

VI. References

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1999;12(4):518-53.
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8. Federal Select Agent Program, ``Select Agents and Toxins
Exclusions,'' http://www.selectagents.gov/SelectAgentsandToxinsExclusions.html.
9. C. Johnston, B. Martin, G. Fichant, P. Polard, and J.P.
Claverys. Bacterial transformation: distribution, shared mechanisms
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of Clostridium botulinum Type A Neurotoxin, in Bacterial Toxins:
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0211990: Aberdeen Proving Ground, Maryland.
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staphylococcal enterotoxin B. J Bacteriol, 1969. 98(1): 4-9.
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Recombinant Or Synthetic Nucleic Acid Molecules (NIH Guidelines).
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Toxicology and Pharmacology, July 2014. 70: 197-202.

[[Page 2814]]

List of Subjects in 42 CFR Part 73

Biologics, Packaging and containers, Penalties, Reporting and
recordkeeping requirements, Transportation.

For the reasons discussed in the preamble, we propose to amend 42
CFR part 73 as follows:

PART 73--SELECT AGENTS AND TOXINS

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

Authority: 42 U.S.C. 262a; sections 201-2014, 221 and 231 of
Title II of Public Law 107-188, 116 Stat 637 (42 U.S.C. 262a).

0
2. Section 73.1 is amended by adding in alphabetical order, definitions
of inactivation and kill curve to read as set forth below.

Sec. 73.1 Definitions.

* * * * *
Inactivation means a method to render a select agent non-viable but
retain characteristic of interest for future use, or to render any
nucleic acids that can produce infectious forms of any select agent
virus non-infectious for future use.
* * * * *
Kill curve means the results of a dose-response experiment where a
select agent is subjected to increasing amounts of the inactivating
treatment to determine the minimum conditions required to render it
non-viable or to render any nucleic acids that can produce infectious
forms of any select agent virus as non-infectious.
* * * * *
0
3. Section 73.3 is amended as follows:
0
a. By revising paragraph (b).
0
b. By adding new paragraphs (d)(2)(i), (ii), and (iii).
0
c. By revising paragraphs (d)(3) introductory text and (d)(3)(i).
0
d. By redesignating paragraph (d)(5) as paragraph (d)(7).
0
e. By adding new paragraphs (d)(5), (d)(6), and (d)(8).
0
f. By adding paragraph (e)(3) to read as set forth below.
The additions and revisions read as follows:

Sec. 73.3 HHS select agents and toxins.

* * * * *
(b) HHS select agents and toxins:

Abrin
Botulinum neurotoxins*
Botulinum neurotoxin producing species of Clostridium*
Crimean-Congo hemorrhagic fever virus
Diacetoxyscirpenol
Eastern equine encephalitis virus
Ebola virus*
Francisella tularensis*
Lassa fever virus
Lujo virus
Marburg virus*
Monkeypox virus
Reconstructed replication competent forms of the 1918 pandemic
influenza A virus containing any portion of the coding regions of all
eight gene segments (Reconstructed 1918 influenza A virus)
Ricin
SARS coronavirus (SARS-CoV)
Saxitoxin
South American hemorrhagic fever viruses:
Chapare
Guanarito
Junin
Machupo
Sabia
Staphylococcal enterotoxins (subtypes A-E)
T-2 toxin
Tetrodotoxin
Tick-borne encephalitis virus
Far Eastern subtype
Siberian subtype
Kyasanur Forest disease virus
Omsk haemorrhagic fever virus
Variola major virus (Smallpox virus) *
Variola minor virus (Alastrim) *
Yersinia pestis*
* * * * *
(d)* * *
(2) Non-viable HHS select agents or nonfunctional HHS toxins.
(i) Unless waived by the HHS Secretary, a select agent or regulated
nucleic acids that can produce infectious forms of any select agent
virus that has been subjected to a validated inactivation process to
remove viability or infectious form (i.e., the ability to reproduce or
produce disease, while maintaining cellular structure) is not excluded
from the requirements of this part until an individual or entity:
(A) Develops a site-specific kill curve to define conditions of
inactivation for each select agent or regulated nucleic acids that can
produce infectious forms of any select agent virus. If there are
strain-to-strain variations in resistance of a select agent to the
inactivation procedure, then a specific kill curve must be developed
for each strain that undergoes the inactivation procedure. A new kill
curve must be created upon any change in procedure or inactivation
equipment.
(B) Develops site-specific standard operating inactivation
procedures to ensure that the material is inactivated by a safety
margin determined by the kill curve.
(C) Subjects representative samples of inactivated select agents or
any nucleic acids that can produce infectious forms of any select agent
viruses to a validated sterility testing protocol to ensure that the
inactivation method has rendered the select agent non-viable or
regulated nucleic acids non-infectious.
(D) Any viability of a select agent or infectivity of regulated
nucleic acids that can produce infectious forms of any select agent
virus that was subjected to a validated inactivation protocol is
reported to APHIS or CDC.
(E) Reviews annually, and revises as necessary, the following:
(1) The kill curve procedure and results;
(2) Site-specific standard operating procedures to ensure that
select agents or regulated nucleic acids that can produce infectious
forms of any select agent virus are inactivated by a safety margin; and
(3) The validated sterility testing protocol used to ensure that
the inactivation method has rendered a select agent non-viable or
regulated nucleic acids that can produce infectious forms of any select
agent virus sample non-infectious.
(F) Reviews, and revises as necessary, documents listed in
paragraph (d)(2)(i)(E) of this section after any change in principal
investigator, change in protocol, or any reported viability of a select
agent or infectivity of regulated nucleic acids that can produce
infectious forms of any select agent viruses previously assessed as
inactive.
(ii) Unless waived by the HHS Secretary, an extract from a select
agent is not excluded from the requirements of this part until an
individual or entity meets the following requirements:
(A) Any extract is subjected to a process that removes all viable
cells, spores, or virus particles.
(B) Any extract is subjected to a validated sterility testing
protocol to ensure that the inactivation method has rendered the
extract free of a select agent.
(C) Any viability of an extract that was subjected to a validated
inactivation protocol is reported to the Responsible Official.
(D) Any viability of a select agent or infectivity of regulated
nucleic acids that can produce infectious forms of any select agent
virus that was previously assessed as inactive by their validated
sterility testing protocol is reported to APHIS or CDC.
(3) Except as required in Sec. 73.16(l), the aggregate amount of
the toxin under the control of a principal investigator, treating
physician or veterinarian, or commercial manufacturer or distributor
does not, at any time, exceed the following amounts: 1000 mg of Abrin;
1 mg of Botulinum neurotoxins; 10,000

[[Page 2815]]

mg of Diacetoxyscirpenol; 1000 mg of Ricin; 500 mg of Saxitoxin; 100 mg
of Staphylococcal enterotoxins (subtypes A-E); 10,000 mg of T-2 toxin;
or 500 mg of Tetrodotoxin.
(i) The toxin is transferred only after the transferor uses due
diligence and documents the identification of the recipient and the
legitimate need (i.e., prophylactic, protective, bona fide research, or
other peaceful purpose) claimed by the recipient to use such toxin.
Information to be documented includes, but is not limited to, the
recipient identity information, including the recipient's name,
institution name, address, telephone number and email address; name of
the toxin and the total amount transferred, and the legitimate need
claimed by the recipient. Notwithstanding the provisions of paragraph
(d) of this section, the HHS Secretary retains the authority to,
without prior notification, inspect and copy or request the submission
of the due diligence documentation to the CDC.
* * * * *
(5) An HHS select toxin identified in an original food sample or
clinical sample.
(6) Select toxins that are produced as a byproduct in the study of
the toxin producing host organism so long as the toxin has not been
intentionally cultivated, collected, purified, or otherwise extracted,
and the material containing the toxin is rendered non-functional and
disposed of within 30 days of the initiation of the culture.
* * * * *
(8) Waste generated during the delivery of patient care from a
patient infected with a select agent that is decontaminated with a
validated method within seven calendar days of the conclusion of
patient care,
(e) * * *
(3) An individual or entity may make a written request to the HHS
Secretary for reconsideration of a decision denying an application for
the exclusion of an attenuated strain of a select agent or a select
toxin modified to be less potent or toxic. The written request for
reconsideration must state the facts and reasoning upon which the
individual or entity relies to show the decision was incorrect. The HHS
Secretary will grant or deny the request for reconsideration as
promptly as circumstances allow and will state, in writing, the reasons
for the decision.
* * * * *
0
4. Section 73.4 is amended as follows:
0
a. By revising paragraph (b).
0
b. By adding new paragraphs (d)(2)(i), (ii), and (iii).
0
c. By adding paragraph (d)(4).
0
d. By adding paragraph (e)(3).
The revision and additions read as follows:

Sec. 73.4 Overlap select agents and toxins.

* * * * *
(b) Overlap select agents and toxins:
Bacillus anthracis*
Burkholderia mallei*
Burkholderia pseudomallei*
Hendra virus
Nipah virus
Rift Valley fever virus
Venezuelan equine encephalitis virus
* * * * *
(d) * * *
(2) * * *
(i) Unless waived by the APHIS Administrator or HHS Secretary, a
select agent or regulated nucleic acids that can produce infectious
forms of any select agent virus that has been subjected to a validated
inactivation process to remove viability or infectious form (i.e., the
ability to reproduce or produce disease, while maintaining cellular
structure) is not excluded from the requirements of this part until an
individual or entity:
(A) Develops a site-specific kill curve to define conditions of
inactivation for each select agent or regulated nucleic acids that can
produce infectious forms of any select agent viruses. If there are
strain-to-strain variations in resistance of a select agent to the
inactivation procedure, then a specific kill curve must be developed
for each strain that undergoes the inactivation procedure. A new kill
curve must be created upon any change in procedure or inactivation
equipment.
(B) Develops site-specific standard operating inactivation
procedures to ensure that the material is inactivated by a safety
margin determined by the kill curve.
(C) Subjects representative samples of inactivated select agents or
nucleic acids that can produce infectious forms of any select agent
viruses to a validated sterility testing protocol to ensure that the
inactivation method has rendered a select agent non-viable or regulated
nucleic acids non-infectious.
(D) Reports any viability of a select agent or infectivity of
regulated nucleic acids that can produce infectious forms of any select
agent virus that was subjected to a validated inactivation protocol to
the Responsible Official.
(E) Reviews annually, and revises as necessary, the following:
(1) The kill curve procedure and results;
(2) Site-specific standard operating procedures to ensure that
select agents or regulated nucleic acids that can produce infectious
forms of any select agent viruses are inactivated by a safety margin;
and
(3) The validated sterility testing protocol used to ensure that
the inactivation method has rendered a select agent non-viable or
regulated nucleic acids that can produce infectious forms of any select
agent viruses non-infectious.
(F) Reviews, and revises as necessary, documents listed in
paragraph (d)(2)(i)(E) of this section after any change in principal
investigator, change in protocol, or any reported viability of a select
agent or infectivity of regulated nucleic acids that can produce
infectious forms of any select agent virus previously assessed as
inactive.
(ii) Unless waived by the APHIS Administrator or HHS Secretary, an
extract from a select agent is not excluded from the requirements of
this part until an individual or entity meets the following
requirements:
(A) Any extract is subjected to a process that removes all viable
cells, spores, or virus particles.
(B) Any extract is subjected to a validated sterility testing
protocol to ensure that the inactivation method has rendered the
extract free of a select agent.
(C) Any viability of an extract that was subjected to a validated
inactivation protocol is reported to the Responsible Official.
(D) Any viability of a select agent or infectivity of regulated
nucleic acids that can produce infectious forms of any select agent
virus that was previously assessed as inactive by the validated
sterility testing protocol is reported to APHIS or CDC.
(d) * * *
(4) Waste generated during the delivery of patient care from a
patient infected with a select agent that is decontaminated with a
validated method within seven calendar days of the conclusion of
patient care.
(e) * * *
(3) An individual or entity may make a written request to the HHS
Secretary or APHIS Administrator for reconsideration of a decision
denying an application for the exclusion of an attenuated strain of a
select agent or a select toxin modified to be less potent or toxic. The
written request for reconsideration must state the facts and reasoning
upon which the individual or entity relies to show the decision was
incorrect. The HHS Secretary or APHIS Administrator will grant or deny
the request for reconsideration as promptly as circumstances allow and
will state, in writing, the reasons for the decision.
* * * * *

[[Page 2816]]

0
5. Section 73.5 is amended as follows:
0
a. By revising paragraph (a)(1).
0
b. By redesignating paragraph (a)(3) as paragraph (a)(4) and revising
newly redesignated paragraph (a)(4).
0
c. By adding new paragraph (a)(3).
The revisions and addition read as follows:

Sec. 73.5 Exemptions for HHS select agents and toxins.

(a) * * *
(1) Unless directed otherwise by the HHS Secretary, within seven
calendar days after identification of the select agent and toxin
(except for Botulinum neurotoxin and/or Staphylococcal enterotoxin
(Subtypes A-E)), or within thirty calendar days after identification of
Botulinum neurotoxin and/or Staphylococcal enterotoxin (Subtypes A-E),
the select agent or toxin is transferred in accordance with Sec. 73.16
or destroyed on-site by a recognized sterilization or inactivation
process,
* * * * *
(3) Unless otherwise directed by the HHS Secretary, the clinical or
diagnostic specimens collected from a patient infected with a select
agent are transferred in accordance with Sec. 73.16 or destroyed on-
site by a recognized sterilization or inactivation process within seven
days after delivery of patient care has concluded, and
(4) The identification of the agent or toxin is reported to CDC or
APHIS, the specimen provider, and to other appropriate authorities when
required by Federal, State, or local law by telephone, facsimile, or
email. This report must be followed by submission of APHIS/CDC Form 4
to APHIS or CDC within 7 calendar days after identification.
* * * * *
0
6. Section 73.6 is amended as follows:
0
a. By redesignating paragraph (a)(3) as paragraph (a)(4) and revising
newly redesignated paragraph (a)(4).
0
b. By adding paragraph (a)(3).
The revision and addition read as follows:

Sec. 73.6 Exemptions for overlap select agents and toxins.

(a) * * *
(3) Unless otherwise directed by the HHS Secretary or
Administrator, the clinical or diagnostic specimens collected from a
patient infected with a select agent are transferred in accordance with
Sec. 73.16 or destroyed on-site by a recognized sterilization or
inactivation process within seven days after delivery of patient care
has concluded, and
(4) The identification of the agent or toxin is reported to CDC or
APHIS, the specimen provider, and to other appropriate authorities when
required by Federal, State, or local law by telephone, facsimile, or
email. This report must be followed by submission of APHIS/CDC Form 4
to APHIS or CDC within 7 calendar days after identification.
* * * * *
0
7. Section 73.7 is amended as follows:
0
a. By redesignating paragraphs (b) through (k) as paragraphs (c)
through (l), respectively.
0
b. By adding a new paragraph (b) to read as follows:

Sec. 73.7 Registration and related security risk assessments.

* * * * *
(b) As a condition of registration, each entity is required to be
in compliance with the requirements of this part for select agents and
toxins listed on the registration regardless of whether the entity is
in actual possession of the select agent or toxin. With regard to
toxins, the entity registered for possession, use or transfer of a
toxin must be in compliance with the requirements of this part
regardless of the amount of toxin currently in possession.
* * * * *
0
8. Section 73.9 is amended as follows:
0
a. In paragraph (a)(6) by removing ``laboratory'' and adding in its
place ``registered space'' and adding ``and the corrections
documented'' after ``corrected'' at the end of the sentence.
0
b. By adding paragraph (a)(7) to read as set forth below.

Sec. 73.9 Responsible Official.

(a) * * *
(7) Ensure that individuals are provided the contact information
for the HHS or USDA Office of Inspector General Hotline so that they
may anonymously report any safety or security concerns related to
select agents and toxins.
* * * * *
0
9. Section 73.10 is amended by adding a new sentence to the end of
paragraph (e) to read as follows:

Sec. 73.10 Restricting access to select agents and toxins; security
risk assessments.

* * * * *
(e) * * * A Responsible Official must immediately notify the
Responsible Official of the visited entity if the person's access to
select agents and toxins has been terminated.
* * * * *
0
10. Section 73.11 is amended as follows:
0
a. In paragraph (c)(5) by adding ``keycards,'' between ``keys,'' and
``passwords'' and removing ``numbers'' and adding in its place
``permissions''.
0
b. By adding paragraph (c)(11).
0
c. By adding paragraph (d)(7)(vi).
0
d. By adding a sentence to the end of paragraph (h).
The additions read as follows:

Sec. 73.11 Security.

* * * * *
(c) * * *
(11) Describe how the entity authorizes the means of entry into
areas where select agents or toxins are stored or used, to include
centralized access control management systems (e.g., keycards) and/or
mechanical key management.
(d) * * *
(7) * * *
(vi) Any loss of computer, hard drive or other data storage device
containing information that could be used to gain access to select
agents or toxins.
* * * * *
(h) * * * Drills or exercises must be documented to include how the
drill or exercise tested and evaluated the plan, any problems that were
identified and corrective action(s) taken, and all individuals who
participated in the drill or exercise.
0
11. Section 73.12 is amended as follows:
0
a. By revising paragraph (a).
0
b. By removing paragraph (c)(2), redesignating paragraph (c)(3) as
(c)(2), and in newly redesignated paragraph (c)(2), removing ``NIH
Guidelines for Research Involving Recombinant DNA Molecules'' and
adding in its place ``NIH Guidelines for Research Involving Recombinant
or Synthetic Nucleic Acid Molecules''.
0
c. By adding a new sentence to the end of paragraph (e).
The revision and addition read as follows:

Sec. 73.12 Biosafety.

(a) An individual or entity required to register under this part
must develop and implement a written biosafety plan that is
commensurate with the risk of the select agent or toxin, given its
intended use. The biosafety plan must contain sufficient information
and documentation to describe the biosafety and containment procedures
for the select agent or toxin, including any animals (including
arthropods) or plants intentionally or accidentally exposed to or
infected with a select agent. Biosafety and containment procedures
specific to each registered laboratory must be available to each
individual working in that laboratory. The current biosafety plan must
be submitted for initial registration, renewal of registration, or

[[Page 2817]]

when requested. The biosafety plan must include the following
provisions:
(1) A written risk assessment for each procedure involving a select
agent or toxin that addresses the hazards associated with the agent or
toxin.
(i) The hazardous characteristics of each agent or toxin listed on
the entity's registration, including probable routes of transmission in
the laboratory and in the environment, infective dose (if known),
stability in the environment, host range, contribution of any genetic
manipulations, and endemicity.
(ii) Hazards associated with laboratory procedures related to the
select agent or toxin;
(2) Safeguards in place with associated work practices to protect
registered entity personnel, the public, and the environment from
exposure to the select agent or toxin including, but not limited to:
Safety training requirements for registered entity personnel performing
the procedure; required personal protective equipment and other safety
equipment; required containment equipment including, but not limited
to, biological safety cabinets, animal caging systems, and centrifuge
safety containers; and required engineering controls and other facility
safeguards.
(3) Written procedures for decontamination with a validated method,
of all contaminated or potentially contaminated materials including,
but not limited to: Cultures and other materials related to the
propagation of select agents or toxins, items related to the analysis
of select agents and toxins, personal protective equipment, animal
caging systems and bedding, and animal carcasses or extracted tissues.
(4) Written procedures for decontamination, with a validated
method, of laboratory surfaces and equipment using manufacturer's
specification.
(5) Effluent decontamination procedures, with a validated method,
that describe the treatment of effluent material contaminated with
select agents and toxins.
(6) Procedures to respond to emergencies such as spills, sharps
injury, or animal bites involving select agents and toxins.
(7) Procedures for the handling of select agents and toxins in the
same spaces with non-select agents and toxins in order to prevent
unintentional contamination.
* * * * *
(e) * * * Drills or exercises must be documented to include how the
drill or exercise tested and evaluated the plan, any problems that were
identified and corrective action(s) taken, and all individuals who
participated in the drill or exercise.
0
12. Section 73.14 is amended as follows:
0
a. By adding a new sentence to the end of paragraph (a).
0
b. By adding a new sentence to the end of paragraph (f).
The additions read as follows:

Sec. 73.14 Incident response.

(a) * * * The current incident response plan must be submitted for
initial registration, renewal of registration, or when requested.
* * * * *
(f) * * * Drills or exercises must be documented to include how the
drill or exercise tested and evaluated the plan, any problems that were
identified and corrective action(s) taken, and all individuals who
participated in the drill or exercise.
0
13. Section 73.15 is amended as follows:
0
a. In paragraph (a)(1) by removing ``before that individual has such
access to select agents and toxins'' and adding in its place ``, within
12 months of that individual's anniversary of receiving such approval
or prior to his or her entry into an area where select agents or toxins
are used or stored, whichever occurs first.''.
0
b. By adding paragraph (e) to read as set forth below.

Sec. 73.15 Training.

* * * * *
(e) The Responsible Official must ensure and document that
individuals are provided the contact information of the HHS or USDA
Office of Inspector General Hotline so that they may anonymously report
any safety or security concerns related to select agents and toxins.
0
14. Section 73.16 is amended by revising paragraph (l)(1) to read as
follows:

Sec. 73.16 Transfers.

* * * * *
(l) * * *
(1) Transfer the amounts only after the transferor uses due
diligence and documents that the recipient has a legitimate need (i.e.,
prophylactic, protective, bona fide research, or other peaceful
purpose) to handle or use such toxins. Information to be documented
includes, but is not limited, to the recipient information, toxin and
amount transferred, and declaration that the recipient has legitimate
purpose to store and use such toxins.
* * * * *
0
15. Section 73.17 is amended as follows:
0
a. In paragraphs (a)(1)(iii) and (a)(3)(v) by adding ``or other storage
container'' after ``freezer''.
0
b. By adding paragraph (a)(1)(ix).
0
c. By adding paragraph (a)(8).
0
d . In paragraph (b) by adding ``legible,'' after ``are''.
0
e. By revising paragraph (c).
The revision and additions read as follows:

Sec. 73.17 Records.

(a) * * *
(1) * * *
(ix) If destroyed, the quantity (e.g., containers, vials, tubes,
etc.) of select agent destroyed, the date of such action, and by whom.
* * * * *
(8) For a select agent or an extract from a select agent that has
been rendered non-viable or regulated nucleic acids that can produce
infectious forms of any select agent virus that have been rendered non-
infectious through inactivation:
(i) A written description of the inactivation process used for
rendering a select agent non-viable or regulated nucleic acids that can
produce infectious forms of any select agent virus non-infectious;
(ii) The sterility testing protocol used to verify non-viability of
a select agent or non-infectivity of regulated nucleic acids that can
produce infectious forms of any select agent virus and the results of
the test, including investigation, of any inactivation process failures
and the corrective actions taken;
(iii) The name of each individual performing the inactivation
method and sterility testing protocols;
(iv) The date(s) the inactivation method and sterility testing
protocols were completed;
(v) The location where the inactivated method and sterility testing
protocols were performed; and
(vi) An inactivation certificate that includes the date of
inactivation, method of inactivation, date of final sterility testing
protocol result, and the Principal Investigator. A copy of the
inactivation certificate must accompany any transfer of inactivated
material.
* * * * *
(c) Any records that contain information related to the
requirements of the regulations. Such records may include, but are not
limited to, biocontainment certifications, laboratory notebooks,
institutional biosafety and/or animal use committee minutes and
approved protocols, and records associated with occupational

[[Page 2818]]

health and suitability programs. All records created under this part
must be maintained for 3 years.
* * * * *

Dated: January 12, 2016.
Sylvia M. Burwell,
Secretary.
[FR Doc. 2016-00758 Filed 1-14-16; 4:15 pm]
BILLING CODE 4163-18-P