Guidance Document for Exclusion of Select Agents and Tox

Form Approved
OMB Control No. 0920-0576
Exp. Date xx/xx/2020

Exclusion Guidance
Document
(42 CFR §§ 73.3, 73.4; 9 CFR §§ 121.3, 121.4; 7
CFR § 331.3)

(March 2017)

Centers for Disease Control and Prevention (CDC)
Division of Select Agents and Toxins
Animal and Plant Health Inspection Service (APHIS)
Agriculture Select Agent Services

Table of Contents
Change/Highlight Section ................................................................................................................................................3
Introduction .....................................................................................................................................................................3
Regulatory Exclusions ......................................................................................................................................................4
Requests for Exclusion of Attenuated Strains or Toxins Modified to be Less Potent or Toxic .......................................7
Review of Exclusion Requests .....................................................................................................................................7
Request to Appeal a Decision Denying an Exclusion Request .....................................................................................7
Exclusion of Select Agents or Toxins Seized by a Federal Law Enforcement Agency ......................................................8

Public reporting burden: Public reporting burden of this collection of information is estimated to average 30 minutes
per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining
the data needed, and completing and reviewing the collection of information. An agency may not conduct or sponsor,
and a person is not required to respond to a collection of information unless it displays a currently valid OMB control
number. Send comments regarding this burden estimate or any other aspect of this collection of information, including
suggestions for reducing this burden to CDC/ATSDR Reports Clearance Officer; 1600 Clifton Road NE, MS D-74, Atlanta,
Georgia 30329; ATTN: PRA (0920-0576).

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Exclusion Guidance Document

Change/Highlight Section
Revisions: This is a living document subject to ongoing improvement. Feedback or suggestions for
improvement from registered select agent entities or the public are welcome. Submit comments
directly to the Federal Select Agent Program at:
CDC: [email protected]
APHIS: [email protected]
Revision History:
March 27, 2013: Initial Posting
March 2017: Updates include new regulatory requirements, improved language and corrected
errors, and changes to Regulatory Exclusions list.

Introduction
The Federal Select Agent Program (FSAP) oversees the use, possession, and transfer of select
agents and toxins at registered entities throughout the United States. The select agent regulations
provide criteria for the exclusion of select agents and toxins (See 42 CFR §§ 73.3, 73.4; 9 CFR §§
121.3, 121.4; 7 CFR § 331.3). This guidance document provides additional information to entities
or individuals who request to exclude attenuated strains of select agents or select toxins modified
to be less potent or toxic from the requirements of the select agent regulations.

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Regulatory Exclusions
In accord with 42 CFR §§ 73.3, 73.4; 9 CFR §§ 121.3, 121.4; 7 CFR § 331.3, select agents or toxins

that meet any of the following criteria are excluded from the select agent regulations:
 Any select agent or toxin that is in its naturally occurring environment provided the select
agent or toxin has not been intentionally introduced, cultivated, collected, or otherwise
extracted from its natural source is excluded.
 Non-viable select agents or nontoxic select toxins are excluded.
 A select agent or toxin that has been subjected to decontamination or a destruction
procedure when intended for waste disposal is excluded.
 If a select agent or regulated nucleic acid that can produce infectious forms has been
subjected to a validated inactivation procedure and confirmed through a viability testing
protocol, it is excluded:
o Surrogate strains known to possess the same inactivation properties can be used to
validate an inactivation procedure.
o In case of strain-to-strain variations of inactivation resistance, the inactivation
procedure validated on a less resistant strain must also be validated on the more
resistant strain.
 Material containing a select agent is excluded when subjected to a procedure that removes
all viable select agent cells, spores, or virus particles and the material is subjected to a
viability testing protocol to ensure that the removal method has rendered the material free
of all viable select agent.
 Select agents or regulated nucleic acids that can produce infectious forms of any select
agent virus not subjected to a validated inactivation procedure or material containing a
select agent not subjected to a procedure that removes all viable select agent cells, spores,
or virus particles may be excluded if:
o After requesting a determination by the FSAP, the material is determined by FSAP
to be effectively inactivated or effectively removed. To apply for such a
determination, an individual or entity must submit a written request and
supporting scientific information to FSAP (see below). FSAP will issue a written
decision granting or denying the request. The purpose of this provision in the
regulations is to allow FSAP to address those rare situations where there may be a
need to take material out of containment without following the exact requirements
for viability testing. For example, consider a situation where an entity filters serum
that contains a select agent but the recovered volume is so low that the
requirement to perform a viability test on every sample would further deplete the
sample volume and not leave enough for experiments. In these situations, an entity
may submit a request to FSAP to apply an alternative select agent removal or
inactivation procedure and/or an alternative means of validation. To apply for this
determination, a registered individual or entity must submit a written request
including:
 A justification regarding the alternative procedure including a description of
what material is to be waived.
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 The inactivation protocol and viability test to be used.
 Validation data.
 Any other supporting information/references, such as scientific references.
o FSAP will issue a written decision granting or denying the request.
Except as required in § 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 is excluded as long as it does not, at any time, exceed the following amounts:
1000 mg of Abrin; 1 mg of Botulinum neurotoxins; 100 mg of short, paralytic alpha
conotoxins containing the following amino acid sequence X1CCX2PACGX3X4X5X6CX71
10,000 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. Provided that,
o (i) The toxin is transferred only after the transferor uses due diligence and
documents the identification of the recipient and the legitimate need (e.g.,
prophylactic, protective, bona fide research, or other peaceful purpose) claimed by
the recipient to use such toxin. Documentation should include, but is not limited to,
the recipient identity information (name, institution, 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 CDC.
An animal inoculated with or exposed to an HHS select toxin is excluded.
HHS select toxins identified in an original food sample or clinical sample are excluded.
For those laboratories that are not exempt under § 73.5 (a) and § 73.6 (a), Botulinum
neurotoxin that is produced as a byproduct in the study of Botulinum neurotoxin
producing species of Clostridium is excluded so long as the toxin has not been intentionally
cultivated, collected, purified, or otherwise extracted, and the material containing the
toxin is rendered non-toxic and disposed of within 30 days of the initiation of the culture.
Waste generated during the delivery of patient care by health care professionals from a
patient diagnosed with an illness or condition associated with a select agent is excluded as
long as the waste is decontaminated or transferred for destruction by complying with state
and federal regulations within seven calendar days of the conclusion of patient care.
o Waste including specimens associated with patient care must be secured against
theft, loss, or release during the period between identification and transfer or

1

C = Cysteine residues (indicated in bold) are all present as disulfides, with the 1st and 3rd Cysteine, and the 2nd and
4th Cysteine forming specific disulfide bridges; The consensus sequence includes known toxins α-MI and α-GI (shown
above) as well as α-GIA, Ac1.1a, α-CnIA, α-CnIB; X1 = any amino acid(s) or Des-X; X2 = Asparagine or Histidine; P =
Proline; A = Alanine; G = Glycine; X3 = Arginine or Lysine; X4 = Asparagine, Histidine, Lysine, Arginine, Tyrosine,
Phenylalanine or Tryptophan; X5 = Tyrosine, Phenylalanine, or Tryptophan; X6 = Serine, Threonine, Glutamate,
Aspartate, Glutamine, or Asparagine; X7 = Any amino acid(s) or Des X;and “Des X” = “an amino acid does not have to
be present at this position.” For example if a peptide sequence were XCCHPA then the related peptide CCHPA would
be designated as Des-X.

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destruction, and any theft, loss, or release of the waste including specimens must
be reported to FSAP. All patient-generated waste including specimens kept more
than seven days after the conclusion of acute patient care are subject to the select
agent regulations. There is no requirement to document the transfer or destruction
of waste, including specimens generated from the patient, provided that the waste
is decontaminated or transferred for destruction by complying with state and
federal regulations within seven calendar days of the conclusion of patient care.
Any South American genotypes of Eastern Equine Encephalitis Virus and any West African
Clade of Monkeypox virus is excluded provided that the individual or entity can identify
that the agent is within the exclusion category.
Any subtypes of Venezuelan equine encephalitis virus except for Subtypes IAB or IC are
excluded, provided that the individual or entity can identify that the agent is within the
exclusion category.
Low pathogenic strains of avian influenza virus are excluded, provided that the individual
or entity can identify that the agent is within the exclusion category.
Any strain of Newcastle disease virus which does not meet the criteria for virulent
Newcastle disease virus are excluded, provided that the individual or entity can identify
that the agent is within the exclusion category.
All subspecies of Mycoplasma capricolum except subspecies capripneumoniae (contagious
caprine pleuropneumonia) and all subspecies Mycoplasma mycoides except subspecies
mycoides small colony (Mmm SC) (contagious bovine pleuropneumonia).

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Requests for Exclusion of Attenuated Strains or Toxins Modified to be Less
Potent or Toxic
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.
If an excluded attenuated strain or modified toxin is subjected to any manipulation that restores
or enhances its virulence or toxic activity, the resulting select agent or toxin will be subject to the
select agent regulations.

Review of Exclusion Requests
FSAP reviews requests for exclusions and may seek input from CDC’S Intragovernmental Select
Agents and Toxins Technical Advisory Committee (ISATTAC), which is comprised of employees
from CDC, NIH, FDA, USDA/Animal and Plant Health Inspection Service (APHIS), USDA/Agricultural
Research Service (ARS), USDA/Center for Veterinary Biologics (CVB) and the Department of
Defense (DOD). The ISATTAC reviews requests for the exclusion of attenuated strains and modified
toxins of HHS only or overlap select agents and toxins. For VS only agents, federal subject matter
experts from APHIS, ARS, and CVB will review the request.
Some of the criteria used to determine if a strain or toxin should be excluded are given below. The
entities request should contain the following:
a) Documented history of not causing disease in humans, or relevant animal or plant models.
b) Defined genetic mutations or alterations known to attenuate virulence in humans or
relevant animal or plant models.
c) Data showing the mutations have a low frequency of reversion to wild-type virulence.
d) Level of difficulty in engineering the attenuated strain to restore wild-type virulence. For
each pathogen, the sample size and type of animal or plant model used to test virulence is
important.
e) Quantitative measures demonstrating a change in virulence in an appropriate animal or
plant model.
f) Information regarding tests that may be conducted to differentiate animals or plants
exposed to the attenuated strain from those infected with the wild-type organism.
g) Related published scientific papers supporting the methods and data provided for the
exclusion.
See the data requirements necessary for consideration of an exclusion request for highly
pathogenic Avian influenza (HPAI) virus on the FSAP website.

Request to Appeal a Decision Denying an Exclusion Request
An individual or entity may make a written request to the HHS Secretary or APHIS
Administrator for reconsideration of a decision denying an exclusion application. The written
request for reconsideration must state the facts and reasoning upon which the individual or entity
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believes the decision was incorrect. FSAP will grant or deny the request for reconsideration as
promptly as circumstances allow and will state, in writing, the reasons for the decision. You may
submit the written request to your FSAP file manager.

Exclusion of Select Agents or Toxins Seized by a Federal Law Enforcement
Agency
Under sections 3(f) and 4(f) of the select agent regulations, certain federal law enforcement
activities are excluded from the select agent regulations (e.g., collecting evidence from a
laboratory crime scene) as long as the law enforcement agency meets the requirements of the
exclusion:
1. As soon as practicable, the federal law enforcement agency transfers the seized agent or
toxin to an entity eligible to receive such agent or toxin or destroys the agent or toxin by a
recognized sterilization or inactivation process.
2. The federal law enforcement agency safeguards and secures the seized agent or toxin
against theft, loss, or release and reports any theft, loss, or release of such agent or toxin.
3. The federal law enforcement agency reports the seizure of the select agent or toxin by
submitting the APHIS/CDC Form 4. For more information please contact FSAP.

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