FAQ: Select Agents & Toxins
The select agent regulations can be found at 42 CFR Part 73, 9 CFR Part 121, and 7 CFR Part 331. The select agent regulations implement the Subtitle A and Subtitle B (also known as the Agricultural Bioterrorism Protection Act of 2002) of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, setting forth the requirements for the possession, use, and transfer of select agents and toxins.
The Centers for Disease Control and Preventions’ (CDC) Division of Regulatory Science and Compliance (DRSC) and the Animal and Plant Health Inspection Services’ (APHIS) Division of Agricultural Select Agents and Toxins (DASAT) jointly constitute the Federal Select Agent Program. See the history of FSAP for more information.
Pursuant to 42 USC 262a and 7 USC 8401, select agents and toxins are a subset of biological agents and toxins that the Departments of Health and Human Services (HHS) and Agriculture (USDA) have determined to have the potential to pose a severe threat to public health and safety, to animal or plant health, or to animal or plant products. The current list of select agents and toxins can be found at 42 CFR §§ 73.3, 73.4, 9 CFR §§ 121.3, 121.4, and 7 CFR § 331.3. Also see the current select agents and toxins list.
A subset of select agents and toxins have been designated as Tier 1 because these biological agents and toxins present the greatest risk of deliberate misuse with significant potential for mass casualties or devastating effect to the economy, critical infrastructure, or public confidence, and pose a severe threat to public health and safety:
|Tier 1 Select Agents and Toxins|
HHS Agents and Toxins
|Bacillus cereus Biovar anthracis
Botulinum neurotoxin producing species
Variola major virus (Smallpox virus)
Variola minor virus (Alastrim)
Entities that possess, use, or transfer Tier 1 select agents and toxins must adhere to the additional requirements detailed within the Select Agent Regulations.
Yes, the requirements apply to both possession and use of Tier 1 select agents or toxin.
In determining whether to include an agent or toxin on the HHS select agent list, the “Public Health Security and Bioterrorism Preparedness and Response Act” requires that the following criteria be considered:
- The effect on human health of exposure to the agent or toxin;
- The degree of contagiousness of the agent or toxin 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 any illness resulting from infection by the agent or toxin; and
- Any other criteria, including the needs of children and other vulnerable populations, that the Secretary considers appropriate.
In determining whether to include an agent or toxin on the USDA list, the “Agricultural Bioterrorism Protection Act of 2002” requires that the following criteria be considered:
- The effect of exposure to the agent or the toxin on animal and plant health, and on the production and marketability of animal or plant products;
- The pathogenicity of the agent or the toxin and the methods by which the agent or toxin is transferred to animals or plants;
- The availability and effectiveness of pharmacotherapies and prophylaxis to treat and prevent any illness or disease caused by the agent or toxin; and
- Any other criteria that the Secretary considers appropriate to protect animal or plant health, or animal or plant products.
The lists are required to be reviewed and republished every 2 years, or revised as necessary.
- FSAP has the authority to deny, suspend, or revoke registration to use, possess, or transfer select agents and toxins. See section 8 of the select agent regulations.
- FSAP has the authority to deny an individual access to select agents and toxins to protect public health and safety. See section 10 of the select agent regulations.
- In addition to any other penalties that may apply under law, any person who violates any provision of select agent regulations shall be subject to the United States for a civil money penalty in an amount not exceeding $250,000 in the case of an individual and $500,000 in the case of any entity.
- Criminal: Violations of 18 USC 175b
- A “restricted person” that possesses a select agent or toxin, or transfers select agent or toxin in interstate or foreign commerce, (and is not excluded or exempted under select agent regulations) is subject to a criminal fine, imprisoned not more than 10 years, or both.
- Whoever transfers a select agent or toxin to a person who the transferor knows or has reasonable cause to believe is not registered with the Federal Select Agent Program in accordance with the select agent regulations is subject to a criminal fine or imprisoned for not more than 5 years, or both.
- Whoever knowingly possesses a select agent or toxin when that person is not registered with the Federal Select Agent Program in accordance with the select agent regulations is subject to a criminal fine and/or imprisoned for not more than 5 years.
In March 2008, FSAP established the Corrective Action Plan (CAP) program to assist entities, identified by FSAP as having systemic biosafety and security deficiencies, to come into compliance with the select agent regulations. After being given the opportunity to participate, an entity begins by submitting a detailed plan, including target completion dates, addressing the specifics of how the entity will address and correct regulatory deficiencies identified by FSAP. An entity’s participation in a CAP allows FSAP to both provide technical assistance as well as monitor an entity’s progress in correcting security or safety shortcomings.
FSAP will withdraw a certificate of registration upon the written request of the entity , if the entity no longer possesses or uses any select agents or toxins and no longer wishes to be registered.
A certificate of registration may be revoked or suspended if:
- The individual or entity, the Responsible Official, or an individual who owns or controls the entity is a restricted person (within any of the categories described in 18 U.S.C 175b).
- The individual or entity, the Responsible Official, or an individual who owns or controls the entity is reasonably suspected by any Federal law enforcement or intelligence agency of any of the following:
- Committing a crime specified in 18 U.S.C. 2332b(g)(5).
- Knowing involvement with an organization that engages in domestic or international terrorism (as defined in 18 U.S.C. 2331) or with any other organization that engages in international crimes of violence.
- Being an agent of a foreign power (as defined in 50 U.S.C 1801).
- The individual or entity does not meet the requirements of select agent regulations.
- It is determined that such action is necessary to protect agricultural or public health and safety.
The select agent regulations place no specific restrictions on the biosafety, incident response, or security plan being made publically available to individuals (e.g., first responders, maintenance workers) that don’t have access approvals from FSAP, or on the publication of research related to select agents or toxins.. However, any records or information systems that could allow an individual to gain access to the select agents or toxins should be safeguarded to prevent unauthorized access, theft, loss, or release of these materials. The Federal Select Agent Program strongly encourages entities to refrain from publishing detailed information about locations or quantities of select agents and toxins on site.
You can notify a Federal Bureau of Investigation Weapons of Mass Destruction Coordinator of any suspicious activity that you believe may be criminal in nature concerning an entity, its personnel, or its select agents or toxins. To locate your Federal Bureau of Investigation Weapons of Mass Destruction Coordinator, refer to the Field Offices.
FSAP has established a confidential means for reporting safety and security issues associated with the possession, use and transfer of select agents and toxins. The Department of Health & Human Services, Office of Inspector General (OIG) maintains a hotline that allows individuals to anonymously report fraud, waste and abuse in all departmental programs. This hotline is now available to anonymously report safety or security issues related to select agents and toxins. When reporting these issues to OIG, please ensure that you indicate it is a “Select Agent Program” issue.
OIG Hotline contact information:
Office of Inspector General
Department of Health & Human Services
P.O. Box 23489
Washington, DC 20026
A “Select Agent Gram” or “SA Gram” is an email sent from FSAP to the regulated community (i.e., Responsible Officials and Alternate Responsible Officials) that communicates information from FSAP.
If anyone besides the Responsible Officials and Alternate Responsible Officials would like to receive FSAP information, FSAP offers the GovDelivery Email Subscription Management System. The System allows website visitors to subscribe to receive email based on their interest in the program. Messages in this system will be of a general nature and will not contain sensitive select agent information. To sign up for updates, the individual would just need to provide his/her email address for the “Subscribe to Federal Select Agent Program email updates” located in the footer on the FSAP website.
See the web page with FSAP’s Regulatory Interpretations for details about regulatory interpretations.
DRSC: the request can be submitted to DRSC via email (firstname.lastname@example.org), FAX (404-718-2096), or mail (Division of Regulatory Science and Compliance, 1600 Clifton Rd MS H21-4, Atlanta, GA 30329)
DASAT: the request can be submitted to APHIS via email (DASAT@usda.gov), FAX (301-734-3652) or mail (Division of Agricultural Select Agents and Toxins, Agriculture Select Agent Services, 4700 River Road, Unit 2, Mailstop 22, Cubicle 1A07, Riverdale, MD 20737).
In response to the request, the Federal Select Agent Program will provide a written interpretation. The interpretation will also be posted posted on the Regulations and Policies page.
The select agent regulations regarding select agent waste generated during the delivery of patient care apply only to the treatment of humans.
See the FSAP policy statement regarding the conclusion of patient care for more information.
As a condition of registration, each entity is required to be in compliance with the regulations for select agents and toxins listed on the registration regardless of whether the entity is in actual possession of the select agent or toxin or not. With regard to toxins, the entity registered for possession, use or transfer of a toxin must be in compliance with the regulations regardless of the amount of toxin currently in its possession.
As a condition of registration, each entity is required to be in compliance with the regulations for select agents and toxins listed on the registration regardless of whether the entity is in actual possession of the select agent or toxin or not.
The regulations do not require entities to:
- Maintain information about all entries (e.g., the name of the individual and date and time of entry) into areas where no select agents or toxins are present.
- Provide training for non-FSAP-approved individuals escorted into areas where no select agents or toxins are present.
- Provide escorts for non-FSAP-approved individuals who enter areas where no select agents or toxins are present.
Select Agents and Toxins
The following genetic elements, recombinant and/or synthetic nucleic acids, and recombinant and/or synthetic organisms are select agents (See section 3(c) of 42 CFR Part 73, 9 CFR Part 121, and 7 CFR Part 331):
- Nucleic acids that can produce infectious forms of any of the select agent viruses.
- Recombinant and/or synthetic nucleic acids that encode for the functional form(s) of select agent toxins if the nucleic acids:
- Can be expressed in vivo or in vitro or,
- Are in a vector or recombinant host genome and can be expressed in vivo or in vitro.
- Select agents and toxins that have been genetically modified.
Additional information is available in the Guidance on the Regulation of Select Agent and Toxin Nucleic Acids.
The FSAP regulates chimeric viruses whose genomes 1) contain the backbone and replication machinery of a select agent virus or 2) contain genes from different select agent viruses. Regulated chimeric viruses are evaluated on a case-by-case basis to determine if the viruses exhibit sufficient attenuation to be excluded. Chimeric viruses that “mix and match” select agent genes with non-select agent genes from the same virus family may be regulated as a select agent virus. It is the entity’s responsibility to determine if the resultant chimera is a select agent; however, the FSAP encourages entities to submit these types of chimeras for review. A list of excluded chimeric viruses is available for the entity to reference.
It depends on the circumstance. If a toxin subunit or fragment is less potent or toxic, then the material is considered excluded from the regulation and therefore not subject to the requirements of 42 CFR Part 73, including the registration and transfer requirements. However, registration is required if toxin subunits or fragments are combined to generate toxic form(s) of any of the toxins and the aggregate amount under the control of a principal investigator, treating physician or veterinarian, or commercial manufacturer or distributor exceeds the amount specified below:
- Abrin 1000 mg
- Botulinum neurotoxins 1 mg
- Short, paralytic alpha conotoxins 100 mg
- Diacetoxyscirpenol (DAS) 10,000 mg
- Ricin 1000 mg
- Saxitoxin 500 mg
- Staphylococcal Enterotoxins (Subtypes A, B, C, D, and E) 100 mg
- T-2 toxin 10,000 mg
- Tetrodotoxin 500 mg
For additional information on nucleic acids that encode for functional forms of a select toxin, please see the Guidance on the regulation of select agent and toxin nucleic acids.
It depends on the circumstance. If the plasmid does not encode for the functional form of any listed toxin, then the material is considered excluded from the regulation and therefore not subject to the requirements of 42 CFR Part 73, including the registration and transfer requirements. However, if the plasmid encodes for the functional form of a listed toxin (not a fragment of the toxin) and is in a vector or host chromosome and/or can be expressed in vivo or in vitro, then the material would be subject to regulation.
Botulinum toxin (serotypes A through G) is produced by Clostridium botulinum (phenotypically classified into 4 Groups -I, II, III, IV) and some isolates of Clostridium baratii (serotype F only), Clostridium butyricum (serotype E only), and Clostridium argentinense (serotype G only). Some strains of C. botulinum have been identified that produce 2 botulinum serotypes (e.g. both A and B).
Demonstration of the production of botulinum neurotoxin, through a toxin detection test, in a suspect culture is critical to the characterization of a Botulinum neurotoxin producing species of Clostridium. Most isolates of C. baratii, C. butyricum, and some isolates of C. argentinense do not contain the genes necessary to produce botulinum toxin. Some non-toxigenic clostridia species (e.g. C. sporogenes) are phenotypically identical to C. botulinum but may result in an identification of C. botulinum on some rapid biochemical identification methods (i.e., 16sRNA sequencing may misidentify a non-toxin producing clostridia as a C. botulinum, particularly Group II strains).
If a laboratory detects botulinum neurotoxin from a culture of any suspected Clostridium species (such as C. botulinum, C. baratii, C. butyricum, and some isolates of C. argentinense), the laboratory will need to report the identification of Botulinum neurotoxin producing species of Clostridium by completing Section 1 of the APHIS/CDC Form 4 within seven calendar days of identification. In addition, if the laboratory is not registered with the Federal Select Agent Program for possession of Botulinum neurotoxin producing species of Clostridium, the laboratory must destroy or transfer the isolate within seven calendar days after identification.
No. This work would be considered experimental research. Botulinum neurotoxin producing species of Clostridium was introduced into the samples intentionally, and the toxin was created as a by-product of bacterial growth. Therefore, the entity must be registered for botulinum neurotoxin producing species of Clostridium, and may have to be registered for the toxin to perform this type of work if the aggregate amount of toxin under the control of the entity or individual is over 1 mg. Please note that Code of Federal Regulations Title 42 Part 73 Section 17 (Records) requires that an individual or entity registered with the Federal Select Agent Program must maintain complete records including an accurate and current inventory for each select agent and toxin held.
It depends on the circumstance. The exclusion limit of a toxin is not determined per experiment, but determined by the aggregate volume of toxin produced, stored, and/or manipulated at any given time per principal investigator (PI). Therefore, if the PI controls more than 100 mg of Staphylococcal enterotoxins at any given time, the toxin is subject to the requirements of the select agent regulations.
Animals injected with or exposed to a select toxin are not considered a “select toxin.” The BMBL provides recommendations regarding decontamination according to to institutions performing work with Botulinum neurotoxins based on the work being performed with the toxin.
SARS-CoV-2 is not a select agent identified in the select agent regulations. Therefore, the possession, use and transfer of SARS-CoV-2 is not regulated by the Federal Select Agent Program (FSAP).
On February 11, 2020, the International Committee on Taxonomy of Viruses (ICTV) announced that taxonomically, what has previously been referred to as 2019-nCoV should now be referred to as SARS-CoV-2. The “Severe acute respiratory syndrome-related coronavirus: The species and its viruses – a statement of the Coronavirus Study Group” indicates that SARS-CoV-2 is not a descendent of SARS-CoV (a select agent), but is genetically closely related.
The select agent regulations currently govern the possession, use and transfer of viruses identified as SARS-CoV, not viruses identified as SARS-CoV-2. The positive strand RNA genome of SARS-COV is also a select agent because this genomic material represents nucleic acids capable of generating infectious virus.
As the Federal Select Agent Program gains more information about the SARS-CoV-2, we will reassess the select agent status as needed. Any changes in the select agent status of SARS-CoV-2 will be published in the Federal Register.
Vials should be accurately labeled as SARS-CoV-2 to ensure that there is a clear distinction between the regulated virus (SARS-CoV) and the unregulated virus (SARS-CoV2).