FAQ: Exclusions

To apply for the exclusion of an attenuated strain of a select agent or select toxin that has been modified to be less potent or toxic, an applicant must submit the request to FSAP. Requests for the exclusion of a select agent or toxin from a registered entity should be sent by the Responsible Official to FSAP through the electronic information system. If the applicant is a non-registered entity, please submit the exclusion request to DRSC or DASAT.

The exclusion request should contain information that is responsive to these criteria:

• Documented history of not causing disease in humans, or relevant animal or plant models.
• Defined genetic mutations or alterations known to attenuate virulence in humans or relevant animal or plant models.
• Data showing the mutations have a low frequency of reversion to wild-type virulence.
• 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.
• Quantitative measures demonstrating a change in virulence in an appropriate animal or plant model.
• 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.
• Related published scientific papers which support 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.

In response to the request for exclusion of an attenuated strain or a toxin that has been modified to be less potent or toxic, FSAP will provide a written decision granting or denying the request. Exclusions are effective upon notification to the applicant.

See the list of excluded agents and toxins that have been granted an exclusion from the regulations. Until such time that exclusions are considered and granted, the attenuated strain of the select agent or select toxin that has been modified to be less potent or toxic is subject to the requirements of select agent regulations.

Currently, the cDNA of select agent viruses are not regulated under the select agent regulations. Therefore, the Federal Select Agent Program does not play a role in determining the biosafety containment of these genetic materials. However, the NIH Guidelines remain applicable to this and other research at institutions receiving NIH funding and performing work involving recombinant DNA (of certain human etiologic agents which are classified into groups according to their relative pathogenicity for healthy adult humans), including review and approval by an Institutional Biosafety Committee. Please refer to the following NIH Office of Biotechnology Activities guidance document for essential elements that should be included in the application to lower containment: “Points to Consider When Applying to the NIH Office of Biotechnology Activities (NIH OBA) for a Reduction in Biosafety Level (BL) Containment for Experiments Involving the Cloning of Full-length cDNA Constructs Derived from Risk Group (RG) 4 Viruses of the Order Mononegavirales“.

For agriculture agents, please submit all biosafety containment questions to the Division of Agricultural Select Agents and Toxins at DASAT@usda.gov.

FSAP thoroughly reviews all exclusion requests. Some requests may require additional information from the entity before the review can proceed; therefore, the length of time varies considerably based upon the type of request proposed. On average, it takes 5-8 weeks for the Program to review the request and notify the entity of the decision. Entities registered with the Federal Select Agent Program may follow up on the status of your request through the electronic information system. Non-registered entities may contact FSAP (lrsat@cdc.gov or DASAT@usda.gov) to follow up on the status of your request.

If an entity modifies an excluded select agent such that virulence is restored or enhanced, then that select agent would be subject to all of the provisions of the select agent regulations including the pre-approval requirements of section 13 (Restricted Experiments). Please note that an attenuated strain of select agent that is excluded from the requirements of the select agent regulations is not exempt from other applicable regulations or guidelines (e.g., NIH guidelines, USDA/APHIS regulatory permits, etc.).

No. Only those attenuated strains of select agents or toxins that have been modified to be less potent or toxic that have been determined by the Federal Select Agent Program not to pose a severe threat to public health and safety, to animal and plant health, or to animal and plant products are excluded from the regulations. However, if an excluded attenuated strain or toxin that has been modified to be less potent or toxic is subjected to any manipulation that restores or enhances its virulence or toxic activity, the resulting agent or toxin will be subject to the requirements of 42 CFR Part 73, 9 CFR Part 121, and 7 CFR Part 331. Attenuated strains and inactive toxins that have been granted an exclusion from the regulations can be found here.

The Federal Select Agent Program does not regulate a select agent or toxin if it is:

• in its naturally occurring environment, provided that it has not been intentionally introduced, cultivated, collected, or otherwise extracted from its natural source
• non-viable select agents or nontoxic toxins.
• an attenuated strain of a select agent or a select toxin modified to be less potent or toxic that has been determined by the Federal Select Agent Program not to pose a significant threat to public health or safety, to animal health, or to animal products. The list of exclusions can be found here.
• a select agent or toxin that has been subjected to decontamination or a destruction procedure when intended for waste disposal.
• 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 procedure that is confirmed through a viability testing protocol. Surrogate strains that are known to possess equivalent properties with respect to inactivation can be used to validate an inactivation procedure; however, if there are known strain-to-strain variations in the resistance of a select agent to an inactivation procedure, then an inactivation procedure validated on a lesser resistant strain must also be validated on the more resistant strains.
• material containing a select agent that is subjected to a procedure that removes all viable select agent cells, spores, or virus particles if 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.
• a select agent 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 if the material is determined by the HHS Secretary or APHIS Administrator to be effectively inactivated or effectively removed.  To apply for a determination an individual or entity must submit a written request and supporting scientific information to CDC or APHIS.  A written decision granting or denying the request will be issued.
• an select toxin identified in an original food sample or clinical sample.
• 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 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, where that 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 low pathogenic strains of avian influenza virus, avian paramyxovirus serotype-1 (APMV-1) viruses which do not meet the criteria for Newcastle disease virus, including those identified as pigeon paramyxovirus-1 (PPMV-1) isolated from non-poultry species, 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), provided that the individual entity can identify that he agent is within the exclusion category.
• an animal inoculated with or exposed to an HHS select toxin.
• select toxins identified in an original food sample or clinical sample.
• any South American genotypes of Eastern Equine Encephalitis Virus and any West African Clade of monkeypox virus provided that the individual or entity can identify that the agent is within the exclusion category.
• any select agent or toxin seized by a Federal law enforcement agency will be excluded from the requirements of this part during the period between seizure of the select agent or toxin and the transfer or destruction of such agent or toxin
• toxin in an amount under the control of a principal investigator, treating physician or veterinarian, or commercial manufacturer or distributor does not exceed, at any time, the amounts indicated in the list 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