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Home , Leukocidin, Taipoxin, Tetanospasmin

§ 725.370 40 CFR Ch. I (7–1–15 Edition)

(2) Health and environmental effects (h) Subparts A through C of this part data. All existing data regarding health apply to any submission under this and environmental effects of the subpart. microorganism must be reported in ac- cordance with § 725.160. § 725.420 Recipient microorganisms. The following recipient microorga- § 725.370 EPA review of the TME appli- nisms are eligible for either exemption cation. under this subpart: General procedures for review of all (a) Acetobacter aceti. submissions under this part are con- (b) Aspergillus niger. tained in §§ 725.28 through 725.60. In ad- (c) Aspergillus oryzae. dition, the following procedures apply (d) Bacillus licheniformis. to EPA review of TME applications (e) Bacillus subtilis. submitted under this subpart: (f) (a) No later than 45 days after EPA acetobutylicum. receives a TME, the Agency will either (g) Escherichia coli K-12. approve or deny the application. (h) Penicillium roqueforti. (b) A submitter may only proceed (i) Saccharomyces cerevisiae. with test marketing activities after re- (j) Saccharomyces uvarum. ceipt of EPA approval. (c) In approving a TME application, § 725.421 Introduced genetic material. EPA may impose any restrictions nec- For a new microorganism to qualify essary to ensure that the microorga- for either exemption under this sub- nism will not present an unreasonable part, introduced genetic material must risk of injury to health and the envi- meet all of the criteria listed in this ronment as a result of test marketing. section. (a) Limited in size. The introduced ge- Subpart G—General Exemptions netic material must consist only of the for New Microorganisms following: (1) The structural gene(s) of interest. § 725.400 Scope and purpose. (2) The regulatory sequences permit- (a) This subpart describes exemptions ting the expression of solely the gene(s) from reporting under subpart D of this of interest. part, and from review under this part (3) Associated nucleotide sequences altogether, for manufacturing and im- needed to move genetic material, in- porting of certain new microorganisms cluding linkers, homopolymers, adap- for commercial purposes. tors, transposons, insertion sequences, (b) Recipient microorganisms eligible and restriction enzyme sites. for the tiered exemption from review (4) The nucleotide sequences needed under this part are listed in § 725.420. for vector transfer. (c) Criteria for the introduced ge- (5) The nucleotide sequences needed netic material contained in the new for vector maintenance. microorganisms are described in (b) Well-characterized. For introduced § 725.421. genetic material, well-characterized (d) Physical containment and control means that the following have been de- technologies are described in § 725.422. termined: (e) The conditions for the Tier I ex- (1) The function of all of the products emption are listed in § 725.424. expressed from the structural gene(s). (f) In lieu of complying with subpart (2) The function of sequences that D of this part, persons using recipient participate in the regulation of expres- microorganisms eligible for the tiered sion of the structural gene(s). exemption may submit a Tier II ex- (3) The presence or absence of associ- emption request. The limited reporting ated nucleotide sequences and their as- requirements for the Tier II exemption, sociated functions, where associated including data requirements, are de- nucleotide sequences are those se- scribed in §§ 725.450 and 725.455. quences needed to move genetic mate- (g) EPA review procedures for the rial including linkers, homopolymers, Tier II exemption are set forth in adaptors, transposons, insertion se- § 725.470. quences, and restriction enzyme sites.

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(c) Poorly mobilizable. The ability of in identification of sequences whose the introduced genetic material to be use is restricted. Although similar or transferred and mobilized is inac- identical sequences may be isolated tivated, with a resulting frequency of from organisms other than those listed transfer of less than 10¥8 transfer below in paragraphs (d)(2) through events per recipient. (d)(7) of this section, these comparable (d) Free of certain sequences. (1) The sequences, regardless of the orga- introduced genetic material must not nism from which they are derived, contain a functional portion of any of must not be included in the introduced the toxin-encoding sequences described genetic material. in this paragraph (d). (2) Sequences for synthesis in- (i) For the purposes of this section, a hibitor. functional portion of a toxin-encoding sequence means any sequence which Sequence Source Toxin Name codes for a polypeptide that has one of Corynebacterium diphtheriae the following effects: & C. ulcerans Pseudomonas aeruginosa A (A) It directly or indirectly contrib- Shigella dysenteriae Shigella toxin (, utes to toxic effects in humans. Di- Shigella dysenteriae type I rectly contributes to toxic effects in toxin, Vero cell toxin) humans means those sequences encod- Abrus precatorius, seeds Ricinus communis, seeds ing polypeptides that have direct tox- icity to target cells. An example of a (3) Sequences for . sequence which directly contributes to Sequence Source Toxin Name toxic effects in humans is one which encodes the portion of diphtheria Neurotoxins A, B, C1, D, E, F, G (Botulinum , toxin, listed in paragraph (d)(2) of this botulinal toxins) section, capable of interacting with toxin elongation factor 2, leading to inhibi- () tion of protein synthesis in target res- Proteus mirabilis Staphylococcus aureus Alpha toxin (alpha lysin) piratory, heart, kidney, and nerve tis- Yersinia pestis Murine toxin sues. Indirectly contributes to toxic ef- Snake toxins fects in humans means a sequence Bungarus caeruleus Caeruleotoxin whose encoded polypeptide is not di- Bungarus multicinctus Beta- (phospholipase) rectly toxic to target cells, yet still ad- Crotalus spp. Crotoxin (phospholipase) versely affects humans. An example of Dendroaspis viridis Neurotoxin a sequence which indirectly contrib- Naja naja varieties Neurotoxin Notechia scutatus Notexin (phospholipase) utes to toxic effects is the sequence Oxyuranus scutellatus which encodes the portion of the botu- toxins linum toxin, listed in paragraph (d)(3) Chironex fleckeri Neurotoxin of this section, capable of blocking the Androctnus australis Neurotoxin release of acetylcholine from Centruroides sculpturatus Neurotoxin gangliosides. affects (4) Sequences for oxygen labile neuromuscular junctions by its block- cytolysins. age of acetylcholine release, leading to irreversible relaxation of muscles and Sequence Source Toxin Name respiratory arrest. Bacillus alve Alveolysin (B) It binds a toxin or toxin precursor Bacillus cereus Cereolysin Bacillus laterosporus Laterosporolysin to target human cells. Bacillus thuringiensis Thuringiolysin (C) It facilitates intracellular trans- Clostridium bifermentans Lysin port of a toxin in target human cells. Clostridium botulinum Lysin Clostridium caproicum Lysin (ii) While these toxins are listed Clostridium chauvoei Delta-toxin (with synonyms in parentheses) in Clostridium histolyticum Epsilon-toxin paragraphs (d)(2) through (d)(7) of this Clostridium novyi Gamma-toxin section according to the source orga- Clostridium oedematiens Delta-toxin Theta-toxin (Perfringolysin) nism, it is use of the nucleotide se- Clostridium septicum Delta-toxin quences that encode the toxins that is Clostridium sordellii Lysin being restricted and not the use of the Clostridium tetani Listeria monocytogenes Listeriolysin (A B) source organisms. The source orga- Streptococcus pneumoniae Pneumolysin nisms are listed to provide specificity Streptococcus pyogene O (SLO)

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(5) Sequences for toxins affecting mem- any facility in which the new micro- brane function. organism will be used for a Tier I ex- emption; these criteria also serve as Sequence Source Toxin Name guidance for a Tier II exemption. Bacillus anthracis Edema factor (Factors I II); (a) Use a structure that is designed Lethal factor (Factors II III) Bacillus cereus (diarrheagenic and operated to contain the new micro- toxin, mouse lethal factor) organism. Bordetella pertussis Adenylate cyclase (Heat-la- (b) Control access to the structure. bile factor); Pertussigen (, islet acti- (c) Provide written, published, and vating factor, histamine implemented procedures for the safety sensitizing factor, of personnel and control of hygiene. lymphocytosis promoting factor) (d) Use inactivation procedures dem- Clostridium botulinum C2 toxin onstrated and documented to be effec- Clostridium difficile Enterotoxin (toxin A) tive against the new microorganism Clostridium perfringens Beta-toxin; Delta-toxin Escherichia coli & other Heat-labile (LT); contained in liquid and solid wastes Enterobacteriaceae spp. Heat-stable enterotoxins prior to disposal of the wastes. The in- (STa, ST1 subtypes ST1a activation procedures must reduce via- ST1b; also STb, STII) Legionella pneumophila Cytolysin ble microbial populations by at least 6 Vibrio cholerae & Vibrio (choleragen) logs in liquid and solid wastes. mimicus (e) Use features known to be effective (6) Sequences that affect membrane in minimizing viable microbial popu- integrity. lations in aerosols and exhaust gases released from the structure, and docu- Sequence Source Toxin Name ment use of such features. Clostridium bifermentans & Lecithinase (f) Use systems for controlling dis- other Clostridium spp semination of the new microorganism Clostridium perfringens Alpha-toxin (phospholipase C, lecithinase); Enterotoxin through other routes, and document Corynebacterium pyogenes & Cytolysin (phospholipase C), use of such features. other Corynebacterium spp. Ovis toxin (g) Have in place emergency clean-up (sphingomyelinase D) Staphylococcus aureus Beta-lysin (beta toxin) procedures. (7) Sequences that are general § 725.424 Requirements for the Tier I cytotoxins. exemption. Sequence Source Toxin Name (a) Conditions of exemption. The manu- facture or import of a new microorga- Adenia digitata Modeccin Aeromonas hydrophila Aerolysin (beta-lysin, nism for commercial purposes is not cytotoxic lysin) subject to review under this part if all Clostridium difficile Cytotoxin (toxin B) of the following conditions are met for Clostridium perfringens Beta-toxin; Epsilon-toxin; Kappa-toxin all activities involving the new micro- Escherichia coli & other Cytotoxin (Shiga-like toxin, organism: Enterobacteriaceae spp. Vero cell toxin) (1) The recipient microorganism is Pseudomonas aeruginosa Proteases Staphylococcus aureus Gamma lysin (Gamma toxin); listed in and meets any requirements Enterotoxins (SEA, SEB, specified in § 725.420. SEC, SED SEE); (2) The introduced genetic material Pyrogenic A B; Toxic shock syndrome tox- meets the criteria under § 725.421. ins (TSST-1) (3) The physical containment and Staphylococcus aureus & Leucocidin (, Pseudomonas aeruginosa cytotoxin) control technologies of any facility in Streptococcus pyogenes Streptolysin S (SLS); which the microorganism will be man- Erythrogenic toxins (scarlet ufactured, processed, or used meet the fever toxins, pyrogenic criteria under § 725.422. exotoxins) Yersinia enterocolitica Heat-stable enterotoxins (ST) (4) The manufacturer or importer submits a certification described in § 725.422 Physical containment and paragraph (b) of this section to EPA at control technologies. least 10 days before commencing initial The manufacturer must meet all of manufacture or import of a new micro- the following criteria for physical con- organism derived from a recipient tainment and control technologies for microorganism listed in § 725.420.

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