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§ 725.370 40 CFR Ch. I (7–1–11 Edition)

the conditions of the proposed test porting of certain new microorganisms marketing activity. for commercial purposes. (e) Persons applying for a TME must (b) Recipient microorganisms eligible also submit the following information for the tiered exemption from review about the proposed test marketing ac- under this part are listed in § 725.420. tivity: (c) Criteria for the introduced ge- (1) Proposed test marketing activity. (i) netic material contained in the new The maximum quantity of the micro- microorganisms are described in organism which the applicant will § 725.421. manufacture or import for test mar- (d) Physical containment and control keting. (ii) The maximum number of persons technologies are described in § 725.422. who may be provided the microorga- (e) The conditions for the Tier I ex- nism during test marketing. emption are listed in § 725.424. (iii) The maximum number of persons (f) In lieu of complying with subpart who may be exposed to the microorga- D of this part, persons using recipient nism as a result of test marketing, in- microorganisms eligible for the tiered cluding information regarding duration exemption may submit a Tier II ex- and route of such exposures. emption request. The limited reporting (iv) A description of the test mar- requirements for the Tier II exemption, keting activity, including its duration including data requirements, are de- and how it can be distinguished from scribed in §§ 725.450 and 725.455. full-scale commercial production and (g) EPA review procedures for the research and development activities. Tier II exemption are set forth in (2) Health and environmental effects § 725.470. data. All existing data regarding health (h) Subparts A through C of this part and environmental effects of the apply to any submission under this microorganism must be reported in ac- subpart. cordance with § 725.160. § 725.420 Recipient microorganisms. § 725.370 EPA review of the TME appli- cation. The following recipient microorga- General procedures for review of all nisms are eligible for either exemption submissions under this part are con- under this subpart: tained in §§ 725.28 through 725.60. In ad- (a) Acetobacter aceti. dition, the following procedures apply (b) Aspergillus niger. to EPA review of TME applications (c) Aspergillus oryzae. submitted under this subpart: (d) Bacillus licheniformis. (a) No later than 45 days after EPA (e) Bacillus subtilis. receives a TME, the Agency will either (f) acetobutylicum. approve or deny the application. (g) Escherichia coli K-12. (b) A submitter may only proceed (h) Penicillium roqueforti. with test marketing activities after re- (i) Saccharomyces cerevisiae. ceipt of EPA approval. (c) In approving a TME application, (j) Saccharomyces uvarum. EPA may impose any restrictions nec- essary to ensure that the microorga- § 725.421 Introduced genetic material. nism will not present an unreasonable For a new microorganism to qualify risk of injury to health and the envi- for either exemption under this sub- ronment as a result of test marketing. part, introduced genetic material must meet all of the criteria listed in this Subpart G—General Exemptions section. for New Microorganisms (a) Limited in size. The introduced ge- netic material must consist only of the § 725.400 Scope and purpose. following: (a) This subpart describes exemptions (1) The structural gene(s) of interest. from reporting under subpart D of this (2) The regulatory sequences permit- part, and from review under this part ting the expression of solely the gene(s) altogether, for manufacturing and im- of interest.

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(3) Associated sequences rectly toxic to target cells, yet still ad- needed to move genetic material, in- versely affects humans. An example of cluding linkers, homopolymers, adap- a sequence which indirectly contrib- tors, transposons, insertion sequences, utes to toxic effects is the sequence and restriction enzyme sites. which encodes the portion of the botu- (4) The nucleotide sequences needed linum , listed in paragraph (d)(3) for vector transfer. of this section, capable of blocking the (5) The nucleotide sequences needed release of acetylcholine from for vector maintenance. gangliosides. affects (b) Well-characterized. For introduced neuromuscular junctions by its block- genetic material, well-characterized age of acetylcholine release, leading to means that the following have been de- irreversible relaxation of muscles and termined: respiratory arrest. (1) The function of all of the products (B) It binds a toxin or toxin precursor expressed from the structural gene(s). to target human cells. (2) The function of sequences that (C) It facilitates intracellular trans- participate in the regulation of expres- port of a toxin in target human cells. sion of the structural gene(s). (ii) While these are listed (3) The presence or absence of associ- (with synonyms in parentheses) in ated nucleotide sequences and their as- paragraphs (d)(2) through (d)(7) of this sociated functions, where associated section according to the source orga- nucleotide sequences are those se- nism, it is use of the nucleotide se- quences needed to move genetic mate- quences that encode the toxins that is rial including linkers, homopolymers, being restricted and not the use of the adaptors, transposons, insertion se- source organisms. The source orga- quences, and restriction enzyme sites. nisms are listed to provide specificity (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 toxin 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 Source Toxin Name sequence means any sequence which codes for a polypeptide that has one of Corynebacterium diphtheriae & C. ulcerans the following effects: Pseudomonas aeruginosa A (A) It directly or indirectly contrib- Shigella dysenteriae Shigella toxin (, utes to toxic effects in humans. Di- Shigella dysenteriae type I toxin, Vero cell toxin) rectly contributes to toxic effects in , humans means those sequences encod- communis, seeds Ricin ing polypeptides that have direct tox- (3) Sequences for . icity to target cells. An example of a sequence which directly contributes to Sequence Source Toxin Name toxic effects in humans is one which Neurotoxins A, B, C1, D, E, encodes the portion of diphtheria F, G (Botulinum toxins, toxin, listed in paragraph (d)(2) of this botulinal toxins) section, capable of interacting with Tetanus toxin () 2, leading to inhibi- Proteus mirabilis tion of protein synthesis in target res- aureus Alpha toxin (alpha lysin) piratory, heart, , and nerve tis- Yersinia pestis Murine toxin sues. Indirectly contributes to toxic ef- Snake toxins Bungarus caeruleus Caeruleotoxin fects in humans means a sequence Bungarus multicinctus Beta- whose encoded polypeptide is not di- (phospholipase)

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Sequence Source Toxin Name (7) Sequences that are general cytotoxins. Crotalus spp. Crotoxin (phospholipase) Dendroaspis viridis Neurotoxin Sequence Source Toxin Name Naja naja varieties Neurotoxin Notechia scutatus Notexin (phospholipase) Adenia digitata Modeccin Oxyuranus scutellatus Aeromonas hydrophila Aerolysin (beta-lysin, toxins cytotoxic lysin) Chironex fleckeri Neurotoxin Clostridium difficile Cytotoxin (toxin B) Androctnus australis Neurotoxin Centruroides sculpturatus Neurotoxin Beta-toxin; Epsilon-toxin; Kappa-toxin (4) Sequences for oxygen labile Escherichia coli & other Cytotoxin (Shiga-like toxin, cytolysins. Enterobacteriaceae spp. Vero cell toxin) Pseudomonas aeruginosa Sequence Source Toxin Name Staphylococcus aureus Gamma lysin (Gamma toxin); (SEA, SEB, Bacillus alve Alveolysin SEC, SED SEE); Bacillus cereus Cereolysin Pyrogenic A B; Bacillus laterosporus Laterosporolysin Toxic syndrome tox- Bacillus thuringiensis Thuringiolysin ins (TSST-1) Clostridium bifermentans Lysin Staphylococcus aureus & Leucocidin (, Clostridium botulinum Lysin Pseudomonas aeruginosa cytotoxin) Clostridium caproicum Lysin Streptococcus pyogenes S (SLS); Clostridium chauvoei Delta-toxin Erythrogenic toxins (scarlet Clostridium histolyticum Epsilon-toxin fever toxins, pyrogenic Clostridium novyi Gamma-toxin exotoxins) Clostridium oedematiens Delta-toxin Clostridium perfringens Theta-toxin (Perfringolysin) Yersinia enterocolitica Heat-stable enterotoxins (ST) Clostridium septicum Delta-toxin Clostridium sordellii Lysin § 725.422 Physical containment and Clostridium tetani control technologies. Listeria monocytogenes Listeriolysin (A B) Streptococcus pneumoniae Pneumolysin The manufacturer must meet all of Streptococcus pyogene Streptolysin O (SLO) the following criteria for physical con- (5) Sequences for toxins affecting mem- tainment and control technologies for brane function. any facility in which the new micro- organism will be used for a Tier I ex- Sequence Source Toxin Name emption; these criteria also serve as Bacillus anthracis factor (Factors I II); guidance for a Tier II exemption. Lethal factor (Factors II III) (a) Use a structure that is designed Bacillus cereus (diarrheagenic and operated to contain the new micro- toxin, mouse lethal factor) Bordetella pertussis Adenylate cyclase (Heat-la- organism. bile factor); Pertussigen (b) Control access to the structure. (, islet acti- (c) Provide written, published, and vating factor, histamine sensitizing factor, implemented procedures for the safety lymphocytosis promoting of personnel and control of hygiene. factor) (d) Use inactivation procedures dem- Clostridium botulinum C2 toxin Clostridium difficile Enterotoxin (toxin A) onstrated and documented to be effec- Clostridium perfringens Beta-toxin; Delta-toxin tive against the new microorganism Escherichia coli & other Heat-labile enterotoxins (LT); contained in liquid and solid wastes Enterobacteriaceae spp. Heat-stable enterotoxins (STa, ST1 subtypes ST1a prior to disposal of the wastes. The in- ST1b; also STb, STII) activation procedures must reduce via- 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 Sequence Source Toxin Name released from the structure, and docu- ment use of such features. Clostridium bifermentans & Lecithinase (f) Use systems for controlling dis- other Clostridium spp Clostridium perfringens Alpha-toxin (phospholipase semination of the new microorganism C, lecithinase); Enterotoxin through other routes, and document Corynebacterium pyogenes & Cytolysin (phospholipase C), use of such features. other Corynebacterium spp. Ovis toxin (sphingomyelinase D) (g) Have in place emergency clean-up Staphylococcus aureus Beta-lysin (beta toxin) procedures.

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§ 725.424 Requirements for the Tier I (i) Compliance with the introduced exemption. genetic material criteria described in (a) Conditions of exemption. The manu- § 725.421. facture or import of a new microorga- (ii) Compliance with the containment nism for commercial purposes is not requirements described in § 725.422, in- subject to review under this part if all cluding the provision in paragraph of the following conditions are met for (a)(3) of this section. all activities involving the new micro- (5) The site of waste disposal and the organism: type of permits for disposal, the permit (1) The recipient microorganism is numbers and the institutions issuing listed in and meets any requirements the permits. specified in § 725.420. (6) The certification statement re- (2) The introduced genetic material quired in § 725.25(b). Certification of meets the criteria under § 725.421. submission of test data is not required (3) The physical containment and for the Tier I exemption. control technologies of any facility in which the microorganism will be man- § 725.426 Applicability of the Tier I ex- ufactured, processed, or used meet the emption. criteria under § 725.422. The Tier I exemption under § 725.424 (4) The manufacturer or importer applies only to a manufacturer or im- submits a certification described in porter of a new microorganism that paragraph (b) of this section to EPA at certifies that the microorganism will least 10 days before commencing initial be used in all cases in compliance with manufacture or import of a new micro- §§ 725.420, 725.421, and 725.422. organism derived from a recipient microorganism listed in § 725.420. § 725.428 Requirements for the Tier II (5) The manufacturer or importer exemption. complies with the recordkeeping re- The manufacturer or importer of a quirements of § 725.65 and maintains new microorganism for commercial records for the initial and subsequent purposes may submit to EPA a Tier II uses of the new microorganism that exemption request in lieu of a MCAN verify compliance with the following: under subpart D of this part if all of (i) The certifications made in para- the following conditions are met: graph (b) of this section. (a) The recipient microorganism is (ii) All the eligibility criteria for the listed in and meets any requirements Tier I exemption including the criteria specified in § 725.420. for the recipient microorganism, the introduced genetic material, the phys- (b) The introduced genetic material ical containment and control tech- meets the criteria under § 725.421. nologies. (c) Adequate physical containment (b) Certification. To be eligible for the and control technologies are used. The Tier I exemption under this subpart, criteria listed under § 725.422 for phys- the manufacturer or importer must ical containment and control tech- submit to EPA a document signed by a nologies of facilities should be used as responsible company official con- guidance to satisfy the Tier II exemp- taining the information listed in this tion request data requirements listed paragraph. at § 725.455(d). EPA will review proposed (1) Name and address of manufac- process and containment procedures as turer or importer. part of the submission for a Tier II ex- (2) Date when manufacture or import emption under this section. is expected to begin. (3) The identification (genus, species) § 725.450 Procedural requirements for of the recipient microorganism listed the Tier II exemption. in § 725.420 which is being used to create General requirements for all submis- the new microorganism which will be sions under this part are contained in used under the conditions of the Tier I § 725.25. In addition, the following re- exemption. quirements apply to requests sub- (4) Certification of the following: mitted under this subpart:

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(a) Prenotice consultation. EPA substantiated by a letter from a cul- strongly suggests that for a Tier II ex- ture collection or a brief summary of emption, the submitter contact the the results of tests conducted for taxo- Agency for a prenotice consultation re- nomic identification. garding eligibility for the exemption. (2) Type of genetic modification and (b) When to submit the Tier II exemp- the function of the introduced genetic tion request. Each person who is eligible material. to submit a Tier II exemption request (3) Site of insertion. under this subpart must submit the re- (4) Certification of compliance with quest at least 45 calendar days before the introduced genetic material cri- the person intends to commence manu- teria described in § 725.421. facture or import. (c) Production volume. Production vol- (c) Contents of the Tier II exemption re- ume, including total liters per year, quest. Each person who submits a re- and the maximum cell concentration quest under this subpart must provide the information described in §§ 725.428 achieved during the production proc- and 725.455, as well as information ess. known to or reasonably ascertainable (d) Process and containment informa- by the person that would permit EPA tion. (1) A description of the process in- to determine that use of the micro- cluding the following: organism, under the conditions speci- (i) Identity and location of the manu- fied in the request, will not present an facturing site(s). unreasonable risk of injury to health (ii) Process flow diagram illustrating or the environment. the production process, including (d) Recordkeeping. Each person who downstream separations, and indi- submits a request under this subpart cating the containment envelope must comply with the recordkeeping around the appropriate equipment. requirements of § 725.65. In addition, (iii) Identities and quantities of feed- the submitter should maintain records stocks. which contain information that (iv) Sources and quantities of poten- verifies compliance with the following: tial releases to both the workplace and (1) The certifications made in the re- environment, and a description of engi- quest. neering controls, inactivation proce- (2) All the eligibility criteria for the dures, and other measures which will Tier II exemption request including the reduce worker exposure and environ- criteria for the recipient microorga- mental releases. nism, the introduced genetic material, (v) A description of procedures which the physical containment and control will be undertaken to prevent fugitive technologies. emissions, i.e. leak detection and re- § 725.455 Information to be included in pair program. the Tier II exemption request. (vi) A description of procedures/safe- The submitter must indicate clearly guards to prevent and mitigate acci- that the submission is a Tier II exemp- dental releases to the workplace and tion request for a microorganism in- the environment. stead of the MCAN under subpart D of (2) Certification of those elements of this part and must submit the fol- the containment criteria described in lowing information: § 725.422 with which the manufacturer (a) Submitter identification. (1) The is in compliance, including stating by name and headquarters address of the number the elements with which the submitter. manufacturer is in full compliance. (2) The name, address, and office tele- (e) The site of waste disposal and the phone number (including area code) of type of permits for disposal, the permit the principal technical contact rep- numbers and the institutions issuing resenting the submitter. the permits. (b) Microorganism identity information. (f) The certification statement re- (1) Identification (genus, species, and quired in § 725.25(b). Certification of strain) of the recipient microorganism. submission of test data is not required Genus, species designation should be for the Tier II exemption.

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§ 725.470 EPA review of the Tier II ex- Agency will either approve or deny the emption request. request. General procedures for review of all (2) In approving a request, EPA may submissions under this part are con- impose any restrictions necessary to tained in §§ 725.28 through 725.60. In ad- ensure that the microorganism will not dition, the following procedures apply present an unreasonable risk of injury to EPA review of Tier II exemption re- to health and the environment as a re- quests submitted under this subpart: sult of general commercial use. (a) Length of the review period. The re- (f) EPA may seek to enjoin the man- view period for the request will be 45 ufacture or import of a microorganism days from the date the Document Con- in violation of this subpart, or act to trol Officer for the Office of Pollution seize any microorganism manufactured Prevention and Toxics receives a com- or imported in violation of this section plete request, or the date EPA deter- or take other actions under the author- mines the request is complete under ity of sections 7 or 17 of the Act. § 725.33, unless the Agency extends the (g) A manufacturer or importer may review period for good cause under only proceed after receipt of EPA ap- § 725.56. proval. (b) Criteria for review. EPA will review the request to determine that the new Subparts H–K [Reserved] microorganism complies with § 725.428 and that its manufacture, processing, Subpart L—Additional Procedures use, and disposal as described in the re- quest will not present an unreasonable for Reporting on Significant risk of injury to health or the environ- New Uses of Microorganisms ment. § 725.900 Scope and purpose. (c) EPA decision regarding the Tier II exemption request. A decision con- (a) This subpart describes additional cerning a request under this subpart provisions governing submission of will be made by the Administrator, or MCANs for microorganisms subject to a designee. significant new use rules identified in (d) Determination that the microorga- subpart M of this part. nism is ineligible for a Tier II review. (1) (b) Manufacturers, importers, and EPA may determine that the manufac- processors described in § 725.105(c) must turer or importer is not eligible for submit a MCAN under subpart D of this Tier II review, because the microorga- part for significant new uses of micro- nism does not meet the criteria under organisms described in subpart M of § 725.428 or the Administrator, or a des- this part, unless they are excluded ignee, decides that there is insufficient under §§ 725.910 or 725.912. information to determine that the con- (c) Section 725.920 discusses exports ditions of manufacture, processing, and imports. use, or disposal of the microorganism (d) Additional recordkeeping require- as described in the request will not ments specific to significant new uses present an unreasonable risk to health of microorganisms are described in or the environment. § 725.950. (2) If the Agency makes this deter- (e) Section 725.975 describes how EPA mination, the Administrator, or a des- will approve alternative means of com- ignee will notify the manufacturer or plying with significant new use re- importer by telephone, followed by a quirements designated in subpart M of letter, that the request has been de- this part. nied. The letter will explain reasons for (f) Expedited procedures for promul- the denial. gating significant new use require- (3) If the request is denied, the manu- ments under subpart M of this part for facturer or importer may submit the microorganisms subject to section 5(e) information necessary to constitute a orders are discussed in §§ 725.980 and MCAN under subpart D of this part. 725.984. (e) Approval or denial of the Tier II ex- (g) This subpart L contains provi- emption request. (1) No later than 45 sions governing submission and review days after EPA receives a request, the of notices for the microorganisms and

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