Molecular Probes, Inc. — Hazardous Materials Safety Interpretation

Page 1U.S. Department of Transportation 400 Seventh St., S.W. Research and APR 15 2004 Washington, D.C. 20590 special Programs Administratior Mr. Bruce H. Bale Molecular Probes, Inc. Regulatory/Safety Manager Reference No. 03-0107 4849 Pitchford Avenue Eugene, OR 97402-9165 Dear Mr. Bale: This is in response to your letter and telephone conversation with a member of my staff asking noW to properly classity and describe three fluorescent reagents under the Hazardous Material Regulations (HMR; 49 CFR Parts 171-180). You describe the reagents as three naturall occurring toxins, phalloidin, phallacidin, and bungarotoxin covalently bonded to fluorescent molecules. Your company offers each product for transportation by aircraft as a dangerous good in excepted quantities and would like to described them as a "Toxic solid, organic, n.o.s., 6.1 (poisonous), UN 2811, PG I or PG II." Your questions are paraphrased and answered below in the order provided. Q1. From our review of the published data on the toxins, it is our opinion that our solid fluorescent conjugates of these toxins would be appropriately assigned to Packing Group I or Packing Group II. Which is correct? Al. As provided in § 173.22, it is the shipper's responsibility to properly classify a hazardous material. This Ottice does not perform that function. However, based on the information and toxicity data you provided, it is this Office's opinion that the classification for this material is, at a minimum, Class 6.1, Packing Group II. Q2. If the appropriate assignment for the material is Packing Group I, it is our opinion that these reagents would not constitute an inhalation hazard in transport. Is that correct? A2: inhalation hazard, under the HMR. It is this Office's opinion that the reagents do not meet the criteria in §173.133(a) for an I hope this information is helpful. Sincerely, Hitte a mished Hattie L. Mitchell, Chief Office of Hazardous Materials Standards Regulatory Review and Reinvention 173.133 030107#

Page 2Edmonson $172,101 8113,133 Packinda for aup Molecular Probes (541) 465-8300 • Fax (541) 344-6504 • www.probes.com 4849 Pitchford Ave. • Eugene, OR 97402-9165 03-0107 April 17, 2003 Edward T. Mazzullo US Department of Transportation Research and Special Program Administration Office of Hazardous Materials Standards.- DHM-10 400 7th St., S.W. Washington, DC 20590-0001 Dear Mr. Mazzullo, This morning I spoke with Dr. George Cushmac at the Office of Hazardous Materials Technology and he recommended that I submit my questions to your office to obtain a written interpretation. Under the Research and Development exemption of TSCA, our company manufactures extremely small quantity, high-purity fluorescent reagents for biochemical research. We sell and distribute approximately 2,500 products worldwide under International Air Transport Regulations (IATA). A few of these products, the focus of this letter, are fluorescent conjugates of three naturally occurring toxins, phalloidin, phallacidin, and bungarotoxin. Essentially, we covalently bond toxin scent enaecule to the ers to The tiesultin quaint reta singful presence of toparent For safety purposes, we conservatively assume that these reagents are toxic. "dangerous goods in excepted quantities." We would like to ship these materials as Toxic solids, We sell these products as solids in 1 mg units. We are experienced in safely shipping by air organic, n.o.s., UN2811, 6.1. To do that, we need to assign the appropriate Packing Group for these reagents and there is no specific health hazard data available for them. There is toxicological data in the open literature for the toxins. In our conversation today, Dr. Cushmac explained that correlations are made from such data to distinguish between the Packing Groups. From our review of the published data on the toxins, it is our opinion that our solid fluorescent conjugates of these toxins would be appropriately assigned to:#

Page 3Packing Group I, or Packing Group II 1. Which group is correct? .!:: Also, if the appropriate assignment is Packing Group I, iț is our opinion that these reagents would not constitute an inhalation häzard in transport. * di 2. Is that correct? I am including copies of the references on published health hazard assessments for each of the three toxins. These references were obtained from the Registry of Toxic Effects of Chemical Substances published by the National Institutes of Occupational Safety and Health. you require any further information. go epine ay it alone made ate to coar me demy offe a 541-05 39 i7 .:0 Thank you. Sincerely, Bruce H. Bale Regulatory/Safety Manager Encl. ; 6; 401. i eh : ...#

Page 4**..* * * * * RTE C S (R) * * * Supplied by : MDI Information Systems,, Inc. * * Provided by : Canadian Centre for Occupational Health and Safety ***** * * 2002) **********Issue: 2002-4 (November, *** CHEMICAL IDENTIFICATION *** RTECS NUMBER CHEMICAL NAME : : EI6100500 CAS REGISTRY NUMBER Bungarotoxin DATA LAST UPDATED 37209-28-2 COMPOUND DESCRIPTOR ITEMS CITED 199703 1 : Natural Product: *** HEALTH HAZARD DATA:*** ** ACUTE TOXICITY DATA ** ROUTE OF EXPOSURE TYPE OF TEST : LD50 - Lethal dose, 50 percent kill SPECIES OBSERVED Intraperitoneal DOSE/DURATION Rodent - mouse TOXIC EFFECTS : : 100 ug/kg REFERENCE : Details of toxic effects not reported other than lethal dose value OX3 OBW, UK) TOXIA6 Toxicon. v.1- (Pergamon Bress Itd., Headington Hill Hall, Oxford Volume (issue)/page/year: 10,227,1972 3** END OF RECORD*** :: ::. ::#

Page 5**-* * * * * * * * * * * -RTE C S(R) •: * Supplied by : MDL Information Systems, Inc. * Provided by : Canadian Centre for Occupational Health and Safety * * * * ****** * Issue: 2002-4. (November, 2002) *** CHEMICAL IDENTIFICATION *** RTECS NUMBER CHEMICAL NAME : : GT8943000 valyl-ery thro-3-hydroxy-D-alpha-asparty1-I-cysteiny1-cis-4-hydroxy-L- cyclic(L-Alanyl-2-mercapto-L-tryptophyl-4,5-dihydroxy-L-leucyl-L- prolyl) cyclic (2-6) -sulfide CAS REGISTRY NUMBER : 26645-35-2 LAST UPDATED BEILSTEIN REFERENCE NO. : 0604129 MOLECULAR FORMULA MOLECULAR WEIGHT : C37-H50-N8-013-S SYNONYMS/ TRADE NAMES : * Phallacidin *** HEALTH HAZARD DATA *** ** ACUTE TOXICITY DATA ** TYPE OF TEST SPECIES OBSERVED ROUTE OF EXPOSURE : ID50 = Lethal dose, 50 percent kill DOSE/DURATION Rodent - mouse : 2 mg/kg REFERENCE : Details of toxic effects hot reported other than lethal dose value 2000 Corporate Blvd., NW, Boca CRBCAI CRC Critical Reviews in Biochemistry. FL 33431) (CRC Press, Volume (issue) /page/year: 5,185, 1978 ROUTE OF EXPOSURE TYPE OF TEST : ID50 - Lethal dose, 50 percent kill DOSE/DURATION SPECIES OBSERVED : Rodent - mouse Unreported TOXIC EFFECTS 2500 ug/kg Details of not reported other than lethal dose value REFERENCE Arzneimittel-Forschüng. Drug Research. (Editio Cantor 1951- Volume (issue) /page/year: 22, 2142, 1972. Verlag, Postfach 1255, W-7960 Aulendorf, •*** : END OF RECORD. ***#

Page 6* * * * * R I ECS (R) * Supplied by : MDI Information Systems, Inc. * Provided by : Canadian: Centre for Occupational Health and Safety * * * * 2002) ***** Issue : 2002-4 (November, *** CHEMICAL IDENFIFICATION *** RTECS NUMBER : SE9800000 CHEMICAL NAME : CAS REGISTRY NUMBER Phalloidin OTHER CAS REGISTRY NOS. : 63-24-1 : 17466-45-4 BEILSTEIN REFERENCE NO. : 4347460 LAST UPDATED DATA ITEMS CITED : 200003 MOLECULAR FORMULA 10 MOLECULAR WEIGHT 788:97 C35-H48-N8-011-S COMPOUND DESCRIPTOR Mutagen SYNONYMS/ TRADE NAMES : Natüral Product * Phalloidine *** FEALTH HAZARD DATA *** ** ACUTE TOXICIIY DATA ** TYPE OF TEST ROUTE OF EXPOSURE : Intraperitoneal : LDIo - Lowest published lethal dose SPECIES OBSERVED : Rodent - rat DOSE/DURATION TOXIC EFFECTS : 1 ng/kg Details of toxic effects not reported other than lethal dose value A42 REFERENCE : TOXIA6 Toxicon. (Pergamon Press Itd., Headington Hill Hall, Oxford 0X3 OBW, UK) v.1- 1962- "Volume (issue) /page/year: 10, 357,1972 TYPE OF TEST : ID50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE SPECIES OBSERVED Rodent Int raperitoneal DOSE/DURATION - mouse TOXIC EFFECTS 2 mg/kg REFERENCE Details of toxic effects not reported other than lethal dose value Soc., 10 Shattuck St., Boston, MA NEJMAG New England Journal of Medicine. 02115) V: 198- (Massachusetts Medical 1928- Volume (issue)/page/year: 269/223,1963 TYPE OF TEST ROUTE OF EXPOSURE Intravenous LDLO - Lowest published lethal dose DOSE/DURATION SPECIES OBSERVED 6600 ug/kg Rodent - mouse SAL: 24. :#

Page 72920: TOXIC EFFECTS : Liver Behavioral - fatty liver degeneration - muscle weakness REFERENCE : und Pharmakologie. AEPPAE Naunyn-Schmiedeberg's Archiv fuer Experimentelle Pathologie Publisher information, see NACC. Volume issue) /page/year: V.110-253; 1925-66. 190,406, 1938 ROUTE OF EXPOSURE : LD50 - Lethal. dose, 50 percent kill DOSE/DURATION SPECIES OBSERVED : Unreported Rodent - mouse : 2 ma/kg REFERENCE : Details of toxic effects not reported other than lethal dose value Verlag, Postfach 1255, ARZNAD Arzneimittel-Forschung. Drug Research. W-7960 Aulendorf, Fed. Rep. Ger.) (Editio Cantor v.I- 1951 - Volume (issue) /page/year! 22, 2142,1972 TYPE OF TEST : ID. - Lethal dose ROUTE OF EXPOSURE SPECIES OBSERVED : Intravenous DOSE/DURATION : Mammal - dog TOXIC EFFECTS >10 mg/kg* REFERENCE : Details of toxic effects not reported other than lethal dose value ARTON Archives of Toxicology. 3, D-1000 Berlin 33, Fed. Rep::. Ger.) (Springer-Verlag, Heidelberger P1. Volume (issue) /page/year: 48,61,1981 v.32- 1974- ROUTE OF EXPOSURE TYPE OF TEST : LDL04- Lowest published lethal dose SPECIES OBSERVED : Mammal - species unspecified Oral" DOSE/DURATION TOXIC EFFECTS : 1000 ug/kg REFERENCE : Details of toxic effects not reported other than lethal dose value publisher information, see JTCTDW. COXAO Clinical Toxicology. (New York, NY) V.1-18, 1968-81. For 17,45,1980 Volume (issue) /page/year: ** OTHER MULTIPLE DOSE TOXICITY DATA ** TYPE OF TEST : IDEo - Lowest published toxic dose SPECIES OBSERVED ROUTE OF EXPOSURE Intraperitoneal DOSE/DURATION : Rodent - rat TOXIC EFFECTS : 2500 ug/kg/5D-I REFERENCE : Liver - other •changes Gastroenterology, JOGAET Journal of Gastroenterology. (Japanese Society of 104 Japan) v.29-1994- Ginza Orient BLDG, Volume (issue) /page/year: 29,172,1994 9-13 Ginza 8, Chuo-ku, Tokyo TYPE OF TEST ROUTE OF EXPOSURE TOLO - Lowest published toxic dosE DOSE/DURATION SPECIES OBSERVED : Intraperitoneal 3500 ug/kg/7D-I#

Page 8TOXIC EFFECTS : Liver - jaundice, cholestatic Liver - changes in liver, Liver - other changes REFERENCE : weight :.: Duluth, MN 55802) GASTAB Gastroenterology. (Academic Press, 1943- Völume (issue) /page/year: 75,450,1978 Inc., 1 E. First St., ** MUTATION DAIA ** TYPE OF TEST TEST SYSTEM : Morphological transformațion : 1 umol/I Rodent - rat Liver REFERENCE : DOSE/DURATION 153: For publisher information, CYTZAM Cytobiologie. (Stuttgart, Fed. Rep: Ger.) •see EJCBDN. Volume (issue) /page/year: V.1-18, 1969-79. 17,73,1978 TEST SYSTEM TYPE OF TEST : DNA, inhibition REFERENCE DOSE/DURATION • Rodent - rat; Liver : 100- nmol/L TOXIA6 : 0x3 OBW, UK) Toxicon. v.1- (Pergamon Press Ltd., Headington Hill Hall, Oxford 1962- Volume (issue) /page/year: 25,1265, 1987 L*** END OF RECORD:*** War :: cha 62 RAP:#