Duloxetine Hydrochloride Capsules                                                         Page 1 of 8









                                           Duloxetine Hydrochloride

                                                   Capsules

Eli Lilly and Company                                 Effective Date: 21-Sep-2005

Material Safety Data Sheet





                 Section 1 - Chemical Product and Company

                                                   Manufacturer's Emergency Phone:

Manufacturer:

                                                   1-317-276-2000

Eli Lilly and Company

                                                   CHEMTREC:

Lilly Corporate Center

                                                   1-800-424-9300 (North America)

Indianapolis, IN 46285

                                                   1-703-527-3887 (International)



Common Name: Duloxetine Hydrochloride Capsules



Chemical Name: 2-Thiophenepropanamine, N-methyl-gamma-(1-naphthalenyloxy)-, hydrochloride,

(gammaS)-

Synonym(s): 10% W/W duloxetine pellets; 20% W/W duloxetine pellets; 5% W/W duloxetine pellets;

Duloxetine hydrochloride capsules, 20 mg; Duloxetine hydrochloride pulvules; Duloxetine

hydrochloride pulvules, 30 mg; Duloxetine hydrochloride pulvules, 60 mg; Pulvules duloxetine

hydrochloride; Encapsulated Duloxetine, 30 mg; Duloxetine pellets; Duloxetine hydrochloride pulvules,

40 mg; Duloxetine hydrochloride pulvules, 20 mg; Duloxetine hydrochloride pellets; Duloxetine

hydrochloride; Duloxetine; Duloxetine capsule mix; 246916 formulation

Trademarks(s): Cymbalta; AriClaim; Yentreve

Lilly Item Code(s): B02426; B02466; B02556; B02558; CK1079; CK1084; ND1068; ND1075;

ND1078; ND1080; ND1109; PU3235; PU3236; PU3237; PU3240; PU3241; PU3242; PU3243;

PU3244; PU3245; QA477P; QA511K; QD477P; UC5985; UC5986; UC5987; UC9542; UC9543;

UC9544; UC9545; UC9564; UC9565; UC9566; UC9567; VF0344



See attached glossary for abbreviations.





          Section 2 - Composition / Information on Ingredients

Ingredient                                           CAS        Concentration %

Duloxetine Hydrochloride                      136434-34-9           1.3 - 20

Excipients                                            NA            80 - 98



Exposure Guidelines:

Duloxetine hydrochloride - LEG 25 micrograms/m3 TWA for 12 hours. LEG 40 micrograms/m3 TWA

for 8 hours. Excursion Limit 300 micrograms/m3 for no more than a total of 30 minutes.





                         Section 3 - Hazards Identification







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Appearance: Capsules containing pellets

Physical State: Solid

Odor: Odorless







 Emergency Overview

 Emergency Overview Effective Date: 17-Aug-2004



 Lilly Laboratory Labeling Codes:

 Health 3               Fire 1                       Reactivity 0



 Primary Physical and Health Hazards: Not hazardous if intact. Corrosive (eyes). Nervous System

 and Liver Effects.



 Caution Statement: Intact Duloxetine Hydrochloride Capsules are not considered to be a health

 hazard. The contents of Duloxetine Hydrochloride Capsules may cause burns or permanent tissue

 damage to the eyes. Effects of exposure may include dizziness, nausea, drowsiness, fatigue, and liver

 effects.





Routes of Entry: Inhalation and skin contact.



Effects of Overexposure: Capsules are intended for human consumption under guidance of a

physician. Intact capsules are not considered hazardous under normal handling procedures. Adverse

events commonly observed during therapeutic administration include nausea, dry mouth, constipation,

decreased appetite, fatigue, dizziness, drowsiness, headache, insomnia, and increased sweating.



Duloxetine, the active ingredient, is harmful if swallowed, may cause burns or permanent tissue damage

to the eyes, and may be slightly irritating to the skin. In animal studies, the major signs of overdose

toxicity would be related to the central nervous (tremors, clonic convulsions, ataxia) and gastrointestinal

(emesis, decreased appetite) systems. Liver effects have been reported in long-term animal studies at

high doses.



Medical Conditions Aggravated by Exposure: None known.



Carcinogenicity:

Duloxetine hydrochloride - Not listed by IARC, NTP, ACGIH, or OSHA.





                            Section 4 - First Aid Measures

Eyes: Hold eyelids open and flush with a steady, gentle stream of water for 15 minutes. See an

ophthalmologist (eye doctor) or other physician immediately.



Skin: Remove contaminated clothing and clean before reuse. Wash all exposed areas of skin with

plenty of soap and water. Get medical attention if irritation develops.









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Inhalation: Move individual to fresh air. Get medical attention if breathing difficulty occurs. If not

breathing, provide artificial respiration assistance (mouth-to-mouth) and call a physician immediately.



Ingestion: Do not induce vomiting. Call a physician or poison control center. If available, administer

activated charcoal (6-8 heaping teaspoons) with two to three glasses of water. Do not give anything by

mouth to an unconscious person. Immediately transport to a medical care facility and see a physician.



Notes to Physician:

Duloxetine - No specific antidote is known. An airway should be established. Monitoring of cardiac and

vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric

lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated

charcoal may be useful in limiting absorption. Duloxetine has a large volume of distribution and forced

diuresis, hemoperfusion, and exchange perfusion are unlikely to be beneficial.





                         Section 5 - Fire Fighting Measures

Flash Point: No applicable information found

UEL: No applicable information found

LEL: No applicable information found



Extinguishing Media: Use water, carbon dioxide, dry chemical, foam, or Halon.



Unusual Fire and Explosion Hazards: As a finely divided material, may form dust mixtures in air

which could explode if subjected to an ignition source.



Hazardous Combustion Products: May emit toxic fumes when exposed to heat or fire.





                    Section 6 - Accidental Release Measures

The following are recommended for manufacturing or other situations where exposure to the contents

may occur.



Spills: Vacuum material with appropriate dust collection filter in place. Be aware of potential for dust

explosion when using electrical equipment. If vacuum is not available, lightly mist material and remove

by sweeping or wet wiping. Wear protective equipment, including eye protection, to avoid exposure

(see Section 8 for specific handling precautions).





                          Section 7 - Handling and Storage

Storage Conditions: Controlled Room Temperature: 15 to 30 C (59 to 86 F).





           Section 8 - Exposure Controls / Personal Protection

See Section 2 for Exposure Guideline information.



 Intact capsules are not considered hazardous under normal handling procedures and protective







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equipment is not required. The following are recommended for manufacturing or other situations where

exposure to contents may occur.



Respiratory Protection: Use an approved respirator.



Eye Protection: Chemical goggles and/or face shield.



Ventilation: Laboratory fume hood or local exhaust ventilation.



Other Protective Equipment: Chemical-resistant gloves and body covering to minimize skin

contact. If handled in a ventilated enclosure, as in a laboratory setting, respirator and goggles or face

shield may not be required. Safety glasses are always required.



Additional Exposure Precautions: In production settings, airline-supplied, hood-type respirators are

preferred. Shower and change clothing if skin contact occurs.





                 Section 9 - Physical and Chemical Properties

Appearance: Capsules containing pellets

Odor: Odorless

Boiling Point: Not applicable

Melting Point: No applicable information found

Specific Gravity: No applicable information found

pH: No applicable information found

Evaporation Rate: No applicable information found

Water Solubility: Soluble

Vapor Density: No applicable information found

Vapor Pressure: No applicable information found





                        Section 10 - Stability and Reactivity

Stability: Stable at normal temperatures and pressures.



Incompatibility: May react with strong oxidizing agents (e.g., peroxides, permanganates, nitric acid,

etc.).



Hazardous Decomposition: May emit toxic fumes when heated to decomposition.



Hazardous Polymerization: Will not occur.





                      Section 11 - Toxicological Information



Acute Exposure

Data for the active ingredient, duloxetine hydrochloride, are reported.



Oral:









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Duloxetine hydrochloride - Rat, median lethal dose 491 mg/kg for males and 279 mg/kg for females,

tremors, convulsions.

Dog, 100 mg/kg, no deaths, reduced activity, slow pupillary response, intermittent tremors, rigidity.



Skin:

Duloxetine hydrochloride - Rabbit, 1000 mg/kg, no deaths or toxicity.



Inhalation: No applicable information found.



Skin Contact:

Duloxetine hydrochloride - Rabbit, slight irritant



Eye Contact:

Duloxetine hydrochloride - Rabbit, corrosive



Chronic Exposure

Data for the active ingredient, duloxetine hydrochloride, are reported.



Target Organ Effects:

Duloxetine hydrochloride - Dilation of the pupil and slow pupillary light response reported in dogs

administered 3, 10, and 30 mg/kg orally for 1 year. Slight increase in liver enzymes reported in the mid-

and high-dose animals. Liver effects (tissue changes, enzyme induction) reported in rats administered

up to 0.08% in diet (47 mg/kg/day) for 6 months.



Reproduction:

Duloxetine - Reproductive performance was not affected in male rats (45 mg/kg/day). In female rats (45

mg/kg/day), reproductive toxicity was demonstrated by a decrease in maternal food consumption and

body weight, estrous cycle disruption, depressions in live birth indices and progeny survival, and

progeny growth retardation. The no-observed- effect level (NOEL) for maternal toxicity, reproductive

toxicity, and developmental toxicity in the female fertility study was 10 mg/kg/day. There was no

evidence of teratogenicity in animal studies. Duloxetine and/or its metabolites are excreted into the milk

of lactating rats.



Sensitization:

Duloxetine hydrochloride - Guinea pig, negative in active systemic anaphylaxis and passive cutaneous

anaphylaxis tests.



Mutagenicity:

Duloxetine - Demonstrated no mutagenic potential in a battery of in vitro and in vivo genotoxicity tests.





Carcinogenicity:

Duloxetine - Administered in the diet to rats and mice for 2 years. In rats, did not cause any increase in

incidence of expected or unusual neoplasms or decrease in the latency for any tumor type. In female

mice, there was an increased incidence of hepatocellular adenomas and carcinomas at the high dose only

(144 mg/kg/day), but these were considered to be secondary to hepatic enzyme induction with

associated centrilobular hypertrophy and vacuolation.





                        Section 12 - Ecological Information





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No environmental data for the mixture or formulation. The environmental information for ingredient(s)

or related material(s) are presented.



Ecotoxicity Data:

Duloxetine

Rainbow trout 96-hour median lethal concentration: 1.3 mg/L

Daphnia magna 48-hour median effective concentration: 2.4 mg/L

Green algae (P. subcapitata) 72-hour median effective concentration (biomass) : 0.064 mg/L

Green algae (P. subcapitata) 72-hour no observable effect concentration (biomass) : 0.011 mg/L

Activated sludge respiration inhibition 3-hour median effective concentration (1.6 g solids/L): 36.5

mg/L

Daphnia magna 21-day no observable effect concentration: 0.011 mg/L

Earthworm 14-day median effective concentration: >1000 mg/L



Environmental Fate:

Duloxetine hydrochloride

Log Kow: 0.78, 1.54, 3.35 (pH 4,7,9)

Bioconcentration factor (calculated): 324

pKa: 9.34

Sludge biodegredation: 91.3% to 62.1% at 8 hours

Sludge adsorption (Koc): 2893, 3150, 2970, 4296 (at 2500, 1250, 625, 313 mg solids/L)

Photolysis: 100% loss calculated over 1 month (pH 4, 7, 9)

Hydrolysis half-life (35 days at 30 C): 41.88, 100.62, 72.48 days (pH 4, 7, 9)

Hydrolysis half-life (35 days at 40 C): 15.73, 31.69, 22.64 days (pH 4, 7, 9)



Environmental Summary:

Duloxetine hydrochloride - Material is highly toxic to green algae and fish, moderately toxic to aquatic

invertebrates and slightly toxic to activated sludge microorganisms. Measurable concentrations of

material in atmosphere are not expected since it is a non-volatile solid. The solubility in water is

high. After 24 hours in activated municipal sludge, the duloxetine concentration declined extensively

(biodegradation and adsorption). Material is not expected to bioconcentrate in aquatic organisms.



Lilly Aquatic Exposure Guideline (LAEG):

Duloxetine hydrochloride

LAEG for Drinking Water: 20 micrograms/L

LAEG for Chronic Exposure of Aquatic Organisms: 1.7 micrograms/L

LAEG for Acute Exposure of Aquatic Organisms: 15 micrograms/L





                       Section 13 - Disposal Considerations

Waste Disposal: Dispose of any cleanup materials and waste residue according to all applicable laws

and regulations.





                        Section 14 - Transport Information

Regulatory Organizations:



DOT: Not Regulated









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ICAO/IATA: Not Regulated



IMO: Not Regulated





                       Section 15 - Regulatory Information

Below is selected regulatory information chosen primarily for possible Eli Lilly and Company

usage. This section is not a complete analysis or reference to all applicable regulatory

information. Please consider all applicable laws and regulations for your country/state.



U.S. Regulations

Duloxetine hydrochloride

TSCA - No

CERCLA - Not on this list

SARA 302 - Not on this list

SARA 313 - Not on this list

OSHA Substance Specific - No



EU Regulations

EC Classification

Xi (Irritant)



Risk Phrases

R 41 - Risk of serious damage to eyes.



Safety Phrases

S 26 - In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.

S 36/37/39 - Wear suitable protective clothing, gloves and eye/face protection.

S 45 - In case of accident or if you feel unwell, seek medical advice immediately (show the label where

possible).





                            Section 16 - Other Information

MSDS Sections Revised: Section 1.



As of the date of issuance, we are providing available information relevant to the handling of this

material in the workplace. All information contained herein is offered with the good faith belief that it

is accurate. THIS MATERIAL SAFETY DATA SHEET SHALL NOT BE DEEMED TO CREATE

ANY WARRANTY OF ANY KIND (INCLUDING WARRANTY OF MERCHANTABILITY OR

FITNESS FOR A PARTICULAR PURPOSE). In the event of an adverse incident associated with this

material, this safety data sheet is not intended to be a substitute for consultation with appropriately

trained personnel. Nor is this safety data sheet intended to be a substitute for product literature which

may accompany the finished product.



For additional information contact:

Eli Lilly and Company









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Hazard Communication

317-651-9533





GLOSSARY:



ACGIH = American Conference of Governmental Industrial Hygienists

AIHA = American Industrial Hygiene Association

BEI = Biological Exposure Index

CAS Number = Chemical Abstract Service Registry Number

CERCLA = Comprehensive Environmental Response Compensation and Liability Act (of 1980)

CHAN = Chemical Hazard Alert Notice

CHEMTREC = Chemical Transportation Emergency Center

DOT = Department of Transportation

EC = European Community

EINECS = European Inventory of Existing Chemical Substances

ELINCS = European List of New Chemical Substances

EPA = Environmental Protection Agency

HEPA = High Efficiency Particulate Air (Filter)

IARC = International Agency for Research on Cancer

ICAO/IATA = International Civil Aviation Organization/International Air Transport Association

IEG = Lilly Interim Exposure Guideline

IMO = International Maritime Organization

Kow = Octanol/Water Partition Coefficient

LEG = Lilly Exposure Guideline

LEL = Lower Explosive Limit

MSDS = Material Safety Data Sheet

MSHA = Mine Safety and Health Administration

NA = Not Applicable, except in Section 14 where NA = North America

NADA = New Animal Drug Application

NAIF = No Applicable Information Found

NCI = National Cancer Institute

NIOSH = National Institute for Occupational Safety and Health

NOS = Not Otherwise Specified

NTP = National Toxicology Program

OSHA = Occupational Safety and Health Administration

PEL = Permissible Exposure Limit (OSHA)

RCRA = Resource Conservation and Recovery Act

RQ = Reportable Quantity

RTECS = Registry of Toxic Effects of Chemical Substances

SARA = Superfund Amendments and Reauthorization Act

STEG = Lilly Short Term Exposure Guideline

STEL = Short Term Exposure Limit

TLV = Threshold Limit Value (ACGIH)

TPQ = Threshold Planning Quantity

TSCA = Toxic Substances Control Act

TWA = Time Weighted Average/8 Hours Unless Otherwise Noted

UEL = Upper Explosive Limit

UN = United Nations

WEEL = Workplace Environmental Exposure Level (AIHA)









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