MSDS Bisoprolol Fumarate Tablets %28Greenstone LLC%29 %28EN%29

MATERIAL SAFETY DATA SHEET Revision date: 22-May-2012

Version: 1.2

Page 1 of 10

1. IDENTIFICATION OF THE SUBSTANCE/PREPARATION AND THE COMPANY/UNDERTAKING Emergency telephone number: CHEMTREC (24 hours): 1-800-424-9300

Greenstone LLC 100 Route 206 North Peapack, NJ 07977 800-435-7095

Material Name: Bisoprolol Fumarate Tablets (Greenstone LLC) Trade Name: Synonyms: Chemical Family: Intended Use:

Not applicable None Not determined Pharmaceutical product used as, antihypertensive

2. HAZARDS IDENTIFICATION Appearance: Signal Word:

Pink or White Tablet WARNING

Statement of Hazard:

Suspected of damaging the unborn child.

Additional Hazard Information: Short Term:

Long Term:

Known Clinical Effects: EU Indication of danger:

Active ingredient may be harmful if swallowed. Antihypertensive drug: has blood pressurelowering properties Animal studies have shown a potential to cause adverse effects on the fetus. May be harmful to aquatic organisms. May have long-term toxic effects on the aquatic environment. (based on components) . The most frequent adverse effects seen during clinical use are headache, chest pain, and dizziness. Due to intended use, dangerous lowering of blood pressure can occur. Toxic to Reproduction: Category 3

EU Hazard Symbols:

EU Risk Phrases: Australian Hazard Classification (NOHSC): Note:

R63 - Possible risk of harm to the unborn child. Hazardous Substance. Non-Dangerous Goods.

This document has been prepared in accordance with standards for workplace safety, which require the inclusion of all known hazards of the active substance or its intermediates regardless of the potential risk. The precautionary statements and warnings included may not apply in all cases. Your needs may vary depending upon the potential for exposure in your workplace.

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MATERIAL SAFETY DATA SHEET Material Name: Bisoprolol Fumarate Tablets (Greenstone Page 2 of 10 LLC) Revision date: 22-May-2012 Version: 1.2 _______________________________________________________________________________________________________

3. COMPOSITION/INFORMATION ON INGREDIENTS Hazardous Ingredient Bisoprolol fumarate

Calcium phosphate dibasic, anhydrous Colloidal silicon dioxide

7757-93-9 7631-86-9

Polyethylene glycol Microcrystalline cellulose Titanium dioxide Magnesium stearate

25322-68-3 9004-34-6 13463-67-7 557-04-0

EU EINECS/ELINCS List EU Classification Not Listed Xn;R22 Repr.Cat.3;R63 R52/53 231-826-1 Not Listed 231-545-4 Not Listed 418-260-2 Not Listed Not Listed 232-674-9 Not Listed 236-675-5 Not Listed 209-150-3 Not Listed

CAS Number 9003-39-8 9005-65-6 9004-65-3

EU EINECS/ELINCS List EU Classification Not Listed Not Listed Not Listed Not Listed Not Listed Not Listed

Ingredient Crospovidone Polysorbate 80 Hydroxypropyl methylcellulose Additional Information:

CAS Number 104344-23-2

% 5 or 10 mg***

% * * *

* * * * * *

* Proprietary *** per tablet/capsule/lozenge/suppository Ingredient(s) indicated as hazardous have been assessed under standards for workplace safety.

For the full text of the R phrases mentioned in this Section, see Section 16

4. FIRST AID MEASURES Eye Contact:

Flush with water while holding eyelids open for at least 15 minutes. Seek medical attention immediately.

Skin Contact:

Remove contaminated clothing. Flush area with large amounts of water. Use soap. Seek medical attention.

Ingestion:

Never give anything by mouth to an unconscious person. Wash out mouth with water. Do not induce vomiting unless directed by medical personnel. Seek medical attention immediately.

Inhalation:

Remove to fresh air and keep patient at rest. Seek medical attention immediately.

Symptoms and Effects of Exposure: For information on potential signs and symptoms of exposure, See Section 2 - Hazards Identification and/or Section 11 - Toxicological Information.

5. FIRE FIGHTING MEASURES Extinguishing Media:

Use carbon dioxide, dry chemical, or water spray.

Hazardous Combustion Products:

Carbon monoxide, carbon dioxide, and oxides of nitrogen may be generated in a fire.

Fire Fighting Procedures:

During all fire fighting activities, wear appropriate protective equipment, including selfcontained breathing apparatus.

Fire / Explosion Hazards:

Fine particles (such as dust and mists) may fuel fires/explosions.

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6. ACCIDENTAL RELEASE MEASURES Health and Safety Precautions:

Personnel involved in clean-up should wear appropriate personal protective equipment (see Section 8). Minimize exposure.

Measures for Cleaning / Collecting:

Contain the source of spill if it is safe to do so. Collect spilled material by a method that controls dust generation. A damp cloth or a filtered vacuum should be used to clean spills of dry solids. Clean spill area thoroughly.

Measures for Environmental Protections:

Place waste in an appropriately labeled, sealed container for disposal. Care should be taken to avoid environmental release.

Additional Consideration for Large Spills:

Non-essential personnel should be evacuated from affected area. Report emergency situations immediately. Clean up operations should only be undertaken by trained personnel.

7. HANDLING AND STORAGE General Handling:

Storage Conditions:

Minimize dust generation and accumulation. If tablets or capsules are crushed and/or broken, avoid breathing dust and avoid contact with eyes, skin, and clothing. When handling, use appropriate personal protective equipment (see Section 8). Wash hands and any exposed skin after removal of PPE. Review and implement appropriate technical and procedural waste water and waste disposal measures to prevent occupational exposure or environmental releases. Potential points of process emissions of this material to the atmosphere should be controlled with dust collectors, HEPA filtration systems or other equivalent controls. Releases to the environment should be avoided. Store as directed by product packaging.

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8. EXPOSURE CONTROLS / PERSONAL PROTECTION Refer to available public information for specific member state Occupational Exposure Limits. Bisoprolol fumarate Manufacturer OEL:

25ug/m3

Calcium phosphate dibasic, anhydrous Latvia OEL - TWA

10 mg/m3

Colloidal silicon dioxide Australia TWA Austria OEL - MAKs Czech Republic OEL - TWA Estonia OEL - TWA Germany - TRGS 900 - TWAs Germany (DFG) - MAK Ireland OEL - TWAs Latvia OEL - TWA OSHA - Final PELs - Table Z-3 Mineral D: Slovakia OEL - TWA Slovenia OEL - TWA Polyethylene glycol Austria OEL - MAKs Germany - TRGS 900 - TWAs Germany (DFG) - MAK Slovakia OEL - TWA Slovenia OEL - TWA Microcrystalline cellulose ACGIH Threshold Limit Value (TWA) Australia TWA Belgium OEL - TWA Estonia OEL - TWA France OEL - TWA Ireland OEL - TWAs Latvia OEL - TWA OSHA - Final PELS - TWAs: Portugal OEL - TWA Romania OEL - TWA Spain OEL - TWA Titanium dioxide ACGIH Threshold Limit Value (TWA) Australia TWA Austria OEL - MAKs Belgium OEL - TWA Bulgaria OEL - TWA

2 mg/m3 4 mg/m3 0.1 mg/m3 4.0 mg/m3 2 mg/m3 4 mg/m3 4 mg/m3 inhalable fraction 6 mg/m3 2.4 mg/m3 1 mg/m3 20 mppcf Listed 4.0 mg/m3 4 mg/m3

1000 mg/m3 1000 mg/m3 1000 mg/m3 inhalable fraction 1000 mg/m3 1000 mg/m3

10 mg/m3 10 mg/m3 10 mg/m3 10 mg/m3 10 mg/m3 10 mg/m3 4 mg/m3 2 mg/m3 15 mg/m3 10 mg/m3 10 mg/m3 10 mg/m3

10 mg/m3 10 mg/m3 5 mg/m3 10 mg/m3 10.0 mg/m3

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MATERIAL SAFETY DATA SHEET Material Name: Bisoprolol Fumarate Tablets (Greenstone Page 5 of 10 LLC) Revision date: 22-May-2012 Version: 1.2 _______________________________________________________________________________________________________ 6 mg/m3 5 mg/m3 10 mg/m3 10 mg/m3 5 mg/m3 10 mg/m3 4 mg/m3 10 mg/m3 5 mg/m3 15 mg/m3 10.0 mg/m3 10 mg/m3 10 mg/m3 10 mg/m3 5 mg/m3

Denmark OEL - TWA Estonia OEL - TWA France OEL - TWA Greece OEL - TWA Ireland OEL - TWAs Latvia OEL - TWA Lithuania OEL - TWA OSHA - Final PELS - TWAs: Poland OEL - TWA Portugal OEL - TWA Romania OEL - TWA Spain OEL - TWA Sweden OEL - TWAs Magnesium stearate ACGIH Threshold Limit Value (TWA) Lithuania OEL - TWA Sweden OEL - TWAs

10 mg/m3 5 mg/m3 5 mg/m3

Engineering Controls:

Engineering controls should be used as the primary means to control exposures. General room ventilation is adequate unless the process generates dust, mist or fumes. Keep airborne contamination levels below the exposure limits listed above in this section.

Personal Protective Equipment:

Refer to applicable national standards and regulations in the selection and use of personal protective equipment (PPE). Impervious gloves are recommended if skin contact with drug product is possible and for bulk processing operations. Wear safety glasses or goggles if eye contact is possible. Impervious protective clothing is recommended if skin contact with drug product is possible and for bulk processing operations. If the applicable Occupational Exposure Limit (OEL) is exceeded, wear an appropriate respirator with a protection factor sufficient to control exposures to below the OEL.

Hands: Eyes: Skin: Respiratory protection:

9. PHYSICAL AND CHEMICAL PROPERTIES Physical State: Molecular Formula:

Tablet Mixture

Color: Molecular Weight:

Pink or White Mixture

10. STABILITY AND REACTIVITY Chemical Stability: Conditions to Avoid: Incompatible Materials:

Stable under normal conditions of use. Fine particles (such as dust and mists) may fuel fires/explosions. As a precautionary measure, keep away from strong oxidizers

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11. TOXICOLOGICAL INFORMATION The information included in this section describes the potential hazards of the individual ingredients.

General Information:

Acute Toxicity: (Species, Route, End Point, Dose) Microcrystalline cellulose Rat Oral LD50 > 5000 mg/kg Rabbit Dermal LD50 > 2000 mg/kg Magnesium stearate Rat Oral LD50 > 2000 mg/kg Rat Inhalation LC50 > 2000 mg/m3 Hydroxypropyl methylcellulose Rat Oral LD50 > 10,000 mg/kg Titanium dioxide Rat Oral LD50 > 7500 mg/kg Rat Subcutaneous LD 50 50 mg/kg Polysorbate 80 Rat Intravenous LD 50 1790 mg/kg Mouse Oral LD 50 25 g/kg Bisoprolol fumarate Rat Oral LD50 940 mg/kg Acute Toxicity Comments:

A greater than symbol (>) indicates that the toxicity endpoint being tested was not achievable at the highest dose used in the test.

Irritation / Sensitization: (Study Type, Species, Severity) Microcrystalline cellulose Skin Irritation Rabbit Non-irritating Eye Irritation Rabbit Non-irritating Polyethylene glycol Eye Irritation Rabbit Skin Irritation Rabbit

Mild Mild

Repeated Dose Toxicity: (Duration, Species, Route, Dose, End Point, Target Organ) Bisoprolol fumarate 4 Week(s) Rat Intravenous 5 mg/kg/day NOAEL None identified 4 Week(s) Dog Intravenous 10 mg/kg/day NOAEL None identified 6 Month(s) Rat Oral 150 mg/kg/day NOAEL None identified 12 Month(s) Rat Oral 75 mg/kg/day NOAEL None identified Reproduction & Developmental Toxicity: (Study Type, Species, Route, Dose, End Point, Effect(s)) Bisoprolol fumarate Reproductive & Fertility

Rat

Oral 150 mg/kg/day

NOAEL

Negative

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MATERIAL SAFETY DATA SHEET Page 7 of 10 Material Name: Bisoprolol Fumarate Tablets (Greenstone LLC) Version: 1.2 Revision date: 22-May-2012 _______________________________________________________________________________________________________

11. TOXICOLOGICAL INFORMATION Embryo / Fetal Development Fetotoxicity Embryo / Fetal Development Toxicity

Rat Rabbit

No route specified 40 mg/kg/day

NOAEL

No route specified 6.25 mg/kg/day

Not Teratogenic, Maternal Toxicity,

NOAEL

Not Teratogenic, Fetotoxicity, Maternal

Genetic Toxicity: (Study Type, Cell Type/Organism, Result) Bisoprolol fumarate In Vitro Bacterial Mutagenicity (Ames) Not specified Negative In Vitro Chromosome Aberration Hamster Negative In Vitro Unscheduled DNA Synthesis Not specified Negative In Vivo Micronucleus Mouse Negative In Vitro Cytogenetics Rat Negative Carcinogenicity: (Duration, Species, Route, Dose, End Point, Effect(s)) Bisoprolol fumarate 26 Month(s) Rat Oral, in feed 125 mg/kg/day NOAEL Not carcinogenic 24 Month(s) Mouse Oral, in feed 240 mg/kg/day NOAEL Not carcinogenic Carcinogen Status:

None of the components of this formulation are listed as a carcinogen by IARC, NTP or OSHA.

Crospovidone IARC:

Group 3 (Not Classifiable)

Titanium dioxide IARC: OSHA:

Group 2B (Possibly Carcinogenic to Humans) Listed

Colloidal silicon dioxide IARC:

Group 3 (Not Classifiable)

12. ECOLOGICAL INFORMATION Environmental Overview:

Environmental properties have not been thoroughly investigated. Releases to the environment should be avoided. Not readily biodegradable ( 4 % after 28 days). (bisoprolol fumarate)

Mobility, Persistence and Degradability: Aquatic Toxicity: (Species, Method, End Point, Duration, Result) Bisoprolol fumarate Daphnia magna (Water Flea) EC50 48 Hours 90 mg/L Fish LC50 96 Hours > 100 mg/L

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13. DISPOSAL CONSIDERATIONS Waste Treatment Methods:

Dispose of waste in accordance with all applicable laws and regulations. Member State specific and Community specific provisions must be considered. Considering the relevant known environmental and human health hazards of the material, review and implement appropriate technical and procedural waste water and waste disposal measures to prevent occupational exposure and environmental release. It is recommended that waste minimization be practiced. The best available technology should be utilized to prevent environmental releases. This may include destructive techniques for waste and wastewater.

14. TRANSPORT INFORMATION The following refers to all modes of transportation unless specified below. Not regulated for transport under USDOT, EUADR, IATA, or IMDG regulations.

15. REGULATORY INFORMATION EU Symbol: EU Indication of danger:

Xn Toxic to Reproduction: Category 3

EU Risk Phrases: R63 - Possible risk of harm to the unborn child. EU Safety Phrases: S22 - Do not breathe dust. S36/37 - Wear suitable protective clothing and gloves. S53 - Avoid exposure - obtain special instructions before use.

OSHA Label: WARNING Suspected of damaging the unborn child.

Canada - WHMIS: Classifications WHMIS hazard class: Class D, Division 2, Subdivision A

Calcium phosphate dibasic, anhydrous Inventory - United States TSCA - Sect. 8(b) Australia (AICS):

Present Present

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MATERIAL SAFETY DATA SHEET Page 9 of 10 Material Name: Bisoprolol Fumarate Tablets (Greenstone LLC) Version: 1.2 Revision date: 22-May-2012 _______________________________________________________________________________________________________

15. REGULATORY INFORMATION 231-826-1

EU EINECS/ELINCS List Crospovidone Inventory - United States TSCA - Sect. 8(b) Australia (AICS):

Present Present

Polysorbate 80 Inventory - United States TSCA - Sect. 8(b) Australia (AICS):

Present Present

Colloidal silicon dioxide Inventory - United States TSCA - Sect. 8(b) Australia (AICS): EU EINECS/ELINCS List

Present Present 231-545-4 418-260-2

Polyethylene glycol Inventory - United States TSCA - Sect. 8(b) Australia (AICS):

Present Present

Microcrystalline cellulose Inventory - United States TSCA - Sect. 8(b) Australia (AICS): EU EINECS/ELINCS List

Present Present 232-674-9

Hydroxypropyl methylcellulose Inventory - United States TSCA - Sect. 8(b) Australia (AICS): Standard for the Uniform Scheduling for Drugs and Poisons:

Present Present Schedule 4

Titanium dioxide Inventory - United States TSCA - Sect. 8(b) Australia (AICS): EU EINECS/ELINCS List


Magnesium stearate Inventory - United States TSCA - Sect. 8(b) Australia (AICS): EU EINECS/ELINCS List


16. OTHER INFORMATION Text of R phrases mentioned in Section 3 R63 - Possible risk of harm to the unborn child. R22 - Harmful if swallowed. R52/53 - Harmful to aquatic organisms, may cause long-term adverse effects in the aquatic environment. Data Sources:

Publicly available toxicity information.

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Reasons for Revision:

Updated Section 1 - Identification of the Substance/Preparation and the Company/Undertaking. Updated Section 9 - Physical and Chemical Properties. Updated Section 2 - Hazard Identification.

Prepared by:

Product Stewardship Hazard Communication Global Environment, Health, and Safety Operations

It is believed that the information contained in this Material Safety Data Sheet is accurate, and while it is provided in good faith, it is without a warranty of any kind, expressed or implied. If data for a hazard are not included in this document there is no known information at this time End of Safety Data Sheet

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MSDS Bisoprolol Fumarate Tablets %28Greenstone LLC%29 %28EN%29

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