ProHance - Gadoteridol injection SDS

Page 1/9 Safety Data Sheet According to OSHA HazCom Standard [2012] Printing date 02/22/2019 Version 4 Reviewed on 02/22/2019

1 Identification

Product identifier Sheet Code: 270 Trade name: ProHance Chemical Name: 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, monogadolinium salt. Synonyms: Gadoteridol Injection Application of the substance / the mixture: Intravenous injection contrast medium formagnetic resonance imaging. We recommend that you use this product in a manner consistent with the listed use. If your intended use is not consistent with the stated use, please contact your sales or technical service representative. Packages of five single dose vials (5 mL fill in15 mL vial, and 10, 15, or 20 mL fills in 30 mL vials). Packages of five single dose prefilled syringes (10 or 17 mL fills in a 20 mL syringes). Details of the supplier of the safety data sheet Manufacturer/Supplier: Bracco Diagnostics Inc. P.O. Box 5225 Princeton, NJ 08543 Phone number: 1-800-257-5181 Email: Hse@bracco.com (responsible for the SDS) Information department: B-Lands Consulting WTC, 5 Place Robert Schuman, BP 1516 38025 Grenoble, FRANCE Tel: +33 476 295 869 Fax: +33 476 295 870 Email: clients@reachteam.eu www.reachteam.eu

2 Hazard(s) identification

Classification of the substance or mixture The product is not classified, according to the Globally Harmonized System (GHS). Label elements GHS label elements Not applicable. Hazard pictograms Not applicable. Signal word Not applicable. Hazard statements Not applicable. Additional Information: Classification system: NFPA ratings (scale 0 - 4) 0 HealthFire = 0= 0 0 0 Reactivity = 0 HMIS-ratings (scale 0 - 4) HEALTH 0 Health = 0 FIRE 0 Fire = 0 REACTIVITY 0 Reactivity = 0

Other hazards No further relevant information available. Results of PBT and vPvB assessment PBT: Not applicable. vPvB: Not applicable. (Contd. on page 2)

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Page 2/9 Safety Data Sheet According to OSHA HazCom Standard [2012] Printing date 02/22/2019 Version 4 Reviewed on 02/22/2019 Trade name: ProHance Chemical Name: 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, monogadolinium salt. Synonyms: Gadoteridol Injection

(Contd. of page 1)

3 Composition/information on ingredients

Chemical characterization: Mixtures Description: Mixture: consisting of the following components. Hazardous Components: Not applicable. Information on components: 7732-18-5 Water USP 50-100% 120066-54-8 (±)-[10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (3 -)] 27.9% Gadolinium

4 First-aid measures

Description of first aid measures General information: No special measures required. After inhalation: Move patient to fresh air, if symptom arise consult a doctor. Supply fresh air. If required, provide artificial respiration. Consult doctor if symptoms persist. After skin contact: Immediately wash with water and soap and rinse thoroughly. If symptoms persist, consult a doctor. Generally the product does not irritate the skin. After eye contact: Rinse opened eye for several minutes under running water. If irritation persists get medical attention. After swallowing: Immediately call a doctor. Vomiting may be induced only if a person is conscious and if ingestion has occurred within the past three hours. Never induce vomiting in a person who is unconscious or experiencing convulsions. Most important symptoms and effects, both acute and delayed No further relevant information available. Indication of any immediate medical attention and special treatment needed No further relevant information available.

5 Fire-fighting measures

Extinguishing media Suitable extinguishing agents: In case of fire, flood with Water Special hazards arising from the substance or mixture In case of fire, the following can be released: Carbon Dioxide (CO2) In the absence of Oxygen: Carbon Monoxide (CO) Nitrogen Oxides (NxOy) Gadolinium Oxide (Gd2O3) Advice for firefighters Protective equipment: Firefighters should wear adequate personal protective equipment with protection of respiratory tract (selfcontained breathing apparatus) (SCBA). In addition, firefighters should wear flame and chemicals resistant clothing, boots and gloves. (Contd. on page 3)

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Page 3/9 Safety Data Sheet According to OSHA HazCom Standard [2012] Printing date 02/22/2019 Version 4 Reviewed on 02/22/2019 Trade name: ProHance Chemical Name: 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, monogadolinium salt. Synonyms: Gadoteridol Injection

(Contd. of page 2)

6 Accidental release measures

Personal precautions, protective equipment and emergency procedures Keep away from ignition sources Wear protective equipment. Keep unprotected persons away. Environmental precautions: Do not allow to enter sewers/ surface or ground water. Methods and material for containment and cleaning up: Absorb with liquid-binding material. Absorb with liquid-binding material (sand, diatomite, vermiculite) or other non combustible absorbent material. Place spilt material in an appropriate container for disposal. The spill area should be ventilated and decontaminated after material is collected. Reference to other sections No dangerous substances are released. See Section 7 for information on safe handling. See Section 8 for information on personal protection equipment. See Section 13 for disposal information. Protective Action Criteria for Chemicals PAC-1: 77-86-1 trometamol 18 mg/m³ PAC-2: 77-86-1 trometamol 190 mg/m³ PAC-3: 77-86-1 trometamol 1,200 mg/m³

7 Handling and storage

Precautions for safe handling Avoid splashes or spray in enclosed areas. Avoid contact with the eyes and skin. Do not break vials Information about protection against explosions and fires: No special measures required. Conditions for safe storage, including any incompatibilities Requirements to be met by storerooms and receptacles: Store in a cool, dry place in well sealed receptacles. Information about storage in one common storage facility: Not required. Further information about storage conditions: Container Requirements: Single dose 15, 30 and 50 mL vials and 20 mL prefilled syringes. Storage Conditions: Store at 25° C, excursions perm itted to 15-30°C. Protect from light and do not fre eze. Specific end use(s) No further relevant information available.

8 Exposure controls/personal protection

Control parameters Components with limit values that require monitoring at the workplace: The product does not contain any relevant quantities of materials with critical values that have to be monitored at the workplace. Additional information: The lists that were valid during the creation were used as basis. (Contd. on page 4)

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Page 4/9 Safety Data Sheet According to OSHA HazCom Standard [2012] Printing date 02/22/2019 Version 4 Reviewed on 02/22/2019 Trade name: ProHance Chemical Name: 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, monogadolinium salt. Synonyms: Gadoteridol Injection

(Contd. of page 3) Exposure controls Personal protective equipment General protective and hygienic measures: The usual precautionary measures for handling chemicals should be followed. Ensure good ventilation/exhaustion at the workplace. Wash hands before breaks and at the end of work.

Do not eat, drink and smoke while working.

Breathing equipment: Not anticipated for normal clinical environment. In non-routine exposure conditions, where risk assessment shows air-purifying respirators are appropriate, use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). Self-contained breathing apparatus should be available for emergency use. Protection of hands:

Protective gloves

The glove material must be impermeable and resistant to the product/ the substance/ the preparation. Due to missing tests no recommendation to the glove material can be given for the product/ the preparation/ the chemical mixture. Selection of the glove material on consideration of the penetration times, rates of diffusion and the degradation Material of gloves Natural rubber, NR Nitrile rubber, NBR The selection of the suitable gloves does not only depend on the material, but also on further marks of quality and varies from manufacturer to manufacturer. As the product is a preparation of several substances, the resistance of the glove material can not be calculated in advance and has therefore to be checked prior to the application. Penetration time of glove material The exact break through time has to be found out by the manufacturer of the protective gloves and has to be observed. Eye protection:

Tightly sealed goggles

Body protection: Protective work clothing

9 Physical and chemical properties

Information on basic physical and chemical properties General Information Appearance: Form: Liquid. Color: Colorless - Slightly Yellow Odor: Undistinguishable (Contd. on page 5)

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Page 5/9 Safety Data Sheet According to OSHA HazCom Standard [2012] Printing date 02/22/2019 Version 4 Reviewed on 02/22/2019 Trade name: ProHance Chemical Name: 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, monogadolinium salt. Synonyms: Gadoteridol Injection

(Contd. of page 4) Odor threshold: Not determined. pH-value: 6.5 - 8.0 Melting point/Melting range: ca 100 °C (~212 °F) Boiling point/Boiling range: ca 0 °C (~32 °F) Flash point: Not determined. Flammability (solid, gaseous): Not applicable. Ignition temperature: Not determined. Decomposition temperature: Not determined. Auto igniting: Product is not selfigniting. Danger of explosion: Product does not present an explosion hazard. Not determined. Flammability Limits: Lower: Not Determined. Upper: Not Determined. Explosion limits: Lower: Not determined. Upper: Not determined. Oxidizing properties Not determined. Vapor pressure: Gadoteridol: T = 26°C, P° < 1.67 x 10-7 Torr Density: (25 °C) 1.140 g/cm3 Bulk density: (25 °C) 1.140 g/cm3 Relative density Not determined. Vapor density Not determined. Evaporation rate 䏌 as water Solubility in / Miscibility with Water: Not miscible or difficult to mix. Partition coefficient (n-octanol/water): pH=7, logKow: -3.57 to -3.58 pH=9, logKow: -3.66 to -3.70 Viscosity: Dynamic: T = 20 °C, η = 2.0 cP T = 37 °C, η = 1.3 cP Kinematic: Not determined. Water: 71.9 % VOC content: 0.00 % Solids content: 0.0 % Other information No further relevant information available.

10 Stability and reactivity

Reactivity No data available. No further relevant information available. (Contd. on page 6)

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Page 6/9 Safety Data Sheet According to OSHA HazCom Standard [2012] Printing date 02/22/2019 Version 4 Reviewed on 02/22/2019 Trade name: ProHance Chemical Name: 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, monogadolinium salt. Synonyms: Gadoteridol Injection

(Contd. of page 5) Chemical stability Thermal decomposition / conditions to be avoided: No decomposition if used according to specifications. Possibility of hazardous reactions No dangerous reactions known. Conditions to avoid No further relevant information available. Incompatible materials: No further relevant information available. Hazardous decomposition products: No dangerous decomposition products known.

11 Toxicological information

Information on toxicological effects Acute toxicity: LD/LC50 values that are relevant for classification: 120066-54-8 (±)-[10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (3 -)] Gadolinium LD50 iv 7,598 mg/kg (Female Mouse) 5,978 mg/kg (Male Mouse) 3,906 mg/kg (Mouse) 5,880 mg/kg (Rat) 77-86-1 trometamol Oral LD50 5,900 mg/kg (Rat) 121915-83-1 Calcium Calteridol LD50 iv 1,200 mg/kg (Mouse) Primary irritant effect: on the skin: No irritant effect. Material contains low concentration of components that are mild irritants or possible irritants. It may have potential to cause mild irritation, however , moderate or severe irritation is not expected. on the eye: No irritating effect. No irritation effects reported. However, the product should be considered as a potential irritant. Sensitization: No sensitizing effects known. The product can cause inflammation in people allergic to gadolinium and its compounds. Other information (about experimental toxicology): By Inhalation: Inhaling small doses of aerosolized material would not be expected to result in symptoms.

By Ingestion: Inadvertent ingestion of trace amounts of this material would not be expected to result in symptoms.

Germ Cell Mutagenicity: GADOTERIDOL has not demonstrated a genotoxic activity in reverse mutation test up performed using Salmonella bacteria T. and E. C., in a mutation assay on mouse lymphoma, in an in vitro cytogenetic assay measuring chromosomal aberrations in ovarian cells hamster, nor in the in vivo micronucleus assay on mice at doses of 5 mmol / kg.

Carcinogenicity: The GADOTERIDOL is not tested for carcinogenic properties.

Reproductive Toxicity: The GADOTERIDOL didn't show teratogenic activity in rats when administered for 12-day gestation period at doses 20 times higher than recommended for Human. An increase in spontaneous motor activity was observed in infants. At high doses, the product has caused maternal toxicity and there was an increase of postimplantation loss. In rabbits, There was no evidence of (Contd. on page 7)

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Page 7/9 Safety Data Sheet According to OSHA HazCom Standard [2012] Printing date 02/22/2019 Version 4 Reviewed on 02/22/2019 Trade name: ProHance Chemical Name: 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, monogadolinium salt. Synonyms: Gadoteridol Injection

(Contd. of page 6) teratogenic activity in rabbits at doses tested up to 1.5 mmol/kg or 840 mg/kg In rabbits, doses 20 times higher than the maximum doses recommended for humans, and administered intravenously for 13 days during gestation, have increased the incidence of miscarriages and premature births, while, there was no evidence of reproductive effects in rats at doses up to 1.5 mmol/kg or 840 mg/kg.

Subacute to Chronic Toxicity: Human data are not available. In studies with rats and dogs performed over a period of one month to doses approximately 3 times higher than therapeutic effects were evident in kidney (eg, vacuolation of renal tubular epithelium). These effects are reversible. The product does not is mutagenic. Other health effects have not been fully evaluated. Additional toxicological information: The product is not subject to classification according to internally approved calculation methods for preparations. When used and handled according to specifications, the product does not have any harmful effects to our experience and the information provided to us. When this product is used clinically, patients with a history of renal or hepatic disease, seizure, asthma or allergic respiratory diseases, and pregnant or breast feeding women are asked to inform their physician of these conditions. The GADOTERIDOL was classified by the FDA in the "Pregnancy Category C" because of the effects observed in animals treated with very high doses intravenously. We recommended the clinical use during pregnancy only when the benefit prevails over potential risk to the fetus. It must be borne in mind that the doses administered for medical reasons are much higher than those due to exposure in the workplace. Carcinogenic categories IARC (International Agency for Research on Cancer) None of the ingredients are listed. NTP (National Toxicology Program) None of the ingredients are listed. OSHA-Ca (Occupational Safety & Health Administration) None of the ingredients are listed.

12 Ecological information

Toxicity Aquatic toxicity: 120066-54-8 (±)-[10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (3 -)] Gadolinium IC50 >1,000 mg/L (Activated Sludge) EC50 >920 mg/L (Daphnia) Persistence and degradability Half-life (hydrolysis: < 10 % after 5-days at 50 degrees C at all pH levels tested; half-life determined to be greater than 28 days. Bioaccumulative potential No further relevant information available. Mobility in soil No further relevant information available. Additional ecological information General notes: Avoid transfer into the environment. Water hazard class 1 (Self-assessment): slightly hazardous for water Do not allow undiluted product or large quantities of it to reach ground water, water course or sewage system. Results of PBT and vPvB assessment PBT: Not applicable. (Contd. on page 8)

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Page 8/9 Safety Data Sheet According to OSHA HazCom Standard [2012] Printing date 02/22/2019 Version 4 Reviewed on 02/22/2019 Trade name: ProHance Chemical Name: 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, monogadolinium salt. Synonyms: Gadoteridol Injection

(Contd. of page 7) vPvB: Not applicable. Other adverse effects No further relevant information available.

13 Disposal considerations

Waste treatment methods Recommendation: Must not be disposed of together with household garbage. Do not allow product to reach sewage system. Reutilise if possible or contact a waste processors for recycling or safe disposal. Uncleaned packagings: Recommendation: Disposal must be made according to official regulations. Packagings that cannot be cleansed are to be disposed of in the same manner as the product.

14 Transport information

UN-Number DOT, ADR, ADN, IMDG, IATA Not applicable. UN proper shipping name DOT, ADR, ADN, IMDG, IATA Not applicable. Transport hazard class(es) DOT, ADR, ADN, IMDG, IATA Class Not applicable. Packing group DOT, ADR, IMDG, IATA Not applicable. Environmental hazards: Marine pollutant: No Special precautions for user Not applicable. Transport in bulk according to Annex II of MARPOL73/78 and the IBC Code Not applicable.

15 Regulatory information

Safety, health and environmental regulations/legislation specific for the substance or mixture Sara

Section 355 (extremely hazardous substances):

None of the ingredients are listed.

Section 313 (Specific toxic chemical listings):

None of the ingredients is listed. Proposition 65 Chemicals known to cause cancer: None of the ingredients is listed. Chemicals known to cause reproductive toxicity for females: None of the ingredients are listed. Chemicals known to cause reproductive toxicity for males: None of the ingredients are listed. (Contd. on page 9)

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Page 9/9 Safety Data Sheet According to OSHA HazCom Standard [2012] Printing date 02/22/2019 Version 4 Reviewed on 02/22/2019 Trade name: ProHance Chemical Name: 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, monogadolinium salt. Synonyms: Gadoteridol Injection

(Contd. of page 8) Chemicals known to cause developmental toxicity: None of the ingredients are listed. Carcinogenic categories EPA (Environmental Protection Agency) None of the ingredients are listed. TLV (Threshold Limit Value established by ACGIH) None of the ingredients are listed. NIOSH-Ca (National Institute for Occupational Safety and Health) None of the ingredients are listed. GHS label elements Not applicable. Hazard pictograms Not applicable. Signal word Not applicable. Hazard statements Not applicable.

16 Other information

This information is based on our present knowledge. However, this shall not constitute a guarantee for any specific product features and shall not establish a legally valid contractual relationship. Training Hints: All persons handling this product should be informed on the existence of the hazard, on any possible risk they might be subjected to and about all required protective measures to prevent such a damage or to reduce the exposition.

WARNINGS: Diagnostic agents are intended for use under direction of a physician and/or under the conditions of use described on the label and in the product’s package insert. As a general precaution, personnel who handle drug substances should avoid contact (ingestion, inhalation, skin and eye contact) with these substances. Contact: Bracco Diagnostics Inc. P.O. Box 5225 Princeton, NJ 08543 Date of preparation / last revision 02/22/2019 / 1 Abbreviations and acronyms: RID: Règlement international concernant le transport des marchandises dangereuses par chemin de fer (Regulations Concerning the International Transport of Dangerous Goods by Rail) ICAO: International Civil Aviation Organisation ADR: Accord européen sur le transport des marchandises dangereuses par Route (European Agreement concerning the International Carriage of Dangerous Goods by Road) IMDG: International Maritime Code for Dangerous Goods DOT: US Department of Transportation IATA: International Air Transport Association ACGIH: American Conference of Governmental Industrial Hygienists EINECS: European Inventory of Existing Commercial Chemical Substances ELINCS: European List of Notified Chemical Substances CAS: Chemical Abstracts Service (division of the American Chemical Society) NFPA: National Fire Protection Association (USA) HMIS: Hazardous Materials Identification System (USA) VOC: Volatile Organic Compounds (USA, EU) LC50: Lethal concentration, 50 percent LD50: Lethal dose, 50 percent

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