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Crestor®

AstraZeneca

Filmdragerad tablett 5 mg
(Rund, gul, präglad med "ZD4522"och "5" på ena sidan och blank på den andra sidan)

HMG-CoA-reduktashämmare

Aktiv substans:
ATC-kod: C10AA07
Läkemedel från AstraZeneca omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan (Läs mer om miljöpåverkan)

Rosuvastatin

Miljörisk: Användning av rosuvastatin har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Rosuvastatin bryts ned i miljön.
Bioackumulering: Rosuvastatin har låg potential att bioackumuleras.


Läs mer

Detaljerad miljöinformation

PEC/PNEC = 0.042 μg/L/1.8 μg/L = 0.023

 PEC/PNEC ≤ 0.1


Environmental Risk Classification


Predicted Environmental Concentration (PEC)


The PEC is based on following data:


PEC (µg/L) = (A*109*(100-R))/(365*P*V*D*100)

PEC (µg/L) = 1.5*10-6*A*(100-R)


A (kg/year) = total sold amount API in Sweden year 2017, data from IQVIA (former IMS Health and Quintiles).

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization,

hydrolysis or biodegradation) = 0 if no data is available.

P = number of inhabitants in Sweden = 9 *106

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ref.1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default)(ref.1)

(Note: The factor 109 converts the quantity used from kg to μg).


A = 283.03 kg 

R = 0

PEC = 1.5 * 10-6 * 283.03 * (100-0) = 0.042 μg/L


Metabolism 

Rosuvastatin calcium undergoes limited metabolism (approximately 10%), mainly to the N-desmethyl form, and 90% is eliminated as unchanged drug in the faeces with the remainder being excreted in the urine (Ref.2).


Ecotoxicity data


Endpoint

Species

Common Name

Method

Time

Result

Reference

NOEC - Based on Largest Specific Growth Rate

Microcystis aeruginosa

Cyano-bacterium (Blue-Green Alga)

US FDA Technical Assistance Document 4.01

16 d

330 mg/L

Note 1

3

LOEC - Based on Largest Specific Growth Rate

640 mg/L

Note 1

NOEC - Based on Largest Specific Growth Rate

96 h

330 mg/L Note 1

ErC50 - Based on Largest Specific Growth Rate

>640 mg/L

Note 1

NOEC - Based on Maximum Standing Crop

16 d

640 mg/L

Note 1

LOEC - Based on Maximum Standing Crop

>640 mg/L

Note 1

NOEC - Based on Largest Specific Growth Rate

Pseudokirchneriella subcapitata (formerly known as Selenastrum capri-cornutum)

Green Alga

US FDA Technical Assistance Document 4.01

10 d

350 mg/L

Note 1

4

LOEC - Based on Largest Specific Growth Rate

800 mg/L

Note 1

NOEC - Based on Largest Specific Growth Rate

96 h

350 mg/L

Note 1

ErC50 - Based on Largest Specific Growth Rate

>800 mg/L

Note 1

NOEC - Based on Maximum Standing Crop

10 d

350 mg/L

Note 1

LOEC - Based on Maximum Standing Crop

800 mg/L

Note 1

LC50

Daphnia magna

Giant Water Flea

US FDA Technical Assistance Document

4.09

48 h

>0.32 mg/L

Note 2

5

LC50

21 d

0.17 mg/L

Note 2

NOEC - Based on Overall Endpoints

Note 3

0.018 mg/L

Note 2

LOEC- Based on Overall Endpoints

Note 3

0.032 mg/L

Note 2

EC50 - Based on Immobili-sation

OECD 202 Part I

92/69/EEC

48 h

63 mg/L

Note 2

6

NOEC - Based on Immobili-sation

OECD 202

92/69/EEC

48 h

5.6 mg/L

Note 2

NOEC - Based on Overall Endpoints

Note 4

Chironomus riparius

Midge

OECD 218

28 d

10 mg/kg (Dry weight)

Note 5

7

LOEC - Based on Overall Endpoints

Note 4

>10 mg/kg (Dry weight)

Note 5

LC50

Oncorhynchus mykiss

Rainbow Trout

US FDA Technical Assistance Document 4.11

96 h

>1000 mg/L

Note 2

8

NOEC - Based on Mortality & Symptoms of Toxicity

1000 mg/L

Note 2

LC50

Lepomis macrochirus

Bluegill Sunfish

US FDA Technical Assistance Document 4.11

96 h

>1000 mg/L

Note 2

9

NOEC - Based on Mortality & Symptoms of Toxicity

560 mg/L

Note 2

NOEC - Based on Overall Endpoints

Note 6

Pimephales promelas

Fathead Minnow

OECD 210

32 d (28 d post-hatch)

1.0 mg/L

Note 2

10

LOEC - Based on Overall Endpoints

Note 6

Pimephales promelas

Fathead Minnow

OECD 210

32 d (28 d post-hatch)

3.2 mg/L

Note 2

EC50 - Based on Activated Sludge Respiration Inhibition

-

-

OECD 209

ETAD 103

3 h

> 100 mg/L

Note 6

11

NOEC - Based on Activated Sludge Respiration Inhibition

100 mg/L

Note 6

Note 1: Results are expressed as time weighted mean measured concentrations.

Note 2: Concentrations were confirmed by analysis, and results expressed as nominal.
Note 3: The population relevant endpoints measured were length and number of surviving offspring.

Note 4: The population relevant endpoints measured were mean and individual emergence times, total number of emerged adult insects and their sex ratio.

Note 5: Concentrations were confirmed by radiochemical analysis, and results expressed as nominal concentrations.

Note 6: The population relevant endpoints measured were survival, hatchability, length and dry weight.


PNEC (Predicted No Effect Concentration)

Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the chronic toxicity to the giant water flea (Daphnia magna), the most sensitive species, and an assessment factor of 10 is applied, in accordance with ECHA (Ref. 12).


PNEC = 18/10 = 1.8 µg/L


Environmental risk classification (PEC/PNEC ratio)


PEC/PNEC = 0.042 / 1.8 μg/L = 0.023

i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of rosuvastatin calcium has been considered to result in insignificant environmental risk”.


In Swedish: “Användning av rosuvastatinkalcium har bedömts medföra försumbar risk för miljöpåverkan” under the heading “Miljörisk”.


Environmental Fate Data


Endpoint

Method

Test Substance Concentration

Time

Result

Reference

Photolysis Half-life

US FDA Technical Assistance Document 3.10

EPA OPPTS 835.2210

61.7 mg/L

-

T1/2 = 7.7 min (Measured)

13

Photolysis Half-life

-

T1/2 = 12.4 min (Estimated at 50°N in summer)

Percentage Hydrolysis

US FDA Technical Assistance Document 3.09

50 mg/L

5 d

< 10 % @

pH 5,7 or 9

14

Hydrolysis Half-life

-

-

T1/2 ≥ 1 yr (Estimated)

Percentage Biodegradation

OECD 301F

50 and 100 mg/L

28 d

<10 % ThOD

15

COD

-

-

-

1.22 g O2/g

BOD

OECD 301F

50 - 100 mg/L

28 d

<0.1 g O2/g

Percentage Dissolved Organic Carbon Removal

<10 %

Percentage Compound Removal

0 %

Percentage Anaerobic Biodegradation

ISO 11734

25 and 50 mg/L Carbon

56 d

<5 % Gas production

16

Percentage Anaerobic Compound Removal

3 - 4 %

Percentage Biodegradation

Modified OECD 302B

1 mg/L and 45 mg/L

28 d

< 1 % Mineralisation

17

Percentage Compound Removal

80 %

(Primary Degradation)

Biodegradation Half-life

1 mg/L

T1/2 = 3.1 d

(Primary Degradation)

Biodegradation Half-life

45 mg/L

T1/2 = 5.2 d

(Primary Degradation)

Degradation Half-life from Aqueous Layer

(sediment from Choptank River)

OECD 308

0.1 mg/kg in Low Organic Matter Content Sediment/Water System

103 d

DT50 = 4.4 d

18

Degradation Half-life from Aqueous Layer

sediment from Choptank River)

OECD 308

1.0 mg/ kg in Low Organic Matter Content Sediment/Water System

103 d

DT50 = 5.2 d

Degradation Half-life from Aqueous Layer
(sediment from Brandywine creek)

0.1 mg/kg in High Organic Matter Content Sediment/Water System

DT50 = 10.5 d

Degradation Half-life from Aqueous Layer

(sediment from Brandywine creek)

1.0 mg/kg in High Organic Matter Content Sediment/Water System

DT50 = 4.2 d

Ultimate Biodegradation

0.1 mg/kg in High Organic Matter Content Sediment/Water System

0.5 - 1.2 %

(Mineralisation)

Ultimate Biodegradation

1.0 mg/kg in High Organic Matter Content Sediment/Water System

0.4 %

(Mineralisation)

Ultimate Biodegradation

0.1 mg/kg in Low Organic Matter Content Sediment/Water System

1.3 - 2.3 %

(Mineralisation)

Ultimate Biodegradation

1.0 mg/kg in Low Organic Matter Content Sediment/Water System

0.6 %

(Mineralisation)

Partition Coefficient Octanol Water

UD FDA Technical Assistance Document 3.02

100 and 1000 mg/L

-

Log P = 1.79 to 1.80 @ pH 5

Log P = 0.26 to 0.30 @ pH 7

Log P = -0.90 to ‑0.97 @ pH 9

19

Biodegradation

Aerobic biodegradation

The aerobic biodegradation of rosuvastatin calcium was assessed according to guideline OECD 301F (ready biodegradability) (ref 15). The results showed that rosuvastatin calcium is not readily biodegradable, with <10% biodegradation after 28 days.


In addition, rosuvastatin calcium is not inherently biodegradable (OECD 302B) (ref 17).


Anaerobic biodegradation

The anaerobic biodegradation of rosuvastatin calcium was assessed according to guideline ISO 11734, UK HMSO (ref 16). Rosuvastatin calcium was shown to be not biodegradable (<5%) under the anaerobic conditions of the test over a period of 56 days.


Aerobic transformation in aquatic sediment systems

The biodegradation of rosuvastatin calcium in aquatic sediment systems was assessed according to the OECD Test Guideline 308. In this test two different sediments were used, one with highand one with low organic matter content. Radiolabelled test substance was dosed into the overlying water and the subsequent dissipation from the water phase, and partitioning and/or degradation in the sediment, was observed over the 103-day test period. For the 1.0 mg/kg high organic sediment, a number of different extraction solvents (acetone, chloroform, hexane, methanol) with 50 mg/L sodium bicarbonate and water, were used to remove radioactivity associated sediment in addition to acidified acetonitrile/ethyl acetate (solvent used throughout the study). Overall, only a small percentage of dosed radioactivity was removed with the additional solvents.


Rosuvastatin calcium demonstrated rapid transformation in each sediment-water type at concentrations of 0.1 and 1.0 mg/kg. The major loss process of rosuvastatin calcium in the test systems was attributable to extensive primary degradation of parent in the aqueous layer, with minimal partitioning of rosuvastatin calcium to sediment in the low organic matter vessels and half of the radioactivity partitioning to sediment in the high organic matter vessels. Less than 10% of the applied radioactivity remained as bound residues on any of the sediments. The maximum percentage of dosed radioactivity recovered as rosuvastatin calcium from the sediment-water test systems at Day 103 was 1.4%. Good mass balances were obtained throughout the study.


Degradation classification

Overall, the evidence from the aquatic-sediment transformation study suggests that rosuvastatin calcium is degraded in the environment (DT50 <32d).


Therefore rosuvastatin calcium has been assigned the phrase “Rosuvastatin calcium is degraded in the environment”. 


In Swedish: “Rosuvastatinkalcium bryts ned i miljön” under the heading “Nedbrytning”.


Hydrolysis

Rosuvastatin calcium is hydrolytically stable, with an estimated half-life of ≥ 1 year at 25°C (Technical Assistance Document 3.09) (ref 14).


Photolysis

The photolysis of rosuvastatin calcium was assessed according to the guideline US Food and Drug Administration Technical Assistance Document 3.10 (ref 13). The measured half-life () of an aqueous solution of rosuvastatin calcium in a solar simulator was 7.7 minutes. The calculated at 50oN in summer was 12.4 minutes. These results indicate that rosuvastatin calcium is susceptible to photodegradation.


Bioaccumulation classification

Since Log P < 4 at pH 7, the substance has been assigned the phrase: “Rosuvastatin calcium  has low potential for bioaccumulation.”


In Swedish: "Rosuvastatinkalcium har låg potential att bioackumuleras” under the heading “Bioackumulering”.


Physical Chemistry Data


Endpoint

Method

Test Conditions

Result

Reference

Dissociation Constant

OECD 112 and

US FDA Technical Assistance Document 3.04

25oC

pKa = 4.76

20

Solubility Water

US FDA Technical Assistance Document 3.01

pH 5

3820 mg/L

21

pH 7

22000 mg/L

pH 9

4860 mg/L

Sorption Distribution Coefficient Corrected for Soil Organic Content

US FDA Technical Assistance Document 3.08

25 mg/L in Sandy Loam Soil, pH 6.2

Koc = 130

Note 7

22

25 mg/L in Clay Loam Soil, pH 6.5

Koc = 68 

Note 7

25 mg/L in Silty Clay Loam Soil, pH 5.0

Koc = 140 

Note 7

Sorption Distribution Coefficient

25 mg/L in Sandy Loam Soil, pH 6.2

Kd = 1.7

Note 7

25 mg/L in Clay Loam Soil, pH 6.5

Kd = 2.7

Note 7

25 mg/L in Silty Clay Loam Soil, pH 5.0

Kd = 2.9

Note 7

Note 7: Results are based on mean measured concentrations.


References

1. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (Version 3.0). February 2016.


2. Investigator's Brochure, Rosuvastatin calcium (AZD4522, CRESTOR), Edition 15. Doc ID-001370265. January 2014.


3. ZD4522 (Ca Salt): Toxicity to the blue-green alga Microcystis aeruginosa. Brixham Environmental Laboratory Report BL6563/B. 1999.


4. ZD4522 (Ca Salt): Toxicity to the green alga Selenastrum capricornutum. Brixham Environmental Laboratpry Report BL6562/B. 1999.


5. ZD4522 (Ca Salt): Chronic toxicity to Daphnia magna. Brixham Environmental Laboratory Report BL6566/B. 1999.


6. ZD4522 (Ca Salt): Acute toxicity to Daphnia magna. Brixham Environmental Laboratory Report BL6858/B. 2000.


7. [14C]Rosuvastatin calcium: Effets in sediment on emergence of the midge, Chironomus riparius. Brixham Environmental Laboratory, Brixham. Report No. BL8463/B August 2007.


8. ZD4522 (Ca Salt): Acute toxicity to rainbow trout (Oncorhynchus mykiss). Brixham Environmental Laboratory Report Bl6567/B. 1999.


9. ZD4522 (Ca Salt): Acute toxicity to bluegill sunfish (Lepornis machochirus). Brixham Environmental Laboratory Report BL6568/B. 1999.


10. Rosuvastatin calcium: Determination of effects on the Early-life Stage of the fathead minnow (Pimephales promelas). Brixham Environmental Laboratory. Report No. BL8416/B. March 2007.


11. ZD4522 (Ca Salt): Effect on the respiration rate of activated sludge. Brixham Environmental Laboratory. Report BL6807/B. 2000.


12. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment. May 2008.


13. ZD4522 (Ca Salt): Photodegradation in water. Brixham Environmental Laboratory. Report Bl6705/B. 1999.


14. ZD4522 (Ca Salt): Hydrolysis as a function of pH. Brixham Environmental Laboratory. Report BL6574/B. 1999.


15. ZD4522 (Ca Salt): Determination of 28 day ready biodegradability. Brixham Environmental Laboratory. Report BL6561/B. 1999.


16. ZD4522 (Ca Salt): Determination of anaerobic biodegrability. Report No. BL8535/B, Project No. BL6560/B, Brixham Environmental Laboratory, Brixham. October 1999.


17. Rosuvastatin: Biodegradation in a modified OECD 302B study. Brixham Environmental Laboratory. Report BL7416/B. 2003.


18. Rosuvastatin: Aerobic transfomation in aquatic sediment systems. Report No. BL8535/B, Project No. 123E-101. Wildlife international, Ltd, Maryland, USA, October 2007.


19. ZD4522 (Ca Salt): Determination of n-octanol-water partition coefficient. Brixham Environmental Laboratory. Report BL6570/B. 1999.


20. ZD4522 (Ca Salt): Determination of dissociation constant. Report No. BL6751/B, Brixham Environmantal Laboratory. Brixham. SafePharm SPL Project No. 659/003. September 1999.


21. ZD4522 (Ca Salt): Determination of water solubility. Brixham Environemtal Laboratory. Report No. BL6569/B. October 1999.


22. [14C]ZD4522 (Ca Salt): Soil sorption and desorption. Brixham Environmental Laboratory. Report BL6706/B. 1999.