Crestor® - FASS Vårdpersonal

Vad är en miljöinformationstext?

Svensk miljöklassificering av läkemedel

Nedspolade rester av läkemedel och substanser som passerar kroppen kan via avloppen hamna i vattendrag om substanserna inte kan renas av reningsverken.

På initiativ av LIF – de forskande läkemedelsföretagen, har Sverige som första land i världen därför infört ett system för miljöklassificering av läkemedel, vilken publiceras här på Fass.se. Modellen har utarbetats av LIF i samarbete med Läkemedelsverket, Sveriges kommuner och Landsting, Apoteket AB (numera genom Sveriges Apoteksförening) samt Stockholms Läns Landsting.

Miljörisk

Miljörisken baserar sig på förhållandet mellan den förväntade koncentrationen av läkemedelssubstansen i svenska vattendrag (PEC, Predicted Environmental Concentration) och den maximala koncentration som förväntas vara säker för de vattenlevande djur och växter som lever där (PNEC, Predicted No Effect Concentration). Testerna har normalt gjorts på alger, vattenloppor och fisk i laboratoriemiljö.

Om den beräknade koncentrationen i miljön är lägre än den koncentration som, baserat på tester, förväntas vara säker för organismer (dvs. PEC/PNEC är lägre än 1), så bedöms risken för miljöpåverkan vara låg eller till och med försumbar. Om däremot kvoten PEC/PNEC är större än 1, så är det en medelhög till hög risk för miljöpåverkan.

En substans kan få klassificeringen ”försumbar”,” låg”, ”medelhög” eller ”hög miljörisk”.

Nedbrytning

En substans som är svårnedbrytbar kan föra med sig att exponeringen ökar på sikt eftersom koncentrationen i miljön ökar, vilket kan öka risken för miljöpåverkan med tiden. Hur snabbt och fullständigt ett organiskt ämne bryts ned i reningsverk eller i naturen, av mikroorganismer, bestäms i strängt standardiserade metoder t.ex. OECDs tester. Ämnen som i naturen bryts ned mycket långsamt eller inte alls benämns persistenta.

En substans kan få klassificering ”bryts ner i miljön”, ”bryts ner långsamt” eller ”potentiellt persistent”.

Bioackumulering

Bioackumulerande substanser har en tendens att lagras i vävnader t.ex. hos vattenlevande organismer såsom fisk. En indikation på ett ämnes bioackumulerbarhet kan bland annat fås genom att studera ämnets fördelning i en blandning av oktanol (som simulerar fettvävnad) och vatten.

En substans kan få klassificeringen ”har inte potential…” respektive ”har potential att bioackumuleras”.

Bakgrundsdata

All bakomliggande data till de bedömningar som redovisas om miljörisk, nedbrytbarhet och bioackumulation redovisas under” Läs mer>>” och visar även hur beräkningar gjorts. Denna nivå vänder sig främst till experter och miljöspecialister.

Läs gärna mer om miljöinformation i Fass

Publiceringsdatum: 2020-02-03

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				16 d	640 mg/L ^{Note 1}
NOEC - Based on Largest Specific Growth Rate				96 h	330 mg/L ^{Note 1}
E_rC50 - Based on Largest Specific Growth Rate				96 h	>640 mg/L ^{Note 1}
NOEC - Based on Maximum Standing Crop				16 d	640 mg/L ^{Note 1}
LOEC - Based on Maximum Standing Crop				16 d	>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				10 d	800 mg/L ^{Note 1}
NOEC - Based on Largest Specific Growth Rate				96 h	350 mg/L ^{Note 1}
E_rC50 - Based on Largest Specific Growth Rate				96 h	>800 mg/L ^{Note 1}
NOEC - Based on Maximum Standing Crop				10 d	350 mg/L ^{Note 1}
LOEC - Based on Maximum Standing Crop				10 d	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}	6
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}	Chironomus riparius	Midge	OECD 218	28 d	>10 mg/kg (Dry weight) ^{Note 5}	7
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	Oncorhynchus mykiss	Rainbow Trout	US FDA Technical Assistance Document 4.11	96 h	1000 mg/L ^{Note 2}	8
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	Lepomis macrochirus	Bluegill Sunfish	US FDA Technical Assistance Document 4.11	96 h	560 mg/L ^{Note 2}	9
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}	10
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	-	-	OECD 209 ETAD 103	3 h	100 mg/L ^{Note 6}	11

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)	13
Percentage Hydrolysis	US FDA Technical Assistance Document 3.09	50 mg/L	5 d	< 10 % @ pH 5,7 or 9	14
Hydrolysis Half-life	US FDA Technical Assistance Document 3.09	-	-	T1/2 ≥ 1 yr (Estimated)	14
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	ISO 11734	25 and 50 mg/L Carbon	56 d	3 - 4 %	16
Percentage Biodegradation	Modified OECD 302B	1 mg/L and 45 mg/L	28 d	< 1 % Mineralisation	17
Percentage Compound Removal		1 mg/L and 45 mg/L		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 (T½) of an aqueous solution of rosuvastatin calcium in a solar simulator was 7.7 minutes. The calculated T½ at 50^oN 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	25^oC	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.

Upp

Cookies

Crestor^®

Miljöinformation

Miljöpåverkan (Läs mer om miljöpåverkan)

Rosuvastatin

Detaljerad miljöinformation