Detaljerad miljöinformation

PEC/PNEC = 0.12 μg/L/1.8 μg/L = 0.07

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)      = 1.37*10^-6*A*(100-R)

PEC                 = 1.37 * 10^-6 * 902.707768219456 * (100-0) = 0.12 μg/L

A (kg/year)      = total sold amount API in Sweden year 2021, data from IQVIA/Lif.

                        = 902.707768219456kg/year

R (%)               = removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 (default)

P                      = number of inhabitants in Sweden = 10*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).

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

Study Type	Method	Result	Ref
Toxicity to blue-green alga (Microcystis aeruginosa Cyanobacterium)	US FDA Technical Assistance Document 4.01	16 d NOEC(growth) = 330mg/L 16 d LOEC(growth) = 640mg/L 16 d NOEC(cell density) = 640mg/L 16 d LOEC(cell density) > 640mg/L	3
Toxicity to Green Alga Pseudokirchneriella subcapitata (formerly known as Selenastrum capricornutum)	US FDA Technical Assistance Document 4.01	10 d NOEC(growth) = 350mg/L 10 d LOEC(growth) = 800mg/L 10 d NOEC(cell density) = 350mg/L 10 d LOEC(cell density) = 800mg/L	4
Chronic toxicity to Daphnia magna	US FDA Technical Assistance Document 4.09	28 d NOEC(reproduction and length) = 0.018mg/L 28d LOEC(reproduction and length) = 0.032mg/L	5
Acute toxicity to Daphnia magna	OECD 202, Part I	48 h EC50(immobilisation) = 63mg/L 48 h NOEC(immobilisation) = 5.6mg/L	6
Toxicitiy to the midge, Chironomus riparius	OECD 218	28 d NOEC(emergence) = 10mg/kg (dry weight) 28 d LOEC(emergence) > 10mg/kg (dry weight)	7
Acute toxicity to Rainbow Trout (Oncorhynchus mykiss)	US FDA Technical Assistance Document 4.11	96 h NOEC = 1000mg/L 96 h LC50 > 1000mg/L	8
Acute toxicity to Bluegill Sunfish (Lepomis macrochirus)	US FDA Technical Assistance Document 4.11	96 h NOEC = 560mg/L 96 h LC50 > 1000mg/L	9
Early-life stage effects of the Fathead Minnow (Pimephales promelas)	OECD 210	32 d NOEC* = 1.0mg/L 32d LOEC*  = 3.2mg/L	10
Activated sludge, respiration inhibition	OECD 209 ETAD 103	3h EC50 > 100 mg/L 3h NOEC = 100 mg/L	11

*biological parameters evaluated include hatch, survival, length and dry weight

NOEC    No Observed Effect Concentration

LOEC     Lowest Observed Effect Concentration

EC50     the concentration of the test substance that results in a 50% effect

LC50      the concentration of the test substance that results in a 50% mortality

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 most sensitive species, the giant water flea (Daphnia magna). An assessment factor of 10 is applied to the NOEC of 0.018mg/L in accordance with ECHA guidance (Ref. 12).

PNEC = 18µg/L / 10 = 1.8 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.12 / 1.8 μg/L = 0.07

As the PEC/PNEC ≤ 0.1 the following phrase is justified “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”.

Environmental Fate Data

Study Type	Method	Result	Ref
Photolysis Half-life	US FDA Technical Assistance Document 3.10 & EPA OPPTS 835.2210	T1/2 (measured) = 7.7 min T1/2 (Estimated) = 12.4 min at 50°N in summer	13
Hydrolysis	US FDA Technical Assistance Document 3.09	< 10 % hydrolysis @ pH 5,7 or 9 after 5 days. T1/2 (estimated) ≥ 1 yr	14
Ready biodegradability	OECD 301F	<10% biodegradation at Day 28 BOD <0.1g O2/g ZD4522 COD = 1.22g O2/g	15
Anaerobic biodegradability	ISO 11734	<5% biodegradation at 56 days	16
Inherent biodegradation	Modified OECD 302B	<1% mineralisation 80% applied radiolabelled rosuvastatin removed after day 28 1mg/L T1/2 = 3.1 days 45mg/L T1/2 = 5.2 days	17
Aerobic transformation in aquatic sediment systems	OECD 308	Low dose HOM system DT50 (water) = 10.5 days DT50 (total system) = 16.1 days* High dose HOM system DT50 (water) =4.2 days DT50 (total system) = 4.85 days* Low dose LOM system DT50 (water) = 4.4 days DT50 (total system) = 3.64 days* High dose LOM system DT50 (water) = 5.2 days DT50 (total system) = 5.62 days* <15% of applied radioactivity remaining as parent compound at the end of the study	18
Soil sorption/ desorption	US FDA Technical Assistance Document 3.08	Sandy loam (pH 6.2) Kd = 1.7 KOC = 130 Clay loam (pH 6.5) Kd = 2.7 KOC = 68 Silty clay loam (pH 5.0) Kd = 2.9 KOC = 140	19

*SFO fit, modelled using CAKE (computer assisted kinetics software, version 3.6, Copyright 2011-2022 Syngenta Limited)

Biodegradation

The biodegradation of rosuvastatin calcium was assessed in 3 separate studies.  A study conducted according to guideline OECD 301F showed that rosuvastatin calcium is not readily biodegradable (Ref 15). An anaerobic biodegradation of rosuvastatin calcium study (according to guideline ISO 11734, UK HMSO, Ref 16) showed <5% degradation under the anaerobic conditions of the test over a period of 56 days. However, in a modified OECD 302 study, 80% of the applied Rosuvastatin was removed under aerobic conditions over the course of the 28-day study (<20% removal in the abiotic controls). Rosuvastatin was dosed at two test concentrations (1 and 45 mg/L), which had little impact on the rates of degradation observed, which were 3.1 and 5.2 days, respectively. No significant adsorption to the activated sludge was observed.  HPLC analyses of sample extracts indicated a number of metabolites.  However, given the very low amount of evolved CO₂ (<1% AR), Rosuvastatin removal is concluded to be the result of partial biodegradation.

In aquatic systems Rosuvastatin calcium is expected to be hydrolytically stable (estimated half-life of ≥ 1 year at 25°C derived in a laboratory study, Ref. 14). The results of a laboratory photolysis study indicate that rosuvastatin calcium is susceptible to photodegradation. The biodegradation of rosuvastatin calcium in aquatic sediment systems was assessed according to the OECD Test Guideline 308 study over a 103-day test period. Rosuvastatin calcium was applied at two concentrations (0.1 and 1.0 mg/kg) to both a high (HOM) and low organic matter (LOM) system. 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 to sediment in the low organic matter vessels and circa one half of the radioactivity partitioning to sediment in the high organic matter vessels. Aqueous layer DT50s ranged from 4.2 – 10.5 days. Less than 10% of the applied radioactivity remained as bound residues on any of the sediments. The maximum percentage of dosed radioactivity recovered as unaltered parent from the sediment-water test systems at Day 103 was 1.4%.

The study did not report sediment or whole system DT50s (stating that relative percentages of parent and metabolites in the non-extractable residues were not resolved). However, a number of supplemental extractions (using a range of solvents incl. acetone, chloroform, hexane, methanol) were conducted in addition to extraction with acidified acetonitrile/ethyl acetate (solvent used throughout the study). Only a small percentage of dosed radioactivity was removed with the additional solvents.

Subsequent investigation of the kinetics of whole system degradation (SFO, FOMC and DFOP fits performed using the Computer Assisted Kinetic Evaluation (CAKE), https://cake-kinetics.org/), was conducted. With exception of the low-dosed HOM system, all systems (high dosed HOM, high and low dosed LOM) showed fast Rosuvastatin decline overall, with whole-system DT50s of less than 1 week. The low-dosed HOM system showed higher residuals at the first sampling time point after application (day 14) in both, water and sediment, indicating a potential lag phase of degradation and resulting in a longer, whole-system DT50 of ~16 days.

Based on the reported half-lives (in water) and whole system half-lives derived in subsequent analysis, all observed DT50s were <32 days.  And as <15% parent compound remained in all systems at the end of the study rosuvastatin calcium has been assigned the phrase “Rosuvastatin calcium is degraded in the environment”.

In Swedish: “Rosuvastatinkalcium bryts ned i miljön”.

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”.

Physical Chemistry Data

Study Type	Method	Result	Ref
n-octanol-water partition coefficient	UD FDA Technical Assistance Document 3.02	LogPow = 1.79 to 1.80 @ pH 5 LogPow = 0.26 to 0.30 @ pH 7 LogPow = -0.90 to ‑0.97 @ pH 9	20
Dissociation Constant	OECD 112 & US FDA Technical Assistance Document 3.04	25 ± 0.5oC pKa = 4.76	21
Water solubility	US FDA Technical Assistance Document 3.01	Day 3 mean solubility pH 5 = 3820 mg/L Day 50 mean solubility pH 7 = 22000 mg/L pH 9 Day 5 – 62 mean solubility = 4860 mg/L	22

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 (ZD4522, CRESTOR®), Edition 18. D3560000000. February 2018.

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

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

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

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

7. [¹⁴C]Rosuvastatin calcium: Effects 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. September 1999.

   
   

9. ZD4522 (Ca Salt): Acute toxicity to bluegill sunfish (Lepomis macrochirus). Brixham Environmental Laboratory Report BL6568/B. September 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. January 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. September 1999.

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

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

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

17. Rosuvastatin: Biodegradation in a modified OECD 302B study. Brixham Environmental Laboratory. Report BL7416/B. December 2002. 

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

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

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

21. ZD4522 (Ca Salt): Determination of dissociation constant. Report No. BL6751/B. SafePharm Laboratories Limited, Derby. SafePharm SPL Project No. 659/003. September 1999.

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