Detaljerad miljöinformation

PEC/PNEC = 0.035 μg/L /0.050 μg/L = 0.70

0.1 < PEC/PNEC ≤ 1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

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)

P = number of inhabitants in Sweden = 9 *10⁶

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

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

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

A = 460.8 kg

R = 50% (adsorption to sludge)*

*The removal during sewage treatment (50%) is estimated using the EUSES model, Simple Treat, described in the ECHA Guidance Document (Ref. 1) where the following assumptions have been made: not readily biodegradable, vapour pressure

(VP) <1*10^-6 Pa, water solubility 0.5 mg/L and Kd_sludge = 2800 L/kg. Felodipin is an involatile solid with negliable VP at ambient conditions, a measured VP is not available, the nominal value used in this calculation assumes no losses to the atmosphere. Water solubility was measured at 22 – 25^oC and may therefore lead to an over estimation of PEC, since at environmentally relevant temperatures water solubility may be lower.

PEC = 1.5 * 10^-6 * 460.8* (100-50) = 0.035 μg/L

Metabolism

Felodipine is extensively metabolised in humans. In healthy volunteers about 62% of an orally given dose of felodipine was excreted into the urine. No parent compound was found in the urine and the identified metabolites (accounting for about 23% of the dose) are known to be less pharmacologically active than the parent compound. The remaining metabolites in urine (i.e. 39% of the dose) were unidentified polar compounds. Approximately 10% of the given oral dose was excreted in faeces, however the identity or pharmacological activity of these excreted products is not known (Ref 2 and 3).

Ecotoxicity data

PNEC (Predicted No Effect Concentration)

Short-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. The PNEC is based on the acute toxicity to rainbow trout (Oncorhynchus mykiss), the most sensitive species, and an assessment factor of 1000 is applied, in accordance with ECHA guidance (Ref. 1).

PNEC = 50 µg/L/1000 = 0.050 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.035 µg/L /0.050 µg/L = 0.70, which justifies the phrase "Use of felodipine has been considered to result in low environmental risk".

In Swedish: ”Användning av felodipin har bedömts medföra låg risk för miljöpåverkan” under the heading ”Miljörisk”.

Environmental Fate Data

Biotic degradation

Felodipine is not readily biodegradable. There are no further studies available regarding degradation of felodipine. Therefore, the substance has been assigned the risk phrase: "Felodipin is potentially persistent".

In Swedish: “Felodipin är potentiellt persistent” under the heading “Nedbrytning”.

Abiotic degradation

Felodipine is photodegradable (T½ = 2.1 h at pH 7).

Bioaccumulation

Since Log P < 4 the phrase "Felodipine has low potential for bioaccumulation" is assigned.

In Swedish: ”Felodipin har låg potential att bioackumuleras” under the heading ”Bioackumulering”.

Physical Chemistry Data

References

1. [ECHA], European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment (Table R10.4). May 2008

   
   

2. Edgar B, Regårdh C G, Johnsson G, Johansson L, Lundborg P, Löfberg I and Rönn, O. Felodipine kinetics in healthy men. Clinical Pharmacology and Therapeutics 38: 205-211. 1985.
   

3. Hoffman, K-J and Andersson L. Metabolism of [¹⁴C] felodipine, a new vasodilating drug, in healthy volunteers. Drugs 34: 43-52. 1987.
   

4. H154/82: Inhibition of growth to the alga Selenastrum capricornutum.

   Covance, USA. Report No. 265/55-D2145. June 1999 (Brixham Environmental Laboratory Report BD3977).
   

5. Ecotoxicological characterisation of felodipine, MK0218.

   Environmental Engineering Laboratory (EEL), UK.

   (Brixham Environmental Laboratory Report BD4166). March 1994.
   

6. Felodipine: Acute toxicity to Rainbow trout, Oncorhynchus mykiss, under static test conditions. Toxikon Environmental Sciences, USA. May 1994. (Brixham Environmental Laboratory Report BD4165).
   

7. Photodegradates of felodipine: Acute toxicity to rainbow trout, Oncorhynchus mykiss, under static conditions. Toxikon Environmental Sciences, USA. Report No J9410003b, USA, April 1995.
   

8. Felodipine: Acute Toxicity to Bluegill, Lepomis macrochirus, under Static Test Conditions. Toxicon Environmental Sciences, USA. Report No: J9312003a. May 1994. (Brixham Environmental Laboratory, Report BD4190).
   

9. H154/82: Assessment of ready biodegradability by measurement of carbon dioxide evolution. Covance, USA. Report No: 98095-1 265/57-1018 Sept 1997. (Brixham Environmental Laboratory Report BD3971).
   

10. Felodipine (MK-218): Determination of the Rate of Hydrolysis as a Function of pH at 50C. Toxicon Environmental Sciences, USA. Report No: J9307008b.December 1993. (Brixham Environmental Laboratory, Report BD4188).
    

11. Felodipine (MK-218): Determination of Aqueous Photolysis.

    Toxicon Environmental Sciences, USA. Report No: J9307008a July 1994. (Brixham Environmental Laboratory Report BD4189)
    

12. Sangster, J., Log KOW Databank, Montreal, Quebec, Canada, Sangster Research Laboratories, 1994
    

13. General Properties for Felodipine. AstraZeneca, June 2006. (Brixham Environmental Laboratory, Report BD4182).
    

14. Felodipine: Adsorption and desorption to activated sludge.

    Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7813

    October 2004

Detaljerad miljöinformation

PEC/PNEC = 2.1 μg/L /7.3 μg/L = 0.29 

PEC/PNEC = ≤ 1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

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 = 13759.66 kg. This figure is based on the total amount of metoprolol succinate and metoprolol tartrate sales figures from 2017, data from IQVIA (former IMS Health and Quintiles).

R = 0

PEC = 1.5 * 10^-6 * 13759.66* (100-0) = 2.10 μg/L

(Note: Whilst metoprolol is extensively metabolised in humans, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for the purpose of this calculation, it is assumed that 100 % of excreted metabolites have the same ecotoxicity as parent metoprolol.)

Metabolism

Metoprolol is extensively metabolised in the body, with only a minor fraction (approximately 5%) excreted as the parent drug. The main route for excretion is via the urine (Ref. 2).

Ecotoxicity data

^{Note1: Studies were conducted with metoprolol succinate, the difference in reported and actual concentrations of metoprolol is anticipated to have negligible impact on this assessment.}

^{Note 2: Concentrations were confirmed by analysis, and results expressed as nominal.}

^{Note 3: Data for metoprolol taken from Cleuvers M. Initial Risk Assessment for Three Beta-Blockers Found in the Aquatic Environment. Chemosphere, 2005, 59, 199-205. Concentrations of metoprolol were as free base in this study.}

^{Note 4: Results are expressed as nominal concentrations.}

PNEC (Predicted No Effect Concentration)

Short-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the acute toxicity to green alga (Desmodemus subspicatus), the most sensitive species, and an assessment factor of 1000 is applied, in accordance with ECHA guidance (Ref. 10).

PNEC = 7300 µg /L/1000 = 7.3 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 2.10 μg/L / 7.3 μg/L = 0.29, i.e. PEC/PNEC ≤ 1 which justifies the phrase

“Use of metoprolol has been considered to result in low environmental risk”. 

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

Environmental Fate Data

Biodegradation

The aerobic biodegradation was determined in accordance with ISO 7827-1984 (E) (Ref. 8), using the OECD guidelines’ criteria for ready biodegradation. According to the results, metoprolol is not readily biodegradable (loss of Dissolved Organic Carbon (DOC) <70% after 28 days). Based on the data above (considering that no other data is available), the statement “Metoprolol is potentially persistent” is justified.

In Swedish: “Metoprolol är potentiellt persistent” under the heading “Nedbrytning”.

Bioaccumulation

Log P = < 4 at pH 7.

Metoprolol has no significant bioaccumulation potential, as indicated by the Log P. Therefore the statement “Metoprolol has low potential for bioaccumulation” is used.

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

Physical Chemistry Data

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.
   http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

   
   

2. Logimax Investigators Brochure, Edition 2 Section 5 Effects in Humans. November 2006.

   
   

3. Aquatic Ecotoxicity of Pharmaceuticals Including the Assessment of Combination Effects. Cleuvers M. Toxicology Letters 2003 v142 n3 p185 – 194.

   
   

4. Metoprolol Succinate: Toxicity to the green alga Selenastrum capricornutum.

   Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7587. October 2003.

   
   

5. Metoprolol Succinate: Acute toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7588. October 2003.

   
   

6. Prediction and Experimental Validation of Acute Toxicity of Beta Blockers in Ceriodaphnia dubia. Fraysse B et al. Environ. Toxicol. Chem 2005 v24 n10 p2470 – 2476.

   
   

7. Metoprolol Succinate: Acute toxicity to rainbow trout (Oncorhynchus mykiss).

   Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7589. October 2003.

   
   

8. Environmental assessment of the pharmaceutical agent "A004" from AB Astra.

   Report No: 4/92, Toxicon. April 1992.

   
   

9. Metoprolol Succinate: Effect on the respiration rate of activated sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7772. December 2003.

   
   

10. ECHA, European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R10. May 2008 . https://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf/bb902be7-a503-4ab7-9036-d866b8ddce69

    
    

11. Metoprolol Succinate: Determination of n-octanol-water partition coefficient.

    Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7827. September 2004.