Detaljerad miljöinformation

PEC/PNEC = 0.029 μg/L / 0.050 μg/L = 0.580

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The PEC is based on the following calculation:

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

PEC (µg/L)      = 1.37*10^-6*A*(100-R)

PEC (µg/L)      = 1.37 * 10^-6 * 422.42 * (100 – 50)

PEC                = 0.029 µg/L

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

                        = 422.420 kg/year

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

                        = 50%*

P                      = number of inhabitants in Sweden

=10*10⁶

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

= 200 L/day (Ref 1)

D                     = factor for dilution of waste water by surface water flow

= 10 (Ref 1)

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

*The removal during sewage treatment (50%) is estimated using the EUSES model, Simple Treat, described in the ECHA Guidance Document (Ref. 2) where the following assumptions have been made based on results reported in the tables below: not readily biodegradable, water solubility 0.5 mg/L and K_OC = 7568 L/kg. A measured vapor pressure (VP) is not available for Felodipine, therefore the Simple Treat model used a nominal value of 1 x10^-6 Pa – which is the lowest value the model allows – which reflects that Felodipine is an involatile solid with negligible VP at ambient conditions and therefore assumes no losses to the atmosphere.

Metabolism

Felodipine is extensively metabolised in humans. In healthy volunteers, about 62% of an orally given dose of felodipine was excreted into the urine (Ref 3). 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 (Ref 4). Approximately 10% of the given oral dose was excreted in faeces, however the identity or pharmacological activity of these excreted products is not known.

Ecotoxicity data

Study Type	Method	Result	Reference
Activated sludge, respiration inhibition test	OECD209	3 h EC50 >10 mg/L	5
Toxicity to freshwater rotifer, Brachionus calyciflorus	ISO 20666	48 h EC50biomass > 0.32 mg/L 48 h EC50growth rate > 0.32mg/L NOEC > 0.32 mg/L LOEC > 0.32 mg/L	6
Toxicity to green algae, Selenastrum capricornutum, growth inhibition test	OECD201	72 h EC50growth rate > 0.322 mg/L 72 h EC50biomass > 0.322 mg/L	7
Acute toxicity to Daphnia magna	US EPA 1985	48 h LC50 = 0.62 mg/L	5
Acute toxicity to fathead minnow, Pimephales promelas	US EPA 1985	96 h LC50 = 0.39 mg/L	5
Acute Toxicity to Rainbow Trout, Oncorhynchus mykiss	US FDA Technical Assistance Document 4.11	96 h LC50 = 0.05 mg/L NOEC < 0.016 mg/L	8
Acute Toxicity to Bluegill, Lepomis macrochirus	US FDA Technical Assistance Document 4.11	96 h LC50 = 0.66 mg/L NOEC = 0.22 mg/L	9

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 = 0.029 μg/L / 0.050 μg/L = 0.58

This 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

Study Type	Method	Result	Reference
Aerobic biodegradation	OECD301B	<5% after 28 days. Not readily biodegradable	10
Adsorption and desorption to sludge	OPPTS guideline 835.1110	Kd(ads) = 2800 L/Kg Kd(des) = 3300 L/kg KOC = 7568 L/kg	11

^*Calculated K_oc = K_d(ads) / 0.37 (ref. 12)

Physical Chemistry Data

Study Type	Method	Result	Reference
Octanol-water distribution coefficient	-	3.86	13
Water solubility	-	0.5 mg/L at 22-25 °C	14
Hydrolysis	FDA 3.09	Stable at pH 5, 7 and 9 at 50°C	15
Photolysis	FDA 3.10	t½ = 2.1 h at pH7	16

Biodegradation

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”.

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”.

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. [ECHA] European Chemicals Agency.  Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment. Version 3 February 2016.

3. Felodipine kinetics in healthy men. Edgar B, et al. Clinical Pharmacology and Therapeutics 38: 205-211. 1985

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

5. Ecotoxicological characterisation of felodipine, MK0218.  Environmental Engineering Laboratory (EEL), UK. March 1994. Soutron reference BD4166.

6. Rotifer Microplate Screening for Felodipine. Williams TD & Liu Q, 2008. Brixham Environmental Laboratory Report BLS3454/B

7. H154/82: Inhibition of growth to the alga Selenastrumcapricornutum. Covance, England. Report No. 265/55-D2145.  June 1999. Soutron reference BD3977

8. Felodipine: Acute toxicity to Rainbow trout, Oncorhynchus mykiss, under static test conditions. Toxikon Environmental Sciences, USA. May 1994. J9312003b. Soutron reference BD4165

9. Felodipine:  Acute Toxicity to Bluegill, Lepomis macrochirus, under Static Test Conditions. Toxikon Environmental Sciences, USA. Report No: J9312003a. May 1994. Soutron reference BD4190

10. H154/82: Assessment of ready biodegradability by measurement of carbon dioxide evolution. Covance, UK. Report No: 98095-1 265/57-1018 Sept 1997. Soutron reference BD3971

11. Felodipine: Adsorption and desorption to sewage sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7813/B, October 2004

12. EUSES - European Union System for the Evaluation of Substances 2.1 background report – Model Calculations. 2019.

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

14. General Properties for Felodipine. AstraZeneca, June 2006. Soutron reference BD4182

15. 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. Soutron reference BD4188

16. Felodipine (MK-218): Determination of Aqueous Photolysis. Toxicon Environmental Sciences, USA. Report No: J9307008a January 1994. Soutron reference BD4189

Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6*A(100-R)

PEC = 1.61 μg/L

Where:

A = 11 786.21 kg (total sold amount API in Sweden year 2020, data from IQVIA).

R = Removal rate = 0% (no data available)

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: 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.)

Excretion (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

Endpoint	Species	Common Name	Method	Time	Result	Ref
ErC50 - Based on Average Specific Growth Rate	Desmodesmus subspicatus	Green Alga	92/69/EEC Annex V C.3	72 h	7.3 mg/L Note 2, 3	3
NOEC - Based on Areas Under the Growth Curve	Pseudokirchneriella subcapitata	Green Alga	OECD 201	72 h	7.5 mg/L Note 1,2	4
LOEC - Based on Areas Under the Growth Curve					15 mg/L Note 1,2
EbC50 - Based on Areas Under the Growth Curve					22.8 mg/L Note 1,2
NOEC - Based on Logarithmic Growth Rate					7.5 mg/L Note 1,2
LOEC- Based on Logarithmic Growth Rate					15 mg/L Note 1,2
ErC50 - Based on Logarithmic Growth Rate					58.3 mg/L Note 1,2
EC50 - Based on Immobilisation	Daphnia magna	Giant Water Flea	OECD 202	48 h	>120 mg/L Note 1,2	5
NOEC - Based on Immobilisation					30 mg/L Note 1,2
EC50	Ceriodaphnia dubia	Cladoceran	EPA 600/4 90/027	48 H	45.3 mg/L	6
LC50	Oncorhynchus mykiss	Rainbow Trout	OECD 203	96 h	130 mg/L Note 1,2	7
NOEC - Based on Symptoms of Toxicity					32 mg/L Note 1,2
LC50	Danio rerio	Zebra Fish	OECD 203	96 h	167 mg/L Note 1,2	8
LOEC - Based on Mortality					157.5 mg/L Note 1, 2
EC50 - Based on Respiration Inhibition	-	-	OECD 209	3 h	>100 mg/L Note 1,4	9
NOEC - Based on Respiration Inhibition				3 h	100 mg/L Note 1, 4

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.

Predicted No Effect Concentration (PNEC)

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 = 1.6/7.3 = 0.22, 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

Endpoint	Method	Test Substance Concentration	Time	Result	Ref
Partition Coefficient Octanol Water	OECD 107	100 mg/L	-	Log P = -0.06 @ pH 5 Log P = -0.90 @ pH 7	11
Percentage DOC removal	ISO 7827-1984 (E)	34 mg DOC/L	28 d	14 %	8

Degradation

Biotic degradation

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

Endpoint	Method	Test Conditions	Result	Reference
Solubility Water	Not specified, method unknown	-	200 mg/L	9

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.