Miljöpåverkan
Miljöinformationen för felodipin är framtagen av företaget AstraZeneca för Felodipin AstraZeneca, Plendil®, Unimax, Unimax mite
Miljörisk:
Användning av felodipin har bedömts medföra låg risk för miljöpåverkan.
Nedbrytning:
Felodipin är potentiellt persistent.
Bioackumulering:
Felodipin har låg potential att bioackumuleras.
Läs mer
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 KOC = 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 Koc = Kd(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
-
[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
-
[ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment. Version 3 February 2016.
-
Felodipine kinetics in healthy men. Edgar B, et al. Clinical Pharmacology and Therapeutics 38: 205-211. 1985
-
Metabolism of [14C] felodipine, a new vasodilating drug, in healthy volunteers. Hoffman, K-J and Andersson L. Drugs 34: 43-52. 1987
-
Ecotoxicological characterisation of felodipine, MK0218. Environmental Engineering Laboratory (EEL), UK. March 1994. Soutron reference BD4166.
-
Rotifer Microplate Screening for Felodipine. Williams TD & Liu Q, 2008. Brixham Environmental Laboratory Report BLS3454/B
-
H154/82: Inhibition of growth to the alga Selenastrumcapricornutum. Covance, England. Report No. 265/55-D2145. June 1999. Soutron reference BD3977
-
Felodipine: Acute toxicity to Rainbow trout, Oncorhynchus mykiss, under static test conditions. Toxikon Environmental Sciences, USA. May 1994. J9312003b. Soutron reference BD4165
-
Felodipine: Acute Toxicity to Bluegill, Lepomis macrochirus, under Static Test Conditions. Toxikon Environmental Sciences, USA. Report No: J9312003a. May 1994. Soutron reference BD4190
-
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
-
Felodipine: Adsorption and desorption to sewage sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7813/B, October 2004
-
EUSES - European Union System for the Evaluation of Substances 2.1 background report – Model Calculations. 2019.
-
Sangster, J., Log KOW Databank, Montreal, Quebec, Canada, Sangster Research Laboratories, 1994
-
General Properties for Felodipine. AstraZeneca, June 2006. Soutron reference BD4182
-
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
-
Felodipine (MK-218): Determination of Aqueous Photolysis. Toxicon Environmental Sciences, USA. Report No: J9307008a January 1994. Soutron reference BD4189
Metoprolol
Miljörisk:
Användning av metoprolol har bedömts medföra låg risk för miljöpåverkan.
Nedbrytning:
Metoprolol är potentiellt persistent.
Bioackumulering:
Metoprolol har låg potential att bioackumuleras.
Läs mer
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
-
[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
-
Logimax Investigators Brochure, Edition 2 Section 5 Effects in Humans. November 2006.
-
Aquatic Ecotoxicity of Pharmaceuticals Including the Assessment of Combination Effects. Cleuvers M. Toxicology Letters 2003 v142 n3 p185 – 194.
-
Metoprolol Succinate: Toxicity to the green alga Selenastrum capricornutum. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7587. October 2003.
-
Metoprolol Succinate: Acute toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7588. October 2003.
-
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.
-
Metoprolol Succinate: Acute toxicity to rainbow trout (Oncorhynchus mykiss). Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7589. October 2003.
-
Environmental assessment of the pharmaceutical agent "A004" from AB Astra. Report No: 4/92, Toxicon. April 1992.
-
Metoprolol Succinate: Effect on the respiration rate of activated sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7772. December 2003.
-
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
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Metoprolol Succinate: Determination of n-octanol-water partition coefficient. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7827. September 2004.