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