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) = 1.37*10^-6 * 1874.12 kg * 100 = 0.256754 μg/L

Where:

A = 1874.12 kg (total sold amount of amlodipinbesilat in Sweden year 2022, data from IQVIA).

R = 0 % 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 = 10 * 10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008).

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green algae - freshwater (Pseudokirchneriella subcapitata) NOTOX Project 490973

EC50 72 h (growth rate) = 0.23 mg/L

NOEC 72 h (growth rate) = 0.029 mg/L

Crustacean (Daphnia magna, waterflea) NOTOX Project 464478

Acute toxicity

EC50 48 h (immobilisation) = 3.2 mg/L

Chronic toxicity

NOEC (21 days) = 0.22 mg/L

Fish fathead minnow (Pimephales promelas)              

Chronic toxicity

NOEC (31 days) = 2.2 mg/L (OECD 203) (NOTOX Project 490974)

Other ecotoxicity data:

Bacterial Respiration Inhibition:

NOEC (3 Hr) = 10.0 mg/L (activated sludge respiration inhibition, OECD209) (NOTOX 464502)

PNEC Derivation:

PNEC = 2.9 µg/L (justification of chosen assessment factor (AF))

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used if chronic toxicity studies from three trophic levels are available. NOEC for green algae growth inhibition has been used for this calculation since it is the most sensitive endpoint of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.26 µg/L / 2.9 µg/L = 0.09, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of amlodipine has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Aerobic and Anaerobic Transformation in Aquatic Sediment Systems (OECD 308) (NOTOX Project 464535):

14C-labelled Amlodipine (VAA489) was incubated aerobically in the laboratory in two non­contaminated water/sediment systems (Goorven [GV] and Schoonrewoerdse Wiel [SW]) at 20 ± 2°c in the dark for 99 days. The initial test substance concentration in the water layer was 0.25 mg/L (GV) and 0.26 mg/L (SW). Duplicate samples of each water/sediment system were taken at 0 (single sample), and after 1, 4, 8, 21, 49, and 99 days. Volatiles were trapped by polyurethane foam, ethylene glycol monoethyl ether, and NaOH traps. The water layer and the sediment layer were analysed (extraction of sediment with acetonitrile and acetonitrile: buffer pH 4 3:1 (v/v)). Bound residues were determined by combustion. For t=99 (GV)/49 (SW) days, bound residues were fractionated into fulvic acids, humic acids, and humins. Extracts were analysed by HPLC. Amlodipine (VAA489) was identified based on a comparison of retention time with a reference standard; identification was confirmed by a second HPLC method. Upon addition of Amlodipine (VAA489)  to the water layer, Amlodipine (VAA489) is partitioned between the water and sediment layer. In the sediment, Amlodipine (VAA489)  is degraded to metabolites that desorb again, causing an increase of the radioactivity in the water layer halfway through the incubation period. At the end of the study, Amlodipine (VAA489) had completely dissipated from both the water layer and the sediment (≤0.4% of applied). Mineralization was a very minor process in both water/sediment systems (0.5-1% CO2 at the end of the study). Bound residues accounted for ~ 25% of the applied substance. The bound residues of one replicate of the t=99/49 days (GV/SW) samples were fractionated into fulvic and humic acids and humins (9/49/43 [GV] and 19/10/73% [SW] of the bound residues).  The mass balances for the Goorven system ranged from 94 to 100% of applied radioactivity up to t=49 days and 87% after 99 days. The mass balances (mean values) for the Schoonrewoerdsewiel system ranged from 96 to 99% of applied radioactivity.

Metabolites

In the GV system, two significant metabolites (>10% of applied) were observed, one of which reached a maximum of 72% of applied and matched with degradation product DP-B that was detected in a photolysis study with VAA489 AMLO and identified as dehydro-amlodipine. The other metabolite represented 11% of applied or less. In the SW system, five significant metabolites were detected, each of which exceeded 10% of applied only once or twice and represented ≤18% of applied with one exception. Met 1, which represented up to 57% of the applied radioactivity, may consist of more than one metabolite (group) based on its peak shape.

The Amlodipine (VAA489) DT50  and DT90  values and coefficients of determination are given below.

Goorven ModelMaker results

Compartment	kinetics	x2 (err)	r2	DT50 (days)	DT90 (days)
Water	SFO	0.69	0.999	1.1	3.5
Sediment	SFO	19.96	0.819	16	53
Total system	SFO	7.44	0.988	1.7	5.6

Schoonrewoerdsewiel ModelMaker results

Compartment	kinetics	x2 (err)	r2                    DT50		DT90 (days)
				(days)
Water	SFO	7.75	0.984	1.9	6.4
Sediment	FOMC	24.01	0.839	3.1	35
Total system	SFO	7.84	0.975	4.6	15

Justification of chosen degradation phrase:

The DT50 for Amlodipine in the total system is < 32 days. Therefore, the phrase "the substance is degraded in the environment" is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log D = - 0.056 (NOTOX 490975)

Justification of chosen bioaccumulation phrase:

Since log D at an environmentally relevant pH is < 4, Amlodipine has a low potential for bioaccumulation.

Excretion (metabolism)

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

PBT/vPvB assessment

Based on the available information, amlodipine does not fulfill the screening criteria for a bioaccumulative substance and can therefore not be considered a potential PBT substance.

References

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• NOTOX Project 490973. Fresh water algal growth inhibition test with amlodipine besylate/DS06.                                      

• NOTOX Project 464478. Daphnia magna, reproduction test with VAA489 AMLO (semi-static).

• NOTOX Project 490974. Fish early-life stage toxicity test with amlodipine besylate/DS 06 (flow-through).                                                                                 

• NOTOX 464502 Activated sludge respiration inhibition test with VAA489 AMLO (contact time: 3 hours).                                                                                                          

• NOTOX Project 464535 Aerobic degradation of VAA489 AMLO in two water/sediment systems.

• NOTOX 490975 Determination of the partition coefficient of amlodipine besylate/DS 06.

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) = 1.37*10^-6 * 1922.79 * 100 = 0.263 μg/L

Where:

A = 1922.79 kg valsartan (sum of 1272.86 kg valsartan and 649.63 kg as valsartan proportion from amount of valsartan in 1429.04 kg sakubitril-valsartannatriumhydrat*) (total sold amount API in Sweden year 2021, data from IQVIA).

*The molecular weight of sacubritil-valsartan (Entresto®) is 1916 g/mol, and this contains two molecules of valsartan (435.5 g/mol x 2), so approx. 45.46% of the sacubritil-valsartan sodium hydrate corresponds to valsartan, which implies that the 1429.04 kg correspond to 649.63 kg valsartan.

R = 0 % 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 = 10 * 10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green algae (Pseudokirchneriella subspicata) (OECD201) (NOTOX Project 490976):

EC50 72 h (growth rate) > 100.0 mg/L

NOEC = 100.0 mg/L

Crustacean (Daphnia magna):

Acute toxicity

EC50 48 h (immobilisation) > 100.0 mg/L (OECD202) (ECOTOXICOLOGY CIGY NO. 948128)

Chronic toxicity

NOEC 21 days (parental mortality and reproduction) = 5.6 mg/L (OECD 211) (NOTOX Study No. 464434)

Fish:

Acute toxicity (Oncorhynchus mykiss, rainbow trout)

LC50 96 h (mortality) > 100.0 mg/L (OECD203) (ECOTOXICOLOGY CIGY NO. 948130)

Chronic toxicity (Pimephales promelas, fathead minnow)

NOEC 30 days = 10.0 mg/L; no effect up to the highest concentration tested (OECD 210) (NOTOX Study No. 464445)

Other ecotoxicity data:

Bacterial respiration inhibition

EC₅₀ 3 h > 750 mg/L

NOEC = 750 mg/L (activated sludge respiration inhibition) (OECD209) (NOTOX Project 490977)

Sediment-dwelling organisms (Chironomus riparius, non-biting midge)

NOEC 28 days = 400.0 mg/kg dry weight (OECD 218) (NOTOX Project 490978)

PNEC derivation:

PNEC = 560 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used if three chronic toxicity studies from three trophic levels are available. The NOEC for Daphnia magna reproduction has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.263 μg/L / 560 μg/L = 0.00047, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of valsartan has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

0 % degradation in 28 days, not readily biodegradable (92/69/EC (L383) C.4-C). (ECOTOXICOLOGY CIGY NO. 948127)

Simulation studies:

DT₅₀ (total system) = 12.0 – 16.1 days 

DT₉₀ (total system) = 39.8 – 53.6 days (OECD 308, 191 days). (RCC Study No. B40590)

< 15 % parent substance remaining at the end of the study

45-50 % non-extractable residues at the end of the study (up to two times: acetonitrile:water (4:1, v/v), followed by soxhlet acetonitrile: water (4:1, v/v))

Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, valsartan can be classified as ‘Valsartan is degraded in the environment' (DT₅₀ for total system < 32 days)

Bioaccumulation

Partitioning coefficient:

Log Dow = 1.2 at pH 7 (OECD117)

Log P = 2.8 at pH 2.5 (NOTOX Project 490979)

Justification of chosen bioaccumulation phrase:

Since log Dow < 4 at pH 7, valsartan has low potential for bioaccumulation.

Excretion (metabolism)

Valsartan is primarily eliminated in feces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. (Diovan^® (valsartan) Core Data Sheet, 2018)

PBT/vPvB assessment

Valsartan cannot be considered a potential PBT substance.

References

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• NOTOX Project 490976. Fresh water algal growth inhibition test with valsartan/DS 21. Final report: August 04, 2009.                                               

• ECOTOXICOLOGY CIGY NO.948128.                                                      

• NOTOX Study No. 464434. Daphnia magna reproduction test with VAA489 VAL (semi-static). Final Report: Sept 26, 2006.                                                           

• ECOTOXICOLOGY CIGY NO. 948130.                                                     

• NOTOX Study No. 464445. Fish early-life stage toxicity test with VAA489 VAL (semi-static). Final Report: July 12, 2006.                                                            

• NOTOX Project 490977. Activated sludge respiration inhibition test with valsartan/DS 21. Final report: August 20, 2009.   

• NOTOX Project 490978. Sediment-water Chironomid toxicity test using sediment spiked with valsartan/DS 21. Final report: October 01, 2009.

• ECOTOXICOLOGY CIGY NO. 948127. PBS 858 DS. Report on the test for ready biodegradability of PBS 858 DS in the carbondioxide evolution test. Final report: September 21, 1995.      

• RCC Study No. B40590. 14C-VAH631 VAL DS. Route and rate of degradation in aerobic aquatic sediment systems. Final report: May 26, 2008.                                           

• NOTOX Project 490979. Determination of the partition coefficient of valsartan/DS 21. Final report: July 01, 2009.                                                                                                                                          

• DIOVAN^® (valsartan). Core Data Sheet. Version 3.0. 10-Sep-2018.