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

*Ramipril is a prodrug. Since all data referenced is for the prodrug ramipril, this risk assessment is for the prodrug and not the active metabolite, ramiprilat.

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 = 0.0173 µg/L

Where:

A = 126.246404 kg (total sold amount API in Sweden year 2020, data from IQVIA)

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 (Ref I)

D = factor of dilution of waste water by surface water flow = 10 (Ref I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green algae, Desmodesmus subspicatus:

Acute toxicity:

EC₅₀ 72 h (biomass): > 100 000 μg/L

EC₅₀ 72 h (growth inhibition): >100 000 μg/L

(Protocol: OCDE Test Guideline 201)

(Ref II)

Pseudokirchneriella subcapitata

Acute toxicity:

EC₅₀ 72 h: > 100 000 μg/L

NOEC 72 h: > 100 000 μg/L

(Protocol: OCDE Test Guideline 201)

(Ref VIII)

Pseudomonas putida

Acute toxicity:

EC₅₀ 16 h: > 1 000 000 μg/L

(Protocol: DIN 38412 T.8)

(Ref IX)

Water flea, Daphnia magna:

Acute toxicity:

EC₅₀ 48 h (survival): > 100 000 μg/L

(Protocol: OCDE Test Guideline 202)

(Ref III)

Chronic toxicity:

EC₅₀ 21 days (reproduction): > 100 000 μg/L

NOEC 21 days (reproduction): ≥ 100 000 μg/L

NOEC 21 days (mortality): ≥ 100 000 μg/L

(Protocol: OCDE Test Guideline 211)

(Ref X)

Zebrafish, Brachydanio rerio:

LC₅₀ 96 h (mortality): > 100 000 μg/L

(Protocol: OECD 203)

(Ref IV)

Zebrafish embryos, Danio rerio:

LC₅₀ 96 h (mortality): > 100 000 μg/L

(Protocol: OECD 236)

(Ref XI)

Other ecotoxicity data:

PNEC = 100 000/1000 = 100 μg/L

The PNEC (μg/L) was calculated using results from the most sensitive acute toxicity endpoint and an assessment factor of 1000 (at least one short-term L(E)C50 from each of three trophic levels). Green algae, daphnia and fish were equally sensitive, all with an E(L)C₅₀ above 100 000 μg/L.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC = 0.0173/100 = 0.000173

PEC/PNEC ≤ 0.1 which justifies the phrase: “Use of ramipril has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready biodegradability:

Test results showed > 20 % degradation in 28 days.

(Protocol: OECD Test Guideline 301A; method of analysis DOC decrease)

According to OECD guidelines, Ramipril is not readily biodegradable yet inherently biodegradable.

(Ref V)

Justification of chosen degradation phrase:

Ramipril failed to pass the ready degradation test according to OECD criteria, hence "Ramipril is potentially persistent"

Bioaccumulation

The substance has a low potential to bioaccumulation, as indicated by a calculated log K_ow of 3.77 (Hansch Leo method) (Ref VI).

Excretion

After oral administration, cleavage (primarily in the liver) of the ester group converts ramipril to its active di-acid metabolite, ramiprilat. Other metabolites identified are the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. About 60 % of the parent drug and its metabolites are eliminated in the urine, and about 40 % is found in the feces. The absolute bioavailabilities of ramipril and ramiprilat were 28 % and 44 %, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously. Less than 2 % of the administered dose is recovered in urine as unchanged ramipril. (Ref VI)

References

1. ECHA, European Chemicals Agency, 2008 Guidance on information requirements and chemical safety assessment. https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment

2. Internal report, Aventis Pharma Deutschland: Growth Inhibition Test with Fresh Water Algae (Desmodesmus subspicatis). OECD 201. Report # PT02-0045, July 2002.

3. Internal report, Aventis Pharma Deutschland Acute Toxicity Study on Daphnia. OECD 202. Report # PT02-0044, June 2002.

4. Internal report, Hoechst: Acute Toxicity Study on Zebra Fish. OECD 203. Report # 94.0289, July 1994.

5. Internal report, Hoechst: Study of Biodegradability of Ramipril, OECD 301B. Report # 94-0057-41, October 1994.

6. Ramipril Safety Data Sheet: Sanofi-Aventis Deutschland GmbH, February 2012.

7. Internal report, Aventis Pharma Deutschland: Growth Inhibition Test with Fresh Water Algae (Desmodesmus subspicatis). OECD 201. Report # PT02-0045, July 2002.

8. Internal report, Ibacon GmbH Germany: Growth Inhibition Test with Fresh Water Algae (Pseudokirchneriella subcapita). OECD 201. Study # 135561210, August 2018.

9. Internal report, Hoechst: Activated sludge respiration inhibition testing of Ramipril, DIN 38412 T.8. Report # 94-0057-13, October 1994.

10. Internal report, Ibacon GmbH Germany, Semi-static reproduction study on Daphnia. OECD 211. Study #135561221, September 2018.

11. Internal report, Ibacon GmbH Germany, Acute Toxicity Study on Danio rerio embryos. OECD 236. Study #135561238, November 2018.