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.