Detaljerad miljöinformation

Detailed background information

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 = 1.7E-05 μg/L

Where:

A = 0.1210 kg (total sold amount API in Sweden year 2021, data from IQVIA) (Ref. I)

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 10*10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus) (OECD 201) (Ref. III):

EC₅₀ 72 h (growth rate) = 3833 ug/L

NOEC 72 h (growth rate) = 958 ug/L

Crustacean, water flea (Daphnia magna) (OECD 211) (Ref. III):

Chronic toxicity

NOEC 21 day (reproduction, mortality) = 70 ug/L

Fish Early Life-Stage, fathead minnow (Pimephales promelas) (OECD 210) (Ref III):

Chronic toxicity

NOEC 28 day (growth) = 3 ug/L

PNEC = 0.3 µg/L (3 ug/L /10) based on the chronic NOEC for the fathead minnow and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 1.7E-05/0.3 = 5.5E-05, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of riociguat has been considered to result in insignificant environmental risk."

Degradation studies

Hydrolysis (EC guideline C.7) (Ref III):

Riociguat is hydrolytically stable at pH 4, 7 and 9 (50°C)

Aerobic biodegradability in water (OECD 301F) (Ref III):

Riociguat was introduced into the test system at a concentration of 200 mg/L as theoretically oxidizable carbon. It was degraded to 2.5 % after 28 days. Hence, it is not readily biodegradable.

Sediment Transformation (OECD 308) (Ref. IV)

In a water/sediment simulation study at 20°C, riociguat showed no degradation during the 100 d test period, no metabolites were detected in water and sediment. At day 100, 9 and 15% bound residue was determined in two sediments, while 93-96% of the substance was present in sediment and 3.3-3.8% in water.

Justification of chosen degradation phrase:

As limited degradation was noted in the above studies, the substance is potentially persistent.

Bioaccumulation

Partitioning coefficient:

Log Kow = 2.37 at pH 7 (OECD 107) (Ref.III)

Justification of chosen bioaccumulation phrase:

Since log Kow < 4 at pH 7, the substance has low potential for bioaccumulation.

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2022 (data 2021)”.

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

3. Bayer, 2012. “Riociguat Statement on the Environmental Risk Assessment”, 19 December 2012.

4. European Medicines Agency, 2017. EPAR Assessment report for riociguat accessed from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002737/WC500165036.pdf on 19 January, 2017.