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) = 0.0000000411 µg/L = 4.11E-8 μg/L

Where:

A = 0.0003 kg (total sold amount API in Sweden year 2022, data from IQVIA / LIF

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) (Reference I)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies*

Algae (green algae, Desmodesmus subspicatus):

NOEC 72 hours (growth rate) = 279 μg/L. Guideline OECD 201. (Reference II)

Crustacean (waterflea, Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) ≥ 1400 μg/L. Guideline OECD 211. (Reference III)

Fish (zebrafish, Danio rerio):

Chronic toxicity

NOEC 28 days (reproduction) ≥ 847 μg/L. Guideline OECD 210. (Reference IV)

The PNEC was calculated by division of the lowest effect level (NOEC) of the most sensitive taxonomic group considering an appropriate assessment factor (AF). The most sensitive taxonomic group were algae and the lowest effect level was reported as NOEC = 279 µg/L. The regulatory default standard AF of 10 was used, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, crustaceans, and fish).

PNEC = 279 µg/L / 10 = 27.9 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated with 0.0000000411 µg/L / 27.9 µg/L = 0.0000000015 = 1.47E-9.

Justification of chosen environmental risk phrase:

A risk quotient of ≤ 0.1 qualifies for the phrase “Use of vericiguat has been considered to result in insignificant environmental risk.”.

Degradation

Biotic degradation

Simulation studies:

The test substance vericiguat was incubated in an aerated system, which contained sediment and overlaying water. Sediments of two locations: “Teltowkanal km 21.7”, Berlin, Germany, mixed with a sample from “Feldsoll”, Müncheberg, Germany (sediment 1), and from a location at the “Teltowkanal km 25.0”, Berlin, Germany (Sediment 2). The sediments selected differed with respect to organic carbon content and texture.

The substance was incubated over a period of 100 days. Each test vessel contained 50 g of intact sediment and 150 g filtered test solution. The vessels were mounted by a glass tube containing sodium hydroxide pellets for trapping evolved CO₂.

No nutrients or other components were added to the system. ¹⁴C-labeled vericiguat was added with final activity of 0.1 MBq (nominal) per vessel. Radioactivity of vericiguat in sediment was quantified by combustion analysis and radioassay. The water fraction was radioassayed by liquid scintillation counting (LSC). Hydrochloric acid was added to the soda lime fraction and evolving ¹⁴CO₂ was absorbed in a scintillation cocktail and radioassayed by LSC. Samples for analyses were taken at the beginning, and at day 2, 15, 29, 43, 65 and 100. 3 vessels were used for each analysis and discarded afterwards.

After 100 days [¹⁴C]-vericiguat remained only to about 2.0 and 3.2% in the water phase of sediment-system 1 and 2, respectively (Table 3 2). After 15 days more than 90 % of the test item were removed from the water fraction. Ultimate biodegradation was low and accounted for 0.5 and 0.2 % of the radioactivity in sediment-system 1 and 2, respectively. Because of the lack of relevant biodegradation, the test item is assumed to accumulate in the sediment and is in parts stable bound (see below). The total mass balance ranged from 88.7 to 135.4 % of the total radioactivity (0.1MBq) in sediment-system 1and from 92.3 to 159.5 % of the total radioactivity (0.1 MBq) in sediment system 2 without showing major differences between the sediment-systems.

The extraction of water did not show significant (>10 %) transformation of Vericiguat, but in both sediment fractions two transformation products (DP3, partly DP1) were detected in increasing amounts. In sediment system 1, DP3 was detected with 11.4 % at day 100. In sediment system 2, DP1and DP3 appeared with 11.2 % (day 100) and 37.4 % (day 64), respectively. Since the kinetics of the transformation products did not follow any standard model, half-lives for disappearance were not calculated. Also, in both sediment systems non-extractable radioactivity was found at levels of 59 % (sediment system 1) and 65 % (sediment system 2) at day 100.

This study reported a half-life of substance vericiguat in water DT₅₀ = 10.21-10.51 days and DT₅₀ = 189.6-1751 in sediment/total system. Guideline OECD 308. (Reference V)

Abiotic degradation

Hydrolysis:

This study reported vericiguat to be stable. Guideline OECD 111. (Reference VI)

Justification of chosen degradation phrase:

Vericiguat established a DT₅₀ > 120 d for the total system and is resistant to hydrolysis, which qualifies for the phrase “Vericiguat is potentially persistent.”.

Bioaccumulation

Partitioning coefficient:

The log D_ow was reported as 2.51 at pH 7. Guideline OECD 107. (Reference VII)

Justification of chosen bioaccumulation phrase:

As the log D_ow was < 4 vericiguat is not considered bioaccumulative which qualifies for the phrase “Vericiguat has low potential for bioaccumulation.”.

References

1. Guidance on information requirements and Chemical Safety Assessment Chapter R.16: Environmental exposure assessment. V3.0, Feb. 2016.

2. Growth inhibition test with BAY 1021189 Vericiguat) on green algae (Desmodesmus subspicatus). Bayer AG. Report No. PH-41483, Study No. T104596-5.

3. Reproduction study with BAY 1021189 (Vericiguat) in Daphnia magna. Bayer AG. Report NO. PH-41471. Study No. T104439-1.

4. BAY 1021189: Toxicity to Zebrafish (Danio rerio) in an Early-Life Stage Test. Bayer AG. Report No. R-13346.Study No. T104460-5.

5. BAY 1021189C14: Aerobic Transformation in an Aquatic Sediment-System with BAY1021189C14 (Vericiguat). Bayer AG. Report No. PH-41467. Study No. T104062-3.

6. BAY 1841788: Hydrolysis as a Function of pH [OECD 111]). Bayer AG. Report No. R-12932. Study No. T103742-7.

7. BAY 1021189: Determination of the Partition Coefficient (n-Octanol/Water) by the Shake Flask Method) at pH7. Bayer AG. Report No. R-12734, study No. T103741-6.