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) = 0.0027 μg/L

Where:

A < 20.0 kg siponimod (maximum worldwide internal sales forecast from 2020 to 2025).

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

Algae (Pseudokirchneriella subcapitata):

NOEC 72 h (growth rate) = 0.37 mg/L (OECD201) (IES Study 20150161)

Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilisation) = 7.5 mg/L (OECD202) (NOTOX Project 491870)

Chronic toxicity

NOEC 21 days (parental mortality, reduced reproduction rates, reduced body length) = 0.22 mg/L (OECD 211) (IES Study 20150163)

Fish:

Chronic toxicity (Danio rerio, zebrafish)

NOEC 30 days (survival of larvae and juvenile fish) = 0.0054 mg/L (OECD 210) (IES Study 20150162)

Other ecotoxicity data:

Bacterial respiration inhibition

NOEC 3 h > 1000 mg/L (activated sludge respiration inhibition) (OECD209) (NOTOX Project 491873)

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

NOEC 28 days = 500.0 mg/kg dry weight (OECD 218) (IES Study 20150166)

PNEC derivation:

PNEC = 0.54 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 zebra fish survival of larvae and juvenile fish has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0027 μg/L / 0.54 μg/L = 0.005, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of siponimod has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready Biodegradability Test

No significant biodegradation. Not readily biodegradable (OECD 301B) (NOTOX Project 491872)

Simulation studies:

DT50 (water; 12°C) = 1.5 – 2.0 days

DT50 (sediment extracts; 12°C) = 397.0 – 405.6 days

DT50 (total system; 12°C) = 127.4 – 182.5 days

DT90 (water; 12°C) = 11.6 – 14.2 days

DT90 (sediment extracts; 12°C) = 2625.4 – 2902.9 days

DT90 (total system; 12°C) = 2924.3 – 4226.3 days

(OECD 308) (IES Study 20150159)

The aquatic sediment systems were incubated under aerobic conditions in the laboratory in the dark at 21.0 ± 0.1 °C. Treated samples were continuously ventilated with moistened air and the outlet air was passed through a trapping system consisting of a flask with ethylene glycol and a flask with sodium hydroxide in series. Duplicate samples were taken for analysis immediately after application (time 0), and after 2, 7, 14, 56 and 100 days of incubation for the river system and at time 0, and after 2, 7, 14, 56 and 105 days for the pond system.

The aqueous phase was withdrawn from the flasks and the radioactivity measured by Liquid Scintillation Counting (LSC). The sediment samples were exhaustively extracted up to five times with acetonitrile/water (4/1; v/v), followed by Soxhlet extraction with acetonitrile/water (1/1; v/v) on selected samples. Room temperature extracts were combined, concentrated and the pooled extracts were analysed by LSC for recovery. Chromatographic analysis of the aqueous phase and extracts was performed by HPLC. TLC analysis was used as confirmatory method for selected samples.

For the river system, the amount of ¹⁴CO₂ increased to a maximum of 13.3% AR at the final sampling interval (100 DAT). For pond system, ¹⁴CO₂ reached a maximum of 14.3% AR 105 DAT (final sampling interval). Organic volatile products absorbed in the ethylene glycol traps did not exceed the 0.4% AR in either the river or pond system at any sampling interval.

The amount of test item in total river system decreased from 89.9% AR on day 0 to 46.8% AR 56 DAT, thereafter remaining essentially stable, with parent representing 46.0% AR at the end of the 100-day incubation period. The corresponding values for the total pond system were 89.1% AR on day 0, decreasing to 43.4% AR 56 DAT, with parent still representing 42.5% AR after 105 days of incubation.

Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, siponimod can be classified as ‘Siponimod is potentially persistent' (DT₅₀ for total system > 120 days)

Bioaccumulation

Partitioning coefficient (OECD 123):

log Dow  at pH 4 = 5.65

log Dow  at pH 7 = 5.28

log Dow  at pH 10 = 4.81

(IES Study 20150165)

Bioconcentration in fish:

Lipid-normalised growth-corrected kinetics BCF (BCF_L,k) = 336 – 429 L/kg (IES Study 20160175)

Justification of chosen bioaccumulation phrase:

Since the lipid-normalised growth-corrected kinetics BCF < 500, siponimod has low potential for bioaccumulation.

Excretion (metabolism)

Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine. (MAYZENT^® (siponimod) Core Data Sheet)

PBT/vPvB assessment

Siponimod has been found to be persistent with the half-life determined in the study on transformation in water/sediment systems exceeding 120 days at 12°C for the total systems. As shown in the bioconcentration study in rainbow trout, siponimod cannot be considered bioaccumulative based on the lipid-normalised, growth-corrected BCF of 336 – 429 L/kg, remaining clearly below the EU criteria for B of 2000. According to the established EU criteria, siponimod can therefore not be regarded a 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

• IES Study 20150161. Effect of BAF312-AEA to Pseudokirchneriella subcapitata in a 72-Hour Algal Growth Inhibition Test. Final Report: 02. August 2016.

• NOTOX Project 491870. Acute toxicity study in Daphnia magna with BAF312-AEA (static). Final report: 30. May 2011.

• IES Study 20150163. Effect of BAF312-AEA on Survival, Growth and Reproduction of Daphnia magna in a Semi-Static Test over Three Weeks. Final Report: 30 August 2016.

• IES Study 20150162. Toxic Effects of BAF312-AEA to Zebra Fish (Danio rerio) in an Early Life Stage Toxicity Test. Final Report: 22. December 2016.

• NOTOX Project 491873. Activated Sludge Respiration Inhibition Test with BAF312-AEA. Final Report: 26. October 2009.

• IES Study 20150166. [¹⁴C]BAF312-AEA - Effects on the Development of Sediment-Dwelling Larvae of Chironomus riparius in Water-Sediment Systems with Spiked Sediment. Final Report: 10. August 2017.

• NOTOX Project 491872. Determination of ‘Ready’ Biodegradability: Carbon Dioxide (CO₂) Evolution Test (Modified Sturm Test) of BAF312-AEA. Final report: 15. December 2009.

• IES Study 20150159. [¹⁴C]BAF312-AEA – Degradation/Metabolism in Two Aquatic Systems under Aerobic Conditions. Amended Final Report: 06. March 2019

• IES Study 20150165. Determination of the Partition Coefficient (n-Octanol / Water) of BAF312-AEA. Final report: 02. August 2016.

• IES Study 20160175. Bioaccumulation of [¹⁴C]BAF312 hemifumarate in Rainbow Trout (Oncorhynchus mykiss) during Aqueous Exposure under Flow-through Conditions. Final Report: 19. March 2018.

• MAYZENT^TM (siponimod) Core Data Sheet Version 1.2. 13 December 2018.