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 * 11.388 kg * 100 = 0.001560 μg/L

Where:

A = 11.388 kg (For the PEC calculation the highest annual amount forecasted to be sold in Sweden in the next 5 years was used)

R = 0 % removal rate

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) (OECD201) (Study No. 20253147):

NOEC 72 h = 92 mg/L

Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilisation) = > 92.0 mg/L (OECD 202) (Study No. 20253145)

Chronic toxicity

NOEC 21 days (reproduction) = 8.3 mg/L (OECD 211) (Study No. 20210455)

Fish:

Acute toxicity (Cyprinus carpio, carp)

LC50 96 h (lethality) > 92.0 mg/L (OECD 203) (Study No. 20253142)

Chronic toxicity (Pimephales promelas, fathead minnow)

NOEC 32 days (growth) = 0.85 mg/L (OECD 210); no effects on hatching and survival (Study No. 20210454)

Other ecotoxicity data:

Bacterial respiration inhibition

NOEC 3 h = 920 mg/L (activated sludge respiration inhibition) (OECD209) (Study No. 20253149)

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

NOEC 28 days (emergence and development rate) = 544.64 mg/kg dry sediment (OECD 218) (Study No. 20210456)

PNEC derivation:

PNEC = 85 μg/L (=0.85 mg/L/10=85 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 the fish species Pimephales promelas, fathead minnow, in a fish early-life stage study has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.001560 μg/L / 85 μg/L = 0.0000184, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of iptacopan has been considered to result in insignificant environmental risk".

Degradation

Biotic degradation

Ready degradability:

4 - 8 % degradation in 28 days, not readily biodegradable (OECD 301B). (Study No. 20253148)

Simulation studies:

DT₅₀ (total system) = 5.7 and 6.8 days (OECD 308) (Study No. 20210453)

The applied radioactivity (AR) steadily decreased from the water phase, with 30.3% and 34.8% AR (mean values), respectively, at the end of the 99-day incubation. This was mostly present as iptacopan transformation products, and iptacopan levels in the water phase at 99 days after treatment (DAT) were only 1.1% and 0.2% AR.

Sediments were exhaustively extracted using THF, ammonium acetate with 5% acetonitrile (pH 5), and acetonitrile. The amount of radioactivity (mean values) extracted from sediment increased to a maximum of 32.4% - 35.1% AR at 7 DAT, and then decreased to 18.3% - 22.3% AR at the end of the incubation. The amount of iptacopan in the sediment extracts decreased to approximately 7% AR at the end of incubation in both test systems. The amount of non-extractable radioactivity increased to a maximum of 40.7 - 46.7% AR by the end of the incubation period (99 DAT). Out of this, an average of 51.5% - 70.6% was associated with the more immobile fractions (humic acids and humin). Mineralisation to ¹⁴CO₂ reached maximum mean amounts of 4.2% - 4.3% AR and organic volatiles were negligible.

Two major metabolites, M3 and M9, were detected with ≥10% AR in both test systems. They were identified by LC-MS as 4-[4-ethoxy-2-piperidyl) benzoic acid and 4-(4-ethoxy-1-pentadeca-trienoyl-2-piperidyl) benzoic acid. M3 was detected with maximum mean amounts of 19.4% and 20.2% AR on 99 DAT for Calwich Abbey and Golden Lake system, respectively. M9 reached its maximum mean amount after 14 days of incubation with 21.3% - 16.3% AR, mostly in the water phase. Besides M3 and M9, several minor metabolites were detected.

Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, iptacopan can be classified as “Iptacopan is degraded in the environment” (DT50 for total system <32 days).

Bioaccumulation

Partitioning coefficient:

log P_ow at pH 5 = 0.12

log P_ow at pH 7 = 0.3

log P_ow at pH 9 = 0.085 (OECD 107) (Study No. 20253141 and 20210451)

Justification of chosen bioaccumulation phrase:

Since log D_ow (at pH 7) < 4, iptacopan has low potential for bioaccumulation.

Excretion (metabolism)

In a study in healthy volunteers, following a single 100 mg oral dose of [14C]-iptacopan, mean total excretion of radioactivity (iptacopan and metabolites) was 71.5% in the faeces and 24.8% in the urine. Specifically, 17.9% of the dose was excreted as parent iptacopan in the urine and 16.8% in faeces. The half-life (t½) of iptacopan at steady state is approximately 25 hours after administration of iptacopan 200 mg twice daily (Fabhalta, SUMMARY OF PRODUCT CHARACTERISTICS).

References

• EMA 2006. Guideline on the environmental risk assessment of medicinal products for human use. EMEA/CHMP/SWP/4447/00 corr 21.

• 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

• Fabhalta, SUMMARY OF PRODUCT CHARACTERISTICS, accessed on 18^th December 2024, available from: https://ec.europa.eu/health/documents/community-register/2024/20240517162437/anx_162437_en.pdf.

• Study No. 20253145

• Study No. 20253148

• Study No. 20210453

• Study No. 20253141

• Study No. 20210451

• Study No. 20253147

• Study No. 20210455

• Study No. 20210454

• Study No. 20253149

• Study No. 20253142

• Study No. 20210456