Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (DOSEai*Fpen)*(100-R))/(V*D*100) = (300,000 * 0.01)*(100 - 0)/(200 * 10 * 100) =

PEC = 1.5 μg/L

Where:

DOSEai = 300,000 μg/inhabitant/day (maximal daily dose)

Fpen = 0.01 (no market data is available, therefore the default for fraction of market penetration is used, as suggested by EMA guidance, 2006)

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) (WIL Research Project 499711):

EC50 72 h (growth rate) > 16 mg/L

NOEC 72 h = 5.6 mg/L

Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilisation) = 18 mg/L (OECD 202) (WIL Research Project 499710)

Chronic toxicity

NOEC 21 days (reproduction) = 0.48 mg/L (OECD 211) (IES Study 20170481)

Fish:

Chronic toxicity (Danio rerio, zebrafish)

NOEC 35 days (growth) = 0.30 mg/L (OECD 210); no effects on hatching and survival (IES Study 20170482)

Other ecotoxicity data:

Bacterial respiration inhibition

NOEC 3 h = 1000 mg/L (activated sludge respiration inhibition) (OECD209) (WIL Research Project 499713)

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

NOEC 28 days (emergence and development rate) = 64 mg/kg dry sediment (OECD 218) (IES Study 20170485)

PNEC derivation:

PNEC = 30 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 Danio rerio in a fish early-life stage study has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 1.5 μg/L / 30 μg/L = 0.05, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of alpelisib has been considered to result in insignificant environmental risk”.

Degradation

Biotic degradation

Ready degradability:

2 - 4 % degradation in 28 days, not readily biodegradable (OECD 301B). (WIL Research Project 499712)

Simulation studies:

DT₅₀ (total system, 12ºC) = 47 – 138 days (OECD 308) (IES Study 20170484)

Following treatment, the amount of radioactivity found in the aqueous phase of the river system decreased to 10.3% AR at the final sampling interval (102 DAT) and to 4.5% AR in the pond system.

For the river system, the amount of radioactivity extracted from sediment at room temperature increased from 5.7% AR on day 0 to a maximum of 58.0% AR 32 DAT. Thereafter, the amount of radioactivity extracted at room temperature from the river sediment decreased slowly back to 47.7% AR by the end of the 102-day incubation period. Additional Soxhlet extractions recovered an additional 5.3% AR from the river sediment 32 DAT, with amounts of radioactivity recovered through this harsh extraction technique increasing throughout the incubation period to a maximum of 9.4% AR at the final sampling interval (102 DAT).

For the pond system, the total amount of radioactivity extracted from sediment at room temperature increased from 6.3% AR (0 DAT) to 52.2% AR at 32 DAT, with still 52.5% AR at the end of the 102-day incubation period. Additional Soxhlet extractions recovered an additional 7.2% AR from the pond sediment 32 DAT, with amounts of radioactivity recovered through Soxhlet extraction increasing to a maximum of 13.9% AR at 102 DAT.

For the river sediment, the amount of non-extractable radioactivity (bound residues) increased from 1.1% AR 0 DAT to a maximum of 24.2% AR (102 DAT). Similarly in the pond system, non-extractable radioactivity increased from 1.5% AR 0 DAT to 23.3% AR by the end of the 102-day incubation period.

The amount of ¹⁴CO₂ increased to a maximum of 12.8% AR (102 DAT) for the river system, and to 10.5% AR for the pond system by the end of the 102-day incubation period. Organic volatile products absorbed in the ethylene glycol traps did not exceed 0.1% AR in either the river or pond system at any sampling interval.

The amount of alpelisib in the total river system decreased from 95.4% AR on day 0 to 34.4% AR at the end of the 102-day incubation period. Correspondingly, in the total pond system, alpelisib decreased from 94.3% AR on day 0 to 9.3% AR after 102 days of incubation.

In the river and pond systems, the test item degraded into a total of eleven different metabolic fractions. Two of the transformation products (TP) were major: TP1 (NVP-BZG791) reached mean amounts of up to 10.6% AR by 32 DAT for the river system and 36.9% AR by 32 DAT for the pond system. Additionally, TP3 (5-(2-tert-butyl-pyridin-4-yl)-4-methyl-thiazol-2-ylamine) increased to 11.5% AR (river) and 38.6% AR (pond) by the end of incubation (102 DAT). All other fractions were, however, classified as minor, as none of them exceeded 10% AR at any individual sampling interval or 5% AR at any two consecutive sampling intervals.

Degradation rates (DT50) extrapolated to 12ºC were 138 days for the river total system, and 47 days for the pond total system.

Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, alpelisib can be classified as “Alpelisib is slowly degraded in the environment” (DT50 for total system <120 days in pond system and > 120 days in river system).

Bioaccumulation

Bioconcentration factor (BCF):

Rainbow trout (Oncorhynchus mykiss)

BCF = 1.7 – 2.1 L/Kg (OECD 305) (IES Study 20180187)

Partitioning coefficient:

log P_ow at pH 5 = 3.04

log P_ow at pH 7 = 3.03

log P_ow at pH 9 = 3.03 (OECD 107) (IES Study 20170480)

Justification of chosen bioaccumulation phrase:

Since BCF < 500, alpelisib has low potential for bioaccumulation.

Excretion (metabolism)

In a human mass-balance study, after oral administration, alpelisib and its metabolites were excreted in the faeces (81.0%), mainly through hepatobiliary export and/or intestinal secretion of alpelisib, or metabolised to BZG791. Excretion in the urine is minor (13.5%), with unchanged alpelisib (2%). Following a single oral dose of [¹⁴C]-alpelisib, 94.5% of the total administered radioactive dose was recovered within 8 days (Piqray, Public Assessment Report, EMA/CHMP/321881/2020).

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

• WIL Research Project 499711. Fresh water algal growth inhibition test with BYL719-NXA. Final report: 24 December 2013.

• WIL Research Project 499710. Acute toxicity study in Daphnia magna with BYL719-NXA. (Static). Final report: 24 December 2013.

• IES Study 20170481. BYL719-NXA - Effect on survival, growth and reproduction of Daphnia magna in a semi-static test over three weeks. Final report: 25 October, 2018.

• IES Study 20170482. BYL719-NXA – Toxic effects to zebrafish (Danio rerio) in an early life stage toxicity test. Final report: 25 October, 2018.

• WIL Research Project 499713. Activated sludge respiration inhibition test (carbon and ammonium oxidation) with BYL719-NXA. Final report: 12 December 2013.

• IES Study 20170485. [14C]BYL719-NXA – Effects on the development of sediment-dwelling larvae of Chironomus riparius in water-sediment systems with spiked sediment. Final report: 14 November 2018.

• WIL Research Project 499712. Determination of ‘ready’ biodegradability: carbon dioxide (CO2) evolution test (modified Sturm Test) of BYL719-NXA. Final report: 12 December 2013.

• IES Study 20170484. BYL719 – Degradation/metabolism of [14C]BYL719 in two aquatic systems under aerobic conditions. Final report: 28 November 2018.

• IES Study 20180187. BYL719-NXA – Bioaccumulation of [14C]BYL719-NXA in rainbow trout (Oncorhynchus mykiss) during aqueous exposure under flow-through conditions. Final report: 28 March 2019.