Detaljerad miljöinformation

PEC/PNEC = 0.00024µg/L /120µg/L = 0.000002

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The PEC is based on the following data:

PEC (µg/L)      = (A*10⁹*(100-R))/(365*P*V*D*100)

PEC (µg/L)      = 1.37*10^-6*A*(100-R)

PEC     = 1.37 * 10^-6 * 1.758 * (100-R)

= 0.00024 µg/L 

A (kg/year)      = total sold amount API in Sweden year 2021, data from IQVIA/Lif.

            = 1.758 kg/year

R (%)            = removal rate (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation)

= 0 (default)

P          = number of inhabitants in Sweden

=10 *10⁶

V (L/day)         = volume of wastewater per capita and day

= 200 L/day (ECHA default) (Ref.1)

D         = factor for dilution of waste water by surface water flow

= 10 (ECHA default) (Ref.1)

(Note: The factor 10⁹ converts the quantity used from kg to μg)

Metabolism and excretion

Following oral administration acalabrutinib is rapidly adsorbed, the time to peak plasma concentrations (Tmax) was 0.5-1.5 hours for acalabrutinib, and 1.0 hour for ACP5862. The absolute bioavailability of Calquence was 25%. In vitro, acalabrutinib is predominantly metabolised by CYP3A enzymes, and to a minor extent by glutathione conjugation and amide hydrolysis. ACP-5862 was identified as the major metabolite in plasma, that was further metabolized primarily by CYP3A-mediated oxidation, with a geometric mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition.  Following administration of a single 100 mg radiolabelled [14C]-acalabrutinib dose in healthy subjects, 84% of the radioactivity was recovered in the faeces and 12% in the urine, with less than 1% of the dose excreted as unchanged acalabrutinib (Ref 2).

Ecotoxicity Data

Study	Method	Result	Reference
Activated sludge, respiration inhibition test	OECD 209	3 hour NOEC = 1000 mg/L 3 hour LOEC > 1000 mg/L 3 hour EC50 >1000 mg/L	3
Toxicity to green algae, Pseudokirchneriella subcapitata,	OECD 201	72 hour NOEC = 2.7 mg/L 72 hour EC10 (growth) = 26 mg/L 72 hour EC50 (growth) > 41 mg/L 72 hour EC50 (biomass) = 29mg/L	4
Chronic toxicity to Daphnia magna	OECD 211	21 day NOEC = 1.2 mg/L 21 day LOEC = 2.7 mg/L (rate of first brood generation)	5
Fish Early-Life Stage toxicity with Pimephales promelas,	OECD 210	32 day NOEC = 3.8 mg/L 32 day LOEC > 3.8 mg/L	6
Acute toxicity test with the cladoceran (Daphnia magna)	OECD 202	NOEC = 35 mg mg/L LOEC > 35 mg mg/L 48-Hour EC50 >35 mg	7
Sediment toxicity test with Chironomus riparius	OECD 218	28-Day NOEC = 461 mg/kg 28-Day LOEC = 244 mg/kg 28-Day EC50 (emergence) = 715 mg/kg	8

NOEC   No Observed Effect Concentration

LOEC   Lowest Observed Effect Concentration

EC₅₀     the concentration of the test substance that results in a 50% effect

Predicted No Effect Concentration (PNEC)

Long-term tests have been undertaken for species from three trophic levels. Therefore, the PNEC is based on the chronic toxicity to Daphnia magna,1.2 mg/L (equivalent to 1200 µ/L), and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref.9)

PNEC = 1200 / 10 = 120 µg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC = 0.00024µg/L /120µg/L = 0.000002

PEC/PNEC = 0.000002

The PEC/PNEC ratio informs the wording of the aquatic environmental risk phrase.The risk phrase for PEC/PNEC = 0.000002 reads as follows;

Use of Acalabrutinib has been considered to result in insignificant environmental risk.

In Swedish: Användning av Acalabrutinib har bedömts medföra försumbar risk för miljöpåverkan.”

Environmental Fate Data

Study	Method	Result		Reference
Biodegradation in activated sludge	OECD 314B	Parent DT50 = 0.711 days Parent DT90 = 3.3 days After 28 days the applied radioactivity was associated as follows: 49.3% = single major transformation product 37.6% = non-extractable residues 3.58% = evolved CO2 5.3% = parent acalbrutinib		10
Adsorption/desorption to sediments, soils and sludge	OECD 106	Sludge Kd(ads) sludge KOC(ads) sludge HOM sediment Kd(ads) KOC(ads) LOM sediment Kd(ads) KOC(ads) HOM soil Kd(ads) KOC(ads) LOM soil Kd(ads) KOC(ads)	= 1.74×102 L/kg (n=2) = 5.05×102 L/kg (n=2) = 5.91×103 L/kg = 1.37×105 L/kg = 4.79×102 L/kg = 1.20×105 L/kg = 2.99×104 L/kg = 8.79×105 L/kg = 1.47×104 L/kg = 1.84×106 L/kg	11
Aerobic transformation in aquatic sediment systems	OECD 308	HOM total system DT50 DT50 [12°C*] LOM total system DT50 DT50 [12°C*] HOM water phase DT50 DT50 [12°C*] LOM water phase DT50 DT [12°C*]	= 14 days = 29 days = 28 days = 59 days = 4.3 days = 9.1 days = 13 days = 28 days	12

HOM    high organic matter

LOM     low organic matter

* DT50 values at 12°C calculated utilising the Arrhenius equation; study conducted at 20°C.

Biodegradation

The aerobic biodegradation of acalabrutinib was assessed according to the OECD 314B Test Guideline over 28 days. At the end of this study, 49.3% of the dosed radioactivity was associated with a single transformation product; 37.6% dosed radioactivity was associated with non-extractable residues in solids, 3.58% was mineralized to CO₂ and 5.30% dosed radioactivity remained as parent.  Acalabrutinib degradation followed double first order in parallel kinetics and DT₅₀ and DT₉₀ values were calculated to be 0.711 and 3.33 days respectively.

Based on this data and the K_OCsludge(ads) of 505 L/kg (observed in an OECD106 study, Ref 12) acalabrutinib is not expected to adsorb significantly to sludge solids, but is expected to be degraded and removed efficiently under waste water treatment.

The degradation of acalabrutinib in aquatic sediment systems was assessed according to the OECD 308 Test Guideline (8) in a high and a low organic matter content system over a 100-day test period.

Acalabrutinib was found to dissipate from the water phase into the sediment in both high and low organic carbon systems. The water DT50s in the high and low organic carbon systems were 3.5 days and 5.8 days, respectively. Residue observed in the sediment increased over the course of the study (maxima reached on days 28 and 100 in high and low organic carbon sediments, respectively).  A single metabolite was transiently detected at levels >10% AR in the low organic sediment (10.7% AR at day 7). Minimal mineralization was observed with radio activity found in CO₂ traps accounting for between 1.7-2.4% of applied radioactivity (AR).

At the end of the study, 28.1% (none of which in water) of acalabrutinib parent remaining was observed in the high organic matter system and 20.2% (1.7% in water + 18.5% in sediment extracts) of acalabrutinib parent remaining was observed in the low organic matter system. Total system DT50s for acalabrutinib were 14 days and 28 days in high and low organic matter systems, respectively.

Based on these findings, the following phrase is therefore assigned: Acalabrutinib is slowly degraded in the environment.

In Swedish: Acalabrutinib bryts ned långsamt i miljön.

Physical Chemistry Data

Study	Method	Result	Reference
Water solubility		70 mg/L at pH 6.8 and 25oC	13
Octanol/water partition coefficient	OECD 107	LogDOW = 1.29 ± 0.013 at pH 5 LogDOW = 1.96 ± 0.013 at pH 7 LogDOW = 1.99 ± 0.0076 at pH 9	14

Acalabrutinib is ionisable, therefore the octanol-water distribution coefficient, Log D_ow, was determined across an environmentally relevant pH-range. The log Dow values are <4.5 (1.29, 1.96 and 1.99 at pH 5, 7 and 9 respectively) which justifies the use of the following statement: Acalabrutinib has low potential for bioaccumulation.

In Swedish: Acalabrutinib har låg potential att bioackumuleras.

References

1. [ECHA] European Chemicals Agency.  Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0). February 2016. http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

2. Calquence 100 mg hard capsules – SUMMARY OF PRODUCT CHARACTERISTICS. https://www.ema.europa.eu/en/documents/product-information/calquence-epar-product-information_en.pdf Accessed February 2023.   

3. Acalabrutinib: an activated sludge, respiration inhibition test. EAG Laboratories Project no.: 123E-116. August 2019.

4. Acalabrutinib: a 72-hour toxicity test with the freshwater alga (Raphidocelis Subcapitata) Eurofins EAG Agroscience, LLC Final Report 123P-104. August 2019

5. Acalabrutinib: a semi-static life-cycle toxicity test with the cladoceran (Daphnia magna) Eurofins EAG Agroscience, LLC Report 123A-121A. August 2019.

6. Acalabrutinib: an early life-stage toxicity test with the fathead minnow (Pimephales promelas) EAG Laboratories Report 123A-122. December 2018.

7. Acalabrutinib: a 48-hour static acute toxicity test with the cladoceran (Daphnia magna) Eurofins EAG Agroscience, LLC Report 123A-120 August 2019.

8. Acalabrutinib: a prolonged sediment toxicity test with the midge (Chironomus riparius) using spiked sediment. Eurofins EAG Agroscience, LLC. Report 123A-123. October 2019.

9. ECHA, European Chemicals Agency. May 2008. Guidance on Information Requirements and Chemical Safety Assessment.  Chapter R.10: Characterisation of dose [concentration]-response for environment http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

10. Acalabrutinib: biodegradation in activated sludge. EAG, Inc. Report 123E-122. July 2019

11. Acalabrutinib: adsorption/desorption characteristics in representative soils, sediments, and activated sludge solids. EAG Laboratories Report 123E-118. July 2019

12. Acalabrutinib: aerobic transformation in aquatic sediment systems Eurofins EAG Agroscience, LLC Report 123E-120 August 2019.

13. S.1.3 General Properties – Acalabrutinib. Version 1.0 19 March 2018. Doc ID-003771967.

14. Determination of the n-octanol/water partition coefficient of acalabrutinib by the shake flask method. Wildlife International (EAG Laboratories) Report 123C-118. April 2017