Detaljerad miljöinformation

PEC/PNEC = 27 μg/L /320 μg/L

PEC/PNEC = 0.08

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) = 1.5*10^-6*A*(100-R)

A (kg/year) = <200000 kg = maximum annual forecast total amount of API sold in Sweden over the next 5 years. (Note: sales data are confidential information, therefore for the purposes of the calculation the kg of sales quoted reflects the maximum sales to achieve a risk classification of insignificant environmental risk, however forecast sales are several orders of magnitude below this value.)

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation). R = 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 L/day (ECHA default) (Ref.1)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Ref.1) (Note: The factor 10⁹ converts the quantity used from kg to μg)

PEC = 1.37 * 10^-6 * 200000 *(100-R) = 27 µg/L

Metabolism and excretion

Capivasertib is primarily metabolised by CYP3A4 and UGT2B7 enzymes. No active metabolites have been identified. Following single oral dose of 400 mg, the mean total recovery of radioactive dose was 45% from urine and 50% from faeces. Renal clearance was 21% of total clearance. Capivasertib is therefore primarily eliminated by metabolism. (Ref. 2).

Ecotoxicity Data

Study Type	Method	Result	Reference
Toxicity to green algae, Pseudokircheriella subcapitata, growth inhibition test	OECD 201	72 hour NOEC (growth rate) = 27mg/L 72 hour EC10 (growth rate) = 39mg/L 72 hour NOEC (biomass) = 27mg/L 72 hour EC10 (biomass) = 23mg/L	4
Activated sludge, respiration inhibition test	OECD 209	3 hour NOEC = 1000mg/L 3 hour EC50 >1000mg/L	5
Chronic toxicity to Daphnia magna	OECD 211	21 day LOEC (survival, reproduction and growth) >11mg/L 21 day NOEC (survival, reproduction and growth) = 11mg/L	6
Fish Early-Life Stage Toxicity with Pimephales promelas,	OECD 210	32 day LOEC (hatch, survival, growth) = 10mg/L 32 day NOEC (hatch, survival, growth) = 3.2mg/L	7
Toxicity to Chironomus riparius	OECD 218	28 day NOEC (total emergence, development rate, sex ratio) = 893mg/kg dry weight 28 day LOEC (total emergence, development rate, sex ratio > 893mg/kg dry weight	8

NOEC      No Observed Effect Concentration

LOEC       Lowest Observed Effect Concentration

ECx          the concentration of the test substance that results in a x% (e.g. EC50 = 50%) effect

LC50       the concentration of the test substance that results in a 50% mortality

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 Pimephales promelas, 3.2 mg/L, and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref.3)

PNEC = 3200 μg/L /10 = 320 µg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC = 27 μg/L /320 μg/L

PEC/PNEC = 0.08

The PEC/PNEC ratio decides the wording of the aquatic environmental risk phrase, and the risk phrase for PEC/PNEC = 0.08 reads as follows; Use of capivasertib has been considered to result in insignificant environmental risk.

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

Environmental Fate Data

Study Type	Method	Result	Reference
Hydrolysis	OECD 111	<10 % (120 hours) at pH 4, 7 and 9 Hydrolytically stable	9
Aerobic biodegradation	OECD 314B	DT50(parent) = 0.15 days, DT90(parent) = 0.49 days 26.9% mineralisation over 28 days	10
Adsorption/ desorption to two sludges, two sediments and two soils	OECD 106	Adsorption - Kd(ads) / KOC(ads) [L/kg] Silty Clay Loam soil (HOC) 9.94×102/ 2.11×104 Loamy Sand soil (LOC) 3.63×103/ 4.53×105 Loam sediment (HOC) 1.35×103/ 2.33×104 Sand sediment (LOC) 22.7 / 3.78×103 ASS, Denton sludge 2.34×102/ 7.02×102 ASS, Easton sludge 3.62×102/ 1.07×103 Desorption - Kd(des) / KOC(des) [L/kg] Silty Clay Loam soil (HOC) 1.32×103/ 2.80×104 Loamy Sand soil (LOC) 3.77×103/ 4.71×105 Loam sediment (HOC) 1.36×102/ 2.35×104 Sand sediment (LOC) 56.0 / 9.34×103 ASS, Denton sludge 3.44×102/ 1.03×103 ASS, Easton sludge 5.64×102/ 1.67×103	11
Aerobic transformation in aquatic sediment systems	OECD 308	Total system and water DT50 values are presented at 20°C and corrected to 12°C. Half-lives at 20°C: HOC DT50 water = 2.9 days LOC DT50 water = 4.6 days HOC DT50 total system = 9.5 days LOC DT50 total system = 15 days Half-lives at 12°C*: HOC DT50 water = 6.2 days LOC DT50 water = 9.8 days HOC DT50 total system = 20 days LOC DT50 total system = 31 days	12

Kd     Distribution coefficient for adsorption 

Koc   Organic carbon normalized adsorption coefficient

HOC High organic carbon system

LOC Low organic carbon system

Biodegradation

While not classed as readily biodegradable, significant primary and secondary degradation occurred in the OECD 314B study, indicating capivasertib is expected to be effectively removed during sewage treatment. Any remaining capivasertib passing to the aquatic environment is expected to be hydrolytically stable.

The OECD 308 study indicated capivasertib will degrade in the aquatic environment with a share of the residue found to partition into the sediment phase. Mean material balances (recoveries) ranged from 92.0% to 104.3% in the HOC system (within the acceptable range of 90% to 110% throughout the study) and in the LOC system mean material balances ranged from 73.8% to 100.2% (acceptable through day 21 but <90% on days 56 and 100). The cause of the low recoveries could not be confirmed but may have been caused by volatile transformation products that were either not captured in the gas traps or escaped during sediment extraction. The mean cumulative amounts of mineralization observed over the 100-day test period were 6.64% (HOC) and 6.32% (LOC), respectively. The test substance dissipated from the water layers of both test systems primarily by partitioning to the sediment layers. The mean amount of 14 C-residue observed in the sediment layers (i.e. sediment extracts + sediment solids) increased during the study to maximums of 89.0% (HOC on day 10) and 68.1% (LOC on day 21). The fractions of radiolabelled residues that could not be extracted from the sediment layers at the end of the test were 73.2% and 42.1%, respectively. Supplemental extractions were performed on the previously extracted sediment solids collected on days 10 and 100 using solvents with a range of dielectric constants. Each of these solvents extracted <7% of additional ¹⁴C.

In addition to capivasertib, eight distinct HPLC ROIs (regions of interest) indicating transformation products (TPs) were observed and quantified in the study. Two TPs (TP Region 2 and TP Region 4) accounted for maxima of 19.1% and 9.6% AR, respectively, and were observed to be forming and declining within the time course of the study (in one or both systems), suggesting they were transient rather than terminal metabolites. All other individual transformation product peaks were <5%. No attempt was made to identify any of the transformation products observed in this study, as the total residue approach is applied in this assessment.

The DT50 of both the low and high organic carbon total systems are below 32 days, and less than 15% unaltered parent were remaining at the end of the study (0.7% and 5.7% in HOC and LOC systems, respectively). The following degradation statement has therefore been assigned; Capivasertib is degraded in the environment

In Swedish: Kapivasertib bryts ned i miljön.

Physical Chemistry Data

Study Type	Method	Result	Reference
Octanol-Water Partition Coefficient	OECD 107	LogDOW at pH 5 = 1.28 LogDOW at pH 7 = 0.014 LogD OW at pH 9 = 0.013	13
Water solubility	OECD 105	pH 5 = 1.87 mg/L pH 7 = 0.151 mg/L pH 9 = 0.135 mg/L	14

The measured octanol-water partition coefficient at pH 7 is below 4, therefore the following bioaccumulation phrase is assigned; Capivasertib has low potential for bioaccumulation.

In Swedish: Kapivasertib 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. Truqap : EPAR - Product information. First published: 11/07/2024. Accessed: 20/08/2024. www.ema.europa.eu/en/documents/product-information/truqap-epar-product-information_en.pdf

3. 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

4. Capivasertib: a 72-hour toxicity test with the freshwater alga (raphidocelis subcapitata). Study number 123P-105. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. June 2020

5. Capivasertib: an activated sludge, respiration inhibition test. Study number 123E-124. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. October 2019.

6. Capivasertib: a semi-static life-cycle toxicity test with the cladoceran (daphnia magna). Study number 123A-127. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. January 2020

7. Capivasertib: an early life-stage toxicity test with the fathead minnow (pimephales promelas). Study number 123A-128. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. June 2020

8. Capivasertib:a prolonged sediment toxicity test with the midge (chironomus riparius) using spiked sediment. Study number: 123A-129. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. March 2023.

9. Capivasertib: an evaluation of hydrolysis as a function of pH. Study number: 123E-123. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. January 2022.

10. Capivasertib: biodegradation in activated sludge. Study number: 123E-130. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. April 2022.

11. Capivasertib: adsorption/desorption characteristics in representative soils, sediments, and activated sludge solids. Study number 123E-126. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. March 2021.

12. Capivasertib: aerobic transformation in aquatic sediment systems. Study number 123E-128. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. February 2021.

13. Determination of the n-octanol/water partition coefficient of capivasertib by the shake flask method. Study number 123K-105. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. January 2020

14. Capivasertib: determination of water solubility by the shake flask method. Study number 123K-106. Eurofins EAG Agroscience, LLC. Easton, Maryland, USA. November 2019.