Detaljerad miljöinformation

PEC/PNEC = 0.0068 µg/L / 32 μg/L = 2.1x10^-4

PEC/PNEC ≤ 0.1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is based on the following data and calculated using the equation outlined in the fass.se guidance (Ref 1):

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 * 49.5236 * (100-0)

= 0.0068 µg/L

A (kg/year) = total sold amount API in Sweden year 2023, data from IQVIA/Lif = 49.5236 kg

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization,

hydrolysis or biodegradation) = 0 (default)

P = number of inhabitants in Sweden = 10 x 10⁶ (default, Ref 1)

V (L/day) = volume of wastewater per capita and day = 200 (default, Ref 1)

D = factor for dilution of wastewater by surface water flow = 10 (default, Ref 1)

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

(Note: Whilst olaparib is extensively metabolised in humans, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for the purpose of this calculation, it is assumed that 100% of excreted metabolites have the same ecotoxicity as parent olaparib.)

Metabolism and excretion

Following administration, 86% of the drug related material is recovered in the urine (approximately 44%) and faeces (approximately 42%). Analyses of excreta showed that up to 19% is typically excreted as unaltered parent and the major share of the dose is excreted as multiple metabolites (Ref 2).

Ecotoxicity data

Study Type	Method	Result	Ref
Activated sludge, respiration inhibition test	OECD209	3 h EC50 >100 mg/L 3 h NOEC = 100 mg/L	3
Toxicity to green algae, Pseudokirchneriella subcapitata, growth inhibition test	OECD201	72 h EC50 (growth rate) > 83 mg/L 72 h NOEC (growth rate) = 83 mg/L	4
Acute toxicity to Daphnia magna	OECD202	48 h EC50 > 74 mg/L 48 h NOEC = 74 mg/L	5
Long-term toxicity to Daphnia magna	OECD211	21 d LOEC (reproduction, survival, length) = 1.0 mg/L 21 d NOEC (reproduction, survival, length) = 0.32 mg/L	6
Fish early-life stage toxicity with fathead minnow, Pimephales promelas	OECD210	32 d LOEC (hatch, survival, length and weight) = 1.0 mg/L 32 d NOEC (hatch, survival, length and weight) = 0.32 mg/L	7
Long-term toxicity to Chironomus riparius	OECD218	28 d LOEC (development rate, total emergence, sex ratio) = 1.25 mg/kg dry weight 28 d NOEC (development rate, total emergence, sex ratio) = 0.6 mg/kg dry weight	8
Long-term toxicity to Hyalella azteca	U.S EPA 600/R-99/064	28 d LOEC (survival, growth) > 89.6mg/kg 28 d NOEC (survival, growth) = 89.6mg/kg	9
Long-term toxicity to Lumbriculus variegatus	OECD225	28 d EC50 (survival, reproduction, growth) > 86mg/kg 28 d LOEC (survival, reproduction, growth) > 86mg/kg 28 d NOEC (survival, reproduction, growth) = 86mg/kg	10

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

NOEC no observed effect concentration

LOEC lowest observed effect concentration

PNEC (Predicted No Effect Concentration)

Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the lowest NOEC value 0.32 mg/L (equivalent to 320 µg/L) which was reported for both Pimephales promelas and Daphnia magna, and an assessment factor of 10 is applied in accordance with ECHA guidance (Ref 11).

PNEC = 0.32 mg/L / 10 = 32 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC = 0.0068 µg/L

PNEC = 32 µg/L

PEC/PNEC = 2.1x10^-4

A PEC/PNEC ratio ≤ 0.1 justifies use of the phrase:

‘Use of olaparib has been considered to result in insignificant environmental risk.’

In Swedish: ‘Användning av olaparib har bedömts medföra försumbar risk för miljöpåverkan.’ under the heading “Miljörisk”.

Environmental fate data for olaparib

Study Type	Method	Result	Ref
Aerobic biodegradation	OECD301F	<6% biodegradation Not readily biodegradable	12
Adsorption/desorption to sludge	OPPTS guideline 835.1110	Kdsludge(ads) = 25 L/Kg	13
Adsorption/desorption to two sediments	OECD106	High carbon, mean Kd = 111 L/Kg KOC = 1986 L/Kg Low carbon, mean Kd = 3.8 L/Kg KOC = 27487 L/Kg	14
Aerobic transformation in aquatic sediment systems	OECD308	HOM total system DT50 = 260 days DT50 (12°C)* = 551 days LOM total system DT50 = 251 days DT50 (12°C)* = 534 days HOM water phase DT50 = 4.2 days DT50 (12°C)* = 8.96 days LOM water phase DT50 = 7.1 days DT50 (12°C)* = 15.0 days	15

*DT50 values at 12^oC were calculated using the Arrhenius equation

Biodegradation

The aerobic biodegradation of olaparib (Ref 12) was assessed according to guideline

OECD 301F. The results of this study showed that olaparib is not readily biodegradable (Day 28 <6% degradation).

Transformation in aquatic sediment systems

The degradation of olaparib in aquatic sediment systems (Ref 15) was assessed according to the OECD 308 Test Guideline. In this test two different sediments were used, one with high organic matter (HOM) and one with low organic matter content (LOM). Radiolabelled test substance was dosed into the overlying water and the subsequent dissipation from the water phase and partitioning and/or degradation in the sediment was observed over a 99-day test period.

In both the high and low organic matter sediment systems, rapid dissipation of olaparib was observed. By Day 7, 70% and 56% of the applied radioactivity had partitioned to the high and low organic matter sediments, respectively. This increased to approximately 90% of the applied radioactivity at Day 99 in both systems. Greater than 60% of the partitioned material was extractable from the sediment using methanol and acetonitrile. Analysis by radio-TLC identified the extracted material as olaparib; this was confirmed by mass spectrometry.

Radio-TLC analysis of the overlying waters identified only olaparib. The dissipation half-lives from the overlying water were calculated as 4.2 days and 7.1 days for the high and low organic matter vessels, respectively. There was no evidence of degradation or dissipation in the sediment phase and specific half-lives could not be calculated. No metabolites >10% were observed in either the overlying waters or sediment extracts. There was no significant mineralisation throughout the study.

Based on the data above, the phrase ‘Olaparib is potentially persistent’ is chosen.

In Swedish: “Olaparib är potentiellt persistent” under the heading “Nedbrytning”.

Physical chemistry data for olaparib

Study Type	Method	Result	Ref
Octanol-water distribution coefficient	OECD107	Log Pow = 1.55 at pH 7	16
Water solubility	OECD105	pH 5 = 90.9 mg/L pH 7 = 75.3 mg/L pH 9 = 82.4 mg/L	17
Hydrolysis	OECD111	<10 % (120 hours) at pH 5, 7 and 9 Hydrolytically stable	18

 

Bioaccumulation

Since Log P < 4 at pH 7, the substance has been assigned the phrase: ‘Olaparib has low potential for bioaccumulation’.

In Swedish: “Olaparib har låg potential att bioackumuleras” under the heading “Bioackumulering”.

References

1. Fass.se (2012).  Environmental classification of pharmaceuticals at www.fass.se: Guidance for pharmaceutical companies https://www.fass.se/pdf/Environmental_classification_of_pharmaceuticals-120816.pdf

2. Investigator’s Brochure. Olaparib (AZD2281, KU-0059436) AstraZeneca. Edition 22.0. January 2023.

3. AZD2281: Effect on the respiration rate of activated sludge. November 2007.  Brixham Environmental Laboratory, Brixham, UK. Report Number BL8490/B.

4. AZD2281: Toxicity to the green alga Pseudokirchneriella subcapitata. June 2008. Brixham Environmental Laboratory, Brixham, UK.  Report Number BL8588/B.

5. AZD2281: Acute toxicitiy to Daphnia magna. July 2008. Brixham Environmental Laboratory, Brixham, UK. Report No BL8600/B.

6. AZD2281: Determination of the effects on survival and reproduction of Daphnia magna.  May 2011.  Brixham Environmental Laboratory, Brixham, UK.  Report Number BL8690/B.

7. AZD2281: Determination of effects on the Early-Life Stage of the fathead minnow (Pimephales promelas). March 2009.  Brixham Environmental Laboratory, Brixham, UK. Report Number BL8623/B.

8. [¹⁴C] AZD2281: Determination of the effects in a water sediment system on the emergence of Chironomus riparius using spiked sediment. November 2010. Brixham Environmental Laboratory, Brixham, UK.  Report Number BL8660/B.

9. Olaparib (CAS #763113-22-0): A 28-day test with the freshwater amphipod (Hyalella azteca) using spiked sediment. November 2019. Eurofins EAG Agroscience, LLC. Easton, USA. Study number 123A-125.

10. Olaparib (CAS #763113-22-0): A prolonged sediment toxicitiy test with Lumbriculus variegatus using spiked sediment. November 2019. Eurofins EAG Agroscience, LLC. Easton, USA. Study number 123A-124.

11. ECHA (European Chemicals Agency) 2008. Guidance on information requirements and chemical safety assessment.  Chapter R.10: Characterisation of dose [concentration]-response for environment

12. AZD2281: Determination of 28 day ready biodegradability. December 2007.  Brixham Environmental Laboratory, Brixham, UK.  Report Number BL8523/B.

13. AZD2281: Activated sludge sorption isotherm. August 2008. Brixham Environmental Laboratory, Brixham, UK. Report Number BL8613/B.

14. Olaparib: Adsorption/desorption to two sediments. July 2013. Brixham Environmental Laboratory, Brixham, UK.  Report Number BR0835/B.

15. AZD2281: Aerobic transformation in aquatic sediment systems. May 2009. Brixham Environmental Laboratory, Brixham, UK. Report Number BL8593/B.

16. AZD2281: Determination of n-octanol/water partition coefficient. December 2007.  Brixham Environmental Laboratory, Brixham, UK.  Report Number BL8475/B.

17. AZD2281: Water solubility. October 2007. Brixham Environmental Laboratory, Brixham, UK. Report Number BL8474/B.

18. AZD2281: Hydrolysis as a function of pH – Preliminary study.  September 2007.  Brixham Environmental Laboratory, Brixham, UK.  Report Number BL8478/B.