Detaljerad miljöinformation

PEC/PNEC = 0.0019 μg/L /32 mg/L = 0.000059

PEC/PNEC ≤ 0.1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is based on following data:

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

PEC (µg/L) = 1.37*10^-6*A*(100-R)

A (kg/year) = 13.87 kg; total sold amount API in Sweden year 2020, data from IQVIA.

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

hydrolysis or biodegradation) = 0.

P = number of inhabitants in Sweden = 10 x 10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default)

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

PEC = 1.37 * 10^-6 * 13.87 * (100-0) = 0.0019 mg/L

(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 oral administration olaparib is rapidly adsorbed and metabolised by dehydrogenation and oxidation, in addition to glucuronide and sulphide conjugation. The majority of the dose is excreted via the faeces (42 %) and urine (44 %) with the main component of the excreted component being unchanged drug (accounting for approximately 21 % of the dose), Ref 1. A total of 36 metabolites were also identified.

Ecotoxicity data

Study Type	Method	Result	Reference
Toxicity to green algae, Pseudokirchinella subcapitata, growth inhibition test	OECD201	72 h EC50 (growth rate) > 83 mg/L 72 h NOEC (growth rate) = 83 mg/L	2
Long-term toxicity to the giant water flea (crustacean), Daphnia magna	OECD211	21 d LOEC (reproduction, survival, length) = 1.0 mg/L 21 d NOEC (reproduction, survival, length) = 0.32 mg/L	3
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	4
Long-term toxicity to the sediment dwelling midge, 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	5

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 results from the chronic toxicity to fathead minnow (Pimephales promelas), the most sensitive species, and an assessment factor of 10 is applied, in accordance with ECHA guidance (ref. 6).

PNEC = 0.32 mg/L /10 = 32 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC = 0.0019 mg/L

PNEC = 32 mg/L

PEC/PNEC = 0.000059

A PEC/PNEC ratio ≤ 0.1 justifies 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

Study Type	Method	Result	Reference
Aerobic biodegradation	OECD301F	<6% biodegradation Not readily biodegradable	7
Adsorption/desorption to sewage sludge	OPPTS 835.1110	Kdsludge(ads) = 25 L/Kg	8
Adsorption/desorption to two sediments	OECD106	High carbon sediment Kd = 111 L/Kg Koc = 1986 L/Kg Low carbon sediment Kd = 3.8 L/Kg Koc = 27487 L/Kg	9
Aerobic transformation in aquatic sediment systems	OECD308	The dissipation half-lives from 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 any degradation in either sediment and specific half-lives could not be calculated. Radio-TLC and mass spectrometry analysis confirmed the presence of olaparib in both the overlying waters and the sediment extracts and no metabolites >10% were observed.	10

Biodegradation

The aerobic biodegradation of olaparib (Ref 7) was assessed according to guideline

OECD 301F. Percentage degradation was calculated as (BOD/ThOD) × 100. The results 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 10) 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

Study Type	Method	Result	Reference
Water solubility	OECD105	pH 5 = 90.9 mg/L pH 7 = 75.3 mg/L pH 9 = 82.4 mg/L	11
Hydrolysis	OECD111	<10 % (120 hours) at pH 5, 7 and 9 Hydrolytically stable	12
Octanol-water distribution coefficient	OECD107	Log Pow = 1.55 at pH7	13

 

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. Deeks, E., 2015. Olaparib: First Global Approval. Drugs  75:231–240

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

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

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

5. [14C] AZD2281: Determination of the effects in a water sediment system on the emergence of Chrionomus riparius using spiked sediment. November 2010. Brixham Environmental Laboratory, Brixham, UK. Report Number BL8660/B

6. ECHA 2008 Guidance on information requirements and chemical safety assessment Chapter R.10: Characterisation of dose [concentration]-response for environment. https://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf/bb902be7-a503-4ab7-9036-d866b8ddce69

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

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

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

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

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

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

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