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AstraZeneca

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Miljöpåverkan (Läs mer om miljöpåverkan)

Olaparib

Miljörisk: Användning av olaparib har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Olaparib är potentiellt persistent.
Bioackumulering: Olaparib har låg potential att bioackumuleras.


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Detaljerad miljöinformation

PEC/PNEC = 0.0012 μg/L /32 μg/L = 0.000038

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


A (kg/year) = 7.9 kg; total sold amount API in Sweden year 2016, data from QuintilesIMS.

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

hydrolysis or biodegradation) = 0.

P = number of inhabitants in Sweden = 9 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 = 1.5 * 10-6 * 7.9 * (100-0) = 0.0012 µg/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 = 0.0012 μg/L

PNEC = 32 μg/L


PEC/PNEC = 0.000038


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

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