Detaljerad miljöinformation

PEC/PNEC = 0.029

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 *15.8483*(100-0)

= 0.0022 µg/L

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

= 15.8483kg

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 L/day (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 osimertinib is known to be metabolised in the body, the ecotoxicity of the metabolites has not been studied.  Hence, this calculation assumes that the excreted metabolites combined have the same ecotoxicity as parent osimertinib.)

Metabolism and excretion

Osimertinib is adsorbed and extensively metabolised in patients. Following intravenous and oral administration, the dose is largely excreted in faeces (~ 68%) and to a lesser extent urine (~14%).  Unchanged osimertinib accounted for approximately 2% of the total elimination with 0.8% in urine and 1.2% in faeces (Ref 2).

Ecotoxicity Data

Study Type	Method	Result	Ref
Activated sludge, respiration inhibition test	OECD209	3 hour NOEC = 31.25 mg/L 3 hour EC50 ≥ 320 mg/L	3
Toxicity to green algae, Pseudokirchneriella subcapitata, growth inhibition test	OECD201	72 hour NOEC (growth rate) =0.014 mg/L 72 hour LOEC (growth rate) =0.076 mg/L 72 hour EC50 (growth rate) = 0.23 mg/L 72 hour NOEC (biomass) = 0.014 mg/L 72 hour LOEC (biomass) = 0.076 mg/L 72 hour EC50 (biomass) = 0.047 mg/L	4
Acute toxicity to the giant water flea, Daphnia magna	OECD202	48 hour EC50 (immobility) = 1.5 mg/L 48 hour LOEC (immobility) = 1.2mg/L 48 hour NOEC (immobility) = 0.61mg/L	5
Chronic toxicity to the giant water flea, Daphnia magna	OECD211	21 day LOEC (survival and growth) = 0.10 mg/L 21 day NOEC (survival and growth) = 0.026 mg/L	6
Fish Early-Life Stage Toxicity with fathead minnows, Pimephales promelas	OECD210	32 day LOEC (growth) = 0.0027 mg/L 32 day NOEC (growth) = 0.00075 mg/L	7
Toxicity to the sediment dwelling midge, Chironomus riparius	OECD218	28 day NOEC (total emergence, development rate, sex ratio) = 79 mg/kg dry weight 28 day LOEC (total emergence, development rate, sex ratio) > 79 mg/kg dry weight	8
Acute toxicity to the Earthworm, Eisenia fetida	OECD207	14 day LC50 > 1000mg/kg NOEC = 1000 mg/kg 9	9
Reproductive toxicity to Collembola, Folsomia candida	OECD232	EC50 = 87.5 mg/kg dry soil NOEC = 53 mg/kg dry soil LOEC = 96 mg/kg dry soil	10
Soil Nitrogen Transformation Test	OECD216	28 day LOEC > 75.5 µg/kg dry soil 28 day NOEC = 75.5 µg/kg dry soil	11
Seedling emergence and growth test	OECD208	LOEC > 0.4 µg/kg dry soil NOEC = 0.4 mg/kg dry soil	12

NOEC No Observed Effect Concentration

LOEC Lowest Observed Effect Concentration

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

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

Predicted No Effect Concentration (PNEC)

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 No Observed Effect Concentration (NOEC) 0.00075 mg/L (equivalent to 0.75 µg/L) which was reported for fathead minnows in the fish early life-stage test, and an assessment factor of 10 is applied, in accordance with EMA guidance (Ref 13).

PNEC = 0.75 µg/L / 10 = 0.075 µg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC = 0.0022 µg/L

PNEC = 0.075 µg/L

PEC/PNEC = 0.029

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

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

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

Environmental Fate Data

Study Type	Method	Result	Ref
Biodegradation in activated sludge	OECD 314B	Degradation followed first-order kinetics;  Biotic DT50 = 2.8 days Abiotic DT50 = 1.1 days There was extensive association of the radioactivity with the sludge solids with no significant formation of 14CO2 One degradation product, present in both biotic and abiotic samples, accounted for greater than 10% of the applied radioactivity	14
Aerobic transformation in aquatic sediment systems	OECD308	Rapid dissipation from the water phase, aqueous phase dissipation half-life < 1 day in both test systems. The disappearance half-lives for the total system in the high and low organic carbon sediments were 1 and 3 days, respectively. DT50 in the sediment phase, first-order kinetics, was in the range 9-16 days	15
Adsorption coefficients to soils, sediments and active sewage sludge	OECD106	Soils: Empingham(pH 7.6, 3.6% OC)  Kd = 3702 L/Kg; Koc = 102830 L/Kg Warsop(pH 4.1, 0.7% OC)  Kd = 5384 L/Kg; Koc = 769189 L/Kg Sediments: Calwich Abbey(pH 7.1, 4.9% OC)  Kd = 9354 L/Kg; Koc = 190886 L/Kg Swiss Lake(pH 5.4, 0.6% OC)  Kd = 6219 L/Kg; Koc =1036439 L/Kg Sewage sludge: Burley Menston(35.8% OC)  Kd = 4784 L/Kg; Koc = 16663 L/Kg	16
Aerobic transformation in soil	OECD307	DT50 = 0.04 – 2.3 days (range of four soils)	17

DT50 Degradation half-life

OC Organic Carbon

Kd Distribution coefficient for adsorption

Koc Organic carbon normalized adsorption coefficient

Biodegradation

Osimertinib mesylate has been shown to strongly adsorb to sewage sludge, sediments and soils (Ref 16).  The degradation of osimertinib mesylate in activated sludge was assessed in an OECD 314B study (Ref 14), the results show that osimertinib mesylate is rapidly removed and degraded in both the biotic and abiotic test systems.  Degradation rates followed first-order kinetics, and the half-life values of osimertinib mesylate were 2.8 and 1.1 days in the biotic and abiotic sludge, respectively. Although osimertinib mesylate cannot be classified as ‘readily biodegradable’, it is anticipated that osimertinib mesylate will undergo significant removal and primary degradation during wastewater treatment. Predictions using SimpleTreat indicate >98% total elimination in waste water treatment (through biodegradation and sludge removal) based on this experimental data. As such osimertinib mesylate is unlikely to be present in aqueous effluents entering surface waters.

The fate and degradation of ¹⁴C-lablled osimertinib mesylate in water-sediment systems (Ref 15) was assessed in an OECD 308 study.  The applied radioactivity partitioned rapidly to the sediment phase, with dissipation half-lives from the water phase of <1 day for both high and low organic carbon sediments. 

Radioactivity associated with the sediment phase was extracted using two solvent extractions of methanol:water (9:1 v:v) containing 1% ammonia. The radioactivity remaining with the sediment after this extraction was subjected to further solvent extractions, using a range of solvents with differing polarity and pH, however these yielded low recoveries of ≤4% applied radioactivity (AR).  The degradation half-lives of [14C]osimertinib mesylate in the sediments extracts were modelled using first order kinetics and found to be in the range of 9 to 16 days.  Multiple minor degradation products were identified in both sediment systems. Only one degradation product was found to account for >10% of the applied radioactivity.

Reflux extraction of the Day 100 sediment samples yielded a further 10% extraction of the AR. Fractionation of the remaining bound residues showed that the majority of radioactivity was associated with the humin fraction, 25 to 41% AR, demonstrating assimilation of the radioactivity into the organic matter, rendering the residue non re-mobilisable.

Throughout the study mineralization was <4% in both test systems.  The disappearance half-lives (DT50) of osimertinib mesylate in the total system were 1 and 3 days, in the high and low organic carbon sediments respectively.

In the absence of ready and inherent biodegradation studies, the findings of the OECD 308 study are used to assess biodegradability. As the total system DT50 is ≤32d and <15% parent compound remains in both the high and low organic carbon sediment systems at Day 100, the following phrase is assigned: ‘Osimertinib mesylate is degraded in the environment.’

In Swedish: Osimertinibmesilat bryts ned i miljön.

Bioaccumulation

Osimertinib mesylate is an ionisable compound, therefore the octanol/water partition coefficient was determined as a function of pH, across the environmentally relevant pH range.  Since the measured Log Dow values were < 4, osimertinib mesylate is considered to have a low potential to bioaccumulate and the following phrase is assigned:

‘Osimertinib mesylate has low potential for bioaccumulation’.

In Swedish: Osimertinibmesilat har låg potential att bioackumuleras.

Physical Chemistry Data

Study Type	Method	Result	Ref
Water solubility	Not-stated	3.1 mg/mL	18
Disassociation constant	Not-stated	pKa = 9.5 (aliphatic amine) pKa = 4.4 (aniline)	18
Octanol – water partition coefficient	OECD 107	pH 4 log Dow = 1.77 pH 7 log Dow = 2.45 pH 9 log Dow = 2.69	19

References

1. Investigator’s Brochure AZD9291, Osimertinib, TAGRISSO™. Edition Number 8. May 2017 Doc ID-003336986.

2. 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

3. AZD9291 Mesylate: Activated Sludge Respiration Inhibition Test. April 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200658

4. Inhibition of Growth to the Alga Pseudokirchneriella subcapitata. February 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200662

5. Acute toxicity to Daphnia magna AZD9291.  February 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200661

6. Daphnia magna Reproduction Test AZD9291. July 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200660

7. Osimertinib: An early life stage toxicity test with the fathead minnow (Pimephales promelas).  July 2017.  EAG Laboratories Maryland 21601 USA.  Project number: 123A-118A

8. [¹⁴C]AZD9291 Sediment-Water Chironomus riparius Toxicity Test using Spiked Sediment. April 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200668

9. AZD9291 Mesylate Salt: Acute toxicity to the earthworm Eisenia fetida. June 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200971.

10. AZD9291 Mesylate Salt: Determination of the Effects on Reproduction of the Collembolan Folsomia candida. August 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK.  Study Number 3200972.

11. AZD9291 Mesylate Salt: Soil Nitrogen Transformation Test. August 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK.  Study Number 3200969.

12. AZD9291 Mesylate Salt: Seedling Emergence and Growth Test. February 2016. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK.  Study Number 3200970.

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

14. [¹⁴C]AZD9291: Determination of Biodegradation in Activated Sludge. April 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK.  Study Number 3200666.

15. [¹⁴C]AZD9291: Degradation in Water-Sediment Systems under Aerobic Conditions. April 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200667.

16. [¹⁴C]AZD9291: Adsorption/Desorption in Two Soils, Two Sediments and One Sludge. April 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200657

17. [¹⁴C]AZD9291: Aerobic soil metabolism study. May 2016. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200968.

18. S.1.3 General properties: Osimertinib mesylate. Version 1.0. February 2023. VV-RIM-01812710

19. [¹⁴C]AZD9291: Distribution coefficient at three pH values. March 2015. Smithers Viscient (ESG) Ltd. Harrogate, Yorkshire, UK. Study Number 3200664.