Detaljerad miljöinformation

PEC = 0.00068 µg/L

PNEC = 0.075 µg/L

PEC/PNEC = 0.0091

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) = 1.37*10^-6*A*(100-R)

Where;

A (kg/year) = 4.96 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). R = 0, this provides a worst-case surface water exposure estimate.

P = number of inhabitants in Sweden = 10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 L/day (Ref 7)

D = factor for dilution of waste water by surface water flow = 10 (Ref 7)

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

PEC = 1.37 * 10^-6 *0.743*(100-0) = 0.00068 µg/L

Metabolism and excretion

Following oral administration osimertinib mesylate is adsorbed and extensively metabolised. After a single oral dose of 20 mg, 67.8% of the dose was recovered in faeces while 14.2% of the administered dose was found in urine. Unchanged osimertinib accounted for approximately 2% of the elimination with 0.8% in urine and 1.2% in faeces.

Ecotoxicity Data

Study Type	Method	Result	Ref
Activated sludge, respiration inhibition test	OECD209	3 hour NOEC = 31 mg/L 3 hour EC50 ≥ 320 mg/L	1
Toxicity to green algae, Pseudokirchinella 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	2
Acute toxicity to the giant water flea, Daphnia magna	OECD202	48 hour EC50 (immobility) = 1.5 mg/L	3
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	4
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	5
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	6

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% mortality

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 growth (length and weight) in fathead minnows (P. promelas) in the fish early life-stage test, and an assessment factor of 10 is applied, in accordance with Ref 7.

PNEC = 0.75 µg/L /10 = 0.075 µg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC = 0.00068 µg/L

PNEC = 0.075 µg/L

PEC/PNEC = 0.0091

The PEC/PNEC ratio of 0.0091 corresponds to the risk 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	8
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	9
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	10

DT50 Degradation half-life

OC Organic Carbon

Kd Distribution coefficient for adsorption

Koc Organic carbon normalized adsorption coefficient

Biodegradation

Osimertinib mesylate is fairly water soluble and has been shown to strongly adsorb to sewage sludge, sediments and soils (Ref 10). As such, it is expected to be significantly removed, via adsorption, during sewage treatment and is unlikely to be present in aqueous effluents entering surface waters. 

The degradation of osimertinib mesylate in activated sludge was assessed in an OECD 314B study (Ref 8), 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 cannot be classified as ‘readily biodegradable’, it is anticipated that osimertinib mesylate will undergo significant removal and primary degradation during wastewater treatment.

The fate and degradation of ¹⁴C-labelled osimertinib mesylate in water-sediment systems (Ref 9) was assessed in an OECD308 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 ≤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.

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.

Overall the evidence from this study shows that osimertinib mesylate is expected to be 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 phrase “Osimertinib mesylate has low potential for bioaccumulation” is assigned.

In Swedish: Osimertinibmesilat har låg potential att bioackumuleras.

Physical Chemistry Data

Study Type	Method	Result	Ref
Water solubility	Not-stated	3.1 mg/mL	11
Disassociation constant	Not-stated	pKa = 9.5 (aliphatic amine) pKa = 4.4 (aniline)	11
Octanol – water partition coefficient	OECD 107	pH 4 log Dow = 1.77 pH 7 log Dow = 2.45 pH 9 log Dow = 2.69	12

References

1. AZD9291 Mesylate: Activated Sludge Respiration Inhibition Test. April 2015. Smithers Viscient (ESG) Ltd. Study Number 3200658

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

3. AZD9291 mesylate: Acute toxicity to Daphnia magna. February 2015. Smithers Viscient (ESG) Ltd, Study Number 3200661

4. AZD9291 mesylate: Daphnia magna Reproduction Test. July 2015. Smithers Viscient (ESG) Ltd, Study Number 3200660

5. OSIMERTINIB: An early life stage toxicity test with the fathead minnow (Pimephales promelas). July 2017. EAG Laboratories. Project number: 123A-118A

6. [14C]AZD9291 Sediment-Water Chironomus riparius Toxicity Test using Spiked Sediment. April 2015. Smithers Viscient (ESG) Ltd, Study Number 3200668

7. Environmental Classification of Pharmaceuticals in www.fass.se – Guidance for Pharmaceutical Companies. (2012).

8. [14C]AZD9291: Determination of Biodegradation in Activated Sludge. April 2015. Smithers Viscient (ESG) Ltd. Study Number 3200666.

9. [14C]AZD9291: Degradation in Water-Sediment Systems under Aerobic Conditions. April 2015. Smithers Viscient (ESG) Ltd. Study Number 3200667.

10. [14C]AZD9291: Adsorption/Desorption in Two Soils, Two Sediments and One Sludge. April 2015. Smithers Viscient (ESG) Ltd. Study Number 3200657

11. AstraZeneca Internal Documents; General properties, Structure

12. [14C]AZD9291: Distribution coefficient at three pH values. January 2015. Smithers Viscient (ESG) Ltd, 108 Woodfield Drive, Harrogate, North Yorkshire, UK. Study Number 3200664.