Detaljerad miljöinformation

PEC/PNEC = 0.000076µg/L / 3.2 μg/L = 0.00002

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 * 0.555 * (100-0)

= 0.000076 µg/L

A (kg/year)      = total amount of API sold in Sweden in 2022, data from IQVIA.

                        = 0.555kg

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 * 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.

Metabolism and excretion

Gefitinib is extensively metabolised, with 3 sites of biotransformation. The metabolites are unlikely to contribute to the clinical activity of Gefitinib. Excretion is predominantly via the faeces with renal elimination of drug and metabolites accounting for less than 4% of the administered dose (Ref 2).

Ecotoxicity data

Study	Method	Result	Ref
Activated sludge respiration inhibition test	OECD 209	3h EC50 >100mg/L 3h NOEC = 100mg/L	3
Toxicity to green algae Pseudokirchneriella subcapitata	OECD 201	72h EC50(biomass) = 1.02mg/L 72h EC50 (growth) > 2.2mg/L NOEC (growth) = 0.23mg/L NOEC (biomass) = 0.23mg/L	4
Acute toxicity to Daphnia magna	OECD 202	48h EC50 3.1mg/L 48h NOEC <0.47mg/L	5
Chronic toxicity to Daphnia magna	OECD 211	NOEC (reproduction) = 1.7mg/L NOEC (length) = 0.52mg/L EC50 (reproduction) > 1.7mg/L LOEC = 1.7mg/L	6
Acute toxicity to rainbow trout Oncorhynchus mykiss	OECD 203	96h LC50 > limit of solubility 96h NOEC = limit of solubility (Mean measured concentration = 7.6mg/L)	7
Fish Early-Life Stage Toxicity with fathead minnow Pimephales promelas	OECD 210	(hatch, survival, length & dry weight) 32d NOEC = 0.032mg/L 32d LOEC = 0.10mg/L	8
Sediment toxicity test with Chironomus riparius	OECD 218	28d NOEC = 13mg/kg (dry weight) 28d LOEC = 42mg/kg (dry weight) 28d EC50 = 61mg/kg (dry weight)	9

PNEC (Predicted No Effect Concentration)

Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. The most sensitive species of these is the fathead minnow. Therefore, the PNEC is based on results from the assessment of the fathead minnow (Pimephales promelas) fish early-life stage study, reporting a NOEC of 0.032mg/L (equivalent to 32 µg/L) and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 10).

PNEC = 32 µg/L / 10 = 3.2 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000076µg/L / 3.2 μg/L = 0.00002

PEC/PNEC = 0.00002

As the PEC/PNEC ratio is ≤0.1, the following phrase is assigned: “Use of Gefitinib has been considered to result in insignificant environmental risk”.

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

Environmental Fate Data

Study	Method	Result	Ref
Determination of ready biodegradability	OECD 301F	Degradation after 28 days <5% Not readily biodegradable	11
Adsorption/desorption to sewage sludge	OPPTS 835.1110	Kd(ads) = 1852 Kd(des) = 5290	12
Aerobic transformation in aquatic sediment systems	OECD 308	Water HOC DT50 = 1.9 Water LOC DT50 = 2.9 Total system HOC DT50 = 3.9 Total system LOC DT50 not calcuable	13 & 14
Hydrolysis as a function of pH	OECD 111	<10% hydrolysis after 5 days at pH 4, 7 & 9.	15

HOC     = high organic carbon

LOC      = low organic carbon

Biodegradation

Gefitinib is not readily biodegradable based on the findings in an OECD 301F study (<5% biodegradation after 28 days). Results reported for the OECD 111 study demonstrate <10% hydrolysis at 50°C and at environmentally relevant pHs over 5 days, indicating that Gefitinib is hydrolytically stable.

The fate of Gefitinib was investigated in two natural aquatic sediment systems in an OECD 308 study. 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 phase was observed over a 99-day test period. In this test two different sediments were used, one with high organic content and one with low organic content.

Gefitinib rapidly dissipated from the aqueous phase into sediment phase. In the HOC system, total radioactivity in the water accounted for ≤0.5% applied radioactivity (AR) in aquatic sediment at each sampling interval. For the LOC system, radioactivity in the water layer represented about 2% AR at 50 days and 0.4% AR at 99 days. The dissipation half-lives of Gefitinib from the water phase are reported as 1.9 and 2.9 days in HOC and LOC systems, respectively.

In the sediment phase, Gefitinib largely became incorporated into the non-extractable fraction. The sediments were sequentially extracted with ethanol, Tetrahydrofuran (THF) and soluene.

In the HOC test vessels, by Day 7, 84% of the Applied Radioactivity (AR) was associated with the sediment phase.  At Day 14, 50 and 99, >90% of the AR was associated with the sediment.  Specific analysis of the ethanol and THF extractions showed that Gefitinib largely remained unchanged.  No degradation products accounting for >10% of the AR were observed. The non-extractable residues (NER) and radioactivity extracted with soluene are not considered bioavailable. Chromatographic analysis of the soluene extract from both system sediments indicated that the applied ¹⁴C remained as parent compound. There was no evidence of any degradation products in this fraction.

In the LOC test vessels very strong adsorption into the sediment was observed.  The ethanol and THF extractions recovered < 2% of the AR with the majority (> 90% at Days 50 and 99) of the radioactivity associated with the non-bioavailable fraction (NER + soluene extracts).

The DT₅₀ for the HOC total system was reported as 3.9 days. However, the report notes a high level of uncertainty associated with this value. As extracts from the LOC system accounted for ≤2.3% AR, analysis was considered unnecessary. Due to this, DT₅₀ value for LOC total system was not calculable.

No significant mineralization or volatile components were detected throughout the study. 

The DT₅₀ for the HOC total system is less than 32 days, however >15% Gefitinib was remaining as parent compound at the end of the study. The half-life reported for the HOC total system is largely due to adsorption into the sediment phase where the residue is expected not to be bioavailable and no evidence of degradation was observed.

Therefore the phrase: ‘Gefitinib is potentially persistent’ has been assigned.

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

Physical Chemistry Data

Study	Method	Result	Ref
n-octanol-water partition coefficient	OECD 107	Log10 Pow = 4.15, at 20.5 ± 1oC at pH 9.	16
Water solubility	OECD 105	1.94x10-3g/L at 20oC ±0.5oC	17
Dissociation constant	-	pKa (HA) = 7.24 pKa (HB) = 5.42	18

Bioaccumulation

Gefitinib is an ionisable (basic) compound with dissociation pKa values of 5.42 and 7.24. The octanol/water partition coefficient of Gefitinib was assessed according to the OECD guideline 107 (Ref. 16) at a pH one unit above the dissociation constant to ensure it existed only as the free base form.

For the assessment of the bioaccumulation potential of ionisable compounds, the predicted distribution coefficient, Dow, may be calculated using the equation below to calculate the Log Dow at pH 7:

Dow = Kow / (1+10(^{abs(pH – pKa))}) or Log Dow = Log Kow – Log(1+10(^{abs(pH – pKa))})

Where Log₁₀ P_ow = 4.15 at pH 9;

Log Dow (pH 7) = 4.15 – Log(1+10^{(abs(7 – 9))}) = 2.15

As the calculated Log Dow at pH 7 < 4, the following statement is assigned: ‘Gefitinib has low potential for bioaccumulation’ is assigned.

In Swedish: “Gefitinib 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 ZD1839, gefitinib, IRESSA™ D7913000000 Edition 21, 26 March 2021 Doc ID-003925292

   
   

3. ZD1839: Effect on the respiration rate of activated sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6940/B. November 2000. Doc ID-002796462

   
   

4. ZD1839: Toxicity to the green alga Selenastrum capricornutum. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6939/B. November 2000. Doc ID-002796463

   
   

5. ZD1839: Acute toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6938/B November 2000. Doc ID-002796468

   
   

6. ZD1839: Chronic toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6942/B May 2001. Doc ID-002796465

   
   

7. ZD1839: Acute toxicity to rainbow trout (Oncorhynchus mykiss). Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6937/B.

   November 2000 Doc ID-002796471

   
   

8. Gefitinib: Determination of effects on the Early-life stage of the fathead minnow (Pimephales promelas). Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8437/B April 2007. Doc ID-002724084

   
   

9. [¹⁴C] Gefitinib: Effects in sediment on emergence of the midge, Chironomous riparius. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8514/B. November 2007. Doc ID-002724087

   
   

10. ECHA, European Chemicals Agency. May 2008. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

    
    

11. ZD1839: Determination of 28 day ready biodegradability. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6941/B. November 2000. Doc ID-002796458

    
    

12. Gefitinib: Adsorption and desorption to sewage sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8453/B. April 2007. Doc ID-002724086

    
    

13. Iressa (gefitinib): Aerobic Transformation in Aquatic Sediment Systems (Day 14 Interim Report). Huntingdon Life Sciences March 2008.  Brixham Report Number BL8583/B. Doc ID-002724085

    
    

14. Gefitinib: Aerobic Transformation in Aquatic Sediment Systems (extended incubation). Huntingdon Life Sciences October 2008. Brixham Report number BL8655/B. Doc ID-002725834

    
    

15. ZD1839: Hydrolysis as a function of pH. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7014/B. January 2001. Doc ID-002796457

    
    

16. ZD1839: Determination of n-octanol-water partition coefficient. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7013/B. January 2001. Doc ID-002796439

    
    

17. ZD1839: Water solubility. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7012/B. January 2001. Doc ID-002796429

    
    

18. S.1.3 General Properties. Gefitinib. GEL Version ID: ONC.000-347-081.3.0. AstraZeneca. March 2008. Doc ID-002666599