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Filmdragerad tablett 250 mg
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  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Gefitinib

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


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Detaljerad miljöinformation

PEC/PNEC = 0.00038 µg/L /3.2 μg/L = 0.00012 

PEC/PNEC ≤0.1


Environmental Risk Classification


Predicted Environmental Concentration (PEC)

The 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) = total sold amount API in Sweden year 2017, data from IQVIA (former IMS Health and Quintiles).

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

hydrolysis or biodegradation) = 0 if no data is available.

P = number of inhabitants in Sweden = 9 *106

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Ref. 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. 1)

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


A = 2.54 kg

R = 0

PEC = 1.5 * 10-6 *2.54 * (100-0) = 0.00038 µg/L


Metabolism

Gefitinib is extensively metabolised in humans. Five metabolites have been fully identified in faeces, the major metabolite identified was O-desmethyl gefitinib (Ref. 2). The metabolites are generally less pharmacologically active than the parent. The excreted parent compound represents approximately 11% of the given dose (Ref. 3).


Ecotoxicity data


Endpoint

Species

Common Name

Method

Time

Result

Ref

EbC50 - Based on Biomass

Pseudokirchneriella subcapitata

Green Algae

OECD 201

72h

1.02 mg/L

Note 1

4

NOEC - Based on Biomass

0.23 mg/L

LOEC - Based on Biomass

0.36 mg/L

ErC50 - Based on Growth Rate

> Limit of solubility (2.2 mg/L)

Note 1

NOEC - Based on Growth Rate

0.23 mg/L

Note 1

LOEC - Based on Growth

0.36 mg/L

Note 1

EC50 - Based on Immobilisation

Daphnia magna

Giant Water Flea

OECD 202 Part I

48 h

> Limit of solubility (3.1 mg/L)

Note 1

5

NOEC - Based on Immobilisation

< 0.47 mg/L

Note 1

EC50 - Based on Reproduction

OECD 211

21 d

>1.7 mg/L

Note 1

6

NOEC - Based on Reproduction

1.7 mg/L

Note 1

NOEC - Based on Length & Reproduction

0.52 mg/L

Note 1

LOEC - Based on Length & Reproduction

1.7 mg/L

Note 1

LC50

Oncorhynchus mykiss

Rainbow Trout

OECD 203

96 h

> Limit of solubility

(7.6 g/L) 

Note 1

7

NOEC

Limit of solubility

(7.6 g/L)

Note 1

NOEC - Based on Weight

Note 2

Pimephales promelas

Fathead Minnow

OECD 210

32 d

0.032 mg/L

Note 3

8

LOEC - Based on Weight

Note 2

0.10 mg/L

Note 3

EC50 - Based on Activated Sludge Respiration Inhibition

-

-

OECD 209

3 h

> 100 mg/L

Note 3

9

NOEC - Based on Activated Sludge Respiration Inhibition

100 mg/L

Note 3

NOEC - Based on Emergence

Chironomous riparius

Midge

OECD 218

28 d

13 mg/kg dry sediment

10

Note 1: Results are expressed as mean measured concentrations.

Note 2: The population relevant endpoints measured were hatch, survival and weight.

Note 3: Results are expressed as nominal concentrations.


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) study, NOEC = 32 µg/L and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 11).


PNEC = 32 µg/L / 10 = 3.2 µg/L µg/L


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00038 µg/L / 3.2 µg/L = 0.00012 µg/L, i.e. PEC/PNEC ≤0.1 which justifies the phrase “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”.


Biodegradation

Gefitinib is not readily biodegradable in accordance to the OECD 301F (Ref. 12), with <5% biodegradation after 28 days.


In the OECD 308 study (Ref. 13 and 14), gefitinib rapidly dissipated from the aqueous phase and into sediment phase, the dissipation half-lives (DT50) of gefitinib from the water phase were 1.9 and 2.9 days in high (HOM) and low (LOM) organic matter test systems, respectively.


In the sediment phase, gefitinib largely became incorporated into the non-extractable fraction. No degradation was observed in the sediment phase, however, gefitinib could only be partially extracted from the sediments after 14 days using ethanol and tetrahydrofuran (26-32% of the applied radioactivity from the HOM sediment and only 2% from the LOM sediment).


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


Although the total system half-life for gefitinib is approximately 4 days this is largely due to adsorption into the solid phase where it is not anticipated to be bioavailable, there was no evidence of degradation. Therefore, the phrase “Gefitinib is potentially persistent” has been assigned.


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


Environmental Fate Data

Endpoint

Method

Test Substance Concentration

Time

Result

Ref

Biological Oxygen Demand

OECD 301F

100 mg/L

28 d

< 0.05 g O2/g

12

Percentage Biodegradation

< 5 % BOD/COD

DT50 (Water)

OECD 308

0.1 mg/L / High Organic Matter Aquatic Sediment

-

1.9 d

13/14

DT50 (Total)

-

3.9 d

DT50 (Water)

0.1 mg/L / Low Organic Matter Aquatic Sediment

-

2.9 d

DT50 (Total)


Not calculated

Percentage Hydrolysis

OECD 111

-

5 d

< 10% @ pH 4,7 and 9

15

Hydrolysis Half-life

-

-

T1/2 ≥ 1 yr


Bioaccumulation

Since Log D at pH 7 (actual measured pH 6.8) < 4, the phrase “Gefitinib has low potential for bioaccumulation” is assigned.


In Swedish: “Gefitinib har låg potential att bioackumuleras” under the heading “Bioackumulering”.


Physical Chemistry Data

Endpoint

Method

Test Substance Concentration

Test Conditions

Result

Ref.

Partition Coefficient Octanol/Water

OECD 107

1 mg/ml

Borate buffer

LogD = 4.15 @ pH 9

Note 4

16

Partition Coefficient Octanol/Water

-

0.1 mg/ml

Sodium acetate or Phosphate buffer

LogD = 2.60 @ pH 5.5

LogD = 3.51 @ pH 6.8

17

Adsorption Coefficient

OPPTS 835.1110

1 mg/L

Activated Sludge

Kd = 1852

18

Water Solubility

OECD 105

-

pH 8 20oC

1.94 mg/L

19

Note 4: This value also represents log P


References


  1. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (Version 3.0), February 2016.


  2. Electronic Medicines Compendium, SmPC Iressa https://www.medicines.org.uk/emc (accessed September 2019).


  3. ZD1839: Nonclinical module 2 summary. Guy, S., Hutchison, M., McKillop, D., Richmond, G. and Wakeling, A. 2001.


  4. ZD1839: Toxicity to the green alga Selenastrum capricornutum. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6939, November 2000.


  5. ZD1839: Acute toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6938, November 2000.


  6. ZD1839: Chronic toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6942, May 2001.


  7. ZD1839: Acute toxicity to rainbow trout (Oncorhynchus mykiss). (Report Corrected). Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6937, November 2000.


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


  9. ZD1839: Effect on the respiration rate of activated sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6940. November 2000


  10. [14C] Gefitinib: Effects in sediment on emergence of the midge, Chironomous riparius. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8514/B. November 2007.


  11. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment, May 2008.


  12. ZD1839: Determination of 28 day ready biodegradability. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6941, November 2000.


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


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


  15. ZD1839: Hydrolysis as a function of pH. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7014, January 2001.


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


  17. Gefitinib: S1-03 General Properties. AstraZeneca Doc ID-002666590 Version 2.0.


  18. Gefitinib: Adsorption and desorption to sewage sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8453, April 2007.


  19. ZD1839: Water solubility. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7012, January 2001.