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  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om 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 = 0.00061 µg/L /3.2 μg/L = 0.00019 

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 2015, data from IMS Health.

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 = 4.0650 kg

R = 0

PEC = 1.5 * 10-6 *4.0650 * (100-0) = 0.00061 µg/L


Metabolism


The intended use of gefitinib is likely to result mainly in metabolites and, to a lesser extent, the parent compound entering the environment, mainly via faeces. The metabolites are generally less pharmacologically active than the parent. The parent compound excreted represents approximately 11% of the given dose (Ref 2).


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

3

NOEC - Based on Biomass

0.23 mg/L

LOEC - Based on Biomass

0.36 mg/L

ECr50 - 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

4

NOEC - Based on Immobilisation

< 0.47 mg/L

Note 1

EC50 - Based on Reproduction

OECD 211

21 d

>1.7 mg/L

Note 1

5

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

6

NOEC

Limit of solubility

NOEC - Based on Weight

Note 2

Pimephales promelas

Fathead Minnow

OECD 210

32 d

0.032 mg/L

Note 3

7

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

8

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

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) study, NOEC = 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 µg/L


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00061 µg/L / 3.2 µg/L = 0.00019 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”.


Environmental Fate Data


Endpoint

Method

Test Substance Concentration

Time

Result

Ref

Biological Oxygen Demand

OECD 301F

100 mg/L

28 d

< 0.05 gO2/g

11

Percentage Biodegradation

< 5 % BOD/COD

DT50 (Water)

OECD 308

0.1 mg/L / High Organic Matter Aquatic Sediment

-

1.9 d

12/13

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 & 9

14

Hydrolysis Half-life

-

-

T1/2 ≥ 1 yr

Partition Coefficient Octanol Water

OECD 107

-

-

LogP = 4.15 @ pH 9

Note 4

15

Partition Coefficient Octanol Water

-

-

-

LogD = 3.51 @ pH 6.8

16

Biodegradation

Gefitinib is not readily biodegradable in accordance to the OECD 301F (Ref 11), with <5% biodegradation after 28 days.


In the OECD 308 study (Ref. 12 & 13), 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 matter (HOM) content and one with low organic matter (LOM) content. Gefitinib rapidly dissipated from the aqueous phase and into sediment phase, the dissipation half lives of gefitinib from the water phase were 1.9 and 2.9 days in HOM and LOM test systems respectively.


In the sediment phase, gefitinib largely became incorporated into the non-extractable fraction. The sediments were sequentically extracted with 1 x ethanol, 2 x Tetrahydrofuran (THF) and 1 x soluene.

In the HOM 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 is not considered bioavailable, however analysis of the soluene extract showed unchanged gefitinib to be the only significant component.


In the LOM 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).


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”.


Bioaccumulation

The octanol/water partition coefficient of gefitnib was assessed according to the OECD guideline 107 (Ref. 14).


Log10 Pow = 4.15, at 20.5 ± 1oC at pH 9.

For the assessment of bioaccumulation of ionisable compounds, the predicted distribution coefficient, Dow, may be calculated using the following equation:

Dow = Kow / (1+10(abs(pH – pKa)))

Or;

Log Dow = Log Kow – Log(1+10(abs(pH – pKa)))

Hence;

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

This Log Dow suggests a low bioaccumulation potential, therefore the statement ‘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

Results

Ref.

Adsorption Coefficient

OPPTS 835.1110

1 mg/L

Activated Sludge

Kd = 1852

17

Water Solubility

OECD 105

-

pH 8

20oC

1.94 mg/L

18

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.

Note 4:The reported Log P is a measured distribution coefficient. For ionisable compounds other AstraZeneca reports often refer to Log D or Log Dow rather than Log P or Log Pow.


References


  1. [ECHA] European Chemicals Agency. February 2016. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0) http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

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

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

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

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

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

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

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

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

  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. November2000

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

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

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

  15. ZD1839: Determination of n-octanol-water partition coefficient.

    Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7013

    January 2001

  16. Gefitinib: General Properties. AstraZeneca Report ONC.000-347-081.3.0

    March 2008

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

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











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