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Casodex®

MiljöinformationReceptstatusFörmånsstatus
AstraZeneca

Filmdragerad tablett 50 mg
(vita, runda, bikonvexa, märkta Cdx 50/pil, diameter 6,5 mm)

Medel mot tumörer, endokrint verksamt

Aktiv substans:
ATC-kod: L02BB03
Läkemedel från AstraZeneca omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Bikalutamid

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


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Detaljerad miljöinformation

PEC/PNEC = 0.098 μg/L /1.0 μg/L= 0.098

PEC/PNEC < 0.1


Environmental Risk Classification


Predicted Environmental Concentration (PEC)


PEC is based on the 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 = 654.48 kg


R = 0


PEC = 1.5 * 10-6 * 654.48 * (100-0) = 0.098 μg/L


(Note: whilst bicalutamide is extensively metabolised in humans, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for the purpose of this calculation, it is assumed that 100% of excreted metabolites have the same ecotoxicity as parent bicalutamide.)


Metabolism

Bicalutamide is excreted by patients in both urine and faeces as a mixture of parent compound and metabolites. Approximately 31% of the given dose is excreted as parent, with the remainder as metabolites, including conjugated bicalutamide and hydroxy-bicalutamide (Ref.2).


Ecotoxicity data

Endpoint

Species

Common Name

Method

Time

Result

Reference

NOEC – Based on Growth Rate & Maximum Standing Crop

Microcystis aeruginosa

Cyano­bacterium (Blue-Green Alga)

FDA Technical Assistance Document 4.01

21 d

1.1 mg/L

3

EC50 - Based on Growth Rate & Maximum Standing Crop

21 d

>1.1 mg/L

ErC50 – Based on Growth Rate

72 h

>1.1 mg/L

NOEC - Based on Growth Rate & Maximum Standing Crop

Pseudo­kirchneriella subcapitata (formerly known as Selenastrum capri-cornutum)

Green Alga

FDA Technical Assistance Document 4.01

14 d

1.1 mg/L

4

EC50 – Based on Growth Rate & Maximum Standing Crop

14 d

>1.1 mg/L

ErC50 – Based on Growth Rate

72 h

>1.1 mg/L

NOEC - Based on Reproduction

Daphnia magna

Giant Water Flea

FDA Technical Assistance Document 4.09

21 d


0.96 mg/L

5

NOEC - Based on Length

0.56 mg/L

LC50

Lepomis macrochirus

Bluegill Sunfish

US FDA Technical Assistance Document 4.11

96 h

>4.4 mg/L

6

NOEC - Based on Symptoms of Toxicity

4.4 mg/L

LC50

Oncorhynchus mykiss

Rainbow Trout

US FDA Technical Assistance Document 4.11

96 h

>7.1 mg/L

7

NOEC - Based on Symptoms of Toxicity

7.1 mg/L

NOEC – Based on Survival, Fecundity, Length & Weight

Pimephales promelas

Fathead Minnow

OECD 210

EPA 540/9-86-137

Reduced fish full life-cycle, starting with adults

124 d

0.01 mg/L

8

LOEC – Based on All Survival, Fecundity, Length & Weight

0.1 mg/L

NOEC - Based on emergence & development rate

Chironomus riparius


Midge


OECD 218


28 d


10 mg/kg (dry weight)

9


LOEC - Based on emergence & development rate

>10 mg/kg (dry weight)

EC50 - Based on Activated Sludge Respiration Inhibition

-

-

Screening study

3 h


>100 mg/L

10


EC50 – Based on Bacterial Nitrification Inhibition

-

-

Screening study

>100 mg/L


PNEC (Predicted No Effect Concentration)


Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the chronic toxicity to the fathead minnow (Pimephales promelas), the most sensitive species, and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref.11).


PNEC = 10/10 µg/L = 1.0 µg/L


Environmental risk classification (PEC/PNEC ratio)


PEC/PNEC = 0.098 / 1.0 μg/L = 0.098 i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of bicalutamide has been considered to result in insignificant environmental risk.”


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


Environmental Fate Data


Endpoint

Method

Test Substance Concentration

Time

Result

Reference

Dissipation Half Life in High Organic Matter (HOM) Sediment

OECD 308

0.1 mg/L

-

Total system DT50 = 39.0 days Overall (9.3 days in the overlying water, N/A in the sediment)

12

Dissipation Half Life in Low Organic Matter (LOM) Sediment

-

Total sytem DT50 = 68.6 days Overall (22.1 days in the overlying water, N/A in the sediment)

Percentage Aerobic Biodegradation

OECD 301C

100 mg/L

28 d

0 % Theroretical Oxygen Demand

13

Percentage Anaerobic Biodegradation

DoE Modified according to ISO/TCL47/SC5/WG4

25 & 50 mg/L as Carbon

51 d

0 % (by gas production, carbon and test substance loss from aqueous phase)

14

Percentage Inherent Biodegradation

OECD 302A
DoE (1993)

0.001 mg/L/day

40 d

<0.9 % Mineralisation

15

Hydrolysis

Not specified

-

5 d

<10 % @ pH 5,7 & 9

16

Hydrolysis Half-life

Not specified

-

5 d

T1/2 > 1 year

Partition Coefficient Octanol Water

Shake-flask

1000 mg/L

-

Log P = 2.35

Partition Coefficient Octanol Water

Shake-flask

100 mg/L

-

Log P = 2.54


Biodegradation

The degradation of bicalutamide in aquatic sediment systems (Ref 12) was assessed according to the OECD 308 Test Guideline. In this test two different sediments, one with high organic matter content (HOM) and one with low organic matter content (LOM), were used. 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, was observed over a 99 day test period.


On Day 0 rapid dissipation of the applied radioactivity (AR) from the water to the sediment was observed in both the HOM (29%) and LOM test system (20%) respectively. The absorption to the sediment in the HOM test system increased to a maximum of 57% by Day 14, decreasing slightly by Day 99. In the LOM sediment system, the increase was slower and peaked on Day 70 to reach a maximum of 39% that was maintained at this level until Day 99.


Two degradation products observed at >10% AR in the overlying water of the HOM and LOM sediment systems. Radioactivity associated with the sediment was investigated using sequential extractions of sediment samples using ethanol and acetonitrile modified with 2% acetic acid. There was no evidence of significant degradation in the sediment, with bicalutamide accounting for 66-96% and 85-95% of the extracted radioactivity in the HOM and LOM sediment throughout the test. As such it was not possible to calculate a degradation half-life for bicalutamide in the sediment compartment


There was minimal mineralization of both sediment types throughout the study, 2.4% and 5.1% respectively in the HOM and LOM sediment systems.


Although there was evidence of both dissipation and degradation of bicalutamide from the overlying waters, there was little evidence of degradation in the sediment. The results indicate that bicalutamide is unlikely to persist in the aqueous phase, however once adsorbed to the sediment phase bicalutamide is unlikely to undergo degradation and is expected to remain unchanged. As such, although the total system DT50 is <120 days, a precautionary approach has been taken and the substance has been assigned the risk phrase “Bicalutamide is potentially persistent”


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


Bioaccumulation

Log P = < 4 at pH 7.


Bicalutamide has no significant bioaccumulation potential, as indicated by the log. P. Therefore the statement: “Bicalutamide has low potential for bioaccumulation” is assigned.


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


Physical Chemistry Data

Endpoint

Method

Test Conditions

Result

Reference

Sludge Adsorption Distribution Coefficient

HMSO 1992

OECD 106

FDA Technical Assistance Document 3.08

0.001 mg/L

Kd = 140

17

Soil Adsorption Coefficient

FDA Technical Assistance Document 3.08

1.5 mg/L

Koc = 420 @ pH 7.7

Koc = 561 @ pH 5

Koc = 612 @ pH 5.8

18

Water Solubility

FDA Technical Assistance Document 3.01

25°C

2.77 mg/L

16


Referenser

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. Metabolism and enantioselective pharmacokinetics of Casodex in man.

D. McKillop et al. Xenobiotica, 1993, VOL.23, NO 11,1241-1243.


3. Casodex: Toxicity to the Blue-green alga, Microcystis aeruginosa.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BL4545

October 1992.


4. Casodex: Toxicity to the green alga, Selenastrum capricornutum.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BL4536

September 1992.


5. Casodex: Chronic toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL4572. October 1992.


6. Casodex: Acute toxicity to Bluegill sunfish (Lepomis macrochirus). Brixham Environmental Laboratory, AstraZeneca, UK, Report BL5191. November 1994.


7. Casodex: Acute toxicity to rainbow trout (Oncorhynchus mykiss). Brixham Environmental Laboratory, AstraZeneca, UK, Report BL5190. November 1994.


8. Bicalutamide: Determination of the effect on F0 reproduction and F1 development, growth and spawning ability, of the fathead minnow (Pimephales promelas).

Brixham Environmental Laboratory, AstraZeneca, UK, Report BR0010. October 2009.


9. [14C] bicalutamide Determination of the effects in a water-sediment system on the emergence of Chironomus riparius using spiked sediment. Brixham Environmental Laboratory, AstraZeneca, UK, Report BR0023/B. November 2009.


10. Casodex: Results of environmental screening studies. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL4084. April 1991.


11. 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

12. [14C] Bicalutamide: Aerobic transformation in aquatic sediment systems. Brixham Environmental Laboratory, AstraZeneca, UK, Report BR8696/B. November 2009.


13. Casodex: Determination of 28 day ready biodegradability. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL4599. October 1992.


14. Casodex: Determination of anaerobic biodegradability. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL4600. October 1992.


15. Casodex: Determination of inherent biodegradability using a modified semi-continuous activated sludge (SCAS) process. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6252. March 1998.


16. Summary of Pharmaceuticals regulatory data on: Casodex Brixham Environmental Laboratory, AstraZeneca, UK, Report BD2892. August 1999.


17. Casodex: Adsorption and desorption to sewage sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6265. April 1998.


18. Casodex: Soil sorption and desorption. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL4597. October 1992.

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