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Environmental Risk Assessment Data Bicalutamide

Bicalutamide is an oral non-steroidal anti- for the treatment of cancer. It acts by blocking the receptors in the body for (the male such as ). Since the growth of is stimulated by testosterone, bicalutamide can help to slow down the growth of the cancer.

Bicalutamide is the active pharmaceutical ingredient in the AstraZeneca product; Casodex.

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

Based on the physico-chemical and fate properties of bicalutamide, it is not predicted to be strongly adsorbed to sewage sludge and is not predicted to be readily biodegradable during wastewater treatment. It is also hydrolytically stable. Consequently, any bicalutamide present in domestic sewage is assumed to be passed to the aquatic environment. In the aquatic environment bicalutamide has potential to be persistent in aquatic sediments but is degraded in surface waters. It is not predicted to bioaccumulate in aquatic organisms.

The Predicted Environmental Concentration (PEC) / Predicted No Effect Concentration (PNEC) is 0.01, which means use of bicalutamide is predicted to present an insignificant risk to the environment.

Predicted Environmental Concentration (PEC) The PEC is based on the following data:

PEC (µg/L) = (A*109*(100-R))/(365*P*V*D*100)

A (kg/year) = total patient consumption of bicalutamide in the European country with the highest per capita use in 2016 (Source: IMS Health1) R (%) = % removal during wastewater (sewage) treatment (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation). For bicalutamide, it is assumed that R = 0 as a worst case. P = number of inhabitants in the country with the highest per capita use (Source: Eurostat2). A/P = 7.34 x 10-5 kg/inhabitant V (L/day) = volume of wastewater per capita and day = 200 (European Medicines Agency (EMA) default value (Ref. 1)) D = factor for dilution of waste water by surface water flow = 10 (EMA default value) (Note: The factor 109 in the equation above converts the quantity used from kg to μg)

PEC = 0.10 µg/L

(Note: Whilst bicalutamide is metabolised in the body, 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).

Predicted No Effect Concentration (PNEC)

1 IMS Health, MIDAS International Data for 2016, available for 22 European markets 2 The number of persons having their usual residence in a country on 1 January 2016. Available from http://ec.europa.eu/eurostat/web/population-demography-migration-projections/population-data/main-tables Accessed: 20/4/17 Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Androgenic appear to be involved with male differentiation and reproduction. Therefore, as an anti-androgen the effects of bicalutamide on reproductive endpoints in fish have been assessed. The PNEC is based on the lowest NOEC value 0.01 mg/L (10 µg/L) which was reported for Pimephales promelas and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 2).

PNEC = 10 /10 µg/L = 1 µg/L

PEC/PNEC PEC = 0.10 µg/L PNEC = 1 µg/L

PEC/PNEC = 0.10

The PEC/PNEC ratio of 0.10 corresponds to the phrase ‘Use of biclutamide has been considered to result in insignificant environmental risk’ in the www.fass.se scheme (Ref 3).

Environmental Fate Summary Based on the physico-chemical and fate properties of bicalutamide, it is not predicted to be strongly adsorbed to sewage sludge and is not readily biodegradable during wastewater treatment. In the water-sediment transformation study there was evidence of both dissipation and degradation of bicalutamide from the overlying waters, with two transformation products accounting for >10% of the applied radioactivity. The total system half-lives were determined to be 39 – 69 days. However, throughout the test there was little evidence for the degradation of bicalutamide in the sediment phase. Overall, 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. Bicalutamide is not ionisable within the environmentally relevant pH range, the octanol-water partition co-efficient is low, therefore bicalutamide is not predicted to bioaccumulate in aquatic organisms.

Aquatic Toxicity Data for Bicalutamide Study Type Method Result Ref Activated sludge respiratory - 3 h EC50 >100 mg/L 4 inhibition Toxicity to green algae, FDA Technical 14 day NOEC (Growth Rate & Maximum Standing Crop) 5 Selenastrum capricornutum, Assistance = 1.1 mg/L growth inhibition test Document 4.01 14 day LOEC (Growth Rate & Maximum Standing Crop) > 1.1 mg/L

# Calculated 72 hour NOEC(Growth Rate) > 1.1 mg/L Toxicity to blue-green algae, FDA Technical 21 day NOEC (Growth Rate & Maximum Standing Crop) 6 Microcystis aeruginosa, Assistance = 1.1 mg/L growth inhibition test Document 4.01 21 day LOEC (Growth Rate & Maximum Standing Crop) > 1.1 mg/L

# Calculated 72 hour NOEC(Growth Rate) > 1.1 mg/L Study Type Method Result Ref

Chronic toxicity to Daphnia FDA Technical 21 day NOEC (length) = 0.56 mg/L 7 Magna (Giant water flea) Assistance 21 day NOEC (reproduction) = 0.96 mg/L Document 4.09 Acute toxicity to FDA Technical 96 hour LC50 (mortality) > 7.1 mg/L 8 Oncorhynchus mykiss Assistance 96 hour NOEC (mortality) = 7.1 mg/L (Rainbow trout) Document 4.11 Acute toxicity to Lepomis FDA Technical 96 hour LC50 (mortality) > 4.4 mg/L 9 macrochirus (Bluegill sunfish) Assistance 96 hour NOEC (mortality) = 4.4 mg/L Document 4.11 Reduced fish full life-cycle OECD210, EPA F0 NOEC(Survival/ Reproduction/Wet weight/Standard 10 with Pimephales promelas 540/9-86-137 length) = 100 µg/L (Fathead minnow) Reduced fish full F0 LOEC(Survival/ Reproduction/Wet weight/Standard reproduction assessment life-cycle (124 length) > 100 µg/L days) starting

with adults F1 NOEC(Hatch/ Time to hatch/Sex ratio) = 100 µg/L F1 LOEC(Hatch/ Time to hatch/Sex ratio/Standard length) >100 µg/L

F1 NOEC(Survival/ Histology/Wet weight/Standard length) = 10 µg/L F1 LOEC(Survival/ Histology/Wet weight/Standard length) = 100 µg/L Toxicity to the sediment OECD218 28 day NOEC(emergence & development rate) = 10 11 dwelling midge, Chironomus mg/kg (dry weight) riparius 28 day LOEC(emergence & development rate) > 10 mg/kg (dry weight) # The 72 hour ErC50 was calculated from the study results subsequent to reporting.

Environmental Fate Data for Bicalutamide Study Type Method Result Ref Aerobic biodegradation OECD301C Percentage Aerobic biodegradation = 0% 12 (of Theoretical Demand) after 28 days at 100 mg/L Not readily biodegradable Inherent Biodegradation OECD 302A <0.9% mineralisation after 40 days at 0.001 13 mg/L/day Anaerobic biodegradation DoE Modified 0% anaerobic biodegradation (by gas 14 according to production, carbon and test substance ISO/TCL47/SCS/ loss) after 51 days at 25 and 50 mg/L WG4 Not inherently biodegradable Hydrolysis - <10% @ pH 5, 7, 9 15 Adsorption to sludge FDA Technical Kd = 140 L/Kg 16 Assistance Document 3.08 Adsorption to soil FDA Technical Koc = 420 L/Kg @ pH 7.7 17 Assistance Koc = 561 L/Kg @ pH 5 Document 3.08 Koc = 612 L/Kg @ pH 5.8 Study Type Method Result Ref Aerobic Transformation in OECD308 High organic matter test system: 18 Aquatic Sediment Total system dissipation half-life = 39 days Systems Aqueous phase half-life = 9.2 days Sediment phase half-life = N/A* Low organic matter test system: Total system dissipation half-life = 69 days Aqueous phase half-life = 22 days Sediment phase half-life = N/A*

* there was no decline in the amount of bicalutamide extracted from the sediment phase

Physical Chemistry Data for Bicalutamide Study Type Method Result Ref Water - 2.77 mg/L at pH7 15 Dissociation constant - pKa is > 12 15 Octanol/water partition Shake-flask Log Pow = 2.54 15 coefficient - Study not conducted to recognised test guidance

References 1. Committee for Medicinal Products for Human Use (CHMP); Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006, EMEA/CPMP/SWP/4447/00 corr2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/W C500003978.pdf 2. 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 3. McKillop D, Boyle G W, Cockshott I D, Jones D C, Phillips P J, Yates R A. 1993. and enantioselective of Casodex in man. Xenobiotica, 23, 11, 1241-1253 4. Adams D S, 1991. Casodex: Results of Environmental Screening Studies. Brixham Environmental Laboratory Report no. BL4084/C. 5. Smyth D V, Morris D S, Cornish S K, 1992. Casodex: Toxicity to green alga Selenastrum capricornutum. Brixham Environmental Laboratory Report no. BL4536/B. 6. Smyth D V, Morris D S, Cornish S K, 1992. Casodex: Toxicity to blue-green alga Microcystis aeruginosa. Brixham Environmental Laboratory Report no. BL4545/B. 7. Stewart K M, Morris D S, Cornish S K, 1992. Casodex: Chronic toxicity to Daphnia Magna. Brixham Environmental Laboratory Report no. BL4572/B. 8. Morris D S, Caunter J E, Cornish S K, 1994. Casodex: Acute toxicity to Rainbow Trout (Oncorhynchus mykiss). Brixham Environmental Laboratory Report no. BL5190/B 9. Morris D S, Caunter J E, Cornish S K, 1994. Casodex: Acute toxicity to Bluegill sunfish (Lepomis macrochirus). Brixham Environmental Laboratory Report no. BL5191/B. 10. Panter G H, Bowles A J. 2009. BICALUTAMIDE: Determination of the effect on F0 reproduction and F1 development, growth and spawning ability, of the fathead minnow (Pimephales promelas). Brixham Environmental Laboratory Report no. BR0010/B. 11. Hayfield A J. 2009. [14C] bicalutamide: Determination of the effects in a water-sediment system on the emergence of Chironomus riparius using spiked sediment. Brixham Environmental Laboratory Report no. BR0023/B. 12. Morris D S, Mather J I, Grinell A J, 1992. Casodex: Determination of 28 day ready biodegradability. Brixham Environmental Laboratory Report no. BL4599/B. 13. Gillings E. 1998. Casodex: Determination of inherent biodegradability using a modified semi- continuous activated sludge (SCAS) process. Brixham Environmental Laboratory Report no. BL6252/B. 14. Morris D S, Grinell A J, 1992. Casodex: Determination of anaerobic biodegradability. Brixham Environmental Laboratory Report no. BL4600/B. 15. Environmental Assessment for Casodex (1-ID-1006231), 14/08/1994. 16. Dunseath J.S. Gilbert J.S. Gillings E. Barrett S. 1998. Casodex: Adsorption and desorption to sewage sludge. Brixham Environmental Laboratory Report no. BL6265/B. 17. Comber M H I C, Morris D S, 1992. Casodex: Soil sorption and Desorption. Brixham Environmental Laboratory Report no. BL4597/B. 18. Jones-Hughes T L, Trollope H T, MacLean S A. 2009. [14C]BICALUTAMIDE: Aerobic Transformation in Aquatic Sediment Systems. Brixham Environmental Laboratory Report no. BR8696/B.