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Faslodex®

MiljöinformationReceptstatusFörmånsstatus
AstraZeneca

Injektionsvätska, lösning i förfylld spruta 250 mg
(klar, färglös till gul, viskös lösning)

Medel mot tumörer, endokrint verksamt, antiöstrogen

Aktiv substans:
ATC-kod: L02BA03
Läkemedel från AstraZeneca omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Fulvestrant

Miljörisk: Användning av fulvestrant har bedömts medföra låg risk för miljöpåverkan.
Nedbrytning: Fulvestrant bryts ned i miljön.
Bioackumulering: Fulvestrant har låg potential att bioackumuleras.


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Detaljerad miljöinformation

PEC/PNEC = 0.00028 μg/L /0.00057 μg/L =0.50

PEC/PNEC ≤ 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 2014, 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 = 1.8955 kg

R = 0

PEC = 1.5 * 10-6 * 1.8955 * (100-0) = 0.00028 µg/L


(Note, whilst fulvestrant 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 fulvestrant.)


Metabolism

Following intramuscular and intravenous administration, fulvestrant is rapidly metabolised, with a metabolism profile in humans similar to that found in non-clinical species. Identified metabolites are either less active or exhibit similar activity to fulvestrant. The major route of excretion is via the faeces (~80-90%) with <1% being excreted in the urine. Faecal metabolite profiles comprised of 10 - 15 components. Unchanged [14C]fulvestrant and the sulphone metabolite were amongst the largest fractions, representing approximately 8-6% of the administered dose. (Ref 2, 3 & 4).


Ekotoxicity data

Endpoint

Species

Common Name

Method

Time

Result

Reference

EC50 – Based on Growth Rate





Selenastrum capricornutum



Green Alga



OECD 201




72 h

> Limit of Solubility

Note 1




5

NOEC – Based on Growth Rate

Limit of Solubility

Note 1

EC50 – Based on Immobilisation







Daphnia magna






Giant Water Flea




OECD 202




48 h 

> Limit of solubility

Note 2




6

NOEC- Based on Immobilisation

Limit of solubility

Note 2

NOEC- Based on Reproduction & Length


OECD 211


21 d

Limit of solubility

Note 3


7


LC50





Oncorhynchus mykiss




Rainbow Trout




OECD 203




96 h

> Limit of solubility

Note 4




8

NOEC – Based on Mortality

Limit of solubility

Note 4

NOEC – Based on F1 length and dry weight








Pimephales promelas







Fathead Minnow



EPA 540/9-86-137 1986 Pair breeding study with embryo-larval test








43 d

0.0000057 mg/L

Note 5








9

LOEC – Based on F1 length and dry weight

0.0000222 mg/L

Note 5

NOEC – Based on F0 fecundity

0.000143 mg/L

LOEC – Based on F0 fecundity

>0.000143 mg/L

NOEC - Based on emergence & development rate




Chironomus riparius



Midge  



OECD 218



28 d


5 mg/kg (dry weight)






10

LOEC - Based on emergence & development rate



Chironomus riparius



Midge  



OECD 218



28 d


>5 mg/kg (dry weight)

EC50 - Based on Activated Sludge Respiration Inhibition







-






-






OECD 209






3 h


>100 mg/L

Note 6






11

NOEC - Based on Activated Sludge Respiration Inhibition


100 mg/L

Note 6



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 results from the assessment of the fathead minnow (Pimephales promelas) study, NOEC = 0.0057µg/L and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 12).


PNEC = 0.0057/10 µg/L = 0.00057 µg/L


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00028 μg/L /0.00057 μg/L =0.50 i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of fulvestrant has been considered to result in low environmental risk.”


In Swedish: ”Användning av fulvestrant har bedömts medföra låg risk för miljöpåverkan” under the heading ”Miljörisk”.


Environmental Fate Data

Endpoint

Method

Concentration

Time

Result

Reference

BOD



OECD 301F



100 mg/l

5 d & 28 d

< 0.05 g O2/g



13

Percentage Aerobic Biodegradation


28 d


< 5 %


Percentage Inherent Biodegradation

OECD 302A
DoE (1981) Method H



0.003 mg/l



41 d



< 0.9 % Mineralisation



14

Percentage Compound Removal (STP Simulation)




OECD 303A




0.001 mg/l (Nominal)



93 d (29 d equilibrium, 64 d exposure)



100 %




15

Biodegradation Half-life (STP Simulation)

T1/2 = 21.7 h Mineralisation

Degradation Half-Life











OECD 308

0.1 mg/l (Nominal) (High Organic Matter Sediment)











99 d


DT50 = <14 days (Total System)











16

0.1 mg/l (Nominal) (Low Organic Matter Sediment)

DT50 = <14 days(Total System)

Percentage Compound Removal

0.1 mg/l (Nominal) (High Organic Matter Sediment)





>75

0.1 mg/l (Nominal) (Low Organic Matter Sediment)

Biodegradation

Fulvestrant is not readily biodegradable in accordance to OECD 301F (Ref 13) and not inherently biodegradable according to OECD 302A (Ref 14). 


However in a sewage simulation test, OECD 303A (Ref 15), [14C] fulvestrant was shown to partition evenly between the aqueous effluent and sludge solids. Unchanged [14C]fulvestrant was not identified in the aqueous effluent extracts and degradation products did not exceed 10% of the applied radioactivity (AR), therefore no further attempt was made to identify them. Samples of the activated sludge at the end of the exposure period were extracted using methanol, which attained 84% recovery of the bound radioactivity, and the radioactivity was characterised in a separate study (Ref 17). This analysis also confirmed that the remaining radioactivity bound to the activated sludge was present as degradation products. Again, no individual degradation product exceeded 10% of AR, therefore no attempt was made to identify them.


Overall, the results from these studies show that fulvestrant is likely to be significantly degraded following sewage treatment. However, the evidence from the OECD 308 study (Ref. 16) shows that fulvestrant entering the aquatic environment is likely to rapidly dissipate from the water phase into the sediment and undergo significant degradation. By Day 14 (the first data point after Day 0) approximately 13% and 9.5% of the AR remained in the aqueous phase, of which <10% was present as fulvestrant.


At Day 14, approximately 82% and 65% of the AR was extracted from the high (HOM) and low (LOM) organic carbon sediments, respectively, using Soxhlet extraction. Specific analysis of the HOM sediment extract showed that fulvestrant accounted for approximately 13% of the AR. No fulvestrant was observed in the extract of the LOM sediment.


The presence of fulvestrant in the HOM sediment extract declined throughout the study, at Day 99 fulvestrant accounted for <2% of the radioactivity extracted from the sediment phase. Non-extractable residues (NER) increased throughout the study. At Day 99, 44% and 56% of the AR in the HOM and LOM, respectively, was associated with the NER. At Day 49 a variety of extraction solvents (methanol, methanol:dichloromethane (DCM) 50:50, acetone, acetonitrile, tetrahydrofurane (THF), hexane, DCM, chloroform, ethyl acetate and toluene) were used to minimise the amount of NER, however no significant increase in recovery was observed.


In the HOM sediment extract two degradation products were observed that accounted for >10% AR. No degradation products accounting for >10% AR were observed in the LOM sediment extract. At the end of the test mineralisation (formation of 14CO2) accounted for 6% in the HOM and 13% in the LOM, a further 3% AR was associated with the volatile organic degradation products.


Evidence from this study suggests that in the aquatic environment fulvestrant will partition to the sediment and be degraded. Although it was not possible to determine a specific degradation half-life, fulvestrant accounted for <25% of the AR by Day 14.


Based on the evidence of the OECD303A and 308 the phrase “Fulvestrant is degraded in the environment” is assigned. 


In Swedish: “Fulvestrant bryts ned i miljön” under the heading “Nedbrytning”.


Bioaccumulation

Endpoint

Species

Common Name

Method

Test Substance Concentration

Result

Reference


Bioconcentration (Whole Body -Based on Total Measured Radioactivity)









Oncorhynchus mykiss








Rainbow trout








OECD 305




0.0001 mg/l (Nominal)

BCF steady state = 342

Kinetic BCF = 355








18


Bioconcentration (Whole Body-Based on Total Measured Radioactivity)




0.001 mg/l (Nominal)

BCF steady state = 338

Kinetic BCF = 357


Physical Chemistry Data

Endpoint

Method

Test Substance Conditions

Result

Reference

Partition Coefficient Octanol Water


OECD 123


-


Log P = 7.67


19

Water Solubility

OECD 105

20oC @ pH7

0.00078 - 0.0032 mg/L

20

Dissociation Constant

Unknown

-

pKa= 10.4

21

Adsorption Coefficient

OECD 308

Sediment/Water

Kd = 2000

Note 7

22

Note 1: Limit of solubility below limit of detection 0.047 mg/L

Note 2: Limit of solubility below limit of detection 0.051 mg/L

Note 3: Limit of solubility below limit of detection 0.030 µg/L

Note 4: Limit of detection 0.028 mg/L

Note 5: Results are expressed as mean measured concentrations.

Note 6: Results are expressed as nominal concentrations.

Note 7: Calculated from partitioning observed in an OECD 308 study.


Based on the measured bioconcentration in fish, the risk of bioaccumulation of fulvestrant in aquatic organisms is low. Therefore the phrase “Fulvestrant has low potential for bioaccumulation” is assigned.


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


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)
    Information requirements


  2. Yates R A. A Phase I Trial to Assess the Metabolism, Excretion and Pharmacokinetics of a Single Intravenous Dose of 10 mg [14C]-ICI-182,780 in Healthy Male and Healthy post-menopausal Female Volunteers. Clinical study report 9238IL/0012. Nov 1999.


  3. Laight A. A Phase I Trial to Assess the Metabolism, Excretion and Pharmacokinetics of a Single Intravenous Dose of 10 mg [14C]-ICI-182,780 in Healthy Male and Healthy post-menopausal Female Volunteers. Clinical study report 9238IL/0029. April 2000.


  4. Harrison M P. To Compare the Metabolite Profiles in Faeces from Rat, Dog and Human Following Intramuscular Dosing of [14C]-ICI 182,780. Non-clinical study KMN084. Nov 2000.


  5. ICI 182,780: Determination of toxicity to the green alga Selenastrum capricornutum.Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6210. May 1998.


  6. ICI 182,780: Determination of acute toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6209. May 1998.


  7. Fulvestrant: Chronic toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8477, September 2007.


  8. ICI 182,780: Determination of acute toxicity to rainbow trout (Oncorhynchus mykiss). Brixham Environmental Laboratory, AstraZeneca, UK, Report BL6208. May 1998.


  9. Fulvestrant: Determination of the effects on the development, growth and reproduction of the fathead minnow (Pimephales promelas). Brixham Enivronmental Laboratory, AstraZenca, UK, Report BL8495. June 2008.


  10. Fulvestrant: Effects in sediment on emergence of the midge, Chironomus riparius. Brixham Environmental Laboratory, Brixham, UK. Report No. BL8558/B. June 2008.


  11. ICI 182,780: Effect on the respiration rate of activated sludge. April 1998. Brixham Environmental Laboratory, Brixham, UK. Report No. BL6206/B.


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


  13. ICI 182,780: Determination of 28 day aerobic biodegradability. Brixham Enivronmental Laboratory, AstraZenca, UK, Report BL6207. May 1998.


  14. ICI 182,780: Determination of inherent biodegradability using a modified semi-continuous activated sludge (SCAS) process. Brixham Enivronmental Laboratory, AstraZenca, UK, Report BL6397 October 1998.


  15. Fulvestrant: Simulation test for aerobic sewage treatment by activated sludge. Brixham Enivronmental Laboratory, AstraZenca, UK, Report BL8546 November 2008.


  16. Fulvestrant: Aerobic transformation in aquatic sediment systems. Garcia de Oteyza Feldeman T. McCormack P. Brixham Enivronmental Laboratory, UK, AstraZenca Report BL8462. June 2008.


  17. Fulvestrant: Extraction and characterisation of radioactivity in the sludge exposed to [14C]fulvestrant at the end of an OECD 303A study. BL8648/B. Brixham Environmental Laboratory, Brixham, UK. November 2008


  18. Fulvestrant: Determination of the accumulation and elimination of [14C]fulvestrant in rainbow trout (Oncorhynchus mykiss). Brixham Enivronmental Laboratory, AstraZenca, UK, Report BL8621. October 2008.


  19. Fulvestrant: Determination of 1-Octanol/Water partition coefficient. Maynard S.J. Johnson J.E. Brixham Enivronmental Laboratory, AstraZenca, UK, Report BL8396. December 2006.


  20. Fulvestrant: Determination of water solubility: slow stir method. Brixham Environmental Laboratory, Brixham, UK. Report No. BL8451/B. January 2008.


  21. AstraZeneca Safety Data Sheet, SDS


  22. Fulvestrant: OECD 308 Screening Test. Brixham Enivronmental Laboratory, AstraZenca, UK, Report BLS3427 June 2008.

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