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CellCept®

Roche

Kapsel, hård 250 mg
(avlång, blå/brun, märkt med CellCept 250 i svart på överdelen och Roche på underdelen)

Immunsuppressivum

Aktiv substans:
ATC-kod: L04AA06
Läkemedel från Roche omfattas av Läkemedelsförsäkringen.
Läkemedlet distribueras också av företag som inte omfattas av Läkemedelsförsäkringen, se Förpackningar.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Mykofenolatmofetil

Miljörisk: Användning av mykofenolatmofetil har bedömts medföra medelhög risk för miljöpåverkan.
Nedbrytning: Mykofenolatmofetil bryts ned långsamt i miljön.
Bioackumulering: Mykofenolatmofetil har låg potential att bioackumuleras.


Läs mer

Detaljerad miljöinformation

The assessment is based on the following entries of sales data (total sold amount API in Sweden year 2017, data from IQVIA):


Substance

CAS no.

M

kg (2017)

Mycophenolate mofetil

128794‑94‑5

433.49

3319.1598 (sales data 2017)

Mycophenolate sodium

37415‑62‑6

342.321

123.0590 (sales data 2017)


The assessment is made for:


Substance

CAS no.

M

kg (2017)

Mycophenolic acid

24280‑93‑1

320.339

2567.9385 (calculated sales data 2017)

Identification and characterisation

CAS number

128794-94-5 mycophenolate mofetil (MPM) [1]

37415-62-6 mycophenolate sodium

24280-93-1 mycophenolic acid (MPA) [2]


Molecular weight

433.49 MPM [1]

342.321 mycophenolate sodium

320.339 MPA [2]


Brand name

CellCept, CellCept i.v. MPM [1]


Physico-chemical properties

Aqueous solubility

Aqueous solubility ≤36 mg/l (ecotoxicity media) MPM [1]

24.8 mg/l (OECD 105) MPA [6]


Dissociation constant, pKa

8.04 - 8.05 MPA [6]


Melting point

93–99 °C MPM [1]

141 °C MPA [2]


Vapour pressure

2.12E-08 Pa (25 °C) QSAR MPA


Boiling point

506.5 °C QSAR MPA


KH


3.08E-07 Pa*m3/mol QSAR MPA



QSAR = QSAR-modelled (EPISuite, SPARC, ACD Solaris)


Predicted Environmental Concentration (PEC)

PEC is calculated according to the formula:

PEC (μg/L) = (A x 1'000'000'000 x (100-R)) / (365 x P x V x D x 100) = 1.5 x 10-6 x A x (100 - R) = 0.385 μg/L


Where:


A Sold quantity = 2567.9385 kg/y calculated sales data 2017 for MPA

R Removal rate = 0 % Default value [3]

P Population of Sweden = 9000000

V Volume of Wastewater = 200 l/day Default value [3]

D Factor for Dilution = 10 Default value [3]

E Excretion = 100


Where excretion as total pharmacological activity of parent is considered:

Excretion

Excretion as parent 0 % (if not filled in/unknown, 100% is assumed by default)

Excretion as metabolite 1 100 %, with 100 % pharmacological activity compared to parent [4, 5]

Excretion as metabolite 2 %, with 100 % pharmacological activity compared to parent

Excretion as others %, with 100 % pharmacological activity compared to parent

Excretion total, E: 100 %, calculated as pharmacological activity of parent


Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Raphidocelis subcapitata): [6]

96 h ErC50 (growth rate) =0.068 mg/l geometric mean (OECD 201) MPA

96 h ErC10 (growth rate) = 0.012 mg/l geometric mean (OECD 201) MPA

96 h EbC50 (biomass) =0.017 mg/l geometric mean (OECD 201) MPA

96 h EbC10 (biomass) = 0.008 mg/l geometric mean (OECD 201) MPA


Green alga (Desmodesmus subspicatus): [7]

72 h ErC50 (growth rate) =0.618 mg/l time-weighted average (OECD 201) MPM

72 h NOErC (growth rate) = 0.085 mg/l time-weighted average (OECD 201) MPM

72 h EbC50 (biomass) =0.229 mg/l time-weighted average (OECD 201) MPM

72 h NOEbC (biomass) = 0.040 mg/l time-weighted average (OECD 201) MPM


Water-flea (Daphnia magna):

48 h EC50 = 755 mg/l measured (OECD 202) MPA [6]

48 h NOEC = 440 mg/l measured (OECD 202) MPA [6]

48 h EC50 >27.7 mg/l time-weighted average (OECD 202) MPM [8]

48 h NOEC = 27.7 mg/l time-weighted average (OECD 202) MPM [8]


Guppy (Poecilia reticulata): [9]

96 h LC50 >0.21 mg/l time-weighted average (OECD 203) MPM

96 h NOEC = 0.21 mg/l time-weighted average (OECD 203) MPM


Micro-organisms:

14 d NOEC (toxicity control) = 100 mg/l (OECD 301 F) MPM [10]

4 h NOEC = 27.8 mg/l measured initial (ISO 9509) MPM [11]


PNEC Derivation

The PNEC is based on the following data:

PNEC (mg/l) = lowest EC50/1000, where 1000 is the assessment factor used. An ErC50 of 68 μg/l for algae has been used for this calculation.

PNEC = 68 / 1000 = 0.068 μg/l


Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.385 μg/L MPA

PNEC Predicted No Effect Concentration = 0.068 μg/L MPA

Ratio PEC/PNEC = 5.7 MPA


PEC/PNEC = 0.385/0.068 = 5.7 for Mycophenolate mofetil/Mycophenolic acid which justifies the phrase 'Use of Mycophenolate mofetil/Mycophenolic acid has been considered to result in moderate environmental risk.'


Degradation

Biotic Degradation

Ready biodegradability: [10]

4% after 28 days of incubation BOD/ThOD (OECD 301 F) MPM

33% after 28 days of incubation DOC/TOC (OECD 301 F) MPM

100% after 28 days of incubation Parent (OECD 301 F) MPM

not readily biodegradable


Inherent biodegradability: ND


Other degradation information:

21.5 - 60.2% mineralisation to 14C-CO2 within 64 days in river/water sediments

100% transformation of MPM to metabolites (FDA 3.11) MPM [12]


Abiotic Degradation

Hydrolysis:

37% (120 h, 22 °C, in the dark) MPM [10]

kHydrolysis = 0.0002 min-1 MPA [14]


Photodegradation:

67% (120 h, 22 °C, light) MPM [10]

highly unstable to aquatic photodegradation: = 117 min (summer) to 420 min (winter; at pH 5; = 40 min (summer) to 142 min (winter) at pH 7; = 22 min (summer) to 80 min (winter) at pH 9; natural sunlight, Palo Alto (Calif., USA) (FDA 3.10) MPA [13]

kSun = 0.004 min-1 (Solar Simulator in SOLAR BOX®) MPA [14]


Mycophenolate mofetil/Mycophenolic acid is not readily degradable. In sediment/water fate systems significant removal (up to >50%) of radio-labelled MPA was noted after 64 days. There is additional evidence for some aquatic photodegradation. This justifies the phrase 'Mycophenolate mofetil/Mycophenolic acid is slowly degraded in the environment.'


Bioaccumulation/Adsorption

log DOW = 2.28 (pH 5, 25 °C) (OECD 107) MPA [6]

= 0.47-0.48 (pH 7, 25 °C) (OECD 107) MPA [6]

= -1.83 - -1.54 (pH 9, 25 °C) (OECD 107) MPA [6]

KOC 444 L/kg QSAR MPA

BCF <10 L/kg QSAR MPA


Mycophenolate mofetil/Mycophenolic acid has low potential for bioaccumulation (log KOW <4).


Excretion/metabolism

Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to mycophenolic acid (MPA), the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. Mycophenolic acid is metabolised mainly by glucuronyl transferase to glucuronidated metabolites, predominantly the phenolic glucuronide, mycophenolic acid glucuronide (MPAG). MPAG does not manifest pharmacological activity. The minor acyl glucuronide metabolite has pharmacological activity similar to mycophenolic acid. In vivo, MPAG is converted back to MPA via enterohepatic recirculation. The mean elimination half-life for MPA ranges from 8 to 16 hours, while that of the MPAG metabolite ranges from 13 to 17 hours. [4, 5]


PBT/vPvB Assessment

P: Freshwater half-life <0.5 d, based on photolysis MPA [13]

Sediment half-life ND

Persistence criteria fulfilled? not P


B: BCF (experimental) ND

alternatively, logDOW(p H 7) 0.48 MPA [6]

Bioaccumulation criteria fulfilled? no significant bioaccumulation potential


T: chronic NOEC < 0.01 mg/l? y T criterion fulfilled

CMR substance? y CMR criterion fulfilled [1]

Endocrine-disrupting effects? n not ED

T criteria fulfilled? T criteria fulfilled


PBT Assessment: not PBT


References


1. F. Hoffmann-La Roche Ltd (2017): Safety Data Sheet for Mycophenolate mofetil, 06.10.2017; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheets-row.htm

2. F. Hoffmann-La Roche Ltd (2017): Safety Data Sheet for Mycophenolic acid, 25.09.2017; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheets-row.htm

3. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

4. DrugBank online. Mycophenolate mofetil. http://www.drugbank.ca/drugs/DB00688. DrugBank: a knowledgebase for drugs, drug actions and drug targets. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. Nucleic Acids Res. 2008 Jan;36 (Database issue): D901-6. PMID: 18048412

5. DrugBank online. Mycophenolic acid. http://www.drugbank.ca/drugs/DB01024. DrugBank: a knowledgebase for drugs, drug actions and drug targets. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. Nucleic Acids Res. 2008 Jan;36 (Database issue): D901-6. PMID: 18048412

6. European Chemicals Agency (ECHA). Registered substances. https://echa.europa.eu/information-on-chemicals/registered-substances

7. Study Report: BMG Project no. 337/b-05: Mycophenolat-Mofetil, fresh water algal growth inhibition test withS cenedesmus subspicatus, October 2005

8. Study Report: BMG Project no. 337/c-05: Mycophenolat-Mofetil, 48-hour acute toxicity toD aphnia magna, limit test (100 mg/l), October 2005

9. Study Report: BMG Project no. 337/d-05: Mycophenolat-Mofetil, 96-hour acute toxicity toP oecilia reticulata (Guppy), limit test (1.7 mg/l), October 2005

10. Study Report: BMG Project no. 337/a-05: Mycophenolat-Mofetil, ready biodegradability - evaluation of the aerobic biodegradability in an aqueous medium: manometric respirometry test, October 2005

11. Study Report: BMG Project no. 1159/d-06: Mycophenolat-Mofetil (wet-milled suspension), Test for assessing the inhibition of nitrification of activated sludge microorganisms: nitrification inhibition test, December 2006

12. Study Report: ABC Project no. 41485: Aerobic Biodegradation of 14C Mycophenolate Mofetil in River Water and Sediments (Metabolism Test), June 1995

13. Study Report: Syntex Project no. IAR WP3442: Photolysis of Mycophenolic Acid in Aqueous Buffers, July 1994

14. Franquet-Griell H, Medina A, Sans C, Lacorte S. 2017. Biological and photochemical degradation of cytostatic drugs under laboratory conditions. J Hazard Mater. 323(Pt A):319-328