Detaljerad miljöinformation

The assessment is based on the following entries of sales data from IQVIA / LIF - kg consumption 2021:

Substance	CAS no.	M	kg
Mycophenolate mofetil	128794‑94‑5	433.49	3767.3121 (sales data 2021)
Mycophenolate sodium	37415‑62‑6	342.321	103.6668 (sales data 2021)

The assessment is made for:

Substance	CAS no.	M	kg
Mycophenolic acid	24280‑93‑1	320.339	2880.9657 (calculated total sales data 2021 from as MPA)

Identification and characterisation
CAS number	128794-94-5 mycophenolate mofetil (MPM) [1] 37415-62-6 mycophenolate sodium 24280-93-1 mycophenolic acid (MPA) [1]
Molecular weight	433.49 MPM [1] 342.321 mycophenolate sodium 320.339 MPA [1]
Brand name	CellCept, CellCept i.v. MPM [1]
Physico-chemical properties
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 [1]
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) = 1.37 x 10^-6 x A x (100 - R) = 0.349 μg/L

Where:

A Sold quantity = 2880.9657 kg/y calculated sales data 2021 as MPA

R Removal rate =11.69 % calculated with SimpleTreat 4.0 using a primary
kbiodeg of 0.017 h-1 (OECD 314B) [15]

P Population of Sweden = 10 000 000

V Volume of Wastewater = 200 l/day Default value [2]

D Factor for Dilution = 10 Default value [2]

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

Cyanobacteria (Anabaena flos-aquae): [16]

72 h ErC50 (growth rate) = 0.423 mg/l geometric mean (OECD 201) MPA

72 h ErC10 (growth rate) = 0.155 mg/l geometric mean (OECD 201) MPA

72 h EyC50 (yield) = 0.176 mg/l geometric mean (OECD 201) MPA

72 h EyC10 (yield) = 0.085 mg/l geometric mean (OECD 201) MPA

72 h NOEC (overall) = 0.084 mg/l geometric mean (OECD 201) MPA

Water-flea (Daphnia magna):

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

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

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

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

Daphnia magna reproduction test:

21 d EC50 (reproduction) 4.29 mg/l mean (OECD 211) MPA [17]

21 d EC10 (reproduction) = 0.929 mg/l mean (OECD 211) MPA [17]

21 d NOEC (reproduction) = 0.630 mg/l mean (OECD 211) MPA [17]

Guppy (Poecilia reticulata): [9]

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

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

Fish partial life cycle test with zebrafish (Danio rerio):

F0 generation

23 d EC10 (survival) 0.0189 mg/l geometric mean (OECD 229/210) MPA [18]

F1 generation

34 d EC10 (mortality) 0.0058 mg/l geometric mean (OECD 229/210) MPA [18]

Shortened life-cycle test with zebrafish – an investigation of effects on F0-Reproduction, F1-early-life stages and F1-survival; test performance based on a detailed review paper by the OECD (2008) [19]

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 (μg/l) = lowest EC10/10, where 10 is the assessment factor used. An EC10 of 5.8 μg/l for the fish F1 generation in the partial life cycle test has been used for this calculation. [1]

PNEC = 5.8 μg/l / 10 = 0.58 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.349 μg/l MPA

PNEC Predicted No Effect Concentration = 0.58 μg/l MPA

Ratio PEC/PNEC = 0.60 MPA

PEC/PNEC = 0.349/0.58 = 0.60 for Mycophenolate mofetil/Mycophenolic acid which justifies the phrase 'Use of Mycophenolate mofetil/Mycophenolic acid has been considered to result in low 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]

Biodegradation in activated sludge

Primary degradation

DT50 = 1.7 d (OECD 314B) MPA [15]

k_biodeg 0.017 h^-1 (OECD 314B) MPA [15]

Ultimate degradation

DT50 = 2.9 d (OECD 314B) MPA [15]

k_biodeg 0.010 h^-1 (OECD 314B) MPA [15]

82% mineralisation (¹⁴CO₂) after 28 d (OECD 314B) MPA [15]

Abiotic Degradation

Hydrolysis:

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

k_Hydrolysis = 0.0002 min^-1 MPA [14]

Photodegradation:

67% (120 h, 22 °C, light) MPM [10]

highly unstable to aquatic photodegradation: t½ = 117 min (summer) to 420 min (winter; at pH 5; t½ = 40 min (summer) to 142 min (winter) at pH 7; t½ = 22 min (summer) to 80 min (winter) at pH 9; natural sunlight, Palo Alto (Calif., USA) (FDA 3.10) MPA [13]

k_Sun = 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. In a biodegradation test in activated sludge according to OECD 314B a mineralisation of 82% was observed within 28 days. This justifies the phrase 'Mycophenolate mofetil/Mycophenolic acid is slowly degraded in the environment.'

Bioaccumulation/Adsorption

log D_OW = 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]

K_OC 168–557 L/kg (soils) (OECD 106) MPA [3]

K_OC 30–37 L/kg (sludges) (OECD 106) MPA [3]

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, logD_OW(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 (2021): Environmental Risk Assessment Summary for Mycophenolate mofetil / Mycophenolic acid. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm.

2. European Medicines Agency (EMA) (2006/2015): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 01 June 2006, EMA/CHMP/SWP/447/00 corr 2.

3. Study Report: TOXI-COOP Study no. 812-106-2004: Adsorption study with Mycophenolic acid using the batch equilibrium method, May 2018.

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

15. Study Report: ECT Study no. 17AZ2BW: Mycophenolic acid, [carboxyl-14C]: A study on the biodegradation in activated sludge, December 2017

16. Study Report: ECT Study no. 16AZ3AB: Mycophenolic acid: A study on the toxicity to blue-green algae (Anabaena flos-aquae), September 2017

17. Study Report: ECT Study no. 16AZ9DB: Mycophenolic acid: A study on the chronic toxicity to Daphnia magna, January 2018

18. Study Report: ECT Study no. 17AZ1FZ: Mycophenolic acid: A shortened life-cycle test with Zebrafish – investigation of effects on F0-reproduction, F1-early-life stages and F1-survival, October 2018

19. Organisation for Economic Co-operation and Development (OECD) (2008): Series on testing and assessment, number 95. Detailed review paper on fish life-cycle tests