Detaljerad miljöinformation

Environmental Risk Classification

Diroximel fumarate (DRF) is a prodrug which is rapidly converted within the body to the active ingredient monomethyl fumarate (MMF). As there is no significant excretion of DRF from the body (based on ADME studies in rats), the risk assessment has been conducted with the active ingredient MMF (Ref. I).

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.35*10^-6*A*(100-R)

PEC = 0.0167 μg/L^-1

Where:

A = 122 kg (Biogen predicted sales data for Sweden in 2026, five years post product launch).

R = 0% removal rate. In this assessment 0% is used as a conservative value.

P = 10,000,000 (default value for number of inhabitants in Sweden)

V = 200 L/day (wastewater per capita per day, default value)

D = 10 (dilution, default value)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (OECD 201) (Ref. II):

EC₅₀ 72 h (growth rate) > 100 mg/L

NOEC (growth rate) = 3.05 mg/L

Crustacean (Daphnia magna):

Chronic toxicity (OECD 211) (Ref. II)

NOEC 21 days (reproduction) = 14 mg/L

Fish (Pimephales promelas):

Chronic toxicity (OECD 210) (Ref. II)

NOEC 28 days (survival) = ≥ 8.63 mg/L

Other ecotoxicity data:

PNEC is calculated by applying a default assessment factor (AF) to the lowest NOEC from the base set of long-term toxicity tests. The lowest NOEC was found to be the growth inhibition test for algae P. subcapitata with the value 305 μg/L. To calculate the PNEC a default AF of 10 is applied. (Ref. II) The PNEC is therefore:

PNEC = 3.05 mg/L /10 = 0.305 mg/L = 305 μg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0167/305 = 0.0000548, i.e. PEC/PNEC ≤ 0.1, which justifies the phrase ‘Use of DMF/MMF has been considered to result in insignificant environmental risk.’

Degradation

Biotic degradation

Ready degradability:

A ready biodegradation study has not been conducted with diroximel fumarate. This is because there is no significant excretion of diroximel fumarate from humans (based on ADME studies in the rat) and therefore environmental testing is conducted with the active metabolite monomethyl fumarate. Monomethyl fumarate is readily biodegradable based on the result from a standard OECD 301F (Manometric Respirometry) study (Ref I).

Justification of chosen degradation phrase:

Since a specific ready biodegradation study has not been conducted with diroximel fumarate, the degradation phrase should be “Diroximel fumarate is potentially persistent”.

Bioaccumulation

Partitioning coefficient:

Log D_ow = -1.065 at pH 7 (OECD 107). (Ref. III)

Justification of chosen bioaccumulation phrase:

Since log D_ow < 4 at pH 7, the substance has low potential for bioaccumulation.

Excretion (metabolism)

DRF is rapidly converted to MMF in the body via esterases. An ADME study in rats using radiolabelled DRF finds that none of the parent compound is excreted from the body. Excretion is as MMF or other inactive metabolites. (Ref I)

References

I. Ricerca (2015) Single-Dose Oral ADME and Metabolite Profiling Study of [14C]RDC-5108 in Rats. Study number: 032357.

II. WCA (2020) Environmental risk assessment for diroximel fumarate/monomethyl fumarate. Final report.

III. Scymaris (2020) Monomethyl fumarate: Partition coefficient (n-octanol/water): Shake flask method. Study number 1089.00118.