Detaljerad miljöinformation

Detailed background information

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.5*10^-6*A (100-R)

PEC = 0.029 µg/L

Where:

A = 194.8145 kg (total sold amount API in Sweden year 2015, data from IMS Health).

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation). This is considered a conservative value.

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)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (OECD 201) (Ref. 2):

EC50 72h (growth rate) > 1 800 µg/mL

NOEC (growth rate) = 37 µg/mL

Crustacean (Daphnia magna):

Chronic toxicity (OECD 211) (Ref. 3)

NOEC 21 days (reproduction) = 55.9 µg/mL

Fish (Pimephales promelas):

Chronic toxicity (OECD 210) (Ref. 4)

NOEC 28 days (survival) = 45.7 µg/mL

Other ecotoxicity data:

Calculation of PNEC is obtained by applying assessment factors (AF) to long-term ecotoxicity data (Ref 1):

Lowest NOEC/AF

PNEC = 3.7 μg/L

Where:

Lowest NOEC = 37 µg/mL (Pseudokirchneriella subcapitata, growth inhibition test)

AF = 10 based on the availability of chronic toxicity studies for three trophic levels

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.029/3.7 = 0.0078, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of dimethyl fumarate has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

Test results showed > 60% degradation within five days (OECD 301) (Ref 5).

Justification of chosen degradation phrase:

Dimethyl fumarate passes the ready degradability test, hence the degradation phrase should be: “Dimethyl fumarate is degraded in the environment.”

Bioaccumulation

Partitioning coefficient: Log Pow= 0.74 at neutral pH (experimentally determined with unknown method) (Ref 6).

Since log Pow < 4 at pH 7, dimethyl fumarate is considered to have “low potential for bioaccumulation”.

Excretion (metabolism)

In humans, dimethyl fumarate is extensively metabolised with less than 0.1% of the dose excreted as unchanged dimethyl fumarate in urine. Exhalation of CO₂ is the primary route of dimethyl fumarate elimination accounting for 60% of the dose. Renal and faecal elimination are secondary routes of elimination, accounting for 15.5% and 0.9% of the dose respectively. Primary active metabolite is monomethyl fumarate (Ref 7.).

References

1. 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

2. Internal document: Smithers Viscient Study No. 3200151. Anderson M. Inhibition of growth to the alga Pseudokirchneriella subcapitata. Report issued April 2013. Smither Viscient (ESG) Ltd., Harrogate, North Yorkshire, United Kingdom.

3. Internal document: Covance Study No. 8253806. Last G. Dimethyl fumarate: Chronic effects to Daphnia magna. Report issued January 2012. Covance Laboratories, Harrogate, North Yorkshire, United Kingdom.

4. Internal document: Covance Study No. 8253807. Last G. Dimethyl fumarate: Fish early life stage test (Pimephales promelas). Report issued January 2012. Covance Laboratories, Harrogate, North Yorkshire, United Kingdom.

5. Environmental risk assessment, CTD module 1.6 of “Tecfidera”

6. Hansch C., et al. 1995, Chem ID+, US National Library of Medicine, National Institute of Health, http://chem.sis.nlm.nih.gov https://chem.nlm.nih.gov/chemidplus/name/dimethyl%20fumarate

7. Tecfidera SmPC 2016-11-17, http://www.ema.europa.eu