Detaljerad miljöinformation

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) = 1.37*10^-6*A*(100-R)

PEC = 0.00335 µg/L

Where:

A = 24.4552 kg (total sold amount API in Sweden year 2021, data from IQVIA)

R = 0% removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Ref I).

D = factor of dilution of waste water by surface water flow = 10 (ECHA default) (Ref I).

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata):

EC₅₀ 72 h (growth rate): 7 410 μg/L

NOEC 72 h (growth rate): 952 µg/l

Test item: Riluzole

Protocol: OECD 201

(Ref II)

Crustacean (Daphnia magna):
EC₅₀ 48 h (immobilisation): 4 900 μg/L
Test item: Riluzole
Protocol: OECD 202
(Ref III)

Fish (Danio rerio):

LC₅₀ 96h (lethality): 3 780 μg/L

Test item: Riluzole

Protocol: OECD 236

(Ref IV)

Other ecotoxicity data:

PNEC = 3.78 μg/L

PNEC (μg/L) = lowest LC₅₀ or EC₅₀/1000, where 1000 is the assessment factor used.

LC₅₀ for Danio rerio has been used for this calculation since it is the most sensitive of the three tested species.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC = 0.00335/3.78 = 8.8* 10^-4

Justification of chosen environmental risk phrase:

PEC/PNEC ≤ 0.1: Use of riluzole has been considered to result in insignificant environmental risk.

Degradation

Biotic degradation

Inherent degradability:

Test showed 0% degradation in 14 days (protocol ISO 9408 [1991])
(Ref V)

Justification of chosen degradation phrase:

Riluzole fails to pass the criteria for inherent biodegradability which justifies the phrase “riluzole is potentially persistent”.

Bioaccumulation

Partitioning coefficient:

Log K_ow = 3.0 (estimated with EPI Suite Kow Win program on uncharged molecules) (Ref VI)

Justification of chosen bioaccumulation phrase:

Since Log K_ow < 4 at pH 7, riluzole has low potential for bioaccumulation.

Excretion (metabolism)

Less than 1% of riluzole is excreted unchanged (Ref VII and Ref VIII).

The metabolites (more than 85% are glucurono-conjugated derivatives) are mainly eliminated in urine (90% of the dose). 20 metabolites are identified (in urine). 5-hydroxy-riluzole and hydroxylamine compounds are active but the maximum concentrations of the metabolites are considered too low to be of importance.

The pharmacological activity of the other metabolites is not known and has not been investigated. (Ref VIII)

References

1. ECHA, European Chemicals Agency, 2008 Guidance on information requirements and chemical safety assessment.

2. Sanofi Internal report: Riluzole: Toxicity to Pseudokirchneriella subcapitata in an algal growth inhibition test. OECD201. Report 143672210, 2020

3. Sanofi Internal report: Riluzole: Toxicity to Daphnia magna in a static 48-hour Immobilisation test. OECD202. Report 143672220, 2020

4. Sanofi Internal report: Riluzole: Acute Toxicity to Zebrafish (Danio rerio) Embryos in a 96-hour static test. OECD236. Report 143671238, 2020

5. SANOFI internal report – Riluzole – “Etude de la toxicité et de la biodégradabilité du riluzole” (2001)

6. Fick J et al. (2010) “Predicted critical environmental concentrations for 500 pharmaceuticals” Regulatory Toxicology and Pharmacology58: 516–523

7. Wokke J. (1996) “Riluzole” The Lancet 348: 795-799

8. EMEA – EPAR Rilutek® scientific discussion (21/10/2005)