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 = 0.00062 µg/L

Where:

A = 4.51 kg (total sold amount API in Sweden year 2020, data from IQVIA)

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available.

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

Green algae (Desmodesmus subspicatus):

Acute toxicity
leflunomide

EC₅₀ 72 h (growth rate, biomass): 22 420 μg/L

(Protocol: OECD 201)

(Ref. II)

Green algae (Selenastrum capricornutum):

Acute toxicity
A771726 (active metabolite)

EC₅₀ 72 h (growth rate, biomass): 22 800 μg/L

(Protocol: OECD 201)

(Ref. III)

Water flea (Daphnia magna):
Acute toxicity

leflunomide

EC₅₀ 48 h (immobility): 17 000 μg/L

(Protocol: OECD 202)

(Ref. IV)

Acute toxicity
A771726 (active metabolite)

EC₅₀ 48 h (immobility): > 100 000 μg/L

(Protocol: OECD 202)

(Ref. III)

Zebrafish, Brachydanio rerio:

Acute toxicity
leflunomide
LC₅₀ 96 h (survival): 2 640 μg/L

(Protocol: OECD 203)

(Ref. V)

Acute toxicity
A771726 (active metabolite)

LC₅₀ 96 h (survival): 50 000 – 100 000 μg/L

(Protocol: OECD 203)

(Ref. III)

Other ecotoxicity data
PNEC = 2.64 ug/L

PNEC (μg/L) = 2 640/1 000, where 1 000 is the assessment factor used (acute toxicity data only).

EC₅₀ for Zebrafish, Brachydanio rerio has been used for this calculation since it is the most sensitive of the three tested species for the parent compound, leflunomide.
Given that the acute toxicity values for the active metabolite A771726 are all greater than those for leflunomide, including by an order of magnitude in fish, the calculated PNEC value is sufficient for classification of environmental risk for leflunomide.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC= 0.00062/2.64 = 0.00023

PEC/PNEC ≤ 0.1 which justifies the chosen summary phrase.

Summary phrases for the environmental risk:

Use of leflunomide has been considered to result in insignificant environmental risk.

This ratio also assumes that 100 % of leflunomide excreted is pharmacologically active, whereas the percentage of the active metabolite is actually 45 – 50 % (see Excretion (metabolism)).

Degradation

Biotic degradation

Leflunomide is potentially persistent with less than 20 % of the substance being degraded in 28 days.
(OECD 301B)
(Ref. VI)

The active metabolite A771726 is not readily biodegradable (approximately 1 %) over a 28 day period.
(OECD 301E)
(Ref. VII)

Abiotic degradation

Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions.

Bioaccumulation

Partitioning coefficient:

Log Pow = 3.49 has been experimentally determined (method unknown) for leflunomide.
(Ref. III)

Log Pow = 0,925 at pH 7 for the active metabolite A771726 teriflunomide.
(Test protocol OECD107)
(Ref. VIII)

Leflunomide is unlikely to be bioaccumulable in living organisms (Log Kow < 4)
(Ref. IX).

Justification of chosen bioaccumulation phrase:

Since log Pow < 4 at pH 7 the active metabolite has low potential for bioaccumulation.

Excretion (metabolism)

Following oral administration, leflunomide is metabolized to one major and pharmacological active metabolite, A771726, responsible for essentially all of its activity in vivo. In addition, many minor metabolites are formed with unknown pharmacological activity. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma in some patients. 45 to 50 % of the total dose is excreted as the active metabolite A771726.
(Ref. X)

References

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

2. Internal report, Aventis Pharma Deutschland: Growth Inhibition Test with Fresh Water Algae (Desmodesmus subspicatis). OECD 201. Report # PT02-0120, January 2003.

3. 7. Internal report, Hoechst AG: Leflunomide Environmental Risk Assessment. Report # 016723, August 1997.

4. 3. Internal report, Hoechst AG: Acute Toxicity Study on Daphnia. OECD 202. Report # 96.0333, May 1996.

5. 4. Internal report, Hoechst AG: Acute Toxicity Study on Zebra Fish. OECD 203. Report # 93.0532, September 1993.

6. 6. Internal report, Hoechst AG: Study of Biodegradability of Leflunomide, OECD 301B. Report # 93-0111-42, October 1993.

7. 9. Internal report, Hoechst AG: Study of Biodegradability of A771726, OECD 301E.

8. Internal report, Wildlife International Ltd: Teriflunomide - Determination of the n-octanol/water partition coefficient by the shake flask method. OECD107. Report # 647C-130, June 2012

9. Internal document by Winthrop, a Sanofi company. February 2017; Third version. Retrieved from www.winthropus.com, 2022-01-17; find here.

10. Package insert: Arava, Sanofi-Aventis U.S. LLC, 2012.