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 = 1.5*10^-6*A*(100-R)

PEC = 0.0003 µg/L

Where:

A = 1.987 kg (total sold amount API in Sweden year 2019, 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 = 9×10⁶

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 inhibition): 30 000 μg/L

NOEC: 12 800 μg/L

(OECD 201)
(Ref II)

Crustacean (Daphnia magna):

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

(OECD 202)
(Ref III)

Fish (Brachydanio rerio):

LC₅₀ 96 h (mortality): 50 000 μg/L

(OECD 203)
(Ref IV)

Other ecotoxicity data:

PNEC = 30 µg/L

The PNEC (μg/L)= lowest EC₅₀/1000, was calculated using results from the most sensitive toxicity endpoint and an assessment factor of 1000 (at least one short-term L(E)C₅₀ from each of three trophic levels of the base set), to add a safety margin to the toxicity endpoint. The most sensitive species was Pseudokirchneriella subcapitata for which the EC₅₀ 72 h was 30 000 μg/L.

Environmental Risk Classification (PEC/PNEC ratio)
PEC/PNEC = 0.0003/30 = 1*10^-5, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of teriflunomide has been considered to result in insignificant environmental risk."

Biodegradation

Ready degradability:
Test showed less than 1 % degradation in 28 days.
(OECD 301)
(Ref V)

Justification of chosen degradation phrase:

Teriflunomide fails to pass the criteria for ready biodegradability which justifies the phrase “Teriflunomide is potentially persistent”.

Bioaccumulation

Partition coefficient:

Log P_ow =0.925 at pH 7
(OECD 107)
(Ref VI)

Justification of chosen bioaccumulation phrase:

Since log P_ow < 4 at pH 7, teriflunomide has low potential for bioaccumulation.

Excretion (metabolism)

Teriflunomide was found to be moderately metabolized. Metabolites identified are nine in the urine, counting the 4‑trifluoro‑methylaniline (TFMA) oxanilic acid, and three in the feces (Ref VII). The pharmacological activity of the metabolites is not known.

References

1. ECHA, European Chemicals Agency: Guidance on information requirements and chemical safety assessment. 2008. https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment

2. Internal Report: A 771726 - Algal growth inhibition - Selenastrum capricornutum. - OECD 201 - Report # CE96/064. April 1997.

3. Internal Report: A 771726 - 48-hour acute toxicity study in Daphnia magna (water flea). - OECD 202 - Report # 96.0377. May 1996.

4. Internal Report: A 771726 - 96-hour acute toxicity study in zebra fish (Brachydanio rerio). - OECD 203 - Report # 96.0409. July 1996.

5. Internal Report: HMR 1726 - Ready biodegradability in a manometric respirometry test. - OECD 301F - Report # 2000.1155. March 2001.

6. Internal Report: Teriflunomide: Determination of the n‑octanol/water partition coefficient by the shake flask method. - OECD 107
   US EPA OPPTS 830.7550 - Report # 647C-130. June 2012.

7. Environmental Risk Assessment Report: Teriflunomide (HMR1726). January 2012.