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 = 0.415 µg/L

Where:

A = 3030.845 kg (total sold amount API in Sweden year 2022, 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, 2008; Ref I).

D = factor of dilution of waste water by surface water flow = 10 (ECHA, 2008; Ref I).

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata):

EC₅₀ 72 h (biomass) = 4440 μg/L

NOEC = 850 μg/L

(Protocol: OECD 201)

(Ref II)

EC₅₀ 72 h (growth inhibition) > 6900 μg/L

MIC/NOEC = 850 μg/L

(Protocol: OECD 201)

(Ref II)

Crustacean (Daphnia magna):

EC₅₀ 48 h (immobilization) = 8300 μg/L

NOEC 48 h (immobilization) = 6200 μg/L

(Protocol: OECD 202)

(Ref III)

EC₅₀ 21 days (growth) > 2300 μg/L

NOEC 21 days (growth) = 710 μg/L

(Protocol: OECD 211)

(Ref IV)

Fish (Oncorhynchus mykiss):

LC₅₀ 96 h (mortality) = 4000 μg/L

NOEC 96 h (mortality) = 1010 μg/L

(Protocol: OECD 203)

(Ref V)

Fish (Pimephales promelas):

NOEC 21 days (growth & survival) = 310 μg/L

(Protocol: OECD 210)

(Ref VI)

Other ecotoxicity data:

PNEC = lowest EC₅₀/10 = 31 µg/L, using results from the most sensitive chronic toxicity endpoint and an assessment factor of 10 (long-term results from at least three species of the base set), to add a safety margin to the toxicity endpoint. The most sensitive species was Pimephales promelas for which the NOEC 21 days was 310 μg/L.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC= 0.415/31 = 0.013, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase:
“Use of clopidogrel has been considered to result in insignificant environmental risk”.

Degradation

Biotic degradation

Simulation studies:

Test results from DT50_{total system} = 7.5 (sediment 1) - 13.5 (sediment 2) days; DT50_water = 7.2 (sediment 1) - 8.1 (sediment 2) days. At the end of the study, there was no parent compound remaining in the total system (in 104 days). The extraction method used was the ISO 14240-2:1997. The total amount of radioactivity in the sediment layers was calculated from the amounts measured in the sediment extracts plus the amounts measured in the sediment solids after extraction. Supplementary extractions were performed to evaluate the potential to remove additional radiolabeled materials from the sediment solids. Supplemental extractions of the solids removed the equivalent of < 5 % of dosed radioactivity.

(Protocol: OECD 308)
(Ref VII)

Justification of chosen degradation phrase:

As DT50_{total system} < 32 days with no clopidogrel detected by the end of the study, the correct phrase to use is: "Clopidogrel is degraded in the environment".

Bioaccumulation

Partition coefficient:

Log P_ow = 3.76 at pH 7 (US EPA & OECD 107)
(Ref VIII)

Justification of chosen bioaccumulation phrase:
Since log P_ow < 4 at pH 7, clopidgrel has low potential for bioaccumulation.

Excretion (metabolism)

Clopidogrel and its metabolites are excreted in urine and in feces; about 50% of an oral dose is recovered from the urine and about 46% from the feces.

Metabolites identified are R‑130964 and SR26334.
(Ref IX)

The pharmacological activity of the metabolites is not known.

References

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

2. Sanofi, internal report: Toxicity of Clopidogrel to the unicellular green alga, Pseudokirchneriella subcapitata. OECD 201. Report # 48678. July 2004.

3. Sanofi, internal report: Clopidogrel: Acute toxicity to daphnids (Daphnia magna) under static conditions. OECD 202. Report # 96-11-6784. January 1999.

4. Sanofi, internal report: Clopidogrel: A flow-through life-cycle toxicity test with the cladoceran (Daphnia magna). OECD 211. Report # 647A-106. January 2009.

5. Sanofi, internal report: Acute toxicity of Clopidogrel to the rainbow trout, Oncorhynchus mykiss, determined under static test conditions. OECD 203 & FDA 4.11. Report # 48677. July 2004.

6. Sanofi, internal report: Clopidogrel: An early life-stage toxicity test with the fathead minnow (Pimephales promelas). OECD 210. Report # 850.1400. January 2009.

7. Sanofi, internal report: Clopidogrel: aerobic transformation in aquatic sediment systems. OECD 308. Report # 647E-109. February 2009.

8. Sanofi, internal report: Determination of n‑octanol/water partition coefficient of Clopidogrel.US EPA & OECD 107. Report # 647C-119. July 2010.

9. Farid NA, Payne CD, Small DS, Winters KJ, Ernest II CS, Brandt JT, Darstein C, Jakubowski JA, Salazar DE. 2007 Cytochrome P450 3A inhibition by Ketoconazole affects Prasugrel and Clopidogrel pharmacokinetics and pharmacodynamics differently. Nature Plublishing group. 81: 735-741.