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 = 0.32 µg/l

Where:
A = 2364.8439 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 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 (biomass): 12 μg/L
NOEC: 4 μg/L

EC₅₀ 72 h (growth inhibition): 45 μg/L
NOEC: 4 μg/L
(Protocol: OECD 201)
(Ref II)

Algae (Anabaena flos-aquae):
EC₅₀ 72 h (biomass): 240 μg/L
NOEC: 730 μg/L

EC₅₀ 72 h (growth inhibition): 250 μg/L
NOEC: 120 μg/L
(Protocol: OECD 201)
(Ref III)

Crustacean (Daphnia magna):

Acute toxicity

EC₅₀ 48 h (immobilization): >430 μg/L
(Protocol: OECD 202)
(Ref IV)

Chronic toxicity

EC₅₀ 21 days (reduction in reproduction): >290 μg/L
NOEC 21 days (reduction in reproduction): 110 μg/L
(Protocol: OECD 211)
(Ref V)

Fish (Oncorhynchus mykiss):

Acute toxicity

LC₅₀ 96 h (mortality): 450 μg/L
(Protocol: OECD 203)
(Ref VI)

Fish (Pimephales promelas):

Chronic toxicity

NOEC 33 days (lethality): 26 μg/L
(Protocol: OECD 210)
(Ref VII)

Other ecotoxicity data:

PNEC = 0.4 µg/L

PNEC (µg/L) = Lowest EC₅₀/10, was calculated using results from the most sensitive 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 Pseudokirchneriella subcapitata for which the NOEC 72 h was 4 μg/l.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC= 0.32/0.4 = 0.8, i.e. 0.1 < PEC/PNEC ≤ 1 which justifies the phrase “Use of dronedarone has been considered to result in low environmental risk”.

Degradation

Biotic degradation

Ready biodegradation:
Test showed < 25% degradation in 28 days (OECD 301B)
(Ref VIII)

Inherent degradability:
Test showed 22.8% degradation in 29 days (OECD 302B)
(Ref IX)

Abiotic degradation

Hydrolysis:
Test showed 1.6% degradation in 5 days (OECD 111)
(Ref X)

Justification for degradation phrase:

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

Bioaccumulation

Partition coefficient:

Log P_ow = 4.63 at pH 7 (OECD 107)

(Ref XI)

Bioconcentration factor (BCF):

Dronedarone has low potential for bioaccumulation, as indicated by a whole fish steady state total radioactive residue (TRR) BCF of 466 and a steady state dronedarone BCF of 134 at the highest test concentration of 11 µg/L. Normalized to 6% body fat, this results in a whole fish TRR BCF of 730 and a Dronedarone BCF of 210. (OECD 305) (Ref XII)

Excretion (metabolism)

Dronedarone is excreted at 6% in urine and 84% in feces almost only as metabolites. The main metabolite identified is N-debutyl metabolite and exhibits pharmacodynamic activity but is 3- to 10 times less potent than the parent compound. This metabolite contributes to the pharmacological activity of dronedarone in humans. (Ref XIII)

References

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

2. Sanofi, internal report: Dromedarone - Acute toxicity to the freshwater green alga, Pseudokirchneriella subcapitata. OECD 201. Report #13570.6109 July 2005.

3. Sanofi, internal report: Dromedarone - Acute toxicity to the freshwater blue-green alga, Anabaena flos-aquae. OECD 201. Report #13570.6159 July 2005.

4. Sanofi, internal report: Dromedarone - Acute toxicity to water fleas, (Daphnia magna) under static conditions. OECD 202. Report #13570.6110 July 2005.

5. Sanofi, internal report: Dromedarone - Full life-cycle toxicity test with water fleas, Daphnia magna under static conditions. OECD 211. Report #13570.6118 May 2008.

6. Sanofi, internal report: Dromedarone - Acute toxicity to Rainbow trout (Oncorhynchus mykiss) under static conditions. OECD 203. Report #13570.6111 July 2005.

7. Sanofi, internal report: Dromedarone - Early life-stage toxicity test with fathead minnow, (Pimephales promelas). OECD 210. Report #13570.6137 May 2008.

8. Sanofi, internal report: Dromedarone - Determination of the biodegradability of a test substance. OECD 301B. Report # 13570.6117 May 2008.

9. Sanofi, internal report: Dromedarone - Determination of the biodegradability based on a modified OECD Method 302B. OECD 302B. Report #13570.6135 May 2008.

10. Sanofi, internal report: Dromedarone - Determination of the abiotic degradability of the tested substance by hydrolysis at three different pH values. OECD 111. Report #13570.6116 May 2008.

11. Sanofi, internal report: Dromedarone - Determination of the n-Octanol/Water partition coefficient. OECD 107. Report # 13570.6113 July 2005.

12. Sanofi, internal report: Dromedarone - Flow-through bioconcentration and metabolism study with bluegill sunfish (Lepomis macrochirus). OECD 305. Report #1102.003.135. May 2008.

13. HSDB: http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~mveE3m:1