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 = 0.0529 µg/L

Where:
A = 384,9709  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): >12 μg/L
NOEC 72 h (growth rate): 12 μg/L

Test item: Amiodarone Hydrochloride
(Protocol: OECD 201)
(Ref II)

Crustacean (Daphnia magna):

NOEC 21 d (reproduction, mortality): 68.4 μg/L
Test item: Amiodarone Hydrochloride

(Protocol: OECD 211)

(Ref III)

Fish (Pimephales promelas):
NOEC 28 days (survival, growth): 623 μg/L
(Protocol: OECD 210)
(Ref IV)

Other ecotoxicity data:

The PNEC (μg/L) = lowest EC₅₀/10 was calculated using results from the most sensitive toxicity endpoint and an assessment factor of 10 (three long-term results from species representing three trophic levels), to add a safety margin to the toxicity endpoint. The most sensitive species was Pseudokirchneriella subcapitata for which the NOEC 72 h was 12 μg/L.

PNEC = 12 μg/L/10 = 1.2 µg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC= 0.053/1.2 = 0.044

PEC/PNEC ≤ 0.1 which justifies the phrase “Use of amiodarone has been considered to result in insignificant environmental risk”.

Degradation

Biotic degradation

Ready degradability:

Test showed 0% degradation in 28 days (OECD 301B) (Ref V).

Justification of chosen bioaccumulation phrase:

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

Bioaccumulation

Partitioning coefficient:
Log Pow 7.96 at pH 7

Test item: Amiodarone Hydrochloride

(Protocol: OECD 123)

(Ref VI).

Justification of chosen bioaccumulation phrase:

Since log P_ow of 7.96 > 4 at pH 7, the substance has high potential for bioaccumulation.

Excretion (metabolism)

Amiodarone is excreted as <1 % as parent compound in urine and most of it is excreted as metabolites, through feces (Ref VII) (Ref VIII).

Metabolites identified are N-desethylamiodarone (main metabolite), di-N-desethylamiodarone (Ref IX). Metabolites may possess some antiarrhythmic activity (Ref IX).

References

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

2. Sanofi, internal report: Growth inhibition test with Amiodarone Hydrochloride on Algae (Pseudokirchneriella subcapitata). OECD 201. Report # 12/358-022AL, June 2013.

3. Sanofi Internal report: Chlorhydrate Amiodarone: Influence to Daphnia magna in a Semi-Static Reproduction Test. OECD 211. Report 135331221, 2019

4. Overturf MD, Overturf CL, Baxter D, Hala DN, Constantine L, Venables B, Huggett DB. 2012. Early life-stage toxicity of eight parmaceuticals to the fathead minnow, Pimephales promelas. 62: 455-464.

5. Sanofi, internal report: Determination of the ready biodegradability CO2 evolution test. OECD 301B. Report # 32145 ECS, January 2007.

6. Sanofi Internal report: Chlorhydrate Amiodarone: Determination or the Partition Coefficient (n-Octanol/Water) by Slow Stirring Method at pH7. OECD123. Report 135331186, 2019

7. Latini R, Tognoni G, Kates RE. 1984. Clinical pharmacokinetics of amiodarone. 9: 136-156.

8. Cohen-Lehman J, Dahl P, Danzi S, Klein I. 2010. Effect of amiodarone therapy on thyroid function. Nature Reviews Endocrinology. 6: 34-41.

9. HSDB, online review, February 2014: http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~we4XnE:1.