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 = 0.025 μg/L

Where:

A = 180.16 kg (total sold amount API free base in Sweden year 2022, data from IQVIA). Total volume of Paroxetine hydrochloride 136.78 = 123.10 Kg Paroxetine free base. Total volume of Paroxetine hydrochloride hemihydrate 64.84 = 57.06 Kg Paroxetine free base. Total paroxetine = 123.10 + 57.06 = 180.16 Kg.

R = 0% removal rate (conservatively, it has been assumed there is no 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) (Reference 1)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference 1)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae

Green Algae (Scenedesmus subspicatus):

IC50 96h (growth) = 140 μg/L (ISO8692) (Reference 3)

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 2,500 μg/L (OECD 202) (Reference 6)

Water flea (Ceriodaphnia dubia):

Chronic toxicity

NOEC 7 days (reproduction) = 250 μg/L (USEPA 1002) (Reference 4)

Bluegill sunfish (Lepomis macrochirus):

Acute toxicity

LC50 48 h (lethality) = 1,600 μg/L (OECD 203) (Reference 8)

Chronic toxicity

No data

Microorganisms in activated sludge:

EC50 3 h (inhibition) = 25,000 µg/L (OECD 209) (Reference 2)

PNEC = 140/1000 = 0.14 μg/L

PNEC (μg/L) = lowest EC50/1000, where 1,000 is the assessment factor applied for three acute EC50s. The EC50 for alga (= 140 µg/L) has been used for this calculation since it is the most sensitive of the three tested species. It is more protective of the environment if hazard assessment is based on the alga EC50, as this is lower than the chronic daphnia NOEC.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.025/0.14 = 0.18 i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of paroxetine has been considered to result in low environmental risk.”

Degradation

Biotic degradation

Ready degradability:

<1% degradation in 28 days (TAD 3.11) (Reference 7)

Primary metabolite (BRL36610):

50% primary degradation in 23 hrs.

Inherent degradability:

No Data

Abiotic degradation

Hydrolysis:

No Data

Photolysis:

t_1/2 = 15.79 h @ 25^oC (pH 5 buffer) (Reference 3)

t_1/2 = 13.11 h @ 25^oC (pH 7 buffer)

t_1/2 = 11.35 h @ 25^oC (pH 9 buffer)

Photolysis may be calculated @ 12^oC (Reference 1)

t_1/2 = 44.69 h @ 12^oC (pH 5 buffer)

t_1/2 = 37.10 h @ 12^oC (pH 7 buffer)

t_1/2 = 32.12 h @ 12^oC (pH 9 buffer)

Justification of chosen degradation phrase:

Paroxetine is not readily degradable or inherently degradable. This substance degrades rapidly via photolysis but fate and effects data is not available for photo degradants. The phrase “paroxetine is potentially persistent in the environment” is thus chosen.

Bioaccumulation

Bioconcentration factor (BCF):

Partitioning coefficient:

Log Dow = 1.30 at pH 7 (TAD 3.04). (Reference 2)

Log Dow at pH 5 = 1.10

Log Dow at pH 7 = 1.30

Log Dow at pH 9 = 3.30

Justification of chosen bioaccumulation phrase:

Since log Dow < 4 at pH 7, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Paroxetine is excreted to 3% as parent compound and to 64% as metabolites. The pharmacological activity of the metabolites is known. (Reference 9)

Metabolites

Primary mammalian metabolism proceeds through a catechol intermediate, which is unstable, to 3 main metabolites which are products of oxidation and methylation followed by conjugation. None of these conjugates can be converted back to the active substance.

Pharmacological activity (potency) for the metabolites vs the mother substance: The major metabolites structurally closest to the active substance have at most 1/50 of parent activity. Other less similar metabolites are considered inactive.

Excretion

Urinary excretion of unchanged paroxetine is generally less than 2% of dose whilst that of metabolites is about 64% of dose. About 36% of the dose is excreted in faeces, probably via the bile, of which unchanged paroxetine represents less than 1% of the dose. Thus paroxetine is eliminated almost entirely by metabolism (Reference 9).

Please, also see Safety data sheets on http://www.msds-gsk.com/ExtMSDSlist.asp.

References

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

2. Virginia L. Cunningham, David J. C. Constable, and Robert E. Hannah. Environmental Risk Assessment of Paroxetine. Environ. Sci. Technol., 2004: 38 (12): 3351-3359.

3. Christensen et al. Mixture and Single-Substance Toxicity of Selective Serotonin Reuptake Inhibitors toward Algae and Crustaceans. Enviromental Toxicology and Chemistry, 2007: 26(1):85-91.

4. Henry et al. Acute and chronic toxicity of five selective serotonin reuptake inhibitors in Ceriodaphnia dubia. Environmental Toxicology and Chemistry, 2004: 23 (9): 2229-2233.

5. British Pharmacopoeia Chemical Reference Substance. Paroxetine Material Safety Data Sheet. British Pharmacopoeia Commission, April 2011.

6. Forbis AD and Herzig R. Acute Toxicity of the free base of BRL-029060-A (Paroxetine HCL) to Daphnia magna. Report No. ERL-ABC39280. ABC Laboratories, Jun 1991.

7. Orvos DR. Paroxetine Hydrochloride (BRL-029060-A) and Paroxetine Metabolite (BRL-036610-A): Summary Report for In house Aerobic Biodegradation and Microbial Toxicity Studies. Report No. ERL9119. SmithKline Beecham, October 1991.

8. FDA-CDER 1996. Retrospective Review of Ecotoxicity Data submitted in Environmental Assessments. FDA Centre for Drug Evaluation and Research, Rockville, MD, USA.

9. Seroxat Oral Suspension Summary of Product Characteristics, GlaxoSmithKline, July 2010.