Detaljerad miljöinformation

Detailed background information

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 = 6.20 x 10^-6 μg/L

Where:

A = 0.0449 kg (total sold amount API in Sweden year 2021, data from IQVIA Health). Reduction of A may be justified based on metabolism data.

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 waste water by surface water flow = 10 (ECHA default) (Reference 1)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae:

No Data

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) >1 mg/L (OECD 202) (Reference 4)

NOEC > 1 mg/L

Water flea

Chronic toxicity

No Data

Fathead Minnow (Juvenile Pimephales promelas):

Chronic toxicity

LOEC 101 days (reproduction) = 79 μg/L (Extended OECD 210) (Reference 9)

NOEC = 21 μg/L

Other ecotoxicity data:

Microorganisms in activated sludge

EC50 3 hours (Inhibition) > 1,000,000 μg/L (OECD 209) (Reference 3)

Terrestrial toxicity

Manure worm (Eisenia foetida)

LC50 28 days (mortality) > 1,010,000 μg/kg (OECD 207) (Reference 7)

NOEC = 1,010,000 μg/kg

PNEC = 21/50 = 0.42μg/L

PNEC (μg/L) = lowest NOEC/50, where 50 is the assessment factor applied for one long-term NOECs but where there is a high degree of confidence that the dataset includes the most sensitive species (fish). On this basis the NOEC for fish has been used in the calculation.

PNEC Justification

An extended Fish ELS study was conducted to investigate the potential of dutasteride, as a 5-alpha-reductase inhibitor, to indirectly act as an endocrine disruptor. This modified extended fish early life stage toxicity test (OECD 210) examined the dose-effect relationship between aquatic dutasteride concentration and the development of secondary sexual characteristics and effects on gonad development in fish. Appropriate LOEC and NOEC values have been generated. Due to the mode of action of dutasteride and the potential receptor-mediated effects there is a high degree of confidence that the fish is the most sensitive species from the species base set and on that basis there is a strong justification for applying an AF of 50 (Reference 1).

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 6.20 x 10^-6 /0.42 = 1.46 x 10^-5, i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of dutasteride has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

<1% degradation in 28 days (OECD 301B) (Reference 8)

Inherent degradability:

<2.3% degradation in 64 days (OECD 304) (Reference 6)

Abiotic degradation

Hydrolysis:

No Data

Photolysis:

No Data

Justification of chosen degradation phrase:

Dutasteride is not readily biodegradable nor inherently biodegradable. The phrase “Dutasteride is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Kow = 3.87 (OECD 117) (Reference 5)

Justification of chosen bioaccumulation phrase:

Since log Pow < 4, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Dutasteride is extensively metabolized in vivo. In vitro, dutasteride is metabolized by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite. Following oral dosing of dutasteride 0.5 mg/day to steady state, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as unchanged dutasteride in the faeces. The remainder is excreted in the faeces as 4 major metabolites comprising 39%, 21%, 7%, and 7% each of drug-related material and 6 minor metabolites (less than 5% each). Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are detected in human urine. The elimination of dutasteride is dose dependent and the process appears to be described by two elimination pathways in parallel, one that is saturable at clinically relevant concentrations and one that is non saturable. At low serum concentrations (less than 3ng/mL), dutasteride is cleared rapidly by both the concentration dependent and concentration independent elimination pathways. Single doses of 5 mg or less showed evidence of rapid clearance and a short half-life of 3 to 9 days. At therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower, linear elimination pathway is dominating and the half-life is approx. 3-5 weeks (Reference 2).

PBT/vPvB assessment

Dutasteride does not fulfil the criteria for PBT and/or vBvP.

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Dutasteride does not fulfil the criteria for PBT and/or vBvP based on a log Dow < 4.

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. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Avodart (Dutasteride) 0.5mg Soft Capsules. GlaxoSmithKline, May 2013.

   
   

3. Mead C and Sewell IG. Assessment of the Inhibitory Effect of Gl198745X on the Respiration of Activated Sewage Sludge. Report No. 303/684. Safepharm Laboratories Limited, February 1995.

   
   

4. Sewell IG and Foulger J. The Acute Toxicity of Gl198745X to Daphnia Magna. Report No. 303/685. Safepharm Laboratories Limited, February 1995.

   
   

5. Tapp JF. Gl198745X: Estimation of Octanol-Water Partition Coefficient by HPLC Correlation (OECD117). Report No. BL5814/B. Brixham Environmental Laboratory, July 1998.

   
   

6. Tapp JF. Gl198745X: Aerobic Biodegradation in Soil. Report No. BL5845/B. Brixham Environmental Laboratory, July 1998.

   
   

7. Gillian N. Subacute Toxicity to the Earthworm. Report No. 70078/K21815. ABC Laboratories Europe, December 1999.

   
   

8. Jenkins WR. Gl198745X: Aerobic Biodegradation in Water with Acclimatised Composite Innoculum. Report No. 96/GLX178/0003. Huntingdon Life Sciences, January1999.

   
   

9. Caunter GE and Panter GH. Dutasteride: Determination of Effects on the Early-Life Stage (Extended) of the Fathead Minnow (Pimephales promelas). Report No. BL8580/B. Brixham Environmental Laboratory, September 2008.