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 =5.10 x 10^-4 μg/L

Where:

A = 3.72  kg (total sold amount AP free base I in Sweden year 2022, data from IQVIA). Total volume of Ropinirole hydrochloride 4.24 = 3.72 Ropinirole free base. Total Ropinirole = 3.72.

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) (Ref. I)

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 (Selenastrum capricornutum):

IC50 96h (growth) = 29,300 μg/L (OECD 201) (Reference 8, 9)

NOEC = 8,800 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 41,100 μg/L (OECD 202) (Reference 16)

Water flea (Ceriodaphnia dubia):

Chronic toxicity

NOEC 8 days (reproduction) = 3,200 μg/L (USEPA 1002) (Reference 15)

Bluegill Sunfish (Lepomis macrochirus):

Acute toxicity

LC50 96 h (lethality) = 33,000 μg/L (OECD 203) (Reference 14)

NOEC = 3,700 μg/L

Chronic toxicity

No data

Other ecotoxicity data:

Microorganisms in activated sludge:

EC50 3 h (inhibition) = 500,000 μg/L @ 3 hrs (OECD 209) (Reference 11)

PNEC = 3,200/50 = 64 μg/L

PNEC (µg/L) = lowest NOEC/50, where 50 is the assessment factor applied for two long-term NOECs. NOEC for ceriodaphnia (= 3,200 µg/L) has been used for this calculation since it is the lowest value from all species tested.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 5.10 x 10^-4 /64 = 7.97 x 10^-6, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of ropinirole has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

No data

Inherent degradability:

< 10% degradation in 28 days (TAD 3.11). (Reference 12-13)

Abiotic degradation

Hydrolysis:

50% degradation @25^oC in 163 days (pH 7.4) (TAD 3.09). (Reference 10)

Photolysis:

50% degradation in 433-13,700 days (TAD 3.10). (Reference 10)

Justification of chosen degradation phrase:

Ropinirole is not considered readily or inherently degradable in microbial degradation tests. However, in alga toxicity and degradation tests the material has been shown to be degraded by green alga with a measured half-life of 8.2 days. The material may not be degraded in wastewater treatment but is expected to be degraded in surface water by alga (Reference 3-9). However, the relevant degradation products have not been identified and ecotoxicity has not been characterised. The phrase “Ropinirole is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow = 0.07 at pH 6.9 (TAD 3.02). (Reference 10)

Log Dow at pH 4.9 = -0.93

Log Dow at pH 6.9 = 0.07

Log Dow at pH 9.1 = 2.08

Log Dow at pH 11.5 = 2.13

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

Ropinirole is primarily cleared by the cytochrome P450 enzyme, CYP1A2, and its metabolites are mainly excreted in the urine. The major metabolite is at least 100 times less potent than ropinirole in animal models of dopaminergic function.

Ropinirole is cleared from the systemic circulation with an average elimination half-life of approximately 6 hours. The increase in systemic exposure (Cmax and AUC) to ropinirole is approximately proportional over the therapeutic dose range. No change in the oral clearance of ropinirole is observed following single and repeated oral administration. Wide inter-individual variability in the pharmacokinetic parameters has been observed (Reference 2).

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: Meatbolism and Elimination. Summary of Product Characteristics Requip (Ropinirole hydrochoride) Tablets. GlaxoSmithKline, February 2013.

   
   

3. Thies.F., Grimme,H.; Pestic. Sci. 1996, 337-346.

   
   

4. Megharar,M., et al; Bull. Environ. Contam. Toxicol. 1994, 53:292-297.

   
   

5. Lee, R.F.; Valkirs, A. O., Seligman, P.F., Environ. Sci. Technol. 1989, Vol.23, No. 12, 1515-1518.

   
   

6. Venkataramani, E.S., et al,   1994, 745(Biochemical Engineering VIII), 51-60.

   
   

7. Warshawsky, D., et al, Chemico-Biological Interactions 1995, 97, 131-148.

   
   

8. Orvos D and Hsu L SKF-101468A (Ropinirole HCI): Acute Algal Toxicity. Report No. ERL9513. SmithKline Beecham, August 1995.

   
   

9. Orvos D and Hannah RE. SKF-101468A (Ropinirole HCI): Ropinirole Algal Metabolites. Report No. ERL95-008. SmithKline Beecham, August 1995.

   
   

10. Physicochemical Characterization of SK&F 101468-A, SmithKline and French Laboratories, SK&F Report CP002BA, August 1986.

    
    

11. Further Physicochemical Characterization of SK&F 101468-A, SmithKline and French Laboratories, SK&F Report CW002BA, July 1987.

    
    

12. SmithKline Beecham Corporate Environmental Research Laboratory study S94019M, SK&F 101468: Continuous Activated Sludge (SCAS) Biodegradation.

    
    

13. SmithKline Beecham Corporate Environmental Research Laboratory study S94022M, SK&F 101468: Continuous Activated Sludge (SCAS) Biodegradation.

    
    

14. SK&F 101468-A (Ropinirole HCl): A 96-hour Static Acute Toxicity Test with the Bluegill Sunfish, report # 374A-101, Wildlife International Ltd, 1995.

    
    

15. Goodband TJ and Hill JWF. Ropinirole HCl: Daphnid, Ceriodaphnia dubia Survival and Reproduction Test. Report No. 1127/1211. Safepharm Laboratories Limited, January 2007.

    
    

16. Material Safety Data Sheet for Requip Tablets. SDS number 2943. GlaxoSmithKline plc, July 2008.