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* 23.4621 *100

PEC = 0.00321 μg/L

Where:

A = 23.4621 kg (total sold amount API in Sweden year 2021, data from IQVIA).

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 (Selenastrum caprocornutum):

IC50 96h (growth) > 500 μg/L (OECD 201) (Reference 6)

NOEC = 500 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 2,900 μg/L (OECD 202) (Reference 5)

NOEC = 2,900 μg/L

Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) = 160 μg/L (OECD 211) (Reference 8)

Rainbow Trout:

Acute toxicity

No data

Fathead minnow (Pimephales promelas):

Chronic toxicity

NOEC 28 days (growth) = 333 μg/L (OECD 210) (Reference 9)

Other ecotoxicity data:

Chironomid (Chironomus riparius)

NOEC 28 days (emergence) = 1,000,000 μg/kg (OECD 218) (Reference 12)

Microorganisms in activated sludge

EC50 3 hours (Inhibition) > 1,083,000 μg/L (OECD 209) (Reference 4)

PNEC = 160/10 = 16 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for water flea (= 160 ug/L) has been used for this calculation since it is the most sensitive of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00321 μg/L / 16 μg/L = 0.0002, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of pazopanib has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

No data

Inherent degradability:

0% degradation in 28 days (OECD 301C) (Reference 3)

Simulation studies:

50% (DT₅₀) degradation > 365 days (OECD 308) (Reference 11)

Non-extractable residues = 8.60% - 10.50%

Abiotic degradation

Hydrolysis:

No data

Photolysis:

No data

Justification of chosen degradation phrase:

Pazopanib is not readily biodegradable nor inherently biodegradable. This substance is predicted to degrade in water sediment systems > 120 days. The phrase “Pazopanib is potentially persistent” is thus chosen.

Bioaccumulation

Bioconcentration factor (BCF):

                      Rainbow trout (Oncorhynchus mykiss)

BCF = 5 - 6 (OECD 305) (Reference 10)

Partitioning coefficient:

Log Dow = 3.33 at pH 7 (OECD 107) (Reference 7)

Log Dow at pH 5 = 2.26

Log Dow at pH 7 = 3.33

Log Dow at pH 9 = 3.92

Justification of chosen bioaccumulation phrase:

Since BCF < 500, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Results from in vitro studies demonstrated that metabolism of pazopanib is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8.

Pazopanib is eliminated slowly with a mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via faeces with renal elimination accounting for < 4 % of the administered dose. (Reference 2)

PBT/vPvB assessment

Pazopanib 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). Pazopanib does not fulfil the criteria for PBT and/or vBvP based on a BCF < 500 and a chronic NOEC > 0.01 mg/L.

References

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

2. Global datasheet Pazopanib. Version 16. 18 October 2016.

3. Mead C and McKenzie J. GW786034B: Assessment of Inherent biodegradability; modified MITI (II) test. Report No. 1127/1081. Safepharm Laboratories Limited, March 2006.

4. Clarke N. GW786034B: Assessment of the inhibitory effect on the respiration of activated sewage sludge. Report No. 1127/1082. Safepharm Laboratories Limited, March 2006.

5. Mead C and McKenzie J. GW786034B: Acute toxicity to Daphnia. Report No. 1127/1080. Safepharm Laboratories Limited, March 2006.

6. Vryenhoef H and Mullee DM. GW786034B: Algal growth inhibition test. Report No.1127/1735. Safepharm Laboratories Limited, September 2008.

7. White DF and Walker JA:  GW786034B: Determination of partition coefficient. Report No.1127/1734. Safepharm Laboratories Limited, September 2008.

8. Goodband TJ and Mullee DM.  GW786034B: Daphnia magna reproduction test. Report No.1127/1736. Safepharm Laboratories Limited, October 2008.

9. Goodband TJ and Mullee DM.  GW786034B: Fish early-life stage toxicity test. Report No.1127/1737. Safepharm Laboratories Limited, January 2009.

10. Goodband TJ. Pazopanib Hydrochloride (GW786034): Bioconcentration: Flow-through fish test. Report No.1127/1888. Safepharm Laboratories Limited, October 2011.

11. Roulstone P. Pazopanib (GW786034): Route and rate of degradation in two aerobic Aquatic sediment systems. Report No.1127/1889. Safepharm Laboratories Limited, May 2011.

12. Goodband TJ and Mullee DM. Pazopanib (GW786034): Sediment –Water Chironomid Toxicity Test using Spiked Sediment. Report No. 41104158. Safepharm Laboratories Limited, June 2012.