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 = 0.00103 μg/L

Where:

A = 7.5272 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) (Ref. I)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Lesser Duckweed (Lemna minor):

IC50 96h (inhibition growth rate) = 1’200 μg/L (OECD 221) (Reference 3)

NOEC = 450 μg/L

Water flea (Daphnia magna)

Acute toxicity

EC50 48 h (immobility) = 1’500 μg/L (OECD 202) (Reference 4)

NOEC = 540 μg/L

Chronic toxicity

NOEC 21 d (reproduction and immobilisation) = 120 µg/L (OEC 211) (Reference 5)

Fish:

Acute toxicity in rainbow trout (Oncorhynchus mykiss)

LC50 96 h (lethality) = 2’500 μg/L (OECD 203) (Reference 6)

NOEC = 1’600 μg/L

Chronic toxicity in zebra fish (Danio rerio)

NOEC 28 d (larval survival, and length and weight) = 52.0 µg/L (Reference 7)

Other ecotoxicity data:

Microorganisms in activated sludge:

          EC50 3 h (inhibition) > 320’000 μg/L @ 3 hrs (OECD 209) (Reference 8)

          NOEC = 25’000 μg/L

Sediment-dwelling organisms (Chironomus riparius, non-biting midge)

NOEC 28 days (development rate and emergence) = 104.0 mg/kg (OECD 218) (Reference 9)

PNEC = 52 µg/L / 10 = 5.2 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three chronic NOECs. The NOEC for fish larval survival and fish larval growth (= 52 µg/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 = 0.00103 μg/L / 5.2 µg/L = 0.000198, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of eltrombopag has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

No data

Inherent degradability:

10% degradation in 14 days (OECD 302). (Reference 10)

This substance is not inherently biodegradable.

Transformation in water-sediment systems:

DT50 in total system > 120.0 days (OECD 308). (Reference 11)

Study duration: 106 days;

Due to rapid degradation in the water and extended lag phases in both test systems approximately 10 to 20 % degradation of Eltrombopag Olamine was observed over too few data points to allow kinetics to be performed. Therefore, no DT50 values were calculated for the water phases, sediment or the entire system, respectively.

Abiotic degradation

Hydrolysis:

50% degradation @14^oC in 14 days (pH 7) (TAD 3.09). (Reference 12)

50% degradation @14^oC in 752 days (pH 9)

Photolysis:

No data

Justification of chosen degradation phrase:

Eltrombopag is not readily biodegradable nor inherently biodegradable. This substance is predicted to degrade via hydrolysis and the half-life is less than 40 days. However, the results from the hydrolysis study were not strongly first order and rates did not scale according to temp. The phrase “Eltrombopag is potentially persistent” is thus chosen.

Bioaccumulation

Bioconcentration Factor (BCF)

Rainbow trout, Oncorhynchus mykiss

BCFss = 14 (OECD 305) (Reference 13)

BCFk = 16-29

Partitioning coefficient:

Log Dow = 1.54 at pH 7.4 (OECD 107) (Reference 14)

Log Dow at pH 1.2 = -0.6

Log Dow at pH 6.0 = -0.1

Log Dow at pH 7.4 = 1.54

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

Eltrombopag is primarily metabolized through cleavage, oxidation and conjugation with glucuronic acid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64 % of plasma radiocarbon AUC0-. Minor metabolites due to glucuronidation and oxidation were also detected. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for oxidative metabolism of eltrombopag. Absorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is via faeces (59 %) with 31 % of the dose found in the urine as metabolites. Unchanged parent compound (eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts for approximately 20 % of the dose. The plasma elimination half-life of eltrombopag is approximately 21-32 hours (Reference 2).

PBT/vPvB assessment

Eltrombopag 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). Eltrombopag does not fulfil the criteria for PBT and/or vBvP based on a BCF ≤ 2000.

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 Revolade (Eltrombopag olamine). GlaxoSmithKline, May 2011.

3. Vryenhoef H and Hill JFW. SB-497115-GR: SB-497115-GR:  Lemna Growth Inhibition Test. Report No. 1127/1200. Safepharm Laboratories Limited, May 2007.

4. Wetton PM and McKenzie J. SB-497115-GR: Acute Toxicity to Daphnia magna. Report No. 1127/896. Safepharm Laboratories Limited, December 2005.

5. Report 2014N194420_00: Eltrombopag Olamine: Effect on Survival and Reproduction of Daphnia magna in a Semi-Static Test over Three Weeks (OECD 211) (Project Number D80342). Harlan Laboratories, March 2014.

6. Sewell IG and JFW Hill. SB-497115-GR: Acute Toxicity to Rainbow Trout (Oncorhynchus mykiss). Report No. 1127/1326. Safepharm Laboratories Limited, March 2007.

7. Report 2014N194417_00: Eltrombopag Olamine: Toxic Effects to Zebra Fish (Danio rerio) in an Early-Life Stage Toxicity Test (OECD 210) (Project Number D80331). Harlan Laboratories, March 2014.

8. Clarke N. SB-497115-GR: Assessment of the Inhibitory Effect on the Respiration of Activated Sewage Sludge. Report No. 1127/898. Safepharm Laboratories Limited, December 2005.

9. Report 2016N274772_00. Eltrombopag olamine: Sediment-Water Chironomid Toxicity Test Using Spiked Sediment. (Study Number 41401355). Envigo Research Limited, March 2016.

10. Mead C and McKenzie J. SB-497115-GR: Assessment of Inherent Biodegradability; Modified MITI (II) Test. Report No. 1127/897. Safepharm Laboratories Limited, February 2006.

11. Report 2014N209349_00: [¹⁴C] Eltrombopag Olamine: Route and Rate of Degradation in Aerobic Aquatic Sediment Systems. (Project Number D80320). Harlan Laboratories, July 2014 

12. Roulstone P. SB-497115-GR: Hydrolysis as a Function of pH. Report No. 1127/1161. Safepharm Laboratories Limited, February 2007.

13. Goodband TJ. Eltrombopag Olamine (SB-497115-GR): Bioconcentration: Flow-Through Fish Test (OECD 305). Report No. 1127/1887. Harlan Laboratories Limited, October 2011.

14. O’Connor BJ and Mullee DM. SB-497115-GR: Determination of Partition Coefficient. Report No. 1127/1302. Safepharm Laboratories Limited, October 2006.