Detaljerad miljöinformation

Physical properties

Solubility at pH 5¹⁰: 30 000 µg/L

Solubility at pH 7¹⁰: 32 000 µg/L

Solubility at pH 9¹⁰: 91 000 µg/L

pKa (pyridinium ion)³: 2,6

pKa (phenol group) ³: 8,3

Molecular weight³: 337.38 Da

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 = 0.000626 μg/L

Where:

A =	5 kg (estimated API sold during 2024).
R =	8.6 % removal rate due to loss by adsorption to sludge particles as calculated in the OECD 106 study, by volatilization, hydrolysis or biodegradation.
P =	number of inhabitants in Sweden = 10×106
V (L/day) =	wastewater volume per capita and day = 200 (ECHA default)1
D =	factor for wastewater dilution by surface water flow = 10 (ECHA default)1

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Species	Guideline (OECD)	Results of chronic toxicity test	Ref
Activated sludge	209	Respiration inhibition 3-hour EC50 = >1000 000 μg/L 3-hour NOEC = 1000 000 μg/L	8
Green algae (Raphidocelis subcapitata)	201	Growth rate 72-hour EC10 = 310 μg/L 72-hour LOEC = 420 μg/L 72-hour NOEC = 80 μg/L	4
Daphnids (Daphnia magna)	211	Reproduction 21-day EC10 = 300 μg/L 21-day LOEC = 800 μg/L 21-day NOEC = 210 μg/L	5
Fish, fathead minnow (Pimephales promelas)	210	Body length 33-day EC10 = 430 μg/L 33-day LOEC = 130 μg/L 33-day NOEC = 40 μg/L Post-hatch survival 33-day EC10 = 340 μg/L 33-day LOEC = 1300 μg/L 33-day NOEC = 420 μg/L	6
Sediment midge larvae (Chironomus riparius)	218	Emergence and development 28-day EC10 = >677 000 µg/kg 28-day NOEC = 677 000 µg/kg	7

Based on the lowest NOEC for the species Pimephales promelas, and using the assessment factor² of 10, the PNEC is calculated to 40/10 = 4 µg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000625 / 4 = 0.000156, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ”Use of voxelotor has been considered to result in insignificant environmental risk.”

Adsorption (guideline OECD 106)⁹

Solid	KF (L/Kg)	KFoc (L/Kg)
Activated sludge (Ipswitch)	580	1190
Activated sludge (Worlingworth)	571	1330
HOM soil (Elmton)	16.6	386
LOM soil (Bromsgrove)	6.49	433
LOM soil (Drayton)	17.6	1170

HOM = high organic matter, LOM = low organic matter

Fraction removed on wasted sludge = (0.165×K_F) / [(0.165×K_F) + 1000] where 0.165 represents the grams of sludge wasted per 1000 grams of wastewater treatment plants' aqueous effluent. Based on the lowest sludge K_F of 571, the fraction of voxelotor removed on wasted sludge is = (0.165×571) / [0.165×571 + 1000] = 0.086 = 8.6 %.

Degradation

Biotic degradation

Ready degradability (guideline OECD 301B)¹¹

The test was made over a 28-day period and showed no biodegradation. Voxelotor is thus not readily biodegradable according to the OECD criteria for ready biodegradability.

Water-sediment transformation simulation (guideline OECD 308)¹²

Length of study:	100 days
High organic sediment system:	Emperor Lake
Low organic sediment system:	Calwich Abbey Lake
Sediment extraction solvent:	Acetonitrile, acetonitrile/water (50:50 v/v), acetonitrile/0.1 M HCl (50:50v/v)
Supplemental extraction solvents:	0.5 NaOH, 1 M HCl

The results from the study are shown in the table below.

Data on day 100 at 20 °C	Emperor Lake	Calwich Abbey Lake
Total system
Half-life (days)	7.1	6.8
Total 14CO2 (% of AR)	4.1	7.2
% Parent (% of AR)	2.2	2.1
Aerobic Water Layer
Half-life (days)	5.8	6.1
Parent (% of AR)	0.2	0.8
Sediment Layer
Half-life (days)	42.0	58.8
Bound/NER (% of AR)	40.6	32.8
Extractables (% of AR)	36.0	24.3
Parent (% of AR)	2.0	1.3

ND = not detected, NER = non-extractable residues, AR = applied radioactivity

Justification of chosen degradation phrase

As the total system DT₅₀ value (water-sediment transformation simulation, OECD 308) was calculated to be 7.1 days, it corresponds to the degradation phrase ”voxelotor is degraded in the environment”

Bioaccumulation

Bioconcentration factor (BCF) (guideline OECD 305)¹³

Species: Rainbow trout (Lepomis macrochirus)

Length of exposure: 23 days

Whole fish kinetic BCF: 113

Partitioning coefficient (guideline OECD 107)¹⁴

pH	Log Pow
5	3.16
7	3.16
9	2.77

Justification of chosen bioaccumulation phrase

Since BCF < 500, and since log D_ow < 4 at pH 7, voxelotor has low potential for bioaccumulation.

References

1. ECHA, European Chemicals Agency. 2016 Guidance on information requirements and chemical safety assessment chapter R16.

2. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment chapter R10.

3. Study report MT41PC. Global Blood Therapeutics, Inc. (Envigo CRS Limited). GBT440: Dissociation Constant. March 2019.

4. Study report NV90VM. Global Blood Therapeutics, Inc. (Covance CRS Research Limited). GBT440: Algal Growth Inhibition Test. July 2019.

5. Study report LH80PL. Global Blood Therapeutics, Inc. (Covance CRS Research Limited). GBT440: Daphnia magna Reproduction Test. July 2019.

6. Study report FT36BR. Global Blood Therapeutics, Inc. (Covance Laboratories Limited). GBT440: Fish, Early Life Stage Toxicity Test. April 2021.

7. Study report JP94YG. Global Blood Therapeutics, Inc. (Covance CRS Research Limited). GBT440: Sediment-Water Chironomid Toxicity Test Using Spiked Sediment. July 2019.

8. Study report PR77DH. Global Blood Therapeutics, Inc. (Envigo Research Limited). GBT440: Toxicity to Activated Sludge in a Respiration Inhibition Test. March 2019.

9. Study report GQ51FL. Global Blood Therapeutics, Inc. (Covance CRS Ltd.). GBT440: Adsorption/Desorption on Soils & Sewage Sludge. October 2019.

10. Study report MV20DW. Global Blood Therapeutics, Inc. (Envigo Research Limited). GBT440: Water Solubility. February 2019.

11. Study report NY38PF. Global Blood Therapeutics, Inc. (Envigo Research Limited). GBT440: Assessment of Ready Biodegradability; CO₂ Evolution Test. March 2019.

12. Study report PM74FF. Global Blood Therapeutics, Inc. (Covance Laboratories Ltd.). GBT440: Aerobic Transformation in Aquatic Sediment Systems. July 2020.

13. Study report JP65LC. Global Blood Therapeutics, Inc. (Covance Laboratories Ltd.). GBT440: Bioaccumulation in Fish. June 2020.

14. Study report MT58NN. Global Blood Therapeutics, Inc. (Envigo CRS Limited). GBT440: Partition coefficient. February 2019.