Detaljerad miljöinformation

Environmental Risk Assessment (ERA)

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula (FASS 2021, Ref I):

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100)

Where:

A= 6.4 kg (Predicted maximum annual amount to be sold in Sweden 2022-2025)

R = 0 (In the OECD 106 adsorption study the Koc for the two sewage sludges were 118 and 123 (Ref I). These values indicated very low adsorption to sewage sludges and when the Koc of 118 was introduced into the EUSES Version 2.2 which includes the current SimpleTreat model, the emission directed to water was >98% (Ref II). The output is provided as an Appendix 1. As a worst case, the value for R has been taken as zero.

P = number of inhabitants in Sweden = 10 x 10⁶ (SCB Statistics Sweden, Ref III)

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default; Ref. IV)

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

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100)

= 6.4x10⁹*(100-0)/365*10x10⁶*200*10*100

PEC = 0.000877 μg/L

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies (Chronic toxicity)

All studies followed the quoted OECD Guideline and were conducted under Good Laboratory Practice. Sotorasib was analysed in the test system media using fully validated analytical methods.

Algae (Raphidocelis subcapitata) (Guideline OECD 201, Ref V):

	Average specific growth rate	Yield
	µg/L
NOEC	8,400	Not determined

72 h NOEC = 8,400 μg/L

Crustacean (Daphnia magna) (Guideline OECD 211, Ref VI):

	Mortalities	Length	Reproduction
			Live neonates per adult
	µg/L
NOEC	10,000	10,000	10,000

NOEC 21 days = 10,000 μg/L

Fish Early Life Stage (Pimephales promelas): (Guideline OECD 210, Ref VII):

Endpoint	Hatching success	Post-hatch survival	Growth
			Length	Wet Weight
	µg/L
NOEC	11,000	11,000	11,000	11,000

NOEC 28 days = 11,000 μg/L

Other ecotoxicity data

Sediment-Dwelling Organism (Chironomus riparius) (Guideline OECD 218, Ref VIII)

Endpoint	Cumulative emergence	Development rate
		Males	Females	Males and Females
	µg/kg dry weight sediment adjusted to 10% organic carbon
NOEC	6x103	6x103	6x103	6x103

NOEC 28 days = 6x10³ µg/kg dry weight sediment adjusted to 10% organic carbon

PNEC = 840 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used. An assessment factor (AF) of 10 is applied because there are long-term results from at least three species (algae, Daphnia and fish) representing three trophic levels. The NOEC for algae has been used for this calculation since it is the most sensitive (i.e., lowest NOEC value) among the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000877/840 = 10,4 x 10^-7

As the PEC/PNEC ≤ 0.01, this justifies the phrase ‘Use of sotorasib has been considered to result in insignificant environmental risk.’

Degradation

Biotic degradation: Ready degradability:

Not determined

Transformation in freshwater sediment (Guideline OECD 308, Ref IX)

The fate of [¹⁴C]-sotarasib was investigated up to 100 days under aerobic conditions after application in two freshwater sediment systems (Calwich Abbey Lake system (CALS) and Emperor Lake system (ELS).

At 100 days, the remaining sotarasib in the water phase was 8.8% (CALS) and 15.5% (ELS) of the applied radioactivity.

The sediment was extracted with solvents (150 mL) by sonicating at ambient temperature for 15 minutes then shaking for 15 minutes. The first two extracts were with acetonitrile followed by a third with acetonitrile: water (1:1, v/v). At 100 days, the remaining sotarasib in the sediment was 7.2% (CALS) and 15.8% (ELS) of the applied radioactivity.

Ten metabolites of sotarasib were detected all at <3% of the applied radioactivity apart from one (coded G in the study report|). This metabolite was found from Day 30 in the CALS and from Day 62 in the ELS. Levels >10% were only found in the sediment in the CALS (11.6% (Day 30), 14.8% (Day 61); 14.5% (Day 100)). Hence, no degradation rates could be calculated for Metabolite G. The tentative structure of metabolite G is given in the study report.

The decline (half-life) of sotorasib in two freshwater sediment systems is summarised below:

Compartment	Calwich Abbey Lake				Emperor Lake
	Model	DT50 (days)			Model	DT50 (days)
		20°C	12°C a)	Chi2		20°C	12°C a)	Chi2
Water	FOMC	25.4	53.9	6.67	SFO	35.1	74.5	6.64
Sediment	FOMC	12.6	26.7	4.79	SFO	298	633	2.56
Total system	SFO	39.4	83.6	2.41	SFO	55.9	118.7	6.64

The data have been extrapolated from 20°C to 12°C using the Arrhenius equation with a conversion factor of 2.123.

Hydrolysis

Not determined.

Justification of chosen degradation phrase

Degradation was only determined in two freshwater sediment systems. Therefore, as the DT₅₀ is <120 days in both systems the phrase ‘Sotorasib is slowly degraded in the environment’ should be used.

Bioaccumulation

The log10 was determined to be 2.44 at pH 7 (Guideline OECD 107, Ref X). Since the log10Dow was < 4 at pH 7, sotorasib has a low potential for bioaccumulation.

Excretion (metabolism)

No metabolic data in excreta are available for sotorasib.

PBT/vPvB assessment

Sotorasib does not fulfil the criteria to be classified as PBT.

REFERENCES

The studies were conducted using the code name AMG 510 for sotorasib.

1. FASS, (2022). Environmental classification of pharmaceuticals at www.fass.se– Guidance for pharmaceutical companies, 2012 v 3.0.

2. AMG 510: OECD 106 Adsorption/Desorption on Soils & Sewage Sludge. Covance Study No. BM67CV, 09 September 2020. Covance Laboratories Limited. Sponsor Reference No. 150954.

3. SCB Statistics Sweden Population Statistics. February 2022.

4. ECHA, European Chemicals Agency, (2008). Guidance on information requirements and chemical safety assessment. Helsinki, Finland.

5. AMG 510: OECD 201 Algal Growth Inhibition Test. Covance Study No.YR39DC, 09 January 2020. Covance CRS research Limited, UK. Sponsor Reference No. 150956.

6. AMG 510: OECD 211 Daphnia magna Reproduction Test. Covance Study No. DB50BL, 29 January 2020. Covance CRS Research Limited, UK. Sponsor Reference No. 150960.

7. AMG 510: OECD 210 Fish Early Life Stage Toxicity Test. Covance Study No. PY83GJ, 31 March 2020. Covance CRS Research Limited, UK. Sponsor Reference No. 150959.

8. AMG 510: OECD 218 Sediment-Water Chironomid Toxicity Test using Spiked Sediment. Covance Study No. BR26CV, 03 September 2020. Covance Laboratories Limited, UK.  Sponsor Reference No. 150974.

9. AMG 510: OECD 308 Aerobic Transformation in Aquatic Sediment Systems. Covance Study No. SS17NP, 25 November 2020. Covance Laboratories Limited, UK Sponsor Reference No. 150955

10. AMG 510: OECD 107 Partition Coefficient. Envigo Study No PQ65PT, 20 December 2018. Envigo CRS Limited, UK. Sponsor Reference No. 150473.

Appendix 1  EUSES Print out

EUSES 2 Compact report	Single substance
Printed on	14 March 2023
Study	New
Substance	Sotarasib
Defaults	Standard Euses 2.2
Assessment types	1A, 1B, 3A, 3B
Base set complete	No
Explanation status column	O = Output; D = Default; S = Set; I = Imported
Name	Value	Units	Status
SUBSTANCE INDENTIFICATION
General name	Sotarasib		S
PHYSICO-CHEMICAL PROPERTIES
Molecular weight	560.6	[g.mol-1]	S
Melting point	??	[°C]	D
Boiling point	??	[°C]	D
Vapour pressure at test temperature	1E-06	[Pa]	S
Temperature at which vapour pressure was measured	25	[°C]	D
Vapour pressure at 25 [°C]	1E-06	[Pa]	O
Octanol-water partition coefficient	??	[log10]	D
Water solubility at test temperature	10.3	[mg.L-1]	S
Temperature at which water solubility was measured	20	[°C]	S
Water solubility at 25 [°C]		[mg.L-1]	O
PARTITION COEFFICIENTS AND BIOCONCENTRATION FACTORS
SOLIDS-WATER
Chemical class for Koc-QSAR	Predominantly hydrophobics		S
Organic carbon-water partition coefficient	118	[L.kg-1]	S
OUTPUT PRODUCTION
Fraction of emission directed to water	98.49	%	S
Fraction of emission via primary settler	1.051	%	S
Fraction of emission via surplus sludge	0.455	%	S
LOCAL [PRODUCTION]
Local emission to wastewater during episode	0.096	[kg.d-1]	S