Detaljerad miljöinformation

1. 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	=	0.00265369 μg/L
Where:
A	=	19,37 kg (total amount API in the sales data from May until December 2021 including forecast 2022 for Sweden (mean value). (The product was not “commercially” launched until 2021, therefore there were no sales during 2020).
R	=	X % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available.
P	=	number of inhabitants in Sweden = 10 *106
V (L/day)	=	volume of wastewater per capita and day = 200 (ECHA default) (Ref. 10)
D	=	factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Ref. 10)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae

Algal growth inhibition test with the green alga (Pseudokirchneriella subcapitata) (OECD 201) (Ref. 1):

EγC₅₀ 72 h (biomass) = 4,3 mg/L

NOECγ (biomass) = 2,4 mg/L

E_rC₅₀ 72 h (growth rate) = > 9,5 mg/L

NOEC_r (growth rate) = 2,4 mg/L

Crustacean

Acute

Acute toxicity in the water-flea (Daphnia magna) (OECD202) (Ref. 2):

EC₅₀ 48 h (immobilization) = > 10 mg/L

Further testing to define the EC50 was not performed as the highest concentration tested closely approximated the functional limit of solubility under testing conditions.

Chronic

Reproduction test with water-flea (Daphnia Magna) (OECD 211) (Ref. 3):

NOEC 21 days (reproduction) = 1,8 mg/L

Fish

Acute

Acute toxicity in Rainbow Trout (Oncorhynchus mykiss) (OECD 203) (Ref. 4):

LC₅₀ 96 h (mortality) = 6,9 mg/L

Chronic

Fish early life stage test with fathead minnow (Pimephales promelas) (OECD 210) (Ref. 5):

NOEC 28 days (survival, development, growth and reproduction) = 6.8 µg/L

Other ecotoxicity data

Activated sludge respiration inhibition test (OECD 209) (Ref. 6):

EC₅₀ (respiration rate) = > 1000 mg/L

EC₁₀ (NOEC) (respiration rate) = > 1000 mg/L

Environmental risk classification (PEC/PNEC ratio)

Calculation of Predicted No Effect Concentration (PNEC)

PNEC (µg/l) = lowest (NOEC)/10, where 10 is the assessment factor used. NOEC for the species fathead minnow (Pimephales promelas) of 6,8 µg/L has been used for this calculation since it is the most sensitive of the three tested species.

PNEC = 6.8 µg/L/AF = 0.68 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00265369/0.68 = 0.003902485i.e. PEC/PNEC ≤ 0.1

Conclusion for environmental risk:

Use of Apalutamide has been considered to result in insignificant environmental risk.

Degradation

Biotic degradation

Ready biodegradation

Test results degradation in 28 days (Guideline OECD 301B) (Ref. 7):

Based on the extent of CO2 evolution during this study, Apalutamide cannot be classified as “readily biodegradable” by the criteria set forth in OECD Guideline 301B since only 0.59% CO2 evolution was achieved by day 28.

Simulation study: Aerobic degradation in aquatic sediment systems:

Apalutamide was investigated for its aerobic degradation in a 100-day aquatic sediment test, according to OECD 308 (Ref. 8):

The transformation of Apalutamide in sediments and natural water was assessed in two different aerobic water/sediment systems at a temperature of 20 ± 2 °C continuously in the dark for 103 days. Average material balance ranged from 94.4 to 101.8% AR (= applied radioactivity) over the course of the 103-day study. The DT50 (half-life) of Apalutamide in the water phase was 30 and 32 days for the Taunton River and Weweantic River aerobic test systems, respectively. The DT50 (half-life) of [14C] Apalutamide in the total water/sediment test systems was 315 and 92 days for the Taunton River and Weweantic River aerobic test systems, respectively.

Evidence of primary biodegradation was observed for [14C] Apalutamide in the aerobic water/sediment test systems. One major peak (≥ 10% AR) was observed in some of the chromatograms for the Taunton River and Weweantic River samples at a retention time of approximately 30 minutes (M1). Several minor peaks were observed in some of the chromatograms for the Taunton River and Weweantic River test samples. In all cases, these minor peaks represented less than 10% AR in the water and sediment extracts and were not considered further.

A proposed structure for observed major metabolite M1 was determined by LC/MS/MS and confirmed against a certified reference standard. A proposed transformation pathway for [14C] Apalutamide was determined based on this proposed structure and HPLC/RAM analysis. It is proposed that the parent material oxidizes to form M1, the parent material and M1 further degrade into CO2 and get incorporated into non-extractable residues.

Ultimate biodegradation of [14C] Apalutamide was observed in the aerobic samples with evolution of 14CO2 reaching an average maximum of 2.152 and 1.532% AR for the Taunton River and Weweantic River aerobic test samples, respectively, at Day 103. Generation of volatile organic compounds was negligible for the Taunton River aerobic test samples at Day 103 and was observed at an average maximum of 0.162% AR for the Weweantic River aerobic test samples at Day 103.

Extraction method:

Extraction with acetonitrile, followed by acetonitrile:purified reagent water (80:20, v:v) and followed by acetonitrile:purified reagent water:formic acid (80:20:0.1, v:v:v), acetonitrile:purified reagent water:hydrochloric acid (80:20:0.1, v:v:v)

Conclusion for degradation:

Apalutamide is slowly degraded in the environment.

Bioaccumulation

Partition coefficient octanol/water

The partition coefficient octanol/water was determined using OECD Test Guideline 107 (Ref. 9).

Analyses of the definitive test samples determined that the mean partition coefficient of the test substance for pH 7 was 805 or log Pow: 2.91

Bioconcentration

No data available

Conclusion for bioaccumulation:

Apalutamide has low potential for bioaccumulation.

Excretion (metabolism)

No data available.

PBT assessment

	PBT-criteria	Results for Apalutamide
Persistence	Half-life in freshwater: DT50 > 40 days Half-life in sediment: DT50 > 120 days	The DT50 (half-life) of [14C] Apalutamide in the total water/sediment test systems was 315 and 92 days for the Taunton River and Weweantic River aerobic test systems, respectively.
Bioaccumulation	BCF > 2000	Log Pow 2.91
Toxicity	Chronic NOEC < 10 µg/L	NOEC algae = 2,4 mg/L NOEC daphnia = 1,8 mg/L NOEC fish = 6.8 µg/L

Conclusion for PBT-assessment:

Apalutamide cannot be classified as “PBT”.

References

1. Staggs M L, ARN-509 – 72-Hour Toxicity Test with the Freshwater Green Alga, Pseudokirchneriella subcapitata Following OECD Guideline #201; Smithers Viscient Study No. 13751.6194; JNJ Study No. RMD 1201; January 30, 2015. 

2. Fournier A E, ARN-509 – Acute Toxicity to Water Fleas, (Daphnia magna) Under Static Conditions, Following OECD Guideline #202; Smithers Viscient Study No. 13751.6195; JNJ Study No. RMD 1202; February 6, 2015. 

3. Fournier A E, ARN-509 – Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static Renewal Conditions, Following OECD Guideline #211; Smithers Viscient Study No. 13751.6197; JNJ Study No. RMD 1204; June 9, 2015. 

4. Fournier A E, ARN-509 – Acute Toxicity to Rainbow Trout (Oncorhynchus mykiss), Under Static Conditions, Following OECD Guideline #203; Smithers Viscient Study No. 13751.6196; JNJ Study No. RMD 1203; January 20, 2015. 

5. Urann K, ARN-509 – Full Life-Cycle Toxicity Test with Fathead Minnow (Pimephales promelas), Following OECD Guideline #210; Smithers Viscient Study No. 13751.6204; JNJ Study No. RMD 1206; June 26, 2017. 

6. Griffith A W, ARN-509 – Activated Sludge Respiration Inhibition Test, Following OECD Guideline #209; Smithers Viscient Study No. 13751.6193; JNJ Study No. RMD 1208; March 25, 2015. 

7. Griffith A W, Determination of the Biodegradability of ARN-509, Following OECD Guideline #301B; Smithers Viscient Study No. 13751.6192; JNJ Study No. RMD 1200; January 13, 2015. 

8. Freedlander S, [¹⁴C]ARN-509 – Aerobic Transformation in Aquatic Sediment Systems, Following OECD Guideline #308; Smithers Viscient Study No. 13751.6199; JNJ Study No. RMD 1207; June 25, 2015. 

9. McLean S, Determining the Partitioning Coefficent (n-Octanol/Water) by the Shake Flask Method, Following OECD Guideline #107; Smithers Viscient Study No. 13751.6191; JNJ Study No. RMD 1198; December 11, 2014. 

10. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm