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*A*(100-R)

PEC = 0.05211206 µg/L

Where:

A	=	total actual API sales in Sweden for the most recent year 380.3800 (total sold amount API in the most recent sales data for Sweden (2020) was distributed by IQVIA in 2021)
R	=	0
P	=	number of inhabitants in Sweden = 10 *106
V (L/day)	=	volume of wastewater per capita and day = 200 (ECHA default) (Reference I)
D	=	factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (guideline eg OECD 201) [Reference II]

EγC₅₀ 72 h (yield inhibition) > 1.0 mg/L

NOECγ (yield inhibition) = 1.0 mg/L

E_rC₅₀ 72 h (growth rate) > 1.0 mg/L

NOEC_r (growth rate) = 1.0 mg/L

Crustacean (Daphnia magna) (water-flea):

Acute toxicity

LC₅₀ 96 h = 0.25 mg/L (guideline eg OECD 202) (Reference III)

NOEC = < 0.048 mg/L

Chronic toxicity

NOEC 21 days (Reproduction and Growth) = 0.47 µg/L (guideline eg OECD 211) (Reference IV)

Fish:

Acute toxicity

Oncorhynchuss mykiss (rainbow trout)

LC₅₀ 96 h = 0.13 mg/L (guideline eg OECD 203) (Reference V)

NOEC = 0.065 mg/L

Chronic toxicity

Pimephales promelas (fathead minnow)

Fish early life stage test

NOEC 35 days (Total body length) = 1.1 µg/L (guideline eg OECD 210) (Reference VI)

Fish partial life cycle study

NOEC 119 days (Number of spawns per female) = 13 ηg/L (guideline eg OECD 229) (Reference VII)

Other ecotoxicity data:

Activated sludge respiration inhibition test according to guideline eg OECD 209 (Reference VIII)

EC₅₀ 3h > 1000 mg/L

NOEC 3h ≥ 1000 mg/L

PNEC (µg/l) = lowest NOEC/10, where 10 is the assessment factor used. NOEC for fathead minnow Pimephales promelas of 13 ηg/L has been used for this calculation since it is the most sensitive of the three tested species.

PNEC = 13 ηg/L/10 = 1.3 ηg/L = 0.0013 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.05211206 μg/L /0.0013 μg/L = 40.0862

i.e. PEC/PNEC > 10 which justifies the phrase ‘Use of Abiraterone acetate has been considered to result in high environmental risk.

Degradation

Biotic degradation

Ready degradability:

According to guideline eg OECD 301B (Reference IX):

Abiraterone acetate was investigated for its ready biodegradation in a 28-day CO₂-evolution test.

Result: Not readily biodegradable.

Inherent degradability: -

Simulation studies:

Aerobic degradation in aquatic sediment systems according to guideline eg OECD 308 (Reference X):

Abiraterone acetate was investigated for its aerobic degradation in a 101-day aquatic sediment test.

For analysis the sediment was extracted once with acetonitrile, once with acetonitrile:trifluoroacetic acid 100:0.5 (v:v) and once (twice

on Day 101) with acetonitrile:water:trifluoroacetic acid 80:20:0.5, (v:v:v) for a maximum of four extractions. The water and sediment extracts were radioassayed by LSC and then analyzed by HPLC/RAM to quantify [¹⁴C]abiraterone

acetate and degradation products in the fractions. The radioactivity in the post extracted solids (sediment bound) were quantified by combustion analysis. The volatile organic traps were radioassayed by LSC.

The rates of dissipation (DT₅₀ and DT₉₀) of Abiraterone acetate from the water phase and the entire system were calculated using first order kinetics:

System	Water		Total system
	DT50 (Days)	DT90 (Days)	DT50 (Days)	DT90 (Days)
Taunton River Aerobic	2.3	7.7	4.9	16
Weweantic River Aerobic	2.3	7.6	3.3	11

In aerobic aquatic sediment systems, Abiraterone acetate rapidly dissipated from the water phase by adsorption to the sediment.

Abiraterone acetate is degraded in the environment.

Abiotic degradation

Hydrolysis: -

Photolysis: -

Bioaccumulation

Partition coefficient octanol/water:

The partition coefficient octanol/water was determined according to guideline eg OECD 117 [Reference XI]:

Log D_ow >6.20 (pH = 6.10)

Bioconcentration factor (BCF):

The bioconcentration and depuration characteristics of Abiraterone acetate in the rainbow trout in a flow through system were examined according to EMA’s assessment report [Reference XII].

BCF_low dose = 903

BCF_high dose = 931

The BCF value of the low and high dose indicates that Abiraterone acetate has high potential to bioconcentrate in the rainbow trout.

Since BCF > 500, Abiraterone acetate has high potential for bioaccumulation.

Excretion (metabolism)

-

PBT/vPvB assessment

	PBT-criteria	Results for Abiraterone acetate
Persistence	Half-life in freshwater: DT50 > 40 days Half-life in sediment: DT50 > 120 days	DT50,river = 2.3 days DT50,system = 4.9 days
Bioaccumulation	BCF > 2000	BCF = 903 (low dose) and 931 (high dose)
Toxicity	Chronic NOEC < 10 µg/L	NOECalgae = 1.0 mg/L NOECdaphnia = 0.47 µg/L NOECfish = 13 ηg/L

According to the established EU-criteria Abiraterone acetate should not be regarded as a PBT substance.

References

1. 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

2. Softcheck K., Abiraterone Acetate – Acute Toxicity to the Freshwater Green Alga, Pseudokirchneriella subcapitata Following OECD Guideline #201; Springborn Smithers Laboratories Study No. 13674.6187; JNJ Study No. RMD 1073; May 27, 2010.

3. Fournier A.; Abiraterone Acetate – Acute toxicity to water fleas (Daphnia magna) under static conditions, following OECD Guideline No. 202; Springborn Smithers Study No. 13674.6188; JNJ Study No. RMD1074; June 14, 2010

4. Sayers L., Abiraterone Acetate – Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static-Renewal Conditions, Following OECD Guidelines #211; Springborn Smithers Laboratories Study No. 13674.6210; JNJ Study No. RMD 1079; October 6^, 2010.

5. Fournier A.; Abiraterone acetate – Acute toxicity to rainbow trout (Oncorhynchus mykiss) under static-renewal conditions, following OECD Guideline No. 13674.6189; JNJ Study No. RMD1075; June 9, 2010.

6. Lee M., Abiraterone Acetate – Early Life Stage Toxicity Test with Fathead Minnow, Pimephales promelas, Following OECD Guideline #210; Springborn Smithers Laboratories Study No. 13674.6211; JNJ Study No. RMD 1080; October 8, 2010.

7. York D., Abiraterone Acetate – Modified Partial Life-Cycle Exposure with Fathead Minnow (Pimephales promelas) Following OECD Guideline 229; Springborn Smithers Study No. 13674.6239; August 7, 2012.

8. Turk R., Abiraterone Acetate – Activated Sludge Respiration Inhibition Test Following OECD Guideline 209; Springborn Smithers Laboratories Study No. 13674.6190; JNJ Study No. RMD 1076; January 28, 2010.

9. McLaughlin S.; Abiraterone acetate – Determination of the biodegradability of a test substance based on OECD Method 301B (CO2-evolution test); Springborn Smithers Study No. 13674.6191; JNJ Study No. RMD1077; January 6, 2010.

10. Turk R., Lentz N., [¹⁴C] Abiraterone Acetate – Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308; Springborn Smithers Study No. 13674.6195; JNJ Study No. RMD 1078; September 14, 2010.

11. Van Meter D., Abiraterone Acetate – Determination of n-Octanol/Water Partition Coefiecent Following OECD Guidelines, Section 117; Springborn Smithers Study No. 13674.6186; JNJ Study No. RMD 1072; March 15, 2010.

12. Assessment report Zytiga; Procedure No. EMEA/H/C/002321/II/0047; Committee for Medicinal Products for Human Use (CHMP); EMA/816845/2017; 12 October 2017.

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*A*(100-R)

PEC = 0.00183239 µg/L

Where:

A	=	total actual API sales in Sweden for the most recent year 13.3751464 (total sold amount API in the most recent sales data for Sweden (2020) was distributed by IQVIA in 2021)
R	=	0
P	=	number of inhabitants in Sweden = 10 *106
V (L/day)	=	volume of wastewater per capita and day = 200 (ECHA default) (Reference I)
D	=	factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (guideline eg OECD 201) (Reference II)

NOEC_r (growth rate) = 0.32 mg/L

NOEC_r (biomass) = 0.32 mg/L

Crustacean (Daphnia magna) (water-flea):

Acute toxicity

-

Chronic toxicity

NOEC 21 days (Reproduction) = 0.32 mg/L (guideline eg OECD 211) (Reference III)

Fish:

Acute toxicity

-

Chronic toxicity

Pimephales promelas (fathead minnow)

Fish early life stage test

NOEC 32 days (Growth - length) = 0.032 mg/L (guideline eg OECD 210) (Reference IV)

Fish early life stage test

LOEC 32 days (Growth - length) = 0.10 mg/L (guideline eg OECD 210) (Reference IV)

Other ecotoxicity data:

Activated sludge respiration inhibition test according to guideline eg OECD 209 (Reference V)

NOELR 3h <= 32 mg/l

PNEC (µg/l) = lowest NOEC/10, where 10 is the assessment factor used. NOEC for fathead minnow Pimephales promelas of 0,032 mg/L has been used for this calculation since it is the most sensitive of the three tested species.

PNEC = 0,032 mg/L/10 = 0,0032 mg/L = 3,2 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00183239 µg/L / 3,2 µg/L = 0.0005726

i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of Niraparib tosylate monohydrate has been considered to result in insignificant environmental risk”.

Degradation

Biotic degradation

Ready degradability: -

Inherent degradability: -

Simulation studies:

Aerobic transformation in aquatic sediment systems according to guideline eg OECD 308 (Reference VII):

Niraparib Tosylate Monohydrate was investigated in two water/sediment systems under aerobic conditions for 100 days.

The half-life calculated for the water layer is not a degradation DT50 but a dissipation half-life because transfer from water to sediment is included in the dissipation process. The half-life calculated for the total system is a true degradation half-life because dissipation from the total system is only the result of degradation and irreversible bonding. For sediment, degradation was assessed from the

maximum onwards at a time no significant amounts of parent were present in the water layer, so that transfer from water to sediment is excluded.

The rates of dissipation (DT₅₀ and DT₉₀) of Niraparib from the water phase, sediment phase and the entire system are:

System	Water		Sediment		Total system
	DT50 (Days)	DT50 (Days)	DT90 (Days)	DT90 (Days)	DT50 (Days)	DT90 (Days)
Schoonrewoerdse Wiel (aerobic)	1.1	8.3	349	1160	225	863
Emperor Lake (aerobic)	6.5	38	469	1560	155	979

DT50 for the total system is > 120days.

Therefore, Niraparib Tosylate Monohydrate is potentially persistent.

Abiotic degradation

Hydrolysis: -

Photolysis: -

Bioaccumulation

Partition coefficient octanol/water:

The partition coefficient octanol/water was determined according to guideline eg OECD 107 [Reference VI]:

Log Pow 0.2 (pH = 7)

Since Pow (at pH 7) < 4,

Niraparib Tosylate Monohydrate has low potential for bioaccumulation.

Bioconcentration factor (BCF): -

Excretion (metabolism)

-

References

1. 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

2. Tobor-Kaplon M.A.; Fresh Water Algal Growth Inhibition Test with Following OECD Guideline #201; Charles River Laboratories Den Bosch Study No. 515878; January 31, 2018.

3. Tobor-Kaplon M.A.; Daphnia magna, Reproduction Test with Niraparib Tosylate Monohydrate (Semi-Static), Following OECD Guideline #211; Charles River Laboratories Den Bosch Study No. 515877; March 2, 2018.

4. Tobor-Kaplon M.A Fish Early-Life Stage Toxicity Test with Niraparib Tosylate Monohydrate (Flow-Through), Following OECD Guideline No. #210; Charles River Laboratories Den Bosch Study No. 515879; March 6, 2018.

5. Buitenweg S., Activated Sludge Respiration Inhibition Test with Niraparib, Following OECD Guidelines #209; Charles River Laboratories Den Bosch Study No. 515880; November 23^, 2017.

6. Comb A.L.; Niraparib: Partition Coefficient, Following OECD Guideline No. #107, Envigo CRS Limited, Envigo Study Number: XP97DJ; October 24, 2016.

7. Brands C.M.J., Aerobic Transformation of Niraparib Tosylate Monohydrate in Aquatic Sediment, Following OECD Guideline #308; Charles River Laboratories Den Bosch Study No. 515876; June 7, 2018.