Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula: (Ref.1)

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

Where:

A (kg/yr)	8,2771 kg	Total upadacitinib sold (kg) in Sweden in 2022 from IQVIA (Ref. 2)
R	0 %	Removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation); use 0 if no data is available. (Ref.1)
P	10*106	Number of inhabitants in Sweden (Ref. 1)
V (L/day)	200	Volume of wastewater per capita and day (200 L/day is the default value) (Ref. 1,3)
D	10	Factor for dilution of wastewater by surface water flow (10 is the default value) (Ref. 1,3).

Note: The factor 10⁹ converts the quantity distressed from kg to mcg.

PEC (μg/L) = (8,2771*10⁹*(100-0))/(365*10*10⁶*200*10*100)

PEC = 0,00113 μg/L

Ecotoxicological Studies with Upadacitinib

Activated Sludge, Respiration Inhibition Test (OECD 209)

The activated sludge, respiration inhibition test (ASRIT) was completed to determine the effects of upadacitinib on activated sludge microorganisms. The microorganism respiration rate was evaluated under defined conditions in the presence of upadacitinib (1000 mg/L), a dilution water control, and 3,5-dichlorophenol reference toxicant. The study was completed according to OECD Guideline 209. (Ref. 4)

The respiration rate in the presence of 1000 mg/L in the limit test exceeded the control treatment. Consequently, 1000 mg/L was considered the no observed effect concentration (NOEC).

           

Freshwater Alga Growth Inhibition Test (OECD 201)

The effect of upadacitinib on the unicellular green algae Pseudokirchneriella subcapitata was evaluated in accordance with OECD Guideline 201. The EC values for yield (E_yC_X) and average growth rate from time zero (E_rC_x) of algae exposed to five concentrations of upadacitinib for 72-hours were determined. The data for average growth rate and yield (EC, NOEC, and lowest observed effect concentration (LOEC) values), based on arithmetic mean measured concentrations, are summarized in the table below. (Ref. 5)

Endpoint	EC Value a		NOEC a	LOEC a
Average Growth Rate	ErC50	61,8 mg/L	31,3 mg/L	77,3 mg/L
Average Yield	EyC50	41,6 mg/L	31,3 mg/L	77,3 mg/L

1. Effective concentration values were estimated using non-linear regression. NOEC and LOEC values were based on statistical comparisons (Dunnett's test; p < 0,05) between treatment and control data.

The NOEC for the average growth rate and yield at 72 hours was 31,3 mg/L.

Daphnia magna Reproduction Test (OECD 211)

The effects of upadacitinib on Daphnia magna were studied in a 21-day static-renewal chronic toxicity test in accordance with OECD 211. The objective of the study was to evaluate the effect of upadacitinib on the survival, growth, and reproductive output of Daphnia magna. The 21-day NOEC, LOEC, and EC_x values for survival, reproduction (young per surviving adult), and growth (length), based on nominal concentrations, are summarized in the table below. (Ref. 6)

Endpoint	EC Value		NOEC	LOEC
Adult Survival	EC50	> 10	10 mg/L	> 10 mg/L
Reproduction b	EC50	> 10 mg/L	1,6 mg/L	4,0 mg/L
Adult Length	EC50	> 10 mg/L	4,0 mg/L	10 mg/L

1. N/C = Not Calculated; data did not demonstrate a concentration dependent response.

2. Reproduction expressed as total young per surviving adult daphnid.

Fish Early-Life Stage Toxicity Test (OECD 210)

The toxicity of upadacitinib to the fathead minnow, Pimephales promelas, was evaluated in accordance with OECD 210. The objective of this study was to assess the effects of upadacitinib on fathead minnow embryos and fry during an early life-stage exposure. The toxicological endpoints of concern were egg hatchability, time to hatch, fry survival, sublethal effects, and growth. The results are below. (Ref. 7)

Endpoint	NOEC a	LOEC a	ECx Estimates a
Egg Hatch	10 mg/L	> 10 mg/L	NC b
Time to Hatch Start	10 mg/L	> 10 mg/L	NC b
Time to Hatch End	10 mg/L	> 10 mg/L	NC b
Fry Survival c	10 mg/L	> 10 mg/L	NC b
Sublethal Effect (Spinal Curvature) d	0,63 mg/L	1,3 mg/L	EC50	6,1 mg/L
Total Length	2,5 mg/L	5,0 mg/L	EC50	> 10 mg/L
Blotted Wet Weight	2,5 mg/L	5,0 mg/L	EC50	> 10 mg/L

1. Expressed as nominal concentration of upadacitinib (mg/L).

2. NC = Not calculated. The ECx estimates could not be calculated due to the lack of a statistically significant response for this parameter up to a nominal concentration of 10 mg/L.

3. Fry survival based on number of hatched fry surviving on Day 28 post-hatch.

4. Based on treatment-related sublethal observations at termination of the 28-day post-hatch exposure.

Predicted No Effect Concentration (PNEC)

PNEC (μg/L) = NOEC/AF

AF = Assessment Factor = 10

Organism	NOEC (mg/L)
Sludge Microorganisms	1000
Freshwater Algae (Pseudokirchneriella subcapitata)	31,3 (Average Specific Growth Rate and Yield)
Daphnia magna	10 (Adult Survival)
	1,6 (Reproduction)
	4,0 (Adult Length)
Fathead Minnow (Pimephales promelas)	10 (Egg Hatch, Time to Hatch Start/End, Fry Survival)
	0,63 (Sublethal effect: Spinal curvature)
	2,5 (Total Length, Blotted Wet Weight)

The PNEC was determined in accordance with ECHA guidance. (Ref. 8)

The chronic aquatic effects of upadacitinib were assessed in green algae, fish, and Daphnia. Based on these studies, fathead minnow was determined to be the most sensitive species tested (NOEC 0,63 mg/L, see table below). Therefore, the predicted no effect concentration (PNEC) for surface waters (PNEC_WATER) was calculated using the NOEC for this species.

NOEC = 0,63 mg/L

Assessment Factor = 10

PNEC = 0,63/10

PNEC = 0,063 mg/L

PNEC = 63 μg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC Ratio:

PEC = 0,00113 μg/L

PNEC = 63 μg/L

PEC/PNEC = 0,00113/63

PEC/PNEC = 0,000018

Justification of environmental risk classification:

Since PEC/PNEC ≤ 0,1, the use of upadacitinib has been considered to result in insignificant environmental risk.

Degradation

Aerobic Transformation in Aquatic Sediment Systems (OECD 308)

The transformation of [¹⁴C]upadacitinib was studied in two different water/sediment systems (Brandywine River and Choptank River) under aerobic conditions in accordance with OECD 308. (Ref. 9)

Test systems were dosed with 86 μg (12.2 μCi) of ¹⁴C-labeled upadacitinib per test chamber. Test systems were incubated in the dark at 20 ± 2 ºC for up to 150 days. Aerobic conditions were maintained by gently bubbling a stream of air through the water layers in each test vessel. Effluent gases were passed through vials containing ethylene glycol to trap volatile organic compounds and vials containing alkali solutions to trap evolved carbon dioxide. Duplicate test chambers were sacrificed for analyses immediately after test substance application and at 3, 7, 14, 28, 56, 100 and 150 days after application. Overlying water layers, sediment extracts, sediment solids, ethylene glycol (EG) traps, and potassium hydroxide (KOH) traps were analyzed separately for total radioactivity by liquid scintillation counting (LSC).

Mean material balances (recoveries) ranged from 98.6% to 109.2% throughout the study, and were within the acceptable range of 90% to 110%; therefore, the study was considered valid. The mean cumulative amount of mineralization observed over the 150-day test period was 1.32% in both test systems. The mean amount of ¹⁴C in the sediment layers (i.e. sediment extracts + sediment solids) increased throughout the study to maximums of 98.7% in Brandywine Creek and 77.1% in Choptank River, on day 150. The fractions of radiolabeled residues that could not be extracted from the sediment layers at the end of the test were 36.8% and 29.3%, respectively. A single supplemental extraction was done with each of four solvents, and each solvent extract removed <5% of the ¹⁴C from the solids.

The mean maximum amount of transformation products in the total test systems (water layers plus sediment extracts) were 7.6% on day 150 in Brandywine Creek and 22.7% on day 100 in Choptank River. In addition to upadacitinib, five separate transformation product peaks were observed at various sample intervals, but each individually accounted for <5% of the applied radioactivity throughout the study. No attempt was made to identify any of the transformation products based on the low percentages present.

The test substance, [¹⁴C]upadacitinib, disappeared from the water layers of both test systems primarily by partitioning to the sediment layers. Therefore, the disappearance of [¹⁴C]upadacitinib from total test systems (water layers + sediment extracts) was best described using a simple first-order (SFO) model. The DT₅₀ values for the Brandywine Creek and Choptank River test systems were 234 and 138 days, respectively.

Test System	Compartment	DT50at 20°C
Brandywine Creek	Water Layer	5.6 days
	Sediment Layer	347 days a
	Total Test System	234 days a
Choptank River	Water Layer	13 days
	Sediment Layer	110 days
	Total Test System	138 days

1. Values extrapolated beyond the 150-day test period.

Justification of chosen degradation phrase:

DT₅₀ > 120d for the total system; therefore, upadacitinib is potentially persistent. 

Bioaccumulation

Partition Coefficient (n-octanol/water): Shake Flask Method (OECD 107)

The Log Pow of upadacitinib was experimentally determined using OECD 107 shake flask method partition coefficient (n octanol/water) at pH 4, 7, and 9 and 25°C. (Ref. 10)

Endpoint	pH	Result
Log Pow	4	1,81 ± 0.03
	7	2,50 ± 0.02
	9	2,48 ± 0.02

Justification of chosen bioaccumulation phrase:

Log P_ow at pH 7 was < 4; therefore, upadacitinib has low potential for bioaccumulation.

References

1. FASS.se. Environmental classification of pharmaceuticals at www.fass.se. Guidance for pharmaceutical companies. 2012 V 3.0. 2021.

2. IQVIA. 2022. IQVIA / LIF - kg consumption/2022,

3. European Chemicals Agency (ECHA). Guidance on Information Requirements and Chemical Safety Assessment Chapter R.16: Environmental exposure assessment. Version 3.0. 2016.

4. EAG Laboratories. R&D/17/0158. ABT-494: Activated Sludge, Respiration Inhibition Test. AbbVie Study TX16-255. 2018.

5. EAG Laboratories. R&D/17/0154. ABT-494: Growth Inhibition Test with the Unicellular Green Alga, Pseudokirchneriella subcapitata. AbbVie Study TX16-251. 2018.

6. EAG Laboratories. R&D/17/0156. ABT-494: Chronic Toxicity Test with the Cladoceran, Daphnia magna, Conducted Under Static-Renewal Conditions. AbbVie Study TX16-253. 2018

7. EAG Laboratories. R&D/17/0157. ABT-494: Early Life-Stage Toxicity Test with the Fathead Minnow, Pimephales promelas, Under Flow-Through Conditions. AbbVie Study TX16-254. 2018.

8. European Chemicals Agency (ECHA). Guidance on information requirements and chemical safety assessment Chapter R.10: Characterisation of dose [concentration]-response for environment. 2008.

9. EAG Laboratories. R&D/17/0759. ABT-494: Aerobic Transformation in Aquatic Sediment Systems. AbbVie Study TX16-257. 2018.

10. Eurofins EAG Agroscience, LLC. R&D/19/1271. ABT-494 (A-1293543): Determination of n-Octanol/Water Partition Coefficient (Shake Flask Method). AbbVie Study TX19-230. 2020.