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 = 0.0025 μg/L

Where:

A = 18 kg (total sold amount API in Sweden year 2021, data from IQVIA) (Ref.I)

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 10 *10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Crustacean, water flea (Daphnia magna):

Acute toxicity (OECD 202) (Ref.III)

EC₅₀ 48 h (immobility, mortality) = 276 μg/L

Chronic toxicity (OECD 211) (Ref. IV)

EC₅₀ 21 day (immobility, reproduction) > 244 μg/L

NOEC 21 d (growth, reproduction) = 244 μg/L

No effects seen at highest concentration tested

Fish, rainbow trout (Oncorhynchus mykiss):

Acute toxicity (OECD 203) (Ref. V)

LC₅₀ 96 h (mortality) > 950 μg/L

NOEC = 950 μg/L

No effects seen at highest concentration tested

Fish early life stage, fathead minnow (Pimephales promelas):

Chronic toxicity (OECD 210) (Ref. VI)

NOEC 33 d (growth) = 206 μg/L

Algae, green algae (Selenastrum capricornutum) (OECD 201) (Ref. VII):

EC₅₀ 96 h (growth rate) > 509 μg/L

NOEC 96 h (cell density, biomass, growth rate) = 41 μg/L

PNEC = 4.1 μg/L (41μg/L / 10 based on the most sensitive chronic NOEC for Selenastrum capricornutum with an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0025/4.1 = 6E-04, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of posaconazole has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Sediment Transformation: (OECD 308) (Ref VIII)

Total system half-life = 0.7 to 13.3 days

Test systems were dosed with 14C-labeled posaconazole at a nominal concentration of 200 ug/L in the water layer. Test systems were incubated in the dark at approximately 20ºC for up to 103 days and maintained under aerobic conditions by gently bubbling air into the water layers. Effluent gasses were passed through charcoal sorbent tubes to trap organic volatiles, followed by alkali solutions to trap evolved carbon dioxide. Duplicate test chambers of each sediment-water type were sacrificed on days 0, 2, 5, 14, 28, 56 and 103. Water layers and sediment layers were extracted and analyzed for total radioactivity by liquid scintillation counting (LSC). The mean percent of applied radioactivity in each fraction is presented in the following table:

Test System	Interval (Days)	Water Layers	Sediment Layers	Gases	Material Balance (Recovery)
Brandywine Creek	0	95.3%	2.0%	--	97.3%
	2	56.7%	41.6%	0.0%	98.2%
	5	36.0%	64.2%	0.0%	100.2%
	14	23.1%	72.3%	0.0%	95.4%
	28	15.8%	84.9%	0.0%	100.8%
	56	11.7%	86.6%	0.0%	98.3%
	103	8.6%	91.6%	0.0%	100.3%
Choptank River	0	97.0%	3.3%	--	100.3%
	2	80.2%	22.2%	0.0%	102.4%
	5	68.8%	33.8%	0.0%	102.6%
	14	27.7%	71.7%	0.1%	99.5%
	28	32.5%	64.7%	0.0%	97.2%
	56	26.7%	68.1%	0.0%	94.8%
	103	19.6%	74.9%	0.2%	94.7%

Extracts from water and sediment layers were analyzed by HPLC for parent test substance and radiolabeled transformation products. The mean percent of applied radioactivity in the samples is presented in the following table:

		Water Layers				Sediment Extracts
Test System	Interval (Days)	Parent Posaconazole	Trans.1 Prod.	Total % of Dose		Parent Posaconazole	Trans.1 Prod.	Total % of Dose
Brandywine Creek	0	87.9%	7.4%	95.3%		NA2	NA2	NA2
	2	6.7%	50.0%	56.7%		3.5%	29.3%	32.8%
	5	3.7%	32.3%	36.0%		4.9%	40.2%	45.1%
	14	1.3%	21.8%	23.1%		2.7%	45.7%	48.5%
	28	0.8%	15.1%	15.8%		1.4%	48.7%	50.1%
	56	0.0%	11.7%	11.7%		0.3%	46.6%	47.0%
	103	0.0%	8.6%	8.6%		0.0%	45.2%	45.2%
Choptank River	0	94.4%	2.6%	97.0%		NA2	NA2	NA2
	2	65.8%	14.3%	80.2%		13.0%	8.4%	21.4%
	5	47.1%	21.7%	68.8%		15.9%	15.2%	31.1%
	14	6.4%	21.3%	27.7%		21.8%	45.3%	67.2%
	28	9.1%	23.4%	32.5%		29.3%	30.2%	59.5%
	56	0.3%	26.4%	26.7%		3.0%	48.8%	51.8%
	103	0.2%	19.4%	19.6%		2.7%	46.5%	49.2%

^{1 Trans. Prod. = transformation products}

^{2 NA = not analyzed (sediment layers were not extracted on day 0)}

Posaconazole disappeared rapidly from the water layers in both test systems by transformation and by partitioning to the sediment layers. The half-lives for Posaconazole were 0.5 and 4.5 days from the Brandywine Creek and Choptank River water layers, respectively.

The mean amounts of posaconazole in the sediment layers increased to a maximum of 4.9% on day 5 in Brandywine Creek samples and 29.3% on day 28 in Choptank River samples. The mean amounts of posaconazole in the total test systems (i.e. water layers extracts plus sediment extracts) at the end of the test were 0.0% and 2.9%, respectively. The half-lives for posaconazole in the total test systems were 0.7 and 13.3 days, respectively.

Through all test intervals, the mean maximum percentages of applied radioactivity recovered as transformation products were 79% on day 2 in Brandywine Creek samples and 75% on day 56 in Choptank River samples. The mean amount of radiolabeled residues that could not be extracted from the sediment layers at the end of the test were 46.5% and 25.7%, respectively. The mean maximum cumulative amount of mineralization or ultimate biodegradation observed from all test jars was <0.5% for both test systems. Total mean recoveries ranged from 94.7% to 102.6% throughout the study.

The calculated half-life of posaconazole and degradates are presented in the

following table:

	Half-life (days)
	Choptank River	Brandywine River
Parent Posaconazole	20.4	21.1
M2	38.0	106.7
M3	358.1	108.1

The overall postulated transformation/metabolism scheme for posaconazole in river waters and sediments in show below.

Justification of chosen degradation phrase:

Posaconazole has a half-life less than 32 days. The phrase “Posaconazole is degraded in the environment” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Posaconazole has a measured bioconcentration factor (BCF) of 20 (OECD 305) (Ref IX).

Justification of chosen bioaccumulation phrase:

Since the BCF < 500, the phrase “Posaconazole has low potential for bioaccumulation” is chosen.

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2022 (data 2021)”.

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

3. Wildlife International, Ltd. 2003. "Posaconazole (SCH 56592): A 48-Hour Flow-Through Acute Toxicity Test with the Cladoceran (Daphnia magna)," Study No., 554A-101, WIL, Easton, MD, USA 14 July 2003.

4. Wildlife International, 2011. "Posaconazole: A Flow-Through Life-Cycle Toxicity Test with the Cladoceran (Daphnia magna)," Project No. 105A-199A, WIL, Easton, MD, 08 November 2011.

5. Wildlife International, Ltd. 2003. "Posaconazole (SCH 56592): A 96-Hour Flow-Through Acute Toxicity Test with the Rainbow Trout (Oncorhynchus mykiss)," Study No., 554A-102, WIL, Easton, MD, USA 14 July 2003.

6. Wildlife International, 2012. "Posaconazole: An Early Life Stage Toxicity Test with the Fathead Minnow (Pimephales promelas)," Project No. 105A-200, WIL, Easton, MD, 14 March 2012.

7. Wildlife International, Ltd. 2003. "Posaconazole (SCH 56592): A 96-Hour Toxicity Test with the Freshwater Alga (Selenastrum capricornutum)," Study No., 554A-103A, WIL, Easton, MD, USA 15 July 2003.

8. Wildlife International, 2012. "Posaconazole: Aerobic Transformation in Aquatic Sediment Systems," Project No. 105E-158, WIL, Easton, MD, 05 December 2012.

9. Wildlife International, 2012. "Posaconazole: A bioconcentration test with the Bluegill (Lepomis macrochirus)," Project No. 105A-203, WIL, Easton, MD, 16 October 2012.