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) =

14.7x 10^-5 μg/L

Where:

A = 1.07217 kg (total sold amount API in Sweden year 2022, data from IQVIA).

R = 0 % removal rate. This is considered a conservative value.

P = number of inhabitants in Sweden = 10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA, 2016)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA, 2016)

Predicted No Effect Concentration (PNEC)

PNEC = 20 μg/L

The PNEC has been derived from the lowest NOEC (Pseudokirchneriella subcapitata, 72h, growth rate) together with as assessment factor of 10 based on the availability of a NOEC for algal growth inhibition in combination with chronic toxicity studies for the other trophic levels.

Algae (Pseudokirchneriella subcapitata) (OECD 201, GLP) (RCC Ltd., 2007a):

EC50 72h (growth rate) = > 920 μg/L

NOEC = 200 μg/L

Crustacean (Daphnia magna):

Acute toxicity

No data on acute toxicity.

Chronic toxicity

NOEC 21d (Mortality, reproduction) = > 1000 μg/L (OECD 211, GLP) (RCC Ltd., 2007b)

Fish (Danio rerio):

Acute toxicity

No data on acute toxicity.

Chronic toxicity

NOEC 35d (Hatching success, developmental rate, survival, length, wet/dry weight) = > 1000 μg/L (OECD 210, GLP) (RCC Ltd., 2007c)

Other ecotoxicity data:

The inhibitory effect of tolvaptan at a nominal concentration of 1000 mg/L on the respiration rate of aerobic wastewater microorganisms of activated sludge was investigated in a 3-hour respiration inhibition test according to OECD Test Guideline No. 209 (RCC Ltd., 2007d). Tolvaptan exhibited no inhibitory effect on the respiration rate of activated sludge under the test conditions.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC =14.7 x 10^-5/20 =7.34 x 10^-6, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of tolvaptan has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

In a 28d ready biodegradability study in accordance with OECD Test Guideline 301B (GLP) no biodegradation of Tolvaptan was observed (RCC Ltd., 2007e). Tolvaptan had no inhibitory effect on the activity of the sludge microorganisms as indicated by degradation of a co-exposed reference compound. Based on these data tolvaptan is considered not readily biodegradable.

Inherent degradability:

No data on inherent biodegradability.

Simulation studies:

The degradation of ¹⁴C-labelled tolvaptan in two aquatic systems (river and pond), incubated under aerobic conditions at 20°C, were investigated according to OECD Test Guideline No. 308 (GLP) (RCC Ltd., 2007f). In both test systems, tolvaptan disappeared rapidly from the water phase, predominantly by distribution to the sediment. At 100 days, radioactivity in the water phase of both systems was roughly 5% of the applied radioactivity, and in the river and pond sediments 92 and 95%, respectively. Tolvaptan was the major fraction at 100 days, representing 74 and 60%, respectively, of the applied radioactivity in the river and pond system. In addition, one major metabolite “M1” was found at a peak concentration of 16 and 31% of the applied radioactivity in the respective systems. Half-lives for its rate of degradation in the total system were 135 (pond) and 218 (river) days, respectively. Degradation of tolvaptan proceeded primarily via degradation to the major metabolite M1 whilst mineralization played only a minor role under the test conditions. Based on these data tolvaptan is considered potentially persistent.

Abiotic degradation

Hydrolysis: No data on hydrolysis

Photolysis: No data on photolysis.

Justification of chosen degradation phrase:

Tolvaptan did not pass the ready degradation test (OECD 301B, GLP) and was potentially persistent in a simulation study in two aquatic systems (OECD 308, GLP). Data on abiotic degradation is lacking. Based on these data Tolvaptan is considered “potentially persistent”.

Bioaccumulation

Bioconcentration factor (BCF):

A BCF for Tolvaptan was calculated in Rainbow trout (Onchorhynchus mykiss) according to OECD Test Guideline 305 (GLP) using two different doses of radiolabelled Tolvaptan - 1.04 µg/L (low dose) and 10.56 µg/L (high dose), respectively, for 14d and with a 14d depuration period (Harlan Laboratories, 2009). The result showed that steady-state was reached within 4 days with average whole-fish levels of Tolvaptan of 0.001 and 0.012 µg/g for the low dose and the high dose, respectively, corresponding to steady-state BCFs of 1.1 ± 0.3 and 1.1 ± 0.2. The concentrations were below the limit of quantification (LOQ) of 5.2 ng/g during the depuration period. Based on these data Tolvaptan is considered not bioaccumulative.

Partitioning coefficient:

The n-octanol/water partition coefficient has been determined using the shake flask method (Otsuka Pharmaceutical Co., Ltd, 2007). The partition coefficient was reported to be 9000 equivalent to a log KOW of 3.95. Based on these data Tolvaptan can be considered to have a low potential for bioaccumulation.

Justification of chosen bioaccumulation phrase:

Based on the data from the OECD Guideline 305 (GLP) study showing a lack of bioaccumulation, Tolvaptan is considered to have “low potential for bioaccumulation”.

Excretion (metabolism)

In a pharmacokinetic study on healthy men ¹⁴C-tolvaptan was extensively metabolized (RCC Laboratories, 2008). In feces, which represented 59% of the excretion, tolvaptan and identified metabolites accounted for 75% of the radioactivity following 96h, of which tolvaptan accounted for 32% and metabolites for 43%. In urine, which represented 40% of the excretion, tolvaptan represented only 1% of the total recovered radioactivity. In a series of tests it was demonstrated that the metabolites of tolvaptan showed either no activity or weak antagonistic activity for human V2- and V1a-receptors when compared with tolvaptan (RCC Laboratories, 2008). Furthermore, they did not show any antagonistic activity for human V1b-receptors (Otsuka Pharmaceutical Co., Ltd, 1999, 2006). Accordingly, the metabolites is not expected to contribute to the pharmacological effects of the drug in vivo, and are, consequently, not expected to exhibit a higher toxicity to aquatic organisms than the parent compound.

PBT/vPvB assessment

Tolvaptan is considered not to fulfil the criteria for PBT or vPvB.

References

ECHA, European Chemicals Agency. 2016 Guidance on information requirements and chemical safety assessment. Chapter R.16: Environmental exposure assessment. Version 3.0 (February 2016)
https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment

Harlan Laboratories (2009). Study Report C16351 - Bioconcentration of ¹⁴C-Tolvaptan: Flow-through test in the Rainbow trout (Onchorhynchus mykiss)

Otsuka Pharmaceutical Co., Ltd (1999). Report No. 012717.

Otsuka Pharmaceutical Co., Ltd (2006). Report No. 018780.

Otsuka Pharmaceutical Co., Ltd (2007). Report No. 07061. Determination of Partition Coefficient for OPC-41061 (for environmental risk assessment).

RCC Laboratories (2008). Environmental risk assessment for medicinal products for human use - Tolvaptan. Revised expert report.

RCC Ltd. (2007a). Tolvaptan (Synonym: OPC-41061): Toxicity to Pseudokirchneriella subcapitata in a 72-hour algal growth inhibition test. RCC Study number A93407.

RCC Ltd. (2007b).Tolvaptan (Synonym: OPC-41061): Effect on survival and reproduction of Daphnia magna in a semi-static test over three weeks. RCC Study number A93418.

RCC Ltd. (2007c). Tolvaptan (Synonym: OPC-41061): Toxic effects to zebra fish (Brachydanio rerio) in an early-life stage toxicity test. RCC study number A93420.

RCC Ltd. (2007d). Tolvaptan (Synonyms: OPC-41061): Toxicity to activated sludge in a respiration inhibition test. RCC study number A93431.

RCC Ltd. (2007e). Tolvaptan (Synonyms: OPC-41061): Ready biodegradability in a CO2 evolution (modified sturm) test. RCC study number A93385.

RCC Ltd. (2007f). 14C-Tolvaptan: Route and rate of degradation in aerobic aquatic sediment systems. RCC study number A93396.