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 = 0.0002719998 μg/L

Where:

A = 1.9854 kg (total API sales) is the sum of API in the current formulation in the most recent sales data for Sweden 0.9975 kg (based on 2023 data from IQVIA distributed in 2024) and the forecasted sales for the new formulation 0.9879 kg

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. 1)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Ref. 1)

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of Macitentan is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit 0.01 μg/L.

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

No data available.

Environmental risk classification (PEC/PNEC ratio)

Calculation of Predicted No Effect Concentration (PNEC)

No data available.

Environmental risk classification (PEC/PNEC ratio)

Conclusion for environmental risk:

Risk of environmental impact of Macitentan cannot be excluded, since no ecotoxicity data are available.

DEGRADATION

Biotic degradation

Ready biodegradation

No data available.

Conclusion for degradation:

The potential for persistence of Macitentan cannot be excluded, due to lack of data.

BIOACCUMULATION

Partition coefficient octanol/water

Data according to open literature [Ref. 2]:

• ChemSpider reports:

  • ACD/LogD (pH 7.4): 2.13

Bioconcentration

Data according to open literature [Ref. 2]:

• ChemSpider reports:

  • ACD/BCF (pH 7.4): 8.44

Conclusion for bioaccumulation:

Macitentan has low potential for bioaccumulation.

Excretion (metabolism)

No data available.

PBT/vPvB assessment

No data available.

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. ChemSpider 2022. http://www.chemspider.com/

Detaljerad miljöinformation

Environmental Information for Tadalafil originates from Lilly for ADCIRCA, Cialis, Cialis^®, Tadalafil Lilly

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 = 0.0065048833 µg/L

Where:

A = 47.4809 kg (total API sales) in Sweden which is the sum of 45.5293 kg (API in the current formulation in the most recent sales data for Sweden data from 2023 distributed by IQVIA in 2024) and 3.9516 kg the forecasted sales for a new formulation in Sweden in the next 5 years

R = 0

P = number of inhabitants in Sweden = 10 *10⁶

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

D = factor for dilution of wastewater by surface water flow = 10 (ECHA 2016)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) 72-hour exposure (OECD 201):

EγC₅₀ 72 h (yield) > 1200 µg/L

NOECγ (yield) = 300 µg/L

E_rC₅₀ 72 h (growth) > 1200 µg/L

NOEC_r (growth) = 1200 µg/L

Abbreviations: EC50 = median effective concentration, LC50 = median lethal concentration, NOEC = no-observed-effect concentration. *While endpoints derived for yield (biomass) are included, only growth rate endpoints will be considered for classification, since growth rate is the preferred observational endpoint (ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7b 2016) [Study 1982.6290]

Crustacean (Daphnia magna) (water-flea) (guideline e.g. OECD 211):

Acute toxicity

Acute Toxicity to water fleas Daphnia magna 48-hr exposure (OECD 202) [Study 303/687]

EC₅₀ 48 h > 2000 µg/L

NOEC = 2000 µg/L (immobility)

Chronic toxicity

Full life-Cycle Toxicity Daphnia magna (21 days) (OECD 211) [Study 1982.6284]:

NOEC 21 days = 480 µg/L (Reproduction, survival, growth)

Fish:

Acute toxicity

Rainbow trout (Oncorhynchus mykiss) 96 hours [Reference F00999]:

LC₅₀ 96 h > 2100 µg/L

NOEC = 2100 µg/L

Chronic toxicity

Fish early life stage test with Fathead minnow (Pimephales promelas) (embryo + 28 days post hatch) OECD 210 [Reference 1982.6283]:

NOEC = 1200 µg/L

Calculation of PNEC (µg/l) = lowest NOEC/10, where 10 is the assessment factor used. NOEC for Daphnia magna of 480 µg/L has been used for this calculation since it is the most sensitive of the three tested species.

PNEC = 480 µg/L/10 = 48 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00650048833 /48 = 1.1279 × 10^-5 i.e. PEC/PNEC < 0,1

Conclusion for environmental risk:

The PEC/PNEC ratio of less than 0.1 justifies the phrase “Use of Tadalafil has been considered to result in insignificant environmental risk”.

Degradation

Biotic degradation

Ready degradability:

Tadalifil has not been tested for ready biodegradability. However, tadalafil is assumed to be not readily biodegradable given the small amount of CO evolved (~5% of applied radioactivity) when C-tadalafil 14 2 14 was incubated with sewage sludge for 85 days (OECD 302A, a test of inherent degradability) [Study 1982.6287]:

Inherent degradability:

Tadalafil is transformed (DT50 = 9 days) to more polar hydroxylated metabolites when incubated with activated sewage sludge under aerobic conditions (SCAS test, modified from OECD 302A) [Study 1982.6287]:

Simulation study:

Tadalafil was transformed in two water-sediment systems in which radiolabelled tadalafil was incubated under aerobic conditions for 108 days (OECD 308) [Study 1982.6288).

Parent tadalafil disappeared from the overlying water with a DT50 of approximately 4 days. Dissipation of tadalafil was due to partitioning to sediment and to primary and ultimate degradation. The sediment was extracted three times with solvent systems of varying polarity (1. Acetonitrile, 2. Acetonitrile:water 80:20, 3. Acetonitrile:water:hydrochloric acid 80:20:0.1 v:v) and the pooled extract was characterized for parent and transformation products. By the end of the study, several polar transformation products were observed and 1,8% and 3,4% of the applied radioactivity evolved as CO over the 108 day study. Approximately 25% and 30% of the radioactivity 14 2 could not be extracted from the sediment. The calculated half-lives for dissipation of tadalafil from the whole system (via degradation and irreversible binding to sediment) were 70 and 117 days.

Abiotic Degradation

Tadalafil is stable with respect to hydrolysis (OECD 111) [Study 1982.6281). Based on the lack of observed degradation in the algae toxicity study (Study 1982.6290) under continuous light conditions for 72 hours, tadalafil is stable with respect to photolysis.

Justification for the degradation phrase:

Tadalafil disappeared from water sediment systems with half-lives of 70 and 117 days and there was evidence of biotransformation and mineralization. Therefore, the degradation phrase “Tadalafil is slowly degraded in the environment” is based on the fate in water-sediment systems

Bioaccumulation

Partition coefficient octanol/water:

The octanol/water partition coefficient of 2,32 was determined using an HPLC correlation method (EEC Method A8) [Study 303/688)]

As tadalafil has no ionizable groups, this value is appropriate over an environmentally relevant range of pH. As the log K_OW is less than 3 and the compound is subject to extensive metabolism, tadalafil is not expected to bioaccumulate in biotic tissues

Justification for the degradation phrase:

The octanol-water partition coefficient is less than 4, justifying the use of the phrase “Tadalafil has low potential for bioaccumulation.”

Excretion (metabolism)

In humans, tadalafil is transformed into metabolites that are at least 45 times less potent based on in vitro phosphodiesterase 5 inhibition. Based on quantification of residue excretion in humans, one-third, at most, of the total dose is excreted as tadalafil. Thus, human metabolism can be estimated to reduce the amount of tadalafil that reaches the sewage treatment facility by at least two-thirds.  For this risk assessment, however, a worst-case total residues approach will be taken; that is, tadalafil and its human metabolites will be considered to have the same activity

PBT/vPvB assessment

Although a bioconcentration factor has not been empirically determined, tadalafil is not considered bioaccumulative because the log octanol-water partition coefficient value is less than 4 and because tadalafil is subject to metabolism. The chronic aquatic NOEC values are all greater than 10 µg/L. The effects of tadalafil in mammals have been summarized elsewhere. The pharmacological target of tadalafil in mammals is not a hormone receptor. Because tadalafil does not meet the criteria for bioaccumulative or toxicity, it is not considered to be PBT or vPvB

Conclusion for PBT-assessment: According to the established EU-criteria, tenofovir alafenamide should not be regarded as a PBT substance.

References

ECHA, European Chemicals Agency. 2016 Guidance on information requirements and chemical safety assessment. Chapter R.16: Environmental Exposure Estimation. Version 3.0 https://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

Eli Lilly and Company Safety Data Sheet. 04 November 2015. Cialis®. http://ehs.lilly.com/msds/Cialis.pdf

Study 1982.6287. 2008. [ C]Tadalafil (¹⁴C-LY450190) - Determination of the Inherent Biodegradability and 14 14 Adsorption by the SCAS Test, Modified from OECD Guideline 302A. Eli Lilly and Company.

Study 1982.6281. 2008. Determination of the Abiotic Degradation of Tadalafil (LY450190) by Hydrolysis at Three Different pH Values Following OECD Guideline 111. Eli Lilly and Company. Study 1982.6290.  2008.

Tadalafil (LY450190) – 72-Hour Acute Toxicity Test with Freshwater Green Alga, Pseudokirchneriella subcapitata, Following OECD Guideline 201. Eli Lilly and Company.

Study 1982.6288. 2008. [¹⁴C]Tadalafil ([¹⁴C]LY450190) - Aerobic Transformation in Aquatic Sediments Following OECD Guideline 308. Eli Lilly and Company. Study F00999. 2009. Pilot Study on the Toxicity of LY450190 to Rainbow Trout in a 96-hr Static Toxicity Test System. Eli Lilly and Company.

Study 1982.6283. 2008. Tadalafil (LY450190) – Early Life-Stage Toxicity Test with Fathead Minnow, (Pimephales promelas), Following OECD Guideline #210. Eli Lilly and Company.

Study 1982.6284. 2008. Tadalafil (LY450190) – Full Life Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static Renewal Conditions, Following OECD Guideline #211. Eli Lilly and Company.

Study 303/687 (Number K20701, Report WPT/94/309). 1994. The Acute Toxicity of GF196960X to Daphnia magna. Glaxo. Study 303/688 (Number K20701, Report WPT/94/309). 1994. GF19696X Determination of Partition Coefficient. Glaxo