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) = 1.37*10^-6 * 2.4 kg * 100 = 0.004142 μg/L = 4.1423 ng/L

Where:

A = 30.2354 kg (sum of 7.1842 kg timolol and 31.5077 kg timolol maleat, equaling 23.0512 kg timolol) (total sold amount API in Sweden year 2022, data from IQVIA).

R = 0 % 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) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008).

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae: no data available

Crustacean (Daphnia magna): no data available

Fish: no data available

Other ecotoxicity data: No data available

PNEC derivation:

No PNEC can be calculated since there is no environmental toxicity data available

Environmental risk classification (PEC/PNEC ratio)

Calculation of a risk ratio is not possible, due to the lack of environmental toxicity data. Therefore, the following phrase is used: "Risk of environmental impact of timolol cannot be excluded, since no ecotoxicity data are available."

Degradation

Biotic degradation

Ready degradability: no data available

Justification of chosen degradation phrase:

As no data on biological degradation is available the following phrase is used: The potential for persistence of timolol cannot be excluded, due to lack of data.

Bioaccumulation

Partitioning coefficient:

logK_ow = 1.8 (method unknown) (Clarkes’s Analysis of Drugs and Poisons, 2017)

Justification of chosen bioaccumulation phrase:

As the logKow remains below the trigger level for a bioaccumlative substance (logKow < 4.0), the following statement is used for timolol: Timolol has low potential for bioaccumulation.

Excretion (metabolism)

Approximately 80% of timolol is metabolized in the liver to inactive metabolites. The unchanged drug and its metabolites are excreted in urine. Only small amounts of the drug are removed by hemodialysis. (AHFS Drug Information, 2017).

PBT/vPvB assessment

Based on screening information, timolol cannot be considered a potential PBT substance as the octanol-water partition coefficient remains below the trigger level for a bioaccumulative substance.

References

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

• Clarkes’s Analysis of Drugs and Poisons, 2017. Medicines Complete. Pharmaceutical Press. https://www.medicinescomplete.com/mc/clarke/current/CLK1616.htm?q=timolol&t=search&ss=text&tot=31&p=1#_hit

• AHFS Drug Information, 2017. Medicines Complete. Pharmaceutical Press.https://www.medicinescomplete.com/mc/ahfs/current/a384029.htm#pkin

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) = 1.37*10^-6 * 0.0301 * 100 = 0.000004 μg/L = 0.04 ng/L

Where:

A = 0.0301 kg travoprost (total sold amount API in Sweden year 2022, data from IQVIA).

R = 0 % 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) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae: no data available

Crustacean (Daphnia magna): no data available

Fish: no data available

Other ecotoxicity data: No data available

PNEC derivation:

No PNEC can be calculated since there is no environmental toxicity data available

Environmental risk classification (PEC/PNEC ratio)

Calculation of a risk ratio is not possible, due to the lack of environmental toxicity data. Therefore, the following phrase is used "Risk of environmental impact of travoprost cannot be excluded, since there is not sufficient ecotoxicity data available. According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of travoprost is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration is below the action limit 0.01 μg/L."

Degradation

Biotic degradation

Ready degradability:

3-4%, not readily biodegradable (OECD301B) (Study No. 511319)

Justification of chosen degradation phrase:

As travoprost does not fulfil the criteria for ready biodegradability, the following phrase is used: Travoprost is potentially persistent.

Bioaccumulation

Partitioning coefficient:

logK_ow = 4.647 (OECD123) (TDOC-0018065)

Justification of chosen bioaccumulation phrase:

As the logK_ow exceeds the trigger level for a bioaccumlative substance (logKow > 4.0), the following statement is used for travoprost: Travoprost has high potential for bioaccumulation.

Excretion (metabolism)

Travoprost is hydrolyzed by esterases in the cornea to the biologically active form (travoprost free acid). Systemically, travoprost free acid is metabolized to inactive metabolites. Travoprost free acid is rapidly eliminated from plasma; plasma levels are below the limit of quantitation within one hour following ocular instillation. Less than 2% of the topical ocular dose is excreted in urine within 4 hours as travoprost free acid. (AHSF Drug Information, 2017)

PBT/vPvB assessment

Based on screening information, travoprost can be considered a potential PBT substance as the criteria for persistence are fulfilled, the octanol-water partition coefficient exceeds the trigger level for a bioaccumulative substance and travoprost is labeled as a category 2 reprotoxic substance.

References

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

• EMA 2006, European Medicines Agency. European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-environmental-risk-assessment-medicinal-products-human-use-first-version_en.pdf

• Study No. 511319. Determination of 'Ready' Biodegradability: Carbon Dioxide (CO2) Evolution Test (Modified Sturm Test) of TRAVOPROST. Final report: 31 October 2016.

• TDOC-0018065. Determination of Partitioning Coefficient (1-Octanol/Water) for Travoprost Using Slow-Stirring Method at 25°C According to OECD/OCDE 123. Final report: 26 June 2014.

AHSF Drug Information, 2017. Medicines Complete. Pharmaceutical Press.

https://www.medicinescomplete.com/mc/ahfs/current/a301016.htm?q=travoprost&t=search&ss=text&tot=3&p=1#_hit