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) = 1.5*10^-6*A (100-R) = 7*10^-9 µg/L

Where:

A = 0.00005 kg olodaterol hydrochloride (total sold amount API in Sweden year 2020, data from IQVIA/LIF).

R = 0 % removal rate.

P = number of inhabitants in Sweden = 10 *10⁶

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

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

Justification of chosen environmental risk phrase:

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of Olodaterol is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01µg/L. However as there is no ecotoxicity data the conclusion is: risk of environmental impact of Olodaterol cannot be excluded, since no ecotoxicity data are available.

Bioaccumulation

Partitioning coefficient

Log D_ow = 1.2 at pH 7.4, and 2.5 at pH 9 (OECD 107). (II)

Justification of chosen bioaccumulation phrase:

Since Log D_ow < 4 at pH 7, Olodaterol has low potential for bioaccumulation.

Degradation

No studies regarding degradation of Olodaterol hydrochloride are available. The low PEC and Log D_ow values did not warrant such investigations.

Justification of chosen degradation phrase:

Since no data are available, the potential for persistence of Olodaterol cannot be excluded, due to lack of data.

Excretion (metabolism)

Olodaterol is excreted to 42.6% as parent compound after intravenous administration; to 60.3% as parent compound after oral administration and to more than 20% as the metabolite desmethyl-olodaterol. The pharmacological activity of the metabolites is not known. (II)

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. Boehringer Ingelheim GmbH internal report (U11-2156-02), 2012

Detaljerad miljöinformation

Predicted Enviromental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (µg/L) = (A*10⁹*(100))/(365*P*V*D*100) = 1.5*10^-4*A = 0.00011 µg/L

Where:

A = 0.08 kg tiotropium bromide monohydrate; total sold API in Sweden year 2020, data from IQVIA)

P = number of inhabitants in Sweden = 10*10⁶

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

D = factor for dilution of waste = 10 (ECHA default) (Ref I)

Predicted No Effect concentration (PNEC)

Environmental assessment was based on toxicity data; however as only one and not three different trophic levels were available, a valid PNEC could not be calculated.

The phrase “Risk of environmental impact of tiotropium bromid cannot be excluded, since there is not sufficient ecotoxicity data available” is therefore used.

Degradation

Tiotropium bromide is not readily biodegradable (OECD 301B) (Ref II).

Justification: As tiotropium bromide did not pass the readily biodegradable test the phrase “Tiotropium bromide is potentially persistent” is used.

Bioaccumulation

The octanol/water partition coefficient was experimentally determined to be:

log D = -2.28 at pH 7.4 (OECD 117) (Ref III)

Justification: Since log D < 4, tiotropium bromide has low potential for bioaccumulation.

Excretion / metabolism

The extent of biotransformation is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers (Ref IV). After dry powder inhalation urinary excretion is 7% of the unchanged dose over 24 hours (Ref V), the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces. The renal clearance of tiotropium exceeds the creatinine clearance (Ref IV, VI, VII) , indicating secretion into the urine.

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. Chapter R.10: Characterization of dose [concentration]-response for environment.

   http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

2. Boehringer Ingelheim GmbH internal report U00-1323 (1999)

3. Boehringer Ingelheim GmbH internal report U00-1492 (2000)

4. Boehringer Ingelheim GmbH internal report U99-1315 (1999)

5. Boehringer Ingelheim GmbH internal report U99-3169 (1996)

6. Boehringer Ingelheim GmbH internal report U13-1531 (2015)

7. Boehringer Ingelheim GmbH internal report U00-1350 (2000)