Detaljerad miljöinformation

PEC/PNEC = 0.0017 µg/L /0.084 µg/L = 0.021

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The PEC is based on the following data and calculated using the equation outlined in the fass.se guidance (Ref 1):

PEC (µg/L)      = (A*10⁹*(100-R))/(365*P*V*D*100)

PEC (µg/L)      = 1.37*10^-6*A*(100-R)

PEC    = 1.37 * 10^-6 * 12.664 * (100-R) = 0.0017 µg/L

Where:

A (kg/year)     = total sold amount API in Sweden year 2021, data from IQVIA / Lif

= 12.66358729112 kg/year

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilisation,

hydrolysis or biodegradation) = 0 (default)

P        = number of inhabitants in Sweden =10*10⁶ (default, Ref 1)

V (L/day)        = volume of wastewater per capita and day = 200 L/day (ECHA default) (Ref.2)

D        = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref.2)

(Note: The factor 10⁹ converts the quantity used from kg to μg)

Metabolism and excretion

In a human pharmacokinetics study with radiolabelled roflumilast, total recovery of radioactivity amounted to 90% of the dose, with 70% being excreted in urine and about 20% in faeces (Ref 4). Roflumilast itself was undetectable in urine in this study and its active metabolite roflumilast N-oxide was detected only in small amounts (1%). Instead, 4 inactive metabolites, each about 10 – 15 % were found in urine. The origin of radioactivity in faeces was not investigated.

Ecotoxicity Data

Study Type	Method	Result	Reference
Toxicity to green algae, Desmodesmus subspicatus, growth inhibition test	OECD201	72 hour NOEC (growth rate) =0.024 mg/l 72 hour LOEC (growth rate) =0.043 mg/l 72 hour EC50 (growth rate) = 0.084 mg/l 72 hour NOEC (biomass) =0.024 mg/l 72 hour LOEC (biomass) =0.043 mg/l 72 hour EC50 (biomass) =0.043 mg/l	5
Acute toxicity to Daphnia magna	OECD202	48 hour EC50 (immobility) > 0.430 mg/L 48 hour NOEC (immobility) = 0.430 mg/L	6
Acute toxicity to Zebra fish, Brachydanio rerio	OECD203	96 hour LC50 (mortality) > 0.295 96 hour NOEC (mortality) = 0.295	7

NOEC   No Observed Effect Concentration

LOEC   Lowest Observed Effect Concentration

EC50    the concentration of the test substance that results in a 50% effect

LC50    the concentration of the test substance that results in a 50% mortality

Predicted No Effect Concentration (PNEC)

Short-term tests have been undertaken for species from three trophic levels.  Therefore, the PNEC is based on the EC50 value for growth rate inhibition for green algae, 0.084 mg/L (equivalent to 84 µg/L), and an assessment factor of 1000 is applied, in accordance with ECHA guidance (Ref.3)

PNEC = 84 µg/L /1000 = 0.084 µg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC = 0.0017 µg/L /0.084 µg/L

PEC/PNEC = 0.02

PEC/PNEC ≤ 0.1 which justifies the phrase:

“Use of Roflumilast has been considered to result in insignificant environmental risk.”

In Swedish: Användning av Roflumilast har bedömts medföra försumbar risk för miljöpåverkan.

Environmental Fate Data

Study Type	Method	Result	Reference
Determination of ready biodegradability	OECD 301D	Degradation after 21 days <11.6% Not readily biodegradable	8

Biodegradation

The potential for Roflumilast to rapidly biodegrade during sewage treatment was investigated in an OECD 301D “Closed bottle test”. In this study the biological degradability of the test item is determined as the percentage of the BOD/ThOD ratio under inclusion of the sample concentration. Roflumilast achieved 11.6% degradation within 21 days.  As Roflumilast was not degraded to 60% in 28 days it is considered as not readily biodegradable.  In the absence of other evidence, Roflumilast must be considered as potentially persistent in the environment.

In Swedish: Roflumilast är potentiellt persistent.

Physical Chemistry Data

Study Type	Method	Result	Reference
Disassociation constant	Not stated	pKa = 8.74 ± 0.04	9
Solubility	Not stated	Water (21 – 22°C) 0.54 ± 0.02mg/L	9
Octanol-water partition coefficient	Not stated	logP at pH 7.4 = 3.99 ± 0.10	9

Roflumilast is a weak acid with a pKa of 8.74, as such aqueous solubility increases from about 0.8 mg/L under neutral conditions to about 35.8 mg/L at pH 10.  Based on the octanol-water partition coefficient; Roflumilast has a low potential for bioaccumulation

In Swedish: Roflumilast har låg potential att bioackumulera.  

References

1. Fass.se (2012).  Environmental classification of pharmaceuticals at www.fass.se: Guidance for pharmaceutical companies https://www.fass.se/pdf/Environmental_classification_of_pharmaceuticals-120816.pdf

2. [ECHA] European Chemicals Agency.  Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0). February 2016. http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

3. ECHA, European Chemicals Agency. May 2008. Guidance on Information Requirements and Chemical Safety Assessment.  Chapter R.10: Characterisation of dose [concentration]-response for environment http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

4. 223/2001 A study to investigate the distribution, metabolism and excretion (mass balance) and pharmacokinetics of [14C]-B9302-107 after oral and intravenous administration to six healthy male volunteers.  Atlanta Pharma 2001

5. 204/2007 Algae growth inhibition test with Roflumilast on Desmodesmus subspicatus. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007

6. 211/2007 Acute toxicity of Roflumilast to Daphnia magna. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007

7. 214/2007 Acute toxicity of Roflumilast to the zebra-fish, Brachydanio rerio. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007

8. 116/2007 Determination of ready biodegradability of Roflumilast “Closed bottle test”.  BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007

9. Internal Report, 3.2.S.1.3 General Properties (Roflumilast), 2009