Miljöpåverkan
Naloxegol
Miljörisk:
Användning av naloxegol har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning:
Naloxegol är potentiellt persistent.
Bioackumulering:
Naloxegol har låg potential att bioackumuleras.
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Detaljerad miljöinformation
Naloxegol oxalate is a once-daily, peripherally-acting mu-opioid receptor antagonist used for the treatment of opioid-induced constipation in adult patients.
Naloxegol oxalate is the active pharmaceutical ingredient in the Kyowa Kirin product Moventig.
Following oral administration, 68% of the dose is excreted in the faeces, and 16% in the urine. Unchanged naloxegol oxalate excreted in the urine accounts for less than 6% of the total administered dose.
Naloxegol oxalate is not readily biodegradable and is not predicted to bioaccumulate in aquatic organisms.
Based on the result of the octanol water portioning coefficient study, it is unlikely that naloxegol will bioaccumulate in aquatic organisms.
Detailed background information
Environmental Risk Classification
PEC/PNEC = 8.52*10-4 /200 = 4.26*10-6 , i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of Naloxegol Oxalate has been considered to result in insignificant environmental risk."
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)
PEC = 8.52*10-4 µg/L
Where:
A = 5.60243 kg (total sold amount API in Sweden year 2019, data from IQVIA).
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 = 9 *106
V (L/day) = volume of wastewater per capita and day = 200 (ECHA default)
D = factor for dilution of waste water by surface water flow = 10 (ECHA default)
(Note: Whilst Naloxegol oxalate is metabolised in the body, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for this calculation, it is assumed that 100% of excreted metabolites have the same ecotoxicity as Naloxegol oxalate)
Predicted No Effect Concentration (PNEC)
Ecotoxicological studies
Study Type |
Method |
Result |
Reference |
Activated sludge, respiration inhibition test |
OECD209 |
3 hour EC50 >100 mg/L 3 hour NOEC = 100 mg/L |
1 |
Toxicity to green algae, Pseudokirchinella subcapitata, growth inhibition test |
OECD201 |
72 hour EC50 (growth rate) = 120 mg/L 72 hour NOEC (growth rate) = 38 mg/L |
2 |
Long-term toxicity to Daphnia magna |
OECD211 |
21 day LOEC reproduction and length) = 100 mg/L 21 day NOEC (reproduction and length) = 32 mg/L |
3 |
Fish early-life stage toxicity with fathead minnow, Pimephales promelas |
OECD210 |
32 day LOEC (hatch, survival, length and dry weight) > 2.0 mg/L 32 day NOEC (hatch, survival, length and dry weight) = 2.0 mg/L |
4 |
Long-term toxicity to Chironomus riparius |
OECD218 |
28 day NOEC (development rate, total emergence, sex ratio) = 10 mg/kg dry sediment 28 day LOEC (development rate, total emergence, sex ratio) > 10 mg/kg dry sediment |
5 |
Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the lowest NOEC value 2 mg/L (equivalent to 2,000 µg/L) which was reported for Pimephales promelas and an assessment factor of 10 is applied, in accordance with ECHA guidance
PNEC = 200 μg/L
Degradation
Naloxegol is potentially persistent.
Study Type |
Method |
Result |
Reference |
Aerobic biodegradation |
OECD301B |
0.7% mineralisation Not readily biodegradable |
6 |
Adsorption/desorption to sludge |
OPPTS 835.1110 |
Kdsludge(ads) = 253 |
7 |
Aerobic transformation in aquatic sediment systems |
OECD308 |
Naloxegol oxalate disappeared quickly from the overlying water in both the high and low organic carbon sediments, with half lives of 3.8 and 2.6 days. The results indicate that Naloxegol oxalate is unlikely to persist in aqueous systems, but is likely to become irreversibly bound to sediment, and to be biologically unavailable. The highest Kd value determined in the study, 120, was for the high organic sediment. |
8 |
Multi-matrix adsorption |
Based on OECD 106 |
Mean Kd: -Soil and 0.01M CaCl2 solution = 19.5 L/Kg -High organic sediment and natural water = 1039 L/Kg -Low organic sediment and natural water = 118 L/Kg Post digester sludge and phosphate buffer = 93 L/Kg |
9 |
Kd= Distribution coefficient for adsorption
Bioaccumulation
Naloxegol oxalate has low potential for bioacculmulation
Study Type |
Method |
Result |
|
Octanol-water distribution coefficient |
OECD107 |
pH 5 log Dow < -0.326 pH 7 log Dow = -0.643 pH 9 log Dow = 0.874 |
10 |
Water solubility |
OECD105 |
pH 5, 7 and 9 > 1000 mg/L |
11 |
Hydrolysis |
OECD111 |
<10% hydrolysis at 120 hours (pH 5, 7 and 9) Hydrolytically stable |
12 |
Since log Dow < 4 at pH 7, the substance has low potential for bioaccumulation.
Excretion (metabolism)
Following oral administration, 68% of the dose is excreted in the faeces, and 16% in the urine. Unchanged naloxegol oxalate excreted in the urine accounts for less than 6% of the total administered dose.
References
1. 14CNKTR-118: Adsorption to activated sludge. July 2012. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0662/B.
2. NKTR-118: Determination of toxicity to the green alga Pseudokirchneriella subcapitata.
January 2012. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0565/B.
3. NKTR-118 Determination of effects on reproduction to Daphnia magna. April 2012. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0584/B.
4. NKTR-118: Determination of the effects on the Early-life Stage of the Fathead minnow (Pimephales promelas). March 2012. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0582/B.
5. [14C]NKTR-118: Determination of the effects in a water-sediment system on the emergence of Chironomus riparius using spiked sediment. May 2012. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0649/B.
6. [14C]NKTR-118: 28 day ready biodegradation, modified OECD 301B. May 2013. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0838/B.
7. 14CNKTR-118: Adsorption to activated sludge. July 2012. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0662/B.
8. NKTR-118: Aerobic transformation in aquatic sediment system - Final report. October 2013. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0778/B.
9. 14CNKTR-118: Multimatrix adsorption study. July 2012. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0678/B.
10. NKTR-118: Determination of the Partition Coefficient (octanol/water): Shake Flask Method. July 2013. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0862/B.
11. NKTR-118: Determination of Water Solubility. October 2011. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0551/B.
12. NKTR-118: Determination of hydrolysis as a function of pH: Prelim. November 2011. Brixham Environmental Laboratory, Brixham, UK. Report Number BR0556/B