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 D_ow < 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