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 *47.31*(100-0)

Where:

A = 47.31 kg (total sold amount buprenorphine and buprenorphine hydrochloride in Sweden year 2022, data from IQVIA).

R = % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available. (If R is not equal to 0 this should be justified under the degradation section) 

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 water by surface water flow = 10 (ECHA default) (Ref. I)

PEC = 0.0064 μg/L

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of buprenorphine is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit 0.01 µg/L.

Predicted No Effect Concentration (PNEC)

No data available

Environmental risk classification (PEC/PNEC ratio)

No data available.

Degradation

No data available.

Bioaccumulation

Partitioning coefficient: Log Dow = 3.7 at pH 7 (guideline OECD 107). (Ref II)

Justification of chosen bioaccumulation phrase:  Since log Dow < 4 at pH 7, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjungation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is a µ-opioid agonist with weak intrinsic activity.

As the main metabolite is pharmacologically active, no reduction of A in the PEC calculation has been made.

References

I. 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

II. Volic, N., 2020. Determination of physico-chemical properties of Buprenorphine: partition coefficient at pH5 and pH7 using shake flask method; partion coefficient at pH 9 using slow-stirring method. Charles River Laboratories Den Bosch, Study No. 20186155

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)

PEC = 0.0076 μg/L

Where:

A = 55.495 kg = (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)
(Ref. I)

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

PEC calculation for naloxone

A = 55.495 kg (addition of 55.4946 kg (naloxone hydrochloride dihydrate) and 0.00015 kg (naloxone hydrochloride, anhydrous))

PEC (µg/L) = 1.37*10^-4*A = 0.0076 μg/L

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata)
EC₅₀ 72 hours (growth rate) = 51.2 mg/L = 51 200 μg/L

NOEC 72 hours (growth rate) = 2.67 mg/L = 2670 μg/L
Guideline: OECD 201 (Growth Inhibition Test)
(Ref. II)

Crustacean (Daphnia sp.)
EC50 48 hours (mobility) > 100 mg/L = 100 000 μg/L 
Guideline: OECD 202 (Acute Immobilisation Test)
(Ref. III)

Fish: No data available.

Other ecotoxicity data: 

PNEC: No PNEC can be calculated since there is not sufficient ecotoxicity data available.

Environmental Risk Classification (PEC/PNEC ratio)

Risk of environmental impact of naloxone cannot be excluded since there is not sufficient data available to calculate a PEC/PNEC ratio.

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of naloxone is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 µg/L.

Degradation

Biotic degradation

Ready degradability:

The degradation rate of naloxone was 0 % after 28 days.
Guideline: OECD 301 F (Ready Biodegradability: Manometric Respirometry Test) 

Naloxone is considered to be not readily biodegradable.
(Ref. IV)

Justification of chosen degradation phrase:

Naloxone is potentially persistent.

Bioaccumulation

Partitioning coefficient:

log K_ow: 2.09 (method and pH not found)

(Ref. V)

Justification of chosen bioaccumulation phrase: 
Since log K_ow < 4, naloxone has low potential for bioaccumulation.

Excretion (metabolism)
Naloxone is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite.
(Ref. VI)

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

2. ECHA – Naloxone Toxicity to aquatic algae and cyanobacteria, retrieved 2024-02-14 from ECHA website.

3. ECHA – Naloxone Short-term toxicity to aquatic invertebrates, retrieved 2024-02-14 from ECHA website.

4. ECHA – Naloxone Biodegradation in water: screening tests, retrieved 2024-02-14 from ECHA website.

5. PubChem – Naloxone, retrieved 2024-02-14 from PubChem webpage.

6. Respinal SmPC, retrieved 2024-02-14 from MPA webpage.