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 = 0.209 μg/l

Where:

A = 1527,6799 kg (total sold amount API in Sweden year 2021, data from IQVIA)
Addition of:
Codeine phosphate hemihydrate = 1527,6795 kg
Codeine hydrochloride dihydrate = 0,0004 kg

R = 0% removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

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 of dilution of waste water by surface water flow = 10 (ECHA default) (Ref I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

No ecotoxicity data available.

Environmental Risk Rlassification (PEC/PNEC ratio)

The PEC/PNEC ratio could not be calculated since no ecotoxicity results are available, hence justifying the phrase: "Risk of environmental impact of codeine cannot be excluded, since no ecotoxicity data are available."

Degradation

No data available, therefore the degradation phrase should be: "The potential for persistence of codeine cannot be excluded, due to lack of data."

Bioaccumulation

Partitioning coefficient:

Log log P = 1.34 (pH unknown, predicted, Chem Axon)

(Ref II)

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

Excretion (metabolism)

Codein is excreted via the kidneys.

Codeine is primarily metabolized by glucuronidation. Through a less metabolic pathway, O-demethylated codeine is morphine.

After metabolization, the substance is excreted in the urine, primarily as codeine and norcodeine conjugates and also (about 20%) as morphine conjugate and free codeine.

(Ref III)

References

1. ECHA, European Chemicals Agency, 2008 Guidance on information requirements and chemical safety assessment. Available at https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment2020-05-14.

2. Drug Bank: log P for codeine phosphate hydrate, retrieved at https://www.drugbank.ca/salts/DBSALT0015922020-04-21.

3. SmPC of Panocod, retrieved from fass.se 2020-04-21.

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 = 91,10 μg/l

Where:

A = 664995.669778993 kg (total sold amount API in Sweden year 2021, data from IQVIA)

R = 0% removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

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 of dilution of waste water by surface water flow = 10 (ECHA default) (Ref I)

 Predicted No Effect Concentration (PNEC) 

 Ecotoxicological studies 

Algae (Pseudokirchneriella subcapitata):

EC₅₀ 72 h (growth rate): > 100 000 μg/L

NOEC 72 h (growth rate): ≥ 100 000 µg/l

Test item: Paracetamol

Protocol: OECD 201

(Ref II)

Crustacean (Daphnia magna):

NOEC 21 d (reproduction): 100 μg/L

NOEC 21 d (mortality): 1 000 µg/l

Test item: Paracetamol

Protocol: OECD 211

(Ref III)

Fish (Danio rerio):

NOEC 30 dph (mortality/survival): 3 160 μg/L

NOEC 30 dph (hatching success, body length, body weight): > 10 000 µg/l

Test item: Paracetamol

Protocol: OECD 210

(Ref IV)

Other ecotoxicity data:

PNEC = 10 μg/L (long-term results from at least three species representing three trophic levels, assessment factor: 10)

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used.

NOEC for Daphnia magna has been used for this calculation since it is the most sensitive of the three tested species.

 Environmental Risk Rlassification (PEC/PNEC ratio) 

PEC/PNEC = 91,10/10 = 9.110

1 < PEC/PNEC ≤ 10: Use of paracetamol has been considered to result in moderate environmental risk.

 Degradation 

No data available, therefore the degradation phrase should be: "The potential for persistence of paracetamol cannot be excluded, due to lack of data." 

 Bioaccumulation 

 Partitioning coefficient: 

Log log P = 0.91 (pH unknown, predicted, Chem Axon)

(Ref V)

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

 Excretion (metabolism) 

Paracetamol is excreted via the kidneys.

Paracetamol is metabolized by conjugation to glucuronide and sulfate. A minor part is also oxidatively metabolized and bound to glutathione and excreted as cysteine and mercapturic acid conjugates.

(Ref VI)

 References 

1. ECHA, European Chemicals Agency, 2008 Guidance on information requirements and chemical safety assessment. Available at https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment 

2. Sanofi Internal report: Paracetamol: Toxicity to Pseudokirchneriella subcapitata in an algal growth inhibition test. OECD201. Report 135441210, 2019

3. Sanofi Internal report: Paracetamol: Influence to Daphnia magna in a semi-static reproduction test. OECD211. Report 135441221, 2019

4. Sanofi Internal report: Paracetamol: Toxicity to Zebrafish (Danio rerio) in an Early-Life Stage Test. OECD210. Report 135441232, 2019

5. Drug Bank: log P for paracetamol, retrieved at https://www.drugbank.ca/drugs/DB00316 2020-04-21.

6. SmPC of Panocod, retrieved from fass.se 2020-04-21.