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) = 1.5*10^-6*A*(100-R)

PEC = 0.057 µg/L

Where:

A = 383.3227 kg (total sold amount API in Sweden year 2019, 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 = 9×10⁶

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 (Selenastrum capricornutum):

EC₅₀ 96 h (growth rate) = 2200 μg/L

NOEC 96 h (growth rate)  = 320 μg/L

(OECD 201)
(Ref II)

Crustacean (Daphnia magna):

EC₅₀ 48 h (immobilization): 120 000 μg/L

NOEC 48 h (immobilization): 16 000 μg/L

(OECD 202)
(Ref III)

Fish (Oncorhyncus mykiss):

EC₅₀ 96 h (mortality): 22 000 μg/L

NOEC 96 h (mortality): 6200 μg/L

(OECD 203)

(Ref IV)

Chronic toxicity to fish embryos (Danio rerio)
LC₅₀ 33 d (mortality) = 955 µg/L

NOEC 33 d (mortality) = 253 µg/L

(OECD 210)

(Ref V)

Other ecotoxicity data:
PNEC = 5,06 µg/L

The PNEC is calculated with the following formula: lowest EC₁₀ or NOEC/50 (Assessment factor justification: two long-term toxicity endpoints available for two trophic levels: algae and fish)

NOEC for Danio rerio has been used for this calculation since it is the most sensitive of the tested species.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC= 0.057 µg/L / 5,06 µg/L = 0.011, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of zolpidem has been considered to result in insignificant environmental risk".

Biodegradation

Ready biodegradability:

Test showed 30 % degradation in 28 days.
(OECD 301)
(Ref VI)

Justification of chosen degradation phrase:
Zolpidem fails to pass the criteria for ready and inherent biodegradability. The phrase: "Zolpidem is potentially persistent” is thus chosen.

Bioaccumulation

Partition coefficient:

Log P = 1.2 at neutral pH (estimated)
(Ref VII)

Justification of chosen bioaccumulation phrase:
Since log P < 4 at pH 7, zolpidem has low potential for bioaccumulation.

Excretion (metabolism)

Zolpidem is metabolized to three pharmacologically by various hepatic cytochrome P450 (CYP) isoenzymes, mainly CYP3A4, but also CYP1A2 and CYP2C9.
Although zolpidem is heavily metabolized, all three metabolites are inactive (Ref VIII).

Zolpidem is eliminated as inactive metabolites in urine (56 %) and in faeces (29-42 %)(Ref IX).

References

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

2. Sanofi, Internal Report: Zolpidem-Toxicity to the freshwater green alga Selenastrum capricornutum. OECD 201. Report # 91-1-3604, February 1991

3. Sanofi, Internal Report: Zolpidem-Acute toxicity to daphnids (Daphnia magna). OECD 202. Report # 90-12-3594, February 1991

4. Sanofi, Internal Report: Zolpidem-Acute toxicity to Rainbow Trout (Oncorhyncus mykiss). OECD 203. Report # 90-12-3599, February 1991

5. Sanofi, Internal Report: Zolpidem tartrate: Fish early-life stage toxicity test with the Brachydanio rerio. Report # BPL14-0011 EPC. 2016

6. Sanofi, Internal Report: Zolpidem-Ready biodegradability by the closed bottle method. OECD 301D. Report # 90-12-3591, February 1991

7. Drug Bank - Zolpidem - retrieved via drugbank.com 2021-08-25; find here and further to T₃DB; find here.

8. Drug Bank - Zolpidem - retrieved from drugbank.com 2021-08-25; find here.

9. SmPC of Stilnoct 5 mg film-coated tablet - retrieved from SE MPA 2021-08-25; find here.