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 = 0.06 µg/L

Where:

A = 403.154 kg (total sold amount API in Sweden year 2016, data from QuintilesIMS)

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 = 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)

Other ecotoxicity data:
PNEC = 2.2 µg/L

The PNEC (μg/L) = lowest EC₅₀/1000 was calculated using results from the most sensitive acute toxicity endpoint and an assessment factor of 1000 at least one short-term result from each of the three trophic levels), to add a safety margin to the toxicity endpoint. The most sensitive species was algae Selenastrum capricornutum for which the EC₅₀ was 2200 μg/L.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC= 0.06 / 2.2 = 0.03, 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 V)

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_ow =1.2 at neutral pH (estimated) (Ref VI)

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

Excretion (metabolism)

Zolpidem is extensively metabolized to three major metabolites, with less than 1% of the parent drug excreted unchanged (Ref VII) (Ref VIII). Three major metabolites have been found in humans, but none appears to be pharmacologically active (Ref VIII).

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

6. Source Drugbank, assessed as of Sep 11, 2018 http://www.drugbank.ca/drugs/DB00425

7. Hempel, G. and Blaschke, G., 1996. Direct determination of zolpidem and its main metabolites in urine using capillary electrophoresis with laser-induced fluorescence detection. Journal of Chromatography B. 675, 131-137.

8. Chouinard, G., Lefko-Singh, K., Teboul, E., 1999. Metabolism of anxiolytics and hypnotics: Benzodiazepines, Buspirone, Zopiclone and Zolpidem. Cellular and Molecular Neurobiology. 19, 533-552.