Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC) (Ref. 1)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100)

PEC (μg/L) = (5879,48*10⁹*(100-0))/(365*10*10⁶*200*10*100)

PEC = 0,81 μg/L

Where:

A (kg/yr)	5879,48 kg	Total sevoflurane sold (kg) in Sweden in 2021 from IQVIA (Ref. 2)
R	0 %	Removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation); use 0 if no data is available. (Ref.1)
P	10*106	Number of inhabitants in Sweden (Ref. 1)
V (L/day)	200	Volume of wastewater per capita and day (200 L/day is the default value) (Ref. 1,3)
D	10	Factor for dilution of wastewater by surface water flow (10 is the default value) (Ref. 1,3).

(Note: the factor 10⁹ converts the quantity used from kg to μg).

Ecotoxicological studies with Sevoflurane

Algae (Pseudokirchneriella subcapitata)

The purpose of this study was to evaluate the toxic effect of sevoflurane on the freshwater green algae, Pseudokirchneriella subcapitata, in accordance with the OECD Guidelines for Testing of Chemicals, Guideline 201: Freshwater Alga and Cyanobacteria, Growth Inhibition Test and ASTM Standard Guide 1218-90E: Standard Guide for Conducting Static 96-Hour Toxicity Tests with Microalgae. The exposure period was 72 hours. The study yielded the following results. (Ref. 5)

EC50 (72h) for cell density > 100 mg/L

EC50 (72h) for biomass > 100 mg/L

EC50 (72h) for growth rate > 100 mg/L

NOAEC (72h) for cell density = 25mg/L

NOAEC (72h) for biomass = 50 mg/L

NOAEC (72h) for growth rate = 25 mg/L

Crustacean (Daphnia magna): Acute toxicity

The toxicity of sevoflurane (Ultane^®) on Daphnia magna was evaluated using the OECD Guidelines for Testing of Chemicals, Guideline 202: Daphnia sp., Acute Immobilization Test and OPPTS Number 850.1010: Aquatic Invertebrate Acute Toxicity Test, Freshwater Daphnids. The exposure period was 48 hours. The results were as follows. (Ref. 5) 

EC₅₀ (48h) for mortality/immobility = 48 mg/L

NOEC for clinical signs of toxicity = 13 mg/L

Fish (Pimephales promelas): Acute toxicity

The toxicity of sevoflurane (Ultane^®) on the fathead minnow (Pimephales promelas) was studied in accordance with OECD Guidelines for Testing of Chemicals, Guideline 203: Fish, Acute Toxicity Test and OPPTS Number 850.1075: Fish Acute Toxicity Test, Freshwater and Marine. The study used a 96-hour exposure period.  The results were as follows. (Ref. 6)

LC50 (96h) for mortality = 43 mg/L

NOEC (96h) for clinical signs of toxicity = 13 mg/L

Predicted No Effect Concentration (PNEC)

PNEC (μg/L) = lowest EC₅₀/AF

AF = Assessment Factor= 1000 (Ref. 7)

Organism	E(L)C50
Microorganisms (spps)	>1000 mg/L
Freshwater Algae (Pseudokirchneriella subcapitata)	EC50 Cell Density >100 mg/L EC50 Biomass >100 mg/L EC50 Growth Rate >100 mg/L
Daphnia magna	EC50 Mortality/Immobility = 48 mg/L
Fathead Minnow (Lepomis macrochirus)	LC50 Mortality = 43 mg/L

The LC₅₀ for the fathead minnow (Pimephales promelas) has been used for this the PNEC calculation since it is the most sensitive of the three tested species (algae, crustacean, fish).

EC₅₀ = 43 mg/L = 43000 μg/L

PNEC (μg/L) = 43000 / 1000

PNEC = 43 μg/L

Environmental Risk classification (PEC/PNEC ratio)

PEC = 0,81 μg/L

PNEC = 43 μg/L

PEC/PNEC = 0,81/43

PEC/PNEC = 0,02

PEC/PNEC ≤ 0.1 which justifies the phrase “Use of sevoflurane has been considered to result in insignificant environmental risk.”

Degradation

Ready degradability

The biodegradability of sevoflurane was evaluated using OECD Guidelines for Testing of Chemicals, Guideline 301D: Ready Biodegradability, Closed Bottle Test and Council of the European Communities, Directive 67/548/EEC. Annex V. Guideline Determine of “Ready” Biodegradability C.4-E, Closed Bottle Method.  Data to evaluate ready biodegradability was collected over a period of 28 days.  It was determined that sevoflurane was not considered readily biodegradable under the conditions of this study.  The summary result of the study is below. (Ref. 8)

4.4% degradation in 28 days

Based on the results of the above study, sevoflurane is potentially persistent.

Bioaccumulation

Partitioning coefficient: (Ref. 9)

Log Kow = 1,75 (KOWWIN v1.67 estimate)

Log D (pH 7,4) = 2,22 (estimated)

Bioaccumulation Estimates from Log Kow (BCFWIN v2.17): (Ref. 9)

BCF = 4.424 (based on Log Kow 1,75, estimated)

Since the Log Kow and Log D values are <4 and the BCF value is <500, it can be concluded that the phrase “sevoflurane has low potential for bioaccumulation” is justified.

References

1. FASS.se.  Environmental classification of pharmaceuticals at www.fass.se.  Guidance for pharmaceutical companies.  2012 V 2.0. 2021.

2. IQVIA. 2018.  IQVIA / LIF - kg consumption/2021.

3. ECHA.  2016.  Guidance on Information Requirements and Chemical Safety Assessment Chapter R.16: Environmental exposure assessment.  Version 3.0.  February 2016.

4. Claude MB & Krueger HO, 2008a. Sevoflurane: A 72-hour toxicity screening test with the freshwater alga (Pseudokirchneriella subcapitata). Wildlife International, Ltd, Easton, Maryland, project number 161A-108.

5. Claude MB & Krueger HO, 2008b. Ultane Sevoflurance: A 48-hour static acute toxicity screening test with the Cladoceran (Daphnia magna). Wildlife International, Ltd, Easton, Maryland, project number 161A-109.

6. Claude MB & Krueger HO, 2008c. Ultane Sevoflurance: A 96-hour static acute toxicity screening test with the fathead minnow (Pimephales promelas). Wildlife International, Ltd, Easton, Maryland, project number 161A-110.

7. European Chemicals Agency (ECHA).  Guidance on information requirements and chemical safety assessment Chapter R.10:  Characterisation of dose [concentration]-response for environment. May 2008.

8. Matthews ME & Schaefer EC, 2008. Sevoflurane: Closed Bottle Test, Wildlife International, Ltd, Easton, Maryland, project number 161E-104.

9. ChemSpider.  2020.  Sevoflurane. 
   Available URL: http://www.chemspider.com/Chemical-Structure.5017.html.  Accessed 25 January 2023.