Detaljerad miljöinformation

Detailed background information

Environmental Risk Classification

The elimination of isoflurane is almost exclusively in unchanged form via the airways (Ref. 1). This means that the use of isoflurane is mainly resulting in the parent compound entering the air and only a minor part of the dose may be emitted as the parent compound and metabolites to the aquatic environment.

Sedaconda is used in combination with the administration system Sedaconda ACD, which can be connected to an activated carbon filter to collect residue gas (please see the instructions for use for Sedaconda ACD). In this way the amount of isoflurane entering the air is reduced to a minimum. In addition, the Sedaconda ACD recycles consumed gas, so the amount of isoflurane needed is minimized.

According to the European Medicines Agency guideline on Environmental Risk Assessment (ERA) (EMA/CHMP/SWP/4447/00 corr 2), an ERA is not necessary since isoflurane enters the environment exclusively via the air, and in Phase I the Predicted Environmental Concentration (PEC) calculation is restricted to the aquatic compartment. However, an environmental risk classification has been carried out for the main metabolite trifluoroacetic acid (CAS number 76-05-1) (see below) and some data are provided for isoflurane (CAS number 26675-46-7).

Metabolism and excretion

Isoflurane undergoes minimal biotransformation in man and the elimination of isoflurane is almost exclusively via the airways in unchanged form. Approximately 95 % of isoflurane is eliminated via this route (Ref. 1). This means only a minor part of the administered dose may reach the aquatic environment.

Figure 1. Isoflurane

Isoflurane is metabolised to trifluoroacetic acid, inorganic chloride and fluoride (Ref. 1). It has been shown that the postoperative increase of urinary excretion of fluoride and organic fluorine accounts for less than 0.2% of fluorine administered as isoflurane (Ref. 2).

Figure 2. Trifluoroacetic acid (TFA)

For the PEC calculation, it is assumed that all excreted organic fluoride is parent compound, i.e. <0.2% of the administered dose is excreted as isoflurane, and that all excreted fluorine is excreted as trifluoroacetic acid (TFA), i.e. <0.2%, in the urine. In addition, it is considered that isoflurane is eliminated via the air to 95 %. This is considered to represent a reasonable worst-case scenario.

Predicted Environmental Concentration (PEC) isoflurane (parent compound)

The PEC is based on the following data and formula:

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

A (kg/year) = 252.95 kg *0.2 % (total sold amount API in Sweden year 2020, data from IQVIA (former IMS Health and Quintiles) reduced by the highest possible fraction excreted as isoflurane – see Metabolism and excretion). This represents a worst-case scenario.

R (%) = 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. 3)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Ref. 3)

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

PEC = (252.95*0.2%*10⁹(100-0))/(365*10*10⁶*200*10*100) = 6.9*10^-5 μg/L

Predicted No Effect Concentration (PNEC) isoflurane

There are no aquatic effect studies available for isoflurane.

Environmental Risk Classification (PEC/PNEC ratio) isoflurane

Since there are no aquatic effect studies available for isoflurane it will not be possible to calculate the PEC/PNEC ratio.

Predicted Environmental Concentration (PEC) trifluoroacetic acid (metabolite)

The PEC is based on the following data and formula:

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

PEC = 4.3 x 10^-5 µg/L

A (kg/year) = 252.95*114.02 g/mol / 184.49 g/mol * 0.2% (total sold amount API in Sweden year 2020, data from IQVIA (former IMS Health and Quintiles) reduced by the highest possible fraction excreted as TFA – see Metabolism and excretion - this represents a worst-case scenario) = 0.312 kg

R (%) = 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. 3)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Ref. 3)

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

PEC = (252.95*114.02 g/mol / 184.49 g/mol * 0.2%*10⁹(100-0))/(365*10*10⁶*200*10*100) = 4.3*10^-5 μg/L

Predicted No Effect Concentration (PNEC) trifluoroacetic acid (TFA) (metabolite)

Ecotoxicity data

The aquatic effect studies for TFA in Table 1 are based on information in the ECHA dossier for the compound (Ref. 4). The studies were performed with sodium trifluoroacetic acid, due to the low pH of TFA, and the results have been recalculated to TFA, according to the ECHA dossier.

Table 1. Trifluoroacetic acid – ecotoxicological studies
Study	Results
Activated sludge, respiration inhibition test (OECD 209) (Ref. 4)	3 h No observed effect concentration (NOEC) = 832 mg/L (1000 mg/L sodium TFA) 3 h EC10 ≥ 832 mg/L (1000 mg/L sodium TFA)
Toxicity to Pseudokirchneriella subcapitata (green microalga) (OECD 201)* (Ref. 4)	72 h NOEC = 2.5 mg/L (growth rate) 72 h ErC10 = 5.6 mg/L (growth rate) 72 h EC50 = 237 mg/L (growth rate)
Chronic toxicity to Daphnia magna (water flea), OECD 211 (Ref. 4)	21 d NOEC = 25 mg/L (reproduction) 21 d EC10≥ 25 mg/L (reproduction)
Acute toxicity to Daphnia magna (water flea), OECD 202 (Ref. 4)	48 h EC50 >999 mg/L
Acute toxicity to Danio rerio (zebrafish), OECD 203 (Ref. 4)	96 h LC50 >999 mg/L

PNEC TFA

Results from two long-term toxicity tests from two trophic levels are available. These tests cover the trophic level with the most sensitive species (microalgae) (lowest L/EC₅₀) in the short-term tests for organisms from three trophic levels (Ref. 4). This means an assessment factor of 50 should be used, according to the REACH guideline (Ref. 5).

PNEC_{surface water} = E_rC₁₀ for P. subcapitata (green microalgae), 5.6 mg/L / 50 = 112 μg/L

Environmental Risk Classification (PEC/PNEC ratio) TFA

PEC/PNEC = 4.3 x 10^-5 µg/L / 112 µg/L = 3.8 x 10^-7

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

In Swedish: “Användning av isofluran har bedömts medföra försumbar risk för miljöpåverkan” under the heading “Miljörisk”.

Environmental Fate Data

Environmental fate data for TFA is presented in Table 2 and are based on information in the ECHA dossier for the compound (Ref. 4).

Table 2. Trifluoroacetic acid – Environmental fate studies
Study	Results
Water solubility (Ref. 4)	1520 g/L at 20°C
pKa at 20°C (Ref. 4)	0.43
Octanol/water partition coefficient (Ref. 4)	log Kow = 0.79 at 25°C (estimated with QSAR)
Biodegradability (Ref. 4)	Not readily biodegradable (OECD 301D) Not inherently biodegradable (OECD 302A)
Hydrolysis (Ref. 4)	Based on the structure of TFA (extremely stable fluorine-carbon bond) and several test results, there is no potential for hydrolysis
Adsorption/desorption to soil (Ref. 4)	Koc at 20°C = 6.22 (estimated using log Kow = 0.79) Kd at 25°C = 0.94 L/kg*

*geometric mean of reported values for representative soils retaining TFA

The pKa is 0.43 which means TFA will primarily exist ionised (anion) in the environment.

Degradation

Biotic degradation

Trifluoroacetic acid is not expected to hydrolyse since it lacks functional groups that hydrolyse under environmental conditions.

Abiotic degradation

Trifluoroacetic acid is not readily biodegradable.

Degradation classification

Since TFA is not readily biodegradable, no other biodegradation data is available for TFA, and there is no biodegradation data for isoflurane, the phrase “Isofluran is potentially persistent” is chosen.

In Swedish: “Isofluran är potentiellt persistent” under the heading “Nedbrytning”.

Bioaccumulation

The octanol/water partition coefficient in Table 2 indicates that trifluoroacetic acid would not be predicted to bioaccumulate in aquatic organisms. The octanol/water partition coefficient (log K_ow) for isoflurane has been estimated with QSAR to 2.06 at pH 7 (Ref. 6).

Bioaccumulation classification

Since log P < 4 at pH 7 for both TFA and isoflurane, the substance has been assigned the phrase: “Isoflurane has low potential for bioaccumulation.”

In Swedish: "Isofluran har låg potential att bioackumuleras” under the heading “Bioackumulering”.

PBT/vPvB assessment

As both isoflurane and its metabolite TFA have low potential for bioaccumulation, they do not fulfil the criteria for PBT and/or vPvB substances. Therefore, according to the established EU criteria, the compound should not be regarded as a PBT/vPvB substance.

Adsorption/desorption to soil

If released to soil, trifluoroacetic acid is expected to be highly mobile. The K_oc value is < 10,000, indicating that the test material is not predicted to adsorb significantly to biosolids.

References

1. Holaday, D.A., Fiserova-Bergerova, V., Latto, I.P., Zumbiel, M.A. 1975. Resistance of isoflurane to biotransformation in man. Anesthesiology, Vol. 43:3.

2. Saber & Hougaard 2009. The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals. 141. Isoflurane, sevoflurane and desflurane. University of Gothenburg and Arbetsmiljöverket.

3. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (Version 3.0). February 2016.

4. ECHA dossier, EC number 200-929-3. 2011:https://echa.europa.eu/sv/registration-dossier/-/registered-dossier/5203 Website accessed March 2022.

5. REACH Guidance on information requirements and chemical safety assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment European Chemicals Agency. 2008.

6. Hansch, C., Leo, A. and Hoekman, D. 1995. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. American Chemical Society, Washington, DC.