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 = 0.051 μg/L

Where:

A = 394.15 kg (total sold amount API in Sweden year 2021, data from IQVIA.)

R = X % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available. For propofol it is assumed that R = 5%*

P = number of inhabitants in Sweden = 10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default)(Ref.1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default)(Ref.1)

*The predicted adsorption to sludge (5%) is based on partitioning calculations within the ECHA Technical Guidance Document (Ref. 1) assuming the following parameter values; Koc = 310 at pH 7.7, log H = 0.53, non-biodegradable. The log H (Henry’s Law constant) is calculated from the solubility (174 mg/L), vapour pressure (3.3 Pa (determined experimentally), Ref. 2) and molecular weight (178.27). A removal rate of 5% has been used in the PEC calculation and assumes a worst case scenario.

(Note: Whilst propofol is extensively metabolised in humans, little is known about the ecotoxicity of the metabolites. Hence as a worst case, for the purposes of this calculation, it is assumed that 100% of excreted metabolities have the same ecotoxicity as the parent propofol).

Metabolism and excretion

Due to the highly lipophilic nature of propofol, it is rapidly distributed around the body into tissues and also easily crosses the blood-brain barrier. Redistribution back to plasma is slow, limited by the slow return of propofol from fat tissue. Propofol undergoes rapid metabolic clearance, primarily eliminated by hepatic conjugation to inactive metabolites, which are excreted by the kidneys. In healthy volunteers 88% of the dose was recovered in the urine as inactive metabolites (40% of this as the metabolite propofol glucuronide and the rest consisted of the 1- and 4-glucuronide and 4-sulfate conjugates of 2,6 diisopropyl-1,4-quinol). 0.3% of the unchanged drug was excreted in the urine. Faeces excretion of unchanged drug and metabolites totals <2% (Refs 3).

Ecotoxicity data

Endpoint	Species	Common Name	Method	Time	Result	Ref
ErC50 - Based on Largest Specific Growth Rate	Microcystis aeruginosa	Cyanobacterium (Blue-Green Alga)	US FDA Technical Assistance Document 4.01	96 h	2.66 mg/L Note 1	4
NOEC - Based on Largest Specific Growth Rate				21 d	3.0 mg/L Note 1
LOEC - Based on Largest Specific Growth Rate					6.6 mg/L Note 1
NOEC - Based on Maximum Standing Crop					1.9 mg/L Note 1
LOEC - Based on Maximum Standing Crop					3.0 mg/L Note 1
ErC50 - Based on Largest Specific Growth Rate	Pseudokirchneriella subcapitata	Green Alga	US FDA Technical Assistance Document 4.01	96 h	11.6 mg/L Note 1	5
NOEC - Based on Largest Specific Growth Rates					0.49 mg/L Note 1
NOEC - Based on Largest Specific Growth Rates				14 d	5.7 mg/L Note 1
LOEC - Based on Largest Specific Growth Rates					11 mg/L Note 1
NOEC - Based on Maximum Standing Crop					0.67 mg/L Note 1
LOEC - Based on Maximum Standing Crop					1.2 mg/L Note 1
EC50 - Based on Immobilisation	Daphnia magna	Giant Water Flea	Note 2	48 h	1 - 10 mg/L Note 3	6
EC50 - Based on Overall Endpoints Note 4	Daphnia magna	Giant Water Flea	US FDA Technical Assistance Document 4.09	21 d	0.36 mg/L Note 1	7
NOEC - Based on Overall Endpoints Note 4					0.23 mg/L Note 1
LOEC - Based on Overall Endpoints Note 4					0.46 mg/L Note 1
MATC - Based on Overall Endpoints Note 4					0.33 mg/L Note 1
LC50	Lepomis macrochirus	Bluegill Sunfish	US FDA Technical Assistance Document 4.11	96 h	0.62 mg/L Note 1	8
NOEC - Symptoms of Toxicity					0.055 mg/L Note 1
LC50	Oncorhynchus mykiss	Rainbow Trout	US FDA Technical Assistance Document 4.11	96 h	0.37 mg/L Note 4	9
NOEC - Based on Symptoms of Toxicity					< 0.032 mg/L Note 4
EC50 - Based on Activated Sludge Respiration Inhibition	-	Activated Sludge Micro-organisms	Not standard method	3 h	> 100 mg/L	6
EC50 - Based on Inhibition of Anaerobic Sludge	-	Anaerobic Sludge Micro-organisms		15 d	> 100 mg/L
EC50 - Based on Inhibition of Bacterial Nitrification	-	Nitrifying Micro-organisms		4 h	> 80 mg/L

Predicted No Effect Concentration (PNEC)
Chronic studies have been performed at two trophic levels, ie algae and Daphna magna, the latter being the most sensitive of these species. However, the most sensitive acute data are for fish. Therefore, the PNEC is based on the most sensitive fish species as a worst case assumption; rainbow trout 96h LC₅₀ of 0.37 mg/L.

 

Since short term effects data are available for species from three trophic levels, an assessment factor of 1000 is used to calculate the PNEC. This is in accordance with ECHA guidance (Ref.10).

 

PNEC = 370/1000 µg/L = 0.37 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.051 μg/L / 0.37 μg/L = 0.14 i.e. 0.1 < PEC/PNEC ≤ 1 which justifies the phrase “Propofol has been considered to result in low environmental risk”.

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

Environmental Fate Data

Endpoint	Method	Test Substance Concentration	Time	Result	Ref
Percentage Biodegradation	OECD 301F	100 mg/L	28 d	3.2 % BOD/COD	11
		50 mg/L		2.3 % BOD/COD
Percentage Carbon Removal		100 mg/L		92.1 % Theoretical Carbon Content
Percentage Carbon Removal		50 mg/L		91.6 % Theoretical Carbon Content
Percentage Compound Removal		50 mg/L		91.6 %
Percentage Compound Removal		100 mg/L		90.6 %
Percentage Biodegradation	UK DoE method, modified according to ISO 11734	25 mgCarbon/L	40 d	0 %	12
Percentage Compound Removal		50 mgCarbon/L		21 %
Percentage Compound Removal		25 mgCarbon/L		32 %
Percentage Hydrolysis	US FDA Technical Assistance Document 3.09	50 mg/L @ pH 9	5 d	3.4 %	13
		50 mg/L @ pH 7		3.9 %
		50 mg/L @ pH 5		< 2.0 %
Hydrolysis Half-life		-		T1/2 >= 1 yr
Soil Adsorption Coefficient	US FDA Technical Assistance Document 3.08	25 mg/L in sandy loam, pH 5.8	-	Kd = 4.8 Koc = 220	14
		25 mg/L in sandy loam, pH 7.7	-	Kd = 9.7 Koc = 310
		25 mg/L in silty clay loam, pH 4.9	-	Kd = 5 Koc = 310

Biodegradation

The biodegradability of propofol has been assessed according to the OECD guideline 301F (Ref. 11). The results showed that propofol is not readily biodegradable, with <5% biodegradation after 28 days. However, >91% removal of propofol from the aqueaous phase was observed, which was noted at the time as being possibly due to absorption to the solid phase. However, this is not supported by the measured sorption/desorption data (see below).

The “ultimate” anaerobic biodegradability of propofol was assessed according to ISO Guideline 11734 (Ref. 12). The results showed that propofol was not biodegradable under the anaerobic conditions of the test, although a degree of elimination was observed.

Based on the information that propofol is not readily biodegradable (no other studies are available) the statement ”propofol is potentially persistent” has been assigned.

In Swedish: “Propofol är potentiellt persistent” under the heading ‘Nedbrytning’.

Hydrolysis

The hydrolysis has been assessed according to the FDA Technical Assistance Document 3.09 (Ref. 13). The results showed that propofol is hydrolytically stable at pH 5, 7 and 9.

Adsorption and desorption to soil

The soil sorption and desorption of propofol was assessed according to the US FDA EA Technical Assistance Document 3.08 (Ref. 14).

Soil type	% organic carbon	% clay	pH	Mean Kd	Mean Koc	% recovery from soil
Silty clay loam	1.6	28	4.9	5	310	93
Sandy loam	2.2	13	5.8	4.8	220	107
Sandy loam	3.1	14	7.7	9.7	310	95

These data indicate that propofol will not be significantly adsorbed into soil.

It should be noted that the Kd values are not proportional to the carbon content, so the Koc is not likely to be a reliable predictor of adsorption to soil (or sewage sludge).

Volatilisation, oxidation and photodegradation

During the aerobic ready biodegradation study (Ref.10) >91% removal of propofol from the aqueous phase was observed. The study report states this may have been due to adsorption to the solid phase, however this was not supported by the Koc data and the soil sorption and desorption study (Ref.14). Losses were also reported in the algae ecotoxicity studies (Refs. 4 and 5), and the Daphnia magna, rainbow trout and blue-gill sunfish studies (Refs. 7 and 8) were all performed as flow-through tests, indicating that there was concern at the time of testing around the stability or dosing of propofol into the test system. The mechanism for these losses was not investigated, but was possibly due to volatilisation, adsorption or oxidation. Under ambient conditions the oxidation rate of propofol is very low (Ref. 15), however it can be readily oxidised under oxidative conditions, for example in the presence of sulfite (Ref. 16), and it is recommended to store propofol under nitrogen.

In order to better understand the degradation mechanism for propofol, so that appropriate assumptions can be made in the PEC calculation, a study was carried out to investigate the potential photodegradation, oxidation and volatilisation of propofol. This study (Ref. 16) showed that volatilisation is likely to be the predominant depletion mechanism for propofol, and that photolysis and oxidation were likely to be much less important. Under controlled conditions, purging gently with nitrogen, approximately 90% volatilisation of propofol from water was observed within 96 hours at 1 and 10 mg/L. These results help to explain observations in the earlier studies and suggest that significant losses to air could be expected during sewage treatment.

Bioaccumulation

Endpoint	Species	Common Name	Method	Test Conditions	Result	Ref
Bioconcentration Factor	Cyprinus carpio	Carp	Japanese Industrial Standard 7260-305	28 d @ 0.002 mg/L	BCF = 27	18
				28 d @ 0.0002 mg/L	BCF = 26
Partition Coefficient Octanol Water	-	-	US FDA Technical Assistance Document 3.02	150 mg/L	LogP = 3.89	19
				1500 mg/L	LogP = 3.86

Log P = 3.9 (Ref 19). The figure indicates that propofol has potential to bioaccumulate in aquatic organisms. However, the bioconcentration factor has been determined for carp, Cyprinus carpio, (Ref.18) and the results are given below.

Bioconcentration factor (BCF) 28 Day uptake = 27 (at 2 µg/L)

Bioconcentration factor (BCF) 28 Day uptake = 26 (at 0.2 µg/L)

These values are well below the triggerof 500, therefore the statement “propofol has low potential for bioaccumulation” has been assigned.

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

Physical Chemistry Data

Endpoint	Method	Test Conditions	Result	Ref
Dissociation Constant	US FDA Technical Assistance Document 3.04	25oC	pKa = 11.13	20
Solubility Water	US FDA Technical Assistance Document 3.01	25oC, pH 6	170 - 174 mg/L	21

Note 1: The results are expressed as measured concentrations.

Note 2: Daphnia magna less than 48 hours old, were exposed to concentrations of test material (100, 10 and 1 mg/L) for 48 hours under static test conditions at 20^oC. The Daphnia were observed for immobilization, after 24 and 48 hours, and the median effective calculation calculated.

Note 3: The results are expressed as nominal concentrations.

Note 4: Based on overall endpoints of survival, reproduction and growth.

Note 5: Concentrations were confirmed by analysis and the results are expressed as nominal concentrations.

References

1. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0). December 2022.

   
   

2. BL5645/B Propofol: Determination of vapour pressure. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5645/B. Sankey S.A.; March 1995.

   
   

3. Cockshott I D (1985). Propofol (’Diprivan’) pharmacokinetics and metabolism – an overview. Postgraduate Medical Journal (1985) 61 (Suppl. 3), 45-50.

   
   

4. BL5358 Propofol: Toxicity to the Blue-Green Alga, Microcystis aeruginosa. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5358. Smyth D.V.; Brown A.R.; Shearing J.M. April 1995

   
   

5. BL5357 Propofol: Toxicity to the Green Alga, Selenastrum capricornutum. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5357. Smyth D.V.; Brown A.R.; Sankey S.A.; Shearing J.M. April 1995

   
   

6. BL4069 Propofol: Results of Environmental Screening Studies. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL4069. Adams D.S. May 1991

   
   

7. BL5444 Chronic Toxicity of Propofol to Daphnia magna. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5444. ABC Laboratories June 1995

   
   

8. BL5356 Propofol: Acute Toxicity to Bluegill Sunfish (Lepomis macrochirus). Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5356. Brown A.R.; Caunter J.E.; Shearing J.M. April 1995

   
   

9. BL5355 Propofol: Acute Toxicity to Rainbow Trout (Oncorhynchus mykiss). Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5355. Brown A.R.; Caunter J.E.; Wallace S.J. April 1995

   
   

10. ECHA, European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R10. May 2012.

    
    

11. BL5360 Propofol: Determination of 28 Day Ready Biodegradability. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5360. Brown A.R.; Sankey S.A.; Mather J.I.; Johnson P.A. April 1995

    
    

12. BL5361 Propofol: Determination of Anaerobic Biodegradability. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5361. Brown A.R.; Sankey S.A.; Johnson P.A. April 1995

    
    

13. BL5363 Propofol: Hydrolysis as a Function of pH. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5363. Brown A.R.; Stanley R.D.; Cornish S.K. March 1995

    
    

14. BL5359 Propofol: Soil Sorption and Desorption. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5359. Woods C.B.; Brown A.R. April 1995

    
    

15. IND Documentation, 1983, section V. GEL version ID PAIN.000-050-780.1.0.

    
    

16. Baker M T, Gregerson M S, Martin S M, Buettner G. 2003. Free radical and drug oxidation products in an intensive care unit sedative: Propofol with sulfite. Crit Care Med Vol. 31, No. 3, 787-792.

    
    

17. The oxidation, photodegradation and volatilisation potential of propofol in water. 2005. AstraZeneca Brixham Environmental Laboratory Report No. BL8223/B.

    
    

18. BX06145 Biodegradation and Bioconcentration of Existing Chemical Substances under the Chemical Substances Control Law, Japan National Institute of Technology and Evaluation 1992.

    
    

19. BL5365 Propofol: Determination of Octanol-Water Partition Coefficient. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5365. Brown A.R.; Stanley R.D.; Cornish S.K. March 1995

    
    

20. BL5364 Propofol: Determination of Dissociation Constant. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5364. Brown A.R.; Stanley R.D.; Wallace S.J. April 1995

    
    

21. BL5362 Propofol: Determination of Water Solubility. Brixham Environmental Laboratory, UK, AstraZeneca. Report BL5362. Brown A.R.; Stanley R.D. March 1995