Nedbrytning: Substansen är potentiellt persistent.
Bioackumulering: Substansen har inte potential att lagras i vattenlevande organismer.
Detaljerad miljöinformation
(Läs mer om detaljerad miljöinformation, riktad till experter, på engelska)
PEC (Predicted Environmental Concentration)
PNEC (Predicted No Effect Concentration)
PEC/PNEC = 0.06/0.37 = 0.16 → 0.1 < PEC/PNEC ≤1
The PEC/PNEC ratio decides the wording of the aquatic environmental risk phrase, and the risk phrase for 0.1 < PEC/PNEC ≤1 reads as follows:
‘Use of the medicine has been considered to result in low environmental risk’
In Swedish: ’Användning av läkemedlet har bedömts medföra låg risk för miljöpåverkan’ under the heading ’Miljörisk’.
PEC is based on following data:
PEC (µg/L) = (A*109*(100-R))/(365*P*V*D*100)
PEC (µg/L) = 1.5*10-6*A(100-R)
A (kg/year) = total actual API sales (active moiety) in Sweden 2009. The sales data is obtained from LIF, and include all products containing the same API as well as enantiomers of the API.
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 = 9 *106
V (L/day) = volume of wastewater per capita and day = 200 (TGD default)
D = factor for dilution of waste water by surface water flow = 10 (TGD default)
(Note: The factor 109 converts the quantity used from kg to μg).
A = 405.6 kg. This figure is based on the total sold amount of propofol in Sweden 2009.
R = 5% to 90%* (predicted removal in sewage treatment, assuming approximately 5% removal by adsorption to sludge and up to 90% potential removal by volatilisation)
*The predicted adsorption to sludge (5%) is based on partitioning calculations within the EU 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 value (Henry’s Law constant) is calculated from the solubility (174 mg/L), vapour pressure (3.3 Pa) and molecular weight (178.27). The potential for 90% volatilisation is based on the observed losses from the biodegradation and other studies discussed in the section ‘Volatilisation, oxidation and photodegradation’. Hence two removal values have been selected to represent the possible range of removal fractions during sewage treatment (R = 5 and R=90).
Thus;
Removal rate, R = 90
PEC = 1.5 * 10-6 * 405.6 * (100-90) = 0.006 µg/L
Removal rate, R = 5
PEC = 1.5 * 10-6 * 405.6 * (100-5) = 0.06 µg/L
As worst case, PEC = 0.06 µg/L, assuming R = 5%, only taking into account the predicted adsorption to sludge, is used for the PEC/PNEC calculation.
Ecotoxicological data
Toxicity to green alga (Selenastrum capricornutum) (FDA guideline 4.01) (Ref. 2):
Growth rate 14d NOEC = 5.7 mg/L
Due to the loss of propofol from the test solutions over the duration of the study, results are based on mean measured concentrations.
Toxicity to blue-green alga (Microcystis aeruginosa) (FDA guideline 4.01) (Ref. 3):
Growth rate 21d NOEC = 3.0 mg/L
Due to the loss of propofol from the test solutions over the duration of the study, results are based on mean measured concentrations.
Chronic toxicity to giant water-flea (Daphnia magna) (FDA guideline 4.09, flow-through conditions) (Ref. 4):
21 d EC50 = 0.36 mg/L
21 d NOEC = 0.23 mg/L
Acute toxicity to rainbow trout (Onchornynchus mykiss) (FDA guideline 4.11, flow-through – no aeration) (Ref. 5):
96 h LC50 = 0.37 mg/L
NOEC = <0.032 mg/L
Acute toxicity to bluegill sunfish (Lepomis macrochirus) (FDA guideline 4.11, flow-through – no aeration) (Ref. 6).
96 h LC50 = 0.62 mg/L
NOEC = 0.055 mg/L
Chronic studies have been performed at two trophic levels, ie algae and Daphnia magna, the latter being the most sensitive of these species. This would give an assessment factor of 50. However, there is no acute data for the Daphnia magna or algae trophic levels, so no comparison to the fish acute data can be made to determine which is actually the most sensitive species Therefore, the PNECsurface water will be based on the most sensitive1 fish species as a worst-case assumption; rainbow trout 96h LC50 of 0.37 mg/L.
Since short-term effect data are available for species from three trophic levels, an assessment factor of 1000 is used to calculate PNEC. This is in accordance with the Technical Guidance Document (TGD) (Ref. 1).
PNEC = 370 / 1000 µg/L = 0.37 µg/L
1Literature data for propofol has been reviewed, but at the time for the search, December 2009, no endpoint with higher sensitivity, compared with the data above, for relevant data was found.
Biodegradation
The biodegradability of propofol has been assessed according to the OECD guideline 301F (Ref. 7). The results showed that propofol is not biodegradable, with <5% biodegradation after 28 days. However, >91% removal of propofol from the aqueous phase was observed, which was noted at the time as being possibly due to adsorption to the solid phase. However, this is not supported by the measured sorption/desorption data (see below).
The anaerobic biodegradability of propofol was assessed according to ISO Guideline 11734 (Ref. 8). 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 ”The medicine is potentially persistent” is used under the heading ”Degradation”. In Swedish: ”Läkemedlet är potentiellt persistent” under the heading ”Nedbrytning”.
Hydrolysis
The hydrolysis has been assessed according to the FDA Technical Assistance Document 3.09 (Ref. 9). 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. 10).
|
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 to 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 biodegradation study (Ref. 7) >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. 10). Losses were also reported in the algae ecotoxicity studies (Refs 2 & 3), and the Daphnia magna, rainbow trout and blue-gill sunfish studies (Refs 4-6) 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. 11), however it can be readily oxidised under oxidative conditions, for example in the presence of sulfite (Ref. 12), 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. 13) 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-1. These results help to explain observations in the earlier studies and suggest that significant losses to air could be expected during sewage treatment.
Bioaccumulation
Log P = 3.9 (at pH 8) (FDA Technical Assistance Document 3.02) (Ref. 14)
The figure indicates that propofol has potential to bioaccumulate in aquatic organisms. However, the bioconcentration factor has been determined for carp, Cyprinus carpio, (Ref. 15) and the results are given below.
Bioconcentration factor (BCF) 28 D = 27 (at 2 µg/L)
Bioconcentration factor (BCF) 28 D = 26 (at 0.2 µg/L)
These values are well below the trigger value for PBT testing of 2000.
Therefore the statement ‘No significant bioaccumulation potential’ is used under the heading ‘Bioaccumulation’. In Swedish: ’Läkemedlet har inte potential att lagras upp i vattenlevande organismer’ under the heading ’Bioackumulering’.
Metabolism/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 16 & 17).
References
1. Technical Guidance Document (TGD) Ex-European Chemicals Bureau: Technical Guidance Document (TGD).
2. Propofol: Toxicity to the green alga Selenastrum capricornutum. 1995. Zeneca Pharmaceuticals, Brixham Environmental Laboratory Report No. BL5357/B.
3. Propofol: Toxicity to the blue-green alga Microcystis aeruginosa. 1995. Zeneca Pharmaceuticals, Brixham Environmental Laboratory Report No. BL5358/B.
4. Chronic Toxiciy of Propofol to Daphnia magna. ABC Laboratories, USA. Report No. BL5444/B, April 1995.
5. Propofol: Acute toxicity to rainbow trout, Oncorhynchus mykiss. 1995. Zeneca Pharmaceuticals, Brixham Environmental Laboratory Report No. BL5355/B.
6. Propofol: Acute toxicity to bluegill sunfish, Lepomis macrochirus. 1995. Zeneca Pharmaceuticals, Brixham Environmental Laboratory Report No. BL5356/B.
7. Propofol: Determination of 28 day ready biodegradability. 1995. Zeneca Pharmaceuticals, Brixham Environmental Laboratory Report No. BL5360/B.
8. Propofol: Determination of anaerobic biodegradability. 1995. Zeneca Pharmaceuticals Brixham Environmental Laboratory Report no. BL5361/B
9. Propofol: Hydrolysis as a function of pH. 1995. Zeneca Pharmaceuticals, Brixham Environmental Laboratory Report No. BL5363/B.
10. Propofol: Soil sorption and desorption. 1995. Zeneca Pharmaceuticals, Brixham Environmental Laboratory Report No. BL5359/B.
11. IND Documentation, 1983, section V. GEL version ID PAIN.000-050-780.1.0.
12. 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.
13. The oxidation, photodegradation and volatilisation potential of propofol in water. 2005. AstraZeneca Brixham Environmental Laboratory Report No. BL8223/B.
14. Propofol: Determination of octanol-water partition coefficient. 1995. Zeneca Pharmaceuticals Brixham Environmental Laboratory Report no. BL5365/B.
15. Biodegradation and Bioconcentration of Existing Chemical Substances under the Chemical Substances. Control Law. Japan National Institute of Technology and Evaluation
http://www.safe.nite.go.jp/data/hazkizon/pk_e_kizon_disp.html?k_no=1497
16. Cockshott I D (1985). Propofol (’Diprivan’) pharmacokinetics and metabolism – an overview. Postgraduate Medical Journal (1985) 61 (Suppl. 3), 45-50.
17. Propofol – DRUGDEX drug evaluations. www.csi.micromedex.com
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