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Transiderm-Nitro®

Novartis

Depotplåster 5 mg/24 timmar
(32×49 mm märkta CG och DOD)

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Aktiv substans:
ATC-kod: C01DA02
Utbytbarhet: Ej utbytbar
Läkemedel från Novartis omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Glyceryltrinitrat

Miljörisk: Användning av glyceryltrinitrat har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Glyceryltrinitrat bryts ned i miljön.
Bioackumulering: Glyceryltrinitrat har låg potential att bioackumuleras.


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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) = 0.0033 μg/L

PEC = 0.0033 μg/L

Where:

A = 22.10130 kg Glyceryl trinitrate (total amount of API sold in Sweden in 2019, data from IQVIA).

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) (ECHA 2008)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (ECHA 2008)


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae

EC50 96 h (growth rate) = 0.4 mg/L (Pseudokirchneriella subcapitata, method unknown) (Japanese Ministry of the Environment)


Crustacean (Daphnia magna):

Acute toxicity

EC50 48 h (immobilization) = 32.0 mg/L (method unknown) (Japanese Ministry of the Environment)


Fish (Lepomis macrochirus, bluegill):

Acute toxicity

LC50 96 h (lethality) = 1.67 mg/L (method unknown) (Japanese Ministry of the Environment)

PNEC derivation:

PNEC = 0.4 μg/L

The PNEC (μg/L) is based on the lowest EC50/1000, where 1000 is the assessment factor used if acute data for 3 trophic levels is available. The EC50 for green algae has been used for this calculation since it is the most sensitive of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0033 μg/L / 0.4 μg/L = 0.0083, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of Glyceryl trinitrate has been considered to result in insignificant environmental risk."

Degradation 

Sewage treatment plants:

53.6 % loss of nitroglycerin (30°C, 5 days, activated sludge inoculum, shake-flask test) (non-standard method)

92.2 % reduction of nitroglycerin (room temperature, 84 hours, continious bench-scale activated sludge apparatus) (non-standard method)

100 % loss of nitrate esters (chemostat, continuous culture, aerobic system, 8-15 hours) (non-standard method)

100 % mineralization (mixed cultures, anaerobic digester, 4 days, digester sludge amended with glucose) (non-standard method)


River water and water-sediment systems:

100% (13 days, river water and river water/sediment microcosms)

Half-life = 1 hour

Glyceryl trinitrate (Nitroglycerin) and other aliphatic nitric acid esters undergo aerobic biodegradation readily via the successive removal of nitrate groups to isomeric derivatives (Rendic et al; 1995). Contrary to some earlier reports that it was recalcitrant to biodegradation, nitroglycerin proved to be readily biodegradable in batch and continuous tests. Results of the shake flask test that was run at 30°C with an activated sludge inoculum showed a 53.6% loss of nitroglycerin in 5 days. In a continuous bench-scale activated sludge apparatus, a mean reduction of 92.2% was obtained. The apparatus was run at room temperature and the residence time was 84 hr. 1,3-Dinitroglycerol and 1,2-dinitroglycerol were identified at intermediate stages of the process, but they were also essentially absent from the effluent. The third experiment employing a chemostat, a continuous culture, an aerobic system with no solids recycling, was designed to simulate a plant where propellant wastes would be treated. After an 8 -15 hr detention period, no nitrate esters were detectable in the effluent. It was found that nitroglycerin is not suitable as a source of carbon and nitrogen so nutrients are essential. It was speculated that the earlier experiments which showed nitroglycerin to be recalcitrant were conducted using concentrations of nitroglycerin that were toxic to the microorganisms (Wendt TM et al; 1978).

Complete mineralization of nitroglycerin (350 umol/l initial concentration) was achieved within 4 days utilizing mixed cultures and an anaerobic digester, using digester sludge from a municipal wastewater treatment plant amended with 2,000 mg/l of glucose. Without glucose amendments, the complete mineralization of nitroglycerin took about 25 days in the digester (Hristodoulatos C et al; 1997).

Nitroglycerin, present at 16 mg/l, was rapidly degraded in a sequencing batch reactor using mixed liquor from an industrial wastewater facility and a domestic wastewater treatment plant, with 1,2-dinitroglycerol and 1,3-dinitroglycerol as the initial products (Accashian et al; 2000)

Nitroglycerin (10-ppm initial concentration) was completely biodegraded in 13 days using river water and river water/sediment microcosms obtained from a river near a munitions facility in Virginia. Pure cultures isolated from river water and sediment near a munitions factory in Virginia degraded nitroglycerin. The first-order rate constant was 0.60 hours-1, which corresponds to a half-life of about 1 hour (Spanggord et al; 1980 and PubChem Hazardous Substance Database)


Justification of chosen degradation phrase:

Based on the weight of evidence presented above from the sewage treatment plant and river water and water-sediment system studies, the following degradation phrase is chosen: ‘Glyceryl trinitrate is degraded in the environment’.


Bioaccumulation

Bioconcentration factor (BCF):

BCF = 5 (method unknown) (PubChem Hazardous Substance Database)


Partitioning coefficient:

Log Kow = 1.62 (method unknown). (PubChem Hazardous Substance Database)

Justification of chosen bioaccumulation phrase:

Since BCF < 500 and log Kow is < 4, glyceryl trinitrate has a low potential for bioaccumulation.


Excretion (metabolism)

Nitroglycerin is rapidly metabolised by glutathione-dependent organic nitrate reductase in the liver. In addition, and probably more importantly, in vitro studies have shown that the human erythrocyte is also a site of biotransformation via a suphydryl-dependent enzymatic process and interaction with reduced haemoglobin. (Core Data Sheet / Basic Prescribing Information, NITRODERM® TTS (nitroglycerin), Novartis, 30-Jun-2011).


PBT/vPvB assessment

Given that Glyceryl trinitrate is degraded in the environment, has a low potential for bioaccumulation, and has a relatively low order of toxicity, it does not fulfill the REACH criteria for PBT/vPvB classification.


References

  • Accashian JV et al; Water Environ Res 72: 499-506 (2000).

  • Core Data Sheet / Basic Prescribing Information, NITRODERM® TTS (nitroglycerin), Novartis, 30-Jun-2011.

  • ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

  • Handbook of environmental data on organic chemicals, 2nd edition, Editor: Karel Verschueren. Van Nostrand Reinhold, New York, 1983. 

  • Hristodoulatos C et al; (1997) Water Res 31: 1462-70.

  • Japanese Ministry of the Environment: http://www.env.go.jp/en/chemi/chemicals/profile_erac/, retrieved 03.12.2009.

  • PubChem Hazardous Substance Database - Nitroglycerin.

  • Rendic S et al; pp. 303-315 in Environ Toxicol Assess. Richardson M, ed. London, UK: Taylor and Francis (1995).

  • Spanggord RJ et al; Environmental Fate Studies on Certain Munition Wastewater Constituents. Final Report, Phase II - Laboratory Studies. NTIS A099256, US Army Med Res Devel, Fredrick, MD (1980).

Wendt TM et al; Appl Environ Microbiol 36: 693-9 (1978).