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Orfadin®

MiljöinformationReceptstatusFörmånsstatus
Swedish Orphan Biovitrum International

Kapsel, hård 2 mg
(vita, ogenomskinliga kapslar märkta NTBC 2mg på ena sidan)

Medel vid hereditär tyrosinemi typ 1

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ATC-kod: A16AX04
Läkemedel från Swedish Orphan Biovitrum International omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Nitisinon

Miljörisk: Risk för miljöpåverkan av nitisinon kan inte uteslutas då ekotoxikologiska data saknas.
Nedbrytning: Det kan inte uteslutas att nitisinon är persistent, då data saknas.
Bioackumulering: Nitisinon har låg potential att bioackumuleras.


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Detaljerad miljöinformation


Environmental risk

The PEC is obtained by using the following formula, and is based on the total sales of API in kg/year in Sweden:


Predicted Environmental Concentration (PEC)

Figur 1


A (kg/year) = 0.23 kg (total sold amount API in Sweden year 2015, data from IMS Health).

R (%) = Removal rate (due to loss by adsorption to sludge particles, by volatization, by hydrolysis, by biodegradation or other specific, naturally occurring processes) = 0 (no data available).

P = Number of inhabitants in Sweden = 9 x 106

V (L/day) = Volume of wastewater per capita and day = 200 (EHCA default)

D = Factor for dilution of waste water by surface water flow = 10 (EHCA default)


Calculation:

PEC (µg /L) = (0.23 x 109 x (100-0))/(365 x 9 x 106 x 200 x 10 x 100) = 3.5 x 10-5 µg /L


Predicted No Effect Concentration (PNEC)

Currently there is no data on the toxicology of nitisinone to algae; however, this has been evaluated in a number of related compounds which work by the same mechanism of action, namely inhibition of HPPD activity. These compounds, which are currently in commercial use, consist of:


1. Mesotrione:

This is a triketone that is structurally related to nitisinone with a ρ-substitution of SO2CH3 in place of the CF3.

Formel

In terms of biological activity against broad-leaf weed species, the LD50 is similar to that of nitisinone with values of 13 g/ha and 14 g/ha respectively for mesotrione and nitisinone (Lee et al., 1998). The EC50 of mesotrione for Selenastrum capricornutum is 4.5 mg/L (Tomlin, 2004).


2. Isoxaflutole:

A structurally related compound that is metabolized opening up the isoxazole ring forming a diketone which is the active species.

Formel

It is not possible to compare the biological activity versus nitisinone as comparative data is not available. However, the EC50 for Selenastrum capricornutum is known with a value of 0.016 mg/L (Tomlin, 2004).


Therefore, while it is not possible to determine the PNEC of nitisinone for algae, an estimate of worst case can be made based on this data for structurally related compounds. Estimations of the PNEC using the data for mesotrione as the most similar compound in terms of activity and structure and isoxaflutole as the most potent against algae have been calculated according to the CPMP Guidance CPMP/SWP/4447/00. These have then been used together with the PEC value to calculate the estimated PEC/PNEC ratios.


Compound

EC50 (μg/L)

PNEC(μg/L), [EC50/1000]

Estimated PEC/PNEC
for nitisinone

Mesotrione

4500

4.5

0.78 x 10-5

Isoxaflutole

16

0.016

2.19 x 10-3


Conclusion

As no data on the toxicology of nitisinone to algae is available, the risk of environmental impact cannot be excluded.


Persistence (resistance to degradation)

The potential for persistence cannot be excluded due to lack of data.


Bioaccumulation

The risk for bioaccumulation is considered to be low for nitisinone. While an octanol/water partition coefficient according to the OECD guidelines has not been conducted, one has been determined using an aqueous phosphate buffer. The partition coefficient (D) at pH 6.5 was determined to be 0.432, and log D = –0.36 (APL 2000). As the partition coefficient value is significantly less than the action limit of 10 000, it is considered that bioaccumulation does not present a significant risk to the environment.


References

Lee DL, Knudsen CG, Michaely WJ, Chin HL, Nguyen NH, Carter CG, Cromartie TH, Lake BH, Shribbs JM, Fraser T. The Structure-Activity Relationships of the Triketone Class of HPPD Herbicides. Pestic. Sci. 1998 54:377-384.

Tomlin C. (ed): The Pesticide Manual, 13th ed., Alton, BCPC Publications, 2004:589-590;631-632;908-909.

Apoteket Produktion & Laboratorier (APL). Internal report LP 542-2, Report Solubility and Permeability of Nitisinone (NTBC) Substance, 2000-06-30.