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Kapsel, hård 150 mg
Avregistreringsdatum: 2018-05-01 (Tillhandahålls ej) (Vit gelatinkapsel ca 22 mm lång, märkt "TMC435 150" i svart)

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ATC-kod: J05AP05
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Miljöinformation

Miljöpåverkan

Simeprevir

Miljörisk: Användning av simeprevir har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Simeprevir är potentiellt persistent.
Bioackumulering: Simeprevir har hög potential att bioackumuleras.


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Detaljerad miljöinformation

1. PREDICTED ENVIRONMENTAL CONCENTRATION (PEC):

The Predicted Environmental Concentration is calculated according to the following formula:


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


Where:


A (kg/year)

=

0,4074 kg (total sold amount API in the most recent sales data for Sweden (2016) was distributed by QuintilesIMS in summer 2017)

R (%)

=

removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)


=

0% (worst-case scenario: no removal)

P

=

number of inhabitants in Sweden (9 x 106)

V (L/day)

=

volume of waste water per capita and day


=

200 (ECHA default) [8]

D

=

factor for dilution of waste water by surface water flow


=

10 (ECHA default) [8]

PEC (µg/L)

=

0,00006201 µg/L


2. PREDICTED NO EFFECT CONCENTRATION (PNEC)

2.1 Ecotoxicological studies

2.1.1 Algae

Algal growth inhibition test with the green alga (Pseudokirchneriella subcapitata) (OECD 201) [1]:

EγC50 72 h (yield) = > 1,07 mg/L (28.2 % inhibition)

NOECγ (yield) = 0.00288 mg/L

ErC50 72 h (growth) = > 1,07 mg/L (6.5% inhibition)

NOECr (growth) = 0,0713 mg/L


2.1.2 Crustacean

Acute

No data available.


Chronic

Reproduction test with water-flea (Daphnia Magna) (OECD 211) [2]:

NOEC 21 days = 0.0173 mg/L


2.1.3 Fish

Acute

No data available.


Chronic

Fish early life stage test with fathead minnow (Pimephales promelas) (OECD 210) [3]:

NOEC 32d = 0.00108 mg/L


2.1.4 Other ecotoxicity data

Activated sludge respiration inhibition test (OECD 209) [4]:

EC50 3h = >390 mg/L

NOEC 3h = 10 mg/L


2.2 Calculation of Predicted No Effect Concentration (PNEC)

PNEC (µg/l) = lowest (NOEC)/10, where 10 is the assessment factor used. NOEC for the fathead minnow (Pimephales promelas) of 1.08 µg/L has been used for this calculation since it is the most sensitive of the three tested species.


PNEC = 1.08 µg/L/10 = 0.108 µg/L


2.3 Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0,00006201 µg/L / 0.108 µg/L = 0,00057416  i.e. PEC/PNEC ≤ 0,1


Conclusion for environmental risk:

Use of Simeprevir has been considered to result in insignificant environmental risk.


3. DEGRADATION

3.1 Biotic degradation

3.1.1 Ready biodegradation

Test results in - % degradation in 28 days (Guideline OECD 301F) [5]:

Result: There was no evidence of oxygen consumption in mixtures containing Simeprevir above that measured in the controls by the end of the test (Day 28).


3.1.2 Simulation study: Aerobic degradation in aquatic sediment systems:

Simeprevir was investigated for its aerobic degradation in a 100-day aquatic sediment test, according to OECD 308 [6]:


Recovery and distribution of radioactivity

In Calwich Abbey Lake aquatic sediment, total radioactivity in the water layer declined from a mean of 89.3% of applied radioactivity at time zero to 8.0% after seven days, and then slowly decreased to 2.2% after 100 days. In the sediment, total radioactivity increased to a mean of 87.3% of applied radioactivity after seven days and remained at a similar level for the remainder of the 100 day incubation period. Non-extractable radioactivity in the sediment (bound residues) increased from a mean value of 2.2% applied radioactivity at time zero to 24.0% applied radioactivity after 100 days. Volatile radioactivity, almost all associated with 14CO2, accounted for a mean of only 0.2% applied radioactivity after 100 days.

Dissipation of radioactivity followed a similar pattern in the Swiss Lake aquatic sediment system. The total radioactivity in the water layer declined from a mean of 88.2% of applied radioactivity at time zero to 19.3% after seven days and then slowly decreased to 3.4% after 100 days. In the sediment, total radioactivity increased to a mean of 72.7% of applied radioactivity after seven days and then slowly increased to 90.0% after 100 days. Nonextractable radioactivity in the sediment (bound residues) increased from a mean value of 0.7% of applied radioactivity at time zero to 53.1% after 100 days. Volatile radioactivity, almost all associated with 14CO2, accounted for a mean of only 0.6% of applied radioactivity after 100 days.


Chromatographic analysis

HPLC analysis with radiodetection of the overlying water and extracts of sediment resolved up to six components in addition to TMC-435350.

The amount of TMC-435350 in the water phase of Calwich Abbey Lake aquatic sediment declined from a mean of 88.8% of applied radioactivity at time zero to 5.9% after seven days of incubation. The decline was slower in Swiss Lake aquatic sediment with TMC-435350 representing a mean of 14.0% of applied radioactivity after seven days and 0.4% after 59 days of incubation. In the sediment of Calwich Abbey Lake systems, TMC-435350 increased to a mean of 76.7% of applied radioactivity after seven days and then slowly declined thereafter, to 52.5% applied radioactivity after 100 days. In the sediment of Swiss Lake systems, TMC-435350 increased to a mean of 65.0% applied radioactivity after seven days and then decreased to 18.3% applied radioactivity after 100 days.

In the Calwich Abbey Lake aquatic sediment most of the metabolites were present in the sediment layer. TMC-435350 was metabolised to O-demethylated TMC-435350 and up to three unidentified metabolites. The amount of O-demethylated TMC-435350 present in the Calwich Abbey Lake aquatic sediment increased to a mean of 14.7% of applied radioactivity after 100 days. The remaining metabolites were present at lower levels (≤3.2% of applied radioactivity).

In the Swiss Lake aquatic sediment metabolites were present in both the water and sediment layers. TMC-435350 was metabolised to O-demethylated TMC-435350 and up to five unidentified metabolites. All of the metabolites were present at low levels (≤7.9% applied radioactivity).

The structure of O-demethylated TMC-435350 was tentatively identified by LC-MS/MS.


Biotransformation pathway

TMC-435350 was hydrolysed to the O-demethylated TMC-435350 and was then further degraded to a number of low level unidentified products including small polar molecules and finally incorporated into bound residue and mineralised to carbon dioxide.


Kinetic analysis

DT50 and DT90 values for the decline of Simeprevir from the water, the sediment and from the total aquatic sediment system are shown below.

Kinetic analysis

Conclusion for degradation:

Simeprevir was not considered to be readily biodegradable. Simeprevir is potentially persistent.


4. BIOACCUMULATION

4.1 Partition coefficient octanol/water

The partition coefficient octanol/water was determined using OECD Test Guideline 107. [7]
Simeprevir was determined to have log10Pow values of greater than 5 (equivalent Pow > 105) over the entire pH range of environmental relevance (4 to 9).


Simeprevir has high potential for bioaccumulation.


4.2 Bioconcentration

No data available


Conclusion for bioaccumulation:

Simeprevir has high potential for bioaccumulation.


5. PBT-ASSESSMENT


PBT-criteria

Results for Simeprevir

Persistence

Half-life in freshwater: DT50 > 40 days
Half-life in sediment: DT50 > 120 days

Simeprevir dissipated rapidly from the water of aquatic sediment systems with DT50 values

of 2.6 days (Calwich Abbey Lake) and 3.4 days (Swiss Lake). Decline in the overall system

corresponded to DT50 values of 124 and 33.5 days.

Bioaccumulation

BCF > 2000

Simeprevir has high potential for bioaccumulation.

Toxicity

Chronic NOEC < 10 µg/L

NOEC algae = 0.00288 mg/L

NOEC daphnia = 0.0173 mg/L

NOEC fish = 0,00108 mg/l 


Conclusion for PBT-assessment:

Simeprevir does not fulfill the criteria for at PBT-substance.


6. REFERENCES

  1. Graham RJ, TMC435350 – Algal growth inhibition assay, Pseudokirchneriella subcapitata Following OECD Guideline #201; Huntingdon Life Sciences No. VMA0018; JNJ Study No. RMD 1057; September 7, 2011.

  2. Graham RJ, TMC435350 – Reproduction Toxicity Test, Daphnia Magna Following OECD Guideline #211; Huntingdon Life Sciences No. VMA0019; JNJ Study No. RMD 1058; September 7, 2011.

  3. Graham RJ, TMC435350 – FISH EARLY LIFE STAGE TOXICITY TEST FOR FATHEAD, Pimephales promelas Following OECD Guideline #210; Huntingdon Life Sciences No. VMA0020; JNJ Study No. RMD 1059; February 10, 2012.

  4. Dickinson RA, TMC435350 – ACTIVATED SLUDGE RESPIRATION INHIBITION TEST Following OECD Guideline #209; Huntingdon Life Sciences No. VMA0021; JNJ Study No. RMD 1060; February 8, 2012.

  5. Dickinson RA, TMC435350 – ASSESSMENT OF READY BIODEGRADABILITY BY RESPIROMETRY, Following OECD Guideline #301F; Huntingdon Life Sciences No. VMA0016; JNJ Study No. RMD 1055; December 6, 2010.

  6. Dickinson RA, TMC435350 – Aerobic Transformation in Aquatic Sediment Systems, Following OECD Guideline #308; Huntingdon Life Sciences No. VMA0017; JNJ Study No. RMD 1056; August 9, 2011.

  7. Sydney P, TMC435350 – Partition Coefficent, Following OECD Guideline #107; Huntingdon Life Sciences No. VMA0014; JNJ Study No. RMD 1053; October 4, 2010.

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