Detaljerad miljöinformation

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/ (365*P*V*D*100) = 1.5*10^-6*A (100-R) = 2.1 x 10^-3 µg/L

Where:

A = 15 kg (total sold amount API in Sweden year 2020, data from IQVIA).

R = 0 % removal rate.

P = number of inhabitants in Sweden =10*10⁶

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

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

Predicted No Effect Concentration (PNEC)

PNEC = 43 μg/L

The PNEC has been derived from the lowest relevant EC50 value of 43 mg/L (Selenastrum capricornutum, 10d, growth rate (preferred endpoint (ECHA, 2014) (II))). An assessment factor of 1000 is used based on the availability of acute toxicity studies for all trophic levels in accordance with ECHA Guidelines (ECHA, 2008) (I). This is considered a conservative value.

 

Algae (Green algae, Selenastrum capricornutum) (FDA, TAD 4.01, GLP)(III):

EC50 10d (growth inhibition) = > 43 mg/L

NOEC 10d (growth inhibition) = 43 mg/L

Crustacean (Water flea, Daphnia magna):

Acute toxicity (92/69/EEC C.2, GLP) (IV):

EC50 48h = > 76.9 mg/L (solubility limit)

NOEC 48h = 76.9 mg/L (solubility limit)

Acute toxicity (FDA, TAD 4.08, GLP) (V)

EC50 48h = > 90 mg/L (solubility limit)

NOEC 48h = 90 mg/L (solubility limit)

Fish (Rainbow trout, Oncorhynchus mykiss) (92/69/EEC C.1, GLP) (VI):

Acute toxicity

LC50 96h = > 65 mg/L (solubility limit)

NOEC 96h = 65 mg/L (solubility limit)

Fish (Fathead Minnow, Pimephales promelas)(FDA, TDA 4.11, GLP) (V):

Acute toxicity

LC50 96h = > 99 mg/L (solubility limit)

NOEC 96h = 99 mg/L (solubility limit)

Other ecotoxicity data

No inhibition of growth of five different microbial strains was observed at concentrations up to 1000 mg/L (FDA, TAD 4.02, GLP) (VII).

No inhibition of activated sludge was observed at concentrations up to 1000 mg/L (HMSO, 1982, GLP) (VIII).

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 2.1 x 10^-3/43 = 4.8 x 10^-5 i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of Nevirapin has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

In a 28d ready biodegradability study in accordance with Test Guideline 92/69/EEC, C.4-D (GLP) 7% biodegradation of Nevirapin was observed (VIII). Based on these data Nevirapin is not considered readily biodegradable.

Inherent degradability:

No data on inherent biodegradability.

Simulation studies:

No data on simulation studies.

Abiotic degradation

Hydrolysis and photolysis:

T½ (pH 5, 7, 9) > 1000d. Nevirapin is hydrolytically unstable under very acidic conditions (not relevant). Relatively stable under light. (IX, X).

Adsorption/Desorption

Nevirapine was found to not readily adsorb to soil or sludge and readily desorb from soils and activated sludge, and was considered highly mobile (FAD, TAD 3.08, GLP) (XI):

Log K_oc (soil) = 1.8 – 2.5

Log K_oc (sludge) = 1.0

Justification of chosen degradation phrase:

Nevirapin did not pass the ready degradation test and was stable under light. Nevirapin was also highly mobile in soil and sludge. Based on these data Nevirapin is considered “potentially persistent”.

Bioaccumulation

Bioconcentration factor (BCF):

QSAR calculations using EPIWIN resulted in a BCF of 4.9 for Nevirapin (V).

Partitioning coefficient:

The n-octanol/water partition coefficient was determined in an 92/69/EEC A.8 Guideline (GLP) study showing a log P_ow of 1.81 at pH 4.9 (XII).

Justification of chosen bioaccumulation phrase:

Based on the data showing an n-octanol/water partition coefficient of 1.81 and a calculated BCF of 4.9, Nevirapin is considered to have “low potential for bioaccumulation”.

Excretion (metabolism)

Only a small part of administered Nevirapine dose is excreted as parent compound. In a metabolism study in humans, the major part of administered dose (about 81 %) was excreted as metabolites via urine, mainly as glucoronide conjugates of hydroxylated metabolites. The pharmacological activity of the metabolites is not known (V).

References

1. European Chemicals Agency (ECHA), 2008. Guidance on information requirements and chemical safety assessment. Chapter R.10: Characterization of dose[concentration]-response for environment. http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf 

2. European Chemicals Agency (ECHA), 2014. V2.0. Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7b: Endpoint specific guidance. http://echa.europa.eu/documents/10162/13632/information_requirements_r7b_en.pdf 

3. Boehringer Ingelheim GmbH internal report U98-3270

4. Boehringer Ingelheim GmbH internal report U99-1260

5. Boehringer Ingelheim ERA data sheet, 2005

6. Boehringer Ingelheim GmbH internal report U99-1259

7. Boehringer Ingelheim GmbH internal report U98-3269

8. Boehringer Ingelheim GmbH internal report U99-1258

9. Boehringer Ingelheim GmbH internal report U97-3223

10. Boehringer Ingelheim GmbH internal report U95-3399

11. Boehringer Ingelheim GmbH internal report U98-3268

12. Boehringer Ingelheim GmbH internal report U03-1434