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) = 0.00291 µg/L

Where:

A = 21.27 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) (ref I)

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

Predicted No Effect Concentration (PNEC)

PNEC = 3.8 μg/L

The PNEC has been derived from the lowest relevant NOEC value of 0.038 mg/L (Danio rerio, 21d, lethality). An assessment factor of 10 is used based on the availability of toxicity studies for all trophic levels in accordance with ECHA Guidelines (ref I, II).

Algae (Green algae, Pseudokirchneriella subcapitata) (OECD 201, GLP, ref III):

EC50 72h (biomass) ≥ 1.0 mg/L

NOEC 72h (biomass) ≥ 1.0 mg/L

EC50 72h (growth rate) ≥ 1.0 mg/L

NOEC 72h (growth rate) ≥ 1.0 mg/L

Crustacean (Water flea, Daphnia magna) (OECD 211, GLP)(ref IV):

Long term toxicity

21 day NOEC (reproduction) = 0.24 mg/L

21 day LOEC (reproduction) = 0.81 mg/L

Fish (Zebrafish, Danio rerio) (OECD 210, GLP)(ref V):

Long term toxicity

35 day NOEC (lethality) = 0.038 mg/L

35 day LOEC (lethality) = 0.12 mg/L

Other ecotoxicity data

EC50 for inhibition of active sludge (3h, OECD 209, GLP, ref VI) ≥1000 mg/L.

NOEC for inhibition of active sludge (3h, OECD 209, GLP, ref VI) ≥1000 mg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00291 / 3.8 =0.00077, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of Nintedanib has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

In a 28d ready biodegradability study in accordance with OECD Test Guideline 301B (GLP, ref VII), Nintedanib was found to not be biodegradable (0% degradation). Based on these data Nintedanib is not considered readily biodegradable.

Inherent degradability:

No data regarding inherent biodegradability is available.

Aerobic transformation in aquatic sediment systems

A 100 day sediment aerobic transformation study in accordance with OECD Test Guideline 308 (GLP, ref VIII) was performed for Nintedanib. The following dissipation rates (DT50) for the parent compound in a river (r) and pond (p) system were determined:

• DT50 water: 0.56 (r) and 0.43 (p)

• DT50 total system: 1.28 (r) and 0.47 (p)

At the end of the study (day 100), 30.9% (r) and 21.1% (p) of applied radioactivity was remaining as parent compound in the total river and pond system, respectively.

The amount of non-extractable radioactivity in the sediment was high for both test systems with bound residues accounting for up to 54.8% (r) and 68.4% (p) at day 100. Several minor degradation products were detected, none individually exceeding 3% of the applied radioactivity.

After removing the water phase from the test system, the sediment was submitted to two extraction steps using acetonitrile at room temperature except day 0 samples which were submitted to two extraction steps using acetonitrile/water (4:1; v/v) followed by one extraction step using acetonitrile.

Except for time 0, Soxhlet extraction using acetonitrile/water (4:1; v/v) for 4 hours was additionally performed on the extracted samples.

Extractions at room temperature were performed in a shaker at about 200-250 strokes per minute each for about 30 minutes. The amount of solvent used was in general about 1 mL/g sediment (wet weight basis).

The radioactivity in the individual extracts was quantified by LSC. The room temperature and Soxhlet extracts were then combined and an aliquot was concentrated under reduced pressure at about 30°C using a rotary evaporator. The concentrated extracts were re-dissolved in acetonitrile/water (2:3; v/v) and submitted to chromatographic analysis (HPLC). Selected samples were additionally analysed by TLC.

After all the extractions, the residual sediments were dried, weighed, homogenised and their radiocarbon content was determined by LSC after combustion of aliquots of up to 1.0 g.

The mineralisation of the test item and the formation of other organic volatiles was very low, accounting for 2.8% or 4.0% during the 100 days of incubation.

In conclusion, Nintedanib rapidly dissipated from the water phase by adsorption to the sediment of both systems. Once in the sediment, its degradation proceeds at a very slow rate, mainly via the formation of bound residues and the formation of minor metabolites. Based on these data, Nintedanib is considered to be "slowly degradaded in the environment".

Simulation studies:

No data on simulation studies.

Abiotic degradation

Hydrolysis: No data on hydrolysis

Photolysis: No data on photolysis.

Justification of chosen degradation phrase:

Nintedanib did not pass the ready degradation test (OECD 301B). In a tranformation study (OECD 308) it was degraded in sediment although more than 15% of the parent compound remained at the end of the study. Based on these data Nintedanib is considered to be “slowly degraded in the enviroment”.

Bioaccumulation

Bioconcentration factor (BCF):

No BCF study has been performed due to the low measured n-octanol/water partition coefficients below. Only a small amount of parent compound will be excreted after intake. The metabolites of Nintedanib is more polar (hydrophilic) than the parent compound and are expected to show lower bioaccumulation potential.

Partitioning coefficient:

The n-octanol/water partition coefficient was determined at pH 5, pH 7 and pH 9 (Draft OECD 122, GLP, ref IX) with the following results:

pH 5: log D = 0.93

pH 7: log D = 2.7

pH 9: log D = 3.34

log P = 3.4

Justification of chosen bioaccumulation phrase:

Based on the data from the OECD Guideline 122 study showing an n-octanol/water partition coefficient of < 4 at pH 7, Nintedanib is considered to have “low potential for bioaccumulation”.

Excretion (metabolism)

Biotransformation of Nintedanib occurs rapidly and to a significant extent. The substance is mainly metabolized by esterases with the by far most frequent metabolites being BIBF 1202 (ester cleavage of nintedanib) and BIBF 1202 glucuronide. The major route of elimination of total drug related [¹⁴C] radioactivity after oral administration of [¹⁴C]Nintedanib was via faecal/biliary excretion (93.4% of dose); the contribution of renal excretion to the total clearance was low (0.649% of dose). The most prevalent species in excreta were BIBF 1202 (59% of dose) and Nintedanib (20% of dose) (ref X). No information on the biological activity of the metabolites was provided.

PBT/vPvB assessment

Nintedanib is not considered to fulfil the criteria for PBT or vPvB.

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.  

2. European Chemicals Agency (ECHA), 2014. V2.0. Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7b: Endpoint specific guidance.  

3. Boehringer Ingelheim GmbH internal report No U09-0243-01, 2009

4. Boehringer Ingelheim GmbH internal report No U09-0244-01, 2009

5. Boehringer Ingelheim GmbH internal report No U10-0055-01, 2010

6. Boehringer Ingelheim GmbH internal report No U09-0245-01, 2009

7. Boehringer Ingelheim GmbH internal report No U09-0242-01, 2009

8. Boehringer Ingelheim GmbH internal report No U10-0062-01, 2010

9. Boehringer Ingelheim GmbH internal report No U08-1552-01, 2008

10. Boehringer Ingelheim Environmental Risk Assessment of Nintedanib, 2013