Detaljerad miljöinformation

Environmental risk assessment of Repaglinide in pharmaceutical products marketed in Sweden in 2024.

This document includes environmental risk assessment of Repaglinide in pharmaceutical products marketed in Sweden in 2024. The risk assessment is performed in accordance with the FASS.se guidelines on environmental classification of pharmaceuticals (ref. 1).

1. Repaglinide

Environmental risk: A valid risk quotient (PEC/PNEC) for Repaglinide cannot be calculated due to lack of eco-toxicity data. Repaglinide is moderate toxic to crustaceans (daphnids).

Degradation: Repaglinide is potentially persistent in the environment.

Bioaccumulation: Repaglinide has low potential for bioaccumulation.

PBT/vPvB assessment: Repaglinide does not meet the criteria for classification as a PBT or vPvB substance.

Since the PEC/PNEC cannot be calculated due to lack of eco-toxicity data the following environmental risk phrase should be applied to pharmaceutical products containing Repaglinide according to the criteria in ref. 1:

”Risk of environmental impact of Repaglinide cannot be excluded due to lack of eco-toxicity data”.

1.1 The pharmaceutical product

Repaglinide is used by Novo Nordisk as the active pharmaceutical ingredient (API) in NovoNorm.

NovoNorm is applied for glycaemic control of type II diabetes and is administered orally via tablets. The API content per tablet is 0.5, 1 or 2 mg and the total maximum daily dose is 16 mg (Ref. 2).

1.2 Detailed background information

• Chemical name: Benzoic acid, 2-ethoxy-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-

• CAS Number: 135062-02-1

• Molecular formula: C₂₇H₃₆N₂O₄

• Molecular weight: 452.6 g/mol

Reference: 3.

Dissociation (Ref. 4):

pH	Ionic form
< 3.9	Cationic
3.9 ≤ pH ≤ 6.1	Zwitter ionic
> 6.1	Anionic

Octanol/Water partition coefficient (Ref. 4):

pH	Log Dow
3.0	2.4
7.4	2.5
9.0	1.7

Water solubility (Ref. 4):

pH	mg/L
2.0	583
5.0	8.6
7.0	55.7
8.3	915

Hydrolysis (Ref. 4):

Repaglinide is only hydrolysed in strong acid media (pH 1).

2. Environmental Risk Assessment (ERA)

2.1 Predicted Environmental Concentration (PEC)

According to ref. 1, PEC (Predicted Environmental Concentration) in surface water is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.4*10^-6*A*(100-R)

PEC_{Surface water} = 0.002 µg/L

where:

• A = 11.38 kg (total amount of API sold in Sweden in year 2022, data from IQVIA and provided by LIF, Ref. 7). Reduction of A may be justified based on metabolism data.

• R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation). R = 0 if no data is available.

• P = number of inhabitants in Sweden = 10 *10⁶

• V (L/day) = volume of wastewater per capital and day = 200 (ECHA default) (Ref. 8)

• D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Ref. 8)

Due to insufficient or lack of data, the calculation of PEC of Repaglinide in surface water is based on the following assumptions:

• no metabolism in the human body

• no removal in the wastewater treatment plants.

According to the European Medicines Agency guideline on environmental risk

assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of Repaglinide is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 μg/L (Ref. 9).

2.2 Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae:

Acute toxicity

No data available.

Chronic toxicity

No data available.

Crustacean (Daphnia Magna) (Ref. 6):

Acute toxicity

EC₅₀ 48h (static) = 66 mg/L (US-FDA, Tech. Assist. Doc.4.08)

Chronic toxicity

NOEC = 34 mg/L (US-FDA, Tech. Assist. Doc.4.08)

Since 1 mg/L < EC50 ≤ 100 mg/L, Repaglinide is considered to be moderate acute toxic to crustaceans.

Fish:

Acute toxicity:

No data available.

Chronic toxicity

No data available.

Since eco-toxicological data is only available for one trophic level (daphnia) a valid PNEC cannot be calculated according to ref. 1.

2.3 Environmental risk classification (PEC/PNEC ratio)

Since eco-toxicological data is only available for one trophic level (daphnia) a valid risk quotient (PEC/PNEC) cannot be calculated according to ref. 1.

3. Degradation

3.1 Biotic degradation

Ready biodegradability:

Test results in 16 % degradation in 28 days (US-FDA, Tech. Assist. Doc. 3.11.), ref. 5. Supporting data: Less than 20% biodegradation in 24 days, ref. 10.

Inherent degradability:

No data available.

Simulation studies:

No data available.

3.2 Abiotic degradation

Hydrolysis:

No data available.

Photolysis:

No data available.

Since only 16% was degraded in the biodegradation test, Repaglinide is thus not readily biodegradable. It cannot be excluded that Repaglinide is potentially persistent in the aquatic environment according to ref. 1.

4. Bioaccumulation

Bioconcentration factor (BCF):

No data available.

Partitioning coefficient:

The highest estimated Log Dow for Repaglinide is 2.5; see section 1.2.

Since Log Dow < 4 at pH 7, it indicates that Repaglinide has low potential for bioaccumulation according to ref. 1.

5. Excretion

Repaglinide is completely metabolised in the body and excreted primarily via the bile. Ca. 8% is excreted via urine, primarily as metabolites, and less than 2% of the parent drug is recovered in faeces.

6. PBT and vPvB assessment

Considering all three PBT aspects stated in EU REACH criteria, Repaglinide does not meet the criteria as a PBT or vPvB substance (Ref. 8).

7. References

1. Environmental classification of pharmaceuticals in www.fass.se – guidance for pharmaceutical companies 2012.

2. Company Core Data Sheet on Repaglinide by Novo Nordisk, 2005.

3. ERA Data sheet on Repaglinide from Boehringer-Ingelheim, 02/2007.

4. Report no. U96-2543, Boehringer-Ingelheim

5. Report no. U98-3272, Boehringer-Ingelheim

6. Report no. U98-3271, Boehringer-Ingelheim

7. Repaglinide sales data for Sweden by IQVIA provided by LIF, 2022

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

9. Guideline on the environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00) by the European Medicines Agency, 2006

10. Markiewicz M; Jungnickel C; Stolte S; Bialk-Bielinska A; Kumirska J; Mrozik W. Ultimate biodegradability and ecotoxicity of orally administered antidiabetic drugs. Journal of Hazardous Materials (2017), 333, 154-161