Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6*A*(100-R) = 0.0023 μg/L

Where:

A = 16.69 kg (total sold amount API in Sweden year 2021, data from IQVIA / LIF)

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

P = number of inhabitants in Sweden = 10 *10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies*

Algae (green algae, Desmodesmus subspicatus):

NOEC 72 hours (growth rate) > 16300 µg/L, E_rC₅₀ 72 hours (growth rate) > 16300 µg/L. Guideline OECD 201. (Reference II)

Crustacean (waterflea, Daphnia magna):

Acute toxicity

EC₅₀ 48 hours (immobilization) > 21500 µg/L. Guideline OECD 202. (Reference III)

Chronic toxicity

NOEC 21 days (reproduction, mortality) ≥ 492 µg/L. Guideline OECD 211. (Reference IV)

Fish (fathead minnow, Pimephales promelas):

Acute toxicity

LC₅₀ 96 hours (survival) ≥ 22200 µg/L. Guideline OECD 203. (Reference V)

Chronic toxicity

NOEC 21+26 d pre-exposure days (hatch and survival) = 0.064 µg/L. Guideline OECD 210 (extended). (Reference IV)

NOEC 61 days post hatch (hatch and survival) = 0.036 µg/L. Guideline OECD 210 (extended). (Reference VII)

The PNEC was calculated by division of the lowest effect level (NOEC) of the most sensitive taxonomic group considering an appropriate assessment factor (AF). The most sensitive taxonomic group were fish and the lowest effect level was reported as NOEC = 0.036 mg/L. The regulatory default standard AF of 10 was used, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, crustaceans, and fish).

PNEC = 0.036 µg/L / 10 = 0.0036 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated with 0.0023 µg/L / 0.0036 µg/L = 0.64.

Justification of chosen environmental risk phrase:

A risk quotient between 0.1 and 1 qualifies for the phrase “Use of dienogest has been considered to result in low environmental risk.”.

Degradation

Biotic degradation

Ready degradability:

Dienogest was studied for aerobic biodegradability in water in a manometric respiration test according with activated municipal sewage sludge. The test item was introduced into the test system at a concentration of approximately 70 mg/L. The study reported less than 3 % biodegradation of dienogest in 28 days. Guideline OECD 301. (Reference VIII)

Simulation studies:

The transformation of dienogest in sediments and natural water was assessed in two different aerobic sediment/water systems. Dienogest was incubated in glass vessels containing sediment and overlaying water over 100 days. The results of the study indicate that dienogest is distributed to the sediment compartment, since dienogest was removed to more than 97 % from the water phase after 100 days. The disappearance half-life DT50 in water could be determined but there was no ultimate biodegradation in sediment or the total test system.

with 5.7 and 12.3 days for the fine and coarse sediment, respectively. There was no ultimate biodegradation and the DT50 could therefore not be calculated for sediment or the total test system.

This study reported a half-life of substance dienogest in water DT₅₀ = 5.7-12.3 days, while no DT₅₀ could be determined in sediment/total system and is therefore considered > 120 days. Guideline OECD 308. (Reference IX)

Abiotic degradation

Hydrolysis:

Dienogest was reported to be hydrolytically stable. Guideline OECD 111. (Reference X)

Justification of chosen degradation phrase:

Dienogest established a DT₅₀ > 120 d for the total system and is resistant to hydrolysis, which qualifies for the phrase “dienogest is potentially persistent.”.

Bioaccumulation

Partitioning coefficient:

The log D_ow was reported with 1.6 at pH 7. Guideline OECD 117. (Reference XI)

Justification of chosen bioaccumulation phrase:

As the log D_ow was < 4 dienogest is not considered bioaccumulative which qualifies for the phrase “dienogest has low potential for bioaccumulation.”.

Excretion (metabolism)

Systemically available dienogest is mainly excreted in the hydroxylated form, a small fraction (6-8 %) has been detected unchanged or as conjugate in urine (Reference XII, XIII)

References

1. Guidance on information requirements and Chemical Safety Assessment Chapter R.16: Environmental exposure assessment. V3.0, Feb. 2016.

2. Growth inhibition test of dienogest (ZK 37659) on the green algae Desmodesmus subspicatus. Experimental Toxicology, Schering AG, study no. TXST20030171, report no. A27674 (2005)

3. Acute immobilization test of dienogest (ZK 37659) with Daphnia magna. Experimental Toxicology, Schering AG, study no. TXST20030176, report no. A16845 (2005)

4. Reproduction study of dienogest (ZK 37659) in Daphnia magna. Nonclinical Drug Safety, Bayer Pharma AG, study no. TXST20070010, report no. A36812 (2007)

5. Acute immobilization test of dienogest (ZK 37659) with fathead minnow (Pimephales promelas). Analytical Development Physical Chemistry, Bayer HealthCare AG, study no TXST20030162, report no. A20904

6. Short-term reproduction test with dienogest (ZK 37659) on the fathead minnow (Pimephales promelas). Analytical Development Physical Chemistry, Bayer HealthCare AG, study no TOXT5079180, report no. A43764

7. Fish extended early life-stage test with dienogest (ZK 37659) on the fathead minnow (Pimephales promelas). Analytical Development Physical Chemistry, Bayer HealthCare AG, study no TOXT6079974, report no. A46535

8. Study on the biodegradability of dienogest (ZK 37659) in the manometric respiration test. Experimental Toxicology, Schering AG, study no. TXST20030132, report no. A16840

9. Aquatic sediment study (aerobic) with dienogest (ZK 37659). Nonclinical Drug Safety, Bayer Schering Pharma AG, study no. TOXT8078698, report no. A42734

10. Dienogest/ZK 37659/Report on physicochemical properties/Rate of hydrolysis. Analytical Development Physical Chemistry, Schering AG, study no. 05600183, report no. A28384

11. Dienogest/ZK 37659/Report on physicochemical properties/Partition coefficient octanol water (HPLC method). Analytical Development Physical Chemistry, Schering AG, study no. 05600195, report no. A28147.

12. Detection and identification of STS 557 metabolites in human (female) urine by liquid chromatography coupled to mass spectrometry. Biotec Centre, Orleans, France. ScheringAG/Biotec Centre, Orleans, France. Original Study No.: 98124, report no. B455 (1994)

13. Tolerability and pharmacokinetics of a single oral dose of DNG in healthy adult Japanese females. Schering AG/Mochida Japan, Original Study no. N/Ap, report no. A00681 (1997)