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) = 0.00037 μg/L

Where:

A = 2.691 kg (total sold amount API in Sweden year 2022, 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) = 117 μg/L, E_rC₅₀ 72 hours (growth rate) = 460 μg/L. Guideline OECD 201. (Reference II)

Crustacean (waterflea, Daphnia magna):

Acute toxicity

EC₅₀ 48 hours (immobilization) = 6400 μg/L. Guideline OECD 202. (Reference III)

Chronic toxicity

NOEC 21 days (reproduction) ≥ 387 μg/L. Guideline FDA TAD 4.09. (Reference IV)

Fish:

Acute toxicity (rainbow trout, Oncorhynchus mykiss)

LC₅₀ 96 hours (survival) = 1600 μg/L. Guideline FDA TAD 4.11. (Reference V)

Chronic toxicity (fathead minnow, Pimephales promelas)

NOEC 300 days (life-cycle test: growth, sexual development) = 0.001 μg/L. Guideline OECD EPA FIFRA Subdev. E, 72-5. (Reference VI)

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 was fish, and the lowest effect level was reported as NOEC = 0.0003 µg/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 = 0.0003 µg/L / 10 = 0.00003 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated with 0.00037 µg/L / 0.00003 µg/L = 12.3.

Justification of chosen environmental risk phrase:

A risk quotient above 10 qualifies for the phrase “Use of ethinylestradiol has been considered to result in high environmental risk.”.

Degradation

Biotic degradation

Ready degradability:

Ethinylestradiol was studied for aerobic biodegradability in water in a CO₂ evolution test according to guideline FDA TAD 3.11 (8). Ethinylestradiol was introduced into the test system at a concentration of 10 mg/L as carbon. The study reported 3 % biodegradation of ethinylestradiol in 28 days, wherefore the substance is considered not readily biodegradable. Guideline FDA TAD 3.11. (Reference VII)

Simulation studies:

A study on transformation in aquatic/sediment systems according to test guideline OECD 308 was conducted. The transformation of [14C] ethinylestradiol in sediments and natural water was assessed in three different aerobic sediment/water systems. The disappearance half-lifes of [14C] ethinylestradiol were in the overlying water of aerobic systems 4.0 and 5.9 days for the high and low organic carbon content, respectively. Since for one of the low organic carbon content sediment the total mass balance was not reached as recommended in the guideline OECD 308 (≥ 90%), this result was not further evaluated.

The extraction from sediments were performed by the following method, which was validated for spiked sediments prior to application to test samples: The sediment is extracted by using 50 mL acetonitrile:water, 80:20, v:v as extraction solvent. If more than 5 % of the applied amount is found in the second extract the sediment is extracted a third time using acetonitrile:1 M HCl 80:20, v:v. A portion of the combined extracts was then reduced by rotary evaporation at 40 °C and at least 60 mbar. The concentrated sample was then analyzed by HPLC for parent compound and extractable metabolites.

The parent compound was recovered to 0 % from all water and sediment samples at day 99. Only slight ultimate biodegradation was observed in the test systems. The accumulative amount of evolved ¹⁴CO₂ for the aerobic test systems was 2.5 and 5.1 % of the applied radioactivity. Primary degradation was observed for ethinylestradiol to a low degree in the water/sediment test samples. One metabolite occurred only occasionally. Most of the introduced radioactivity was sediment-bound (50-62 %).

In the total water/sediment systems the DT₅₀ of [14C] ethinylestradiol was 24, 36, and 28 days for the 2 systems. The DT₅₀ values differed ranked in two cases below the threshold of 32 days and exceeded this threshold in one case. Since two of three water-sediment systems report DT₅₀ below the criterion and the exceedance of one system is moderate, ethinylestradiol can be classified as being degradable.

In conclusion, this study reported a half-life of ethinylestradiol of 4.0-5.9 days in water and 24-36 days in sediment/total system. Guideline OECD 308. (Reference VIII)

Abiotic degradation

Hydrolysis:

This study reported that ethinylestradiol is hydrolytically stable. Guideline FDA TAD 3.09. (Reference IX)

Justification of chosen degradation phrase:

The degradation half-life in the total system of the OECD 308 study qualifies for the phrase “ethinylestradiol is degraded in the environment”.

Bioaccumulation

Partitioning coefficient:

The log D_ow was reported as 4.2. Guideline FDA TAD 3.02. (Reference X)

Bioconcentration factor (BCF):

A bioaccumulation study with ethinylestradiol was conducted in the bluegill sunfish Lepomis macrochirus. The fish were exposed to concentrations of 1 and 10 ng/L [14C] ethinylestradiol, over 35 days with a subsequent depuration phase of 29 days. The steady state bioconcentration factors (BCFs) for total radioactive residue were 371 and 634 for the 1.0 and 10 ng/L treatment level, respectively. The steady state bioconcentration factors for total radioactive residue (TRR) based on lipid content of 3.61 % were 371 at the 1.0 ng/L treatment level and 634 at the 10 ng/L treatment level. Normalised to 5 % fat tissue, the BCFss for total radioactive residues for whole fish are 514 and 878 for the 1.0 and 10 ng/L treatment levels, respectively. Guideline OECD 305. (Reference XI)

Justification of chosen bioaccumulation phrase:

As the log D_ow was > 4 and BCF > 500 ethinylestradiol is considered bioaccumulative which qualifies for the phrase “ethinylestradiol has high potential for bioaccumulation.”.

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 ethinylestradiol (ZK 4944) on the green algae Desmodesmus subspicatus. Experimental Toxicology, Schering AG, Study no. TXST20020060, Report no. A12518 (2004).

3. Acute immobilization of ethinylestradiol with Daphnia magna. Experimental Toxicology, Schering AG, Study no. TXS94269, Report no. AG47 (1997).

4. Chronic toxicity study of ethinylestradiol on Daphnia magna. Experimental Toxicology, Schering AG, Study no. TXS94268, Report no. AG95 (1999).

5. Acute toxicity test of ethinylestradiol with rainbow trout. Experimental Toxicology, Schering AG, Study no. TX93145, Report no. A987 (1995).

6. Ethinylestradiol: Determination of the chronic toxicity to fathead minnow Pimephales promelas full lifecycle. Experimental Toxicology, Schering AG, Zeneca study no. AA1099/B, Schering study no. TX95192 (1997).

7. Study on aerobic biodegradation of ethinylestradiol. Experimental Toxicology, Schering AG, Study no. TX93157, Report no. AA74 (1995).

8. [14C] Ethinylestradiol: Aerobic and anaerobic transformation in aquatic sediment systems. Bayer Schering Pharma AG, Nonclinical drug Safety, Springborn Smithers Laboratories, Horn, Switzerland study no. 1121.000.753 (2008).

9. Physicochemical data for environmental risk assessment of ethinylestradiol (ZK 4944). General Physical Chemistry, Schering AG, report no. KO 41 (1993).

10. [14C] Ethinylestradiol: Bioconcentration study with bluegill sunfish (Lepomis macrochirus) under flow-through conditions. Bayer Schering Pharma AG, Nonclinical drug Safety, Springborn Smithers Laboratories, Horn, Switzerland study no. 1121.000.135 (2008).

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) = 0.0013 μg/L

Where:

A = 9.36 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) = 5.6 μg/L, E_rC₅₀ 72 hours (growth rate) = 25.3 μg/L. Guideline OECD 201. (Reference II)

Crustacean (waterflea, Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) ≥ 752 μg/L. Guideline OECD 211. (Reference III)

Fish (fathead minnow, Pimephales promelas):

Chronic toxicity

EC₁₀ 21 days (reproduction) = 0.00001 μg/L. Guideline OECD 229. (Reference IV)

Fish (zebrafish, Danio rerio):

Chronic toxicity

NOEC 126 days (reproduction) = 0.00016 μg/L. Guideline OECD 210. (Reference V)

The PNEC was calculated by division of the lowest effect level (NOEC) of the fish full life cycle study considering an appropriate assessment factor (AF). The most sensitive taxonomic group were fish, and the lowest relevant effect level was reported as EC₁₀ = 0.00016 µg/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 = 0.00016 µg/L / 10 = 0.000016 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated with 0.0013 µg/L / 0.000016 µg/L = 81.3.

Justification of chosen environmental risk phrase:

A risk quotient above 10 qualifies for the phrase “Use of levonorgestrel has been considered to result in high environmental risk.”

Degradation

Biotic degradation

Ready degradability:

Levonorgestrel was also studied for aerobic biodegradability in water in a manometric respiration test according to guideline OECD 301F. The test item was introduced

into the test system at a concentration of 200 mg/L as theoretically oxidizable carbon.

The study reported 0 % biodegradation of levonorgestrel in 28 days. Guideline OECD 301F. (Reference VI)

Simulation studies:

A study on transformation in aquatic/sediment systems according to test guideline OECD 308 was conducted. The transformation of [¹⁴C] levonorgestrel in sediments and natural water was assessed in two different aerobic sediment/water systems. Levonorgestrel was incubated in glass vessels containing sediment and overlaying water over 100 days.

The entire sediment sample was extracted first with acetonitrile, afterwards with acetonitrile/water, 70/30, v/v and acetonitrile/water/HCl, 70/30/5, v/v/v until the last extract contained ≤ 5% of the applied radioactivity. The samples were shaken for 5 minutes and thereafter centrifuged for 5 minutes at 2000 rpm. The supernatant was transferred into a graduated cylinder. In cases where a phase separation was observed, portions of 20 mL of Milli- Q water were added to the extracts until no separation was visible anymore. The total volume was recorded and duplicate 1 mL aliquots were measured by LSC for radioactivity.

The results of the study indicate that levonorgestrel is distributed to the sediment compartment, however, relevant amounts remained in the water phase (22 and 43 % for the fine and coarse sediment, respectively). The degradation rate was 6-7 % at the end of the incubation period. The DT₅₀ (disappearance half-life from the water phase) for parent compound in water was estimated with 2.5 and 3.2 days for the fine and coarse sediment, respectively.

This study reported a half-life of levonorgestrel in water DT₅₀ = 2-5-3.2 days while the DT₅₀ in sediment/total system could not be determined and the substance is considered potentially persistent in the environment. Guideline OECD 308. (Reference VII)

Abiotic degradation

Hydrolysis:

Levonorgestrel was reported to be resistant to hydrolysis at pH 5, 7, and 9 and 25 °C. Guideline FDA TAD 3.09. (Reference VIII)

Justification of chosen degradation phrase:

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

Bioaccumulation

Partitioning coefficient:

The log D_ow was reported as 3.55. Guideline FDA TAD 3.02. (Reference IX)

Bioconcentration factor (BCF):

Fish (bluegill sunfish Lepomis macrochirus) were exposed in two treatment groups to ¹⁴C-labeled levonorgestrel for 28 days followed by a depuration phase of 14 days. The mean measured concentration of levonorgestrel (based on ¹⁴C analysis) was 6.1 and 42.1 ng/L for the low and high concentration, respectively, during the exposure phase. The concentration of ¹⁴C in fish tissue decreased rapidly during the exposure phase most likely due to increased metabolization and subsequent rapid excretion. The BCFss (bioconcentration factor at steady state) was 250 and 119 for group 2 and 3, respectively. Normalized to a standard lipid content of 5 % the BCFss calculated as 192 and 92 for group 2 and 3, respectively. Guideline OECD 305. (Reference X)

Other data

Justification of chosen bioaccumulation phrase:

As the log D_ow was < 4 and/or BCF < 500 levonorgestrel is not considered bioaccumulative which qualifies for the phrase “Levonorgestrel has low potential for bioaccumulation.”

Excretion (metabolism)

Systemically available levonorgestrel is mainly excreted in the hydroxylated and to a lesser extent, in a conjugated form. Only a small fraction is released unchanged. (Reference XI)

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 levonorgestrel (BAY 86-5028) on the green algae Desmodesmus subspicatus. Nonclinical Drug Safety, Bayer Pharma AG, study no. TOXT2082435, report no. A52865.

3. Reproduction study of levonorgestrel (ZK18206) in Daphnia magna. Nonclinical Drug Safety, Bayer Pharma AG, study no. TOXT6081124, report no. A49686.

4. Short-term reproduction tests with levonorgestrel (ZK 18206) on the fathead minnow (Pimephales promelas). Nonclinical Drug Safety, Bayer Schering Pharma AG, study no TOXT4078685, report no. A39905.

5. Zebrafish (Danio rerio) Partial life stage test, Flow through conditions. Drug Discovery, Bayer AG, study no. T103549-2, report no. R-12907.

6. Study on the biodegradability of Levonorgestrel (ZK 18206) in the manometric respiration test. Nonclinical Drug Safety, Bayer Schering Pharma AG, study no. TOXT2082138, report no. A51399.

7. Levonorgestrel (BAY 86-5028): Aerobic Transformation in Aquatic Sediment Systems. Nonclinical Drug Safety, Bayer Healthcare AG, study no.T5081646EXT, report no. A56339.

8. Levonorgestrel, ZK18206, Report on physicochemical properties, Rate of hydrolysis. General Physical Chemistry, Schering AG, study no. APC 94/158, report no. LD06EY10.

9. The octanol/water partition coefficient of levonorgestrel (ZK18206). General Physical Chemistry, Schering AG, study no. APC 93/103a, report no. LD16.

10. Bioconcentration flow-through fish test with levonorgestrel [BAY 86-5028 (14-C)], Nonclinical Drug Safety, Bayer HealthCare AG, study no. TOXT9082441, report no. A53418.

11. Stancyk, F., Roy, S.: Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids. Contraception 42, 67-96.