Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

Cyproterone acetate consists of the active pharmaceutical moiety cyproterone (base) and acetate (salt), which is not active. For the PEC calculation, the total sale volume in 2022 can be adjusted to the volume of the active moiety. This was done by taking account of the molecular weight of the active moiety: molecular weight of cyproterone acetate is 416.94 g/mol, that of cyproterone is 374.91 g/mol, which equals 89.92 % of the total molecular weight. The sale volume of the active moiety calculates as 16.26 kg x 89.92 % = 14.62 kg.

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) = 0.00000411 µg/L

Where:

A = 14.62 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, Scenedesmus subspicatus):

E_rC₅₀ 72 hours (growth rate) = 3.4 mg/L. Guideline OECD 201. (Reference II)

Crustacean (waterflea, Daphnia magna):

Acute toxicity

EC₅₀ 48 hours (immobilization) = 2.4 mg/L. Guideline OECD 202. (Reference III)

Environmental risk classification (PEC/PNEC ratio)

Due to insufficient data neither the PNEC nor the PEC/PNEC ratio may be calculated.

Justification of chosen environmental risk phrase:

Insufficient data to calculate the PEC/PNEC ratio qualifies for the phrase “Risk of environmental impact of cyproterone acetate cannot be excluded, since there is not sufficient ecotoxicity data available.”.

Degradation

There is no data on degradation.

Justification of chosen degradation phrase:

The lack of data qualifies for the phrase “The potential for persistence of cyproterone acetate cannot be excluded, due to lack of data.”.

Bioaccumulation

Partitioning coefficient:

The log D_ow was reported as 3.36 at pH 7. Guideline OECD 117. (Reference IV)

Justification of chosen bioaccumulation phrase:

As the log D_ow was < 4 cyproterone acetate is not considered bioaccumulative which qualifies for the phrase “Cyproterone acetate has low 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 ZK 5560 on the green algae Scenedesmus subspicatus. Schering AG, Study no. TXST19970157, Report no. A09645.

3. Acute immobilization test of cyproterone acetate with Daphnia magna. Experimental Toxicology, Schering AG, Study no. TXST19970152, Report no. X373.

4. The determination of the n-octanol/water partition coefficient of ZK 9471 and estimation of its acid-base properties (pka value). General Physical Chemistry, Schering AG, study no. 1440, report no. ME47 (1997).

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).