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Gestagen och estrogen, p-piller av kombinationstyp

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Miljöpåverkan (Läs mer om miljöpåverkan)

Dienogest

Miljörisk: Användning av dienogest har bedömts medföra låg risk för miljöpåverkan.
Nedbrytning: Dienogest är potentiellt persistent.
Bioackumulering: Dienogest har låg potential att bioackumuleras.


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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) = 1.5*10-6*A(100-R)

PEC = 0,001 μg/L

Where:

A = 6,634 kg (total sold amount API in Sweden year 2016, data from QuintilesIMS).

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 = 9 *106 

V (L/day) = volume of waste water per capita and day = 200 (ECHA default (1))

D = factor for dilution of waste water by surface water flow = 10 (ECHA default (1))



Predicted No Effect Concentration (PNEC)

Ecotoxicological studies


Algae (Desmodesmus subspicatus):

EC50 /72 h (growth inhibition, growth rate) > 16300 µg/L (guideline OECD 201) (2)

Crustacean (waterflea Daphnia magna):

Acute toxicity

EC50 /48 h (immobilization) > 21500 μg/L (saturated solution) (guideline OECD 202) (3)

Chronic toxicity

NOEC /21 days (reproduction, mortality) ≥ 491 μg/L (guideline OECD 211) (4)

Fish (fathead minnow Pimephales promelas):

Chronic toxicity

NOEC 21 days (+ 26 d pre-exposure) (fecundity, sexual reversal) = 0.064 μg/L (OECD 230 draft, fish adult reproduction test) (5)

NOEC 65 days (hatch survival, growth, histopathology of gonads) = 0.044 μg/L (extended early life stage test, non-standard) (6)

The non-standard extended early life stage test was performed in order to study any potential developmental abnormalities in fish after dienogest exposure during early stages. Freshly fertilized eggs (60 per treatment group) from a laboratory culture of adult fathead minnow were used for each test solution of dienogest and for the control group. For each test vessel two separate cylinders, each with 30 eggs, were introduced.

The eggs and larvae were exposed to three test solutions of dienogest with mean measured concentrations of 44, 152 and 334 ng/L and additionally to a tap water control for a period of 60 days post hatch (dph). Hatching; survival, growth and gross morphology and histopathological changes of the gonads were the main parameters studied.

Hatching and survival was affected by the test substance from the dienogest concentration of 152 ng/L. Additionally, the growth of the treated fish increased at the highest concentration (334 ng/L), probably due to the lack of food competition. The histopathological examination showed no effects, which were indicative for an endocrine mechanism.

The results of this study showed that dienogest has effects on hatch and survival of fish (fathead minnow) at concentrations from 152 ng/L onwards. Thus, the overall no observed effect concentration (NOEC) was 44 ng/L, the lowest observable effect concentration (LOEC) was 152 ng/L.

Microorganisms (activated sludge, respiration inhibition):

EC50 /30 min > 4000 µg/L (guideline OECD 209) (9)

PNEC = 0.0044 μg/L (Lowest chronic NOEC fish = 0.044 µg/L; AF 10)



Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0.001/0.0044 = 0,24, i.e. 0,1 < PEC/PNEC ≤ 1 which justifies the phrase Use of dienogest has been considered to result in low environmental risk.



Degradation

Biotic degradation

Ready degradability: not readily biodegradable

Dienogest was studied for aerobic biodegradability in water in a manometric respiration test according to guideline OECD 301F (10). Dienogest was introduced into the test system at a concentration of approximately 70 mg/L. It was degraded to <3 % after 28 days. Hence, it is not readily biodegradable.

A study on transformation in aquatic/sediment systems according to test guideline OECD 308 was conducted (11). 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 of incubation and no ultimate biodegradation was observed. The DT50 (disappearance half-life from the water phase) for parent compound in water was estimated with 5.7 and 12.3 days for the fine and coarse sediment, respectively.

The overall disappearance half-life from the system exceeded the threshold of 120d described in the FASS guidance. Therefore, dienogest can be classified as being potentially persistent.

Abiotic degradation

Hydrolysis:

Dienogest is hydrolytically stable ( > 1 year at pH 4, 7 and 9 and 25 ºC) (HPLC- method; EC C7) (12)


Bioaccumulation

Partitioning coefficient:

Log POW 1.6 at pH 7 and 25°C (Shake flask method, OECD 117) (13)

Justification of chosen bioaccumulation phrase:

Since Log POW (at pH 7) < 4, 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 (14), (15).


References

(1) ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

(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). Experimental Toxicology, Schering AG, study no TXST20030162, report no. A20904 (2004)

(6) Short-term reproduction test with dienogest (ZK 37659) on the fathead minnow (Pimephales promelas). Nonclinical Drug Safety, Bayer Schering Pharma AG, study no TOXT5079180, report no. A43764 (2009)

(7) Nagahama Y. Endocrine regulation of gametogenesis in fish. Int J Dev Biol 38, 217-229 (1994).

(8) Kime D.E. ‘Classical’ and ‘non-classical’ reproductive steroids in fish. Rev Fish Biol and Fisheries Rev Fish Biol Fisheries 3, 160-180 (1993).

(9) Respiration inhibition test of dienogest (ZK 37659) on activated sludge microorganisms. Nonclinical Drug Safety, Bayer Schering Pharma AG, study no TXST20070059, report no. A37712 (2007)

(10) Study on the biodegradability of dienogest (ZK 37659) in the manometric respiration test. Experimental Toxicology, Schering AG, study no. TXST20030132, report no. A16840 (2004)

(11) Aquatic sediment study (aerobic) with dienogest (ZK 37659). Nonclinical Drug Safety, Bayer Schering Pharma AG, study no. TOXT8078698, report no. A42734 (2009)

(12) Dienogest/ZK 37659/Report on physicochemical properties/Rate of hydrolysis Analytical Development Physical Chemistry, Schering AG, study no. 05600183, report no. A28384 (2005)

(13) 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 (2005)

(14) 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)

(15) 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)


Estradiol

Miljörisk: Användning av estradiol har bedömts medföra hög risk för miljöpåverkan.
Nedbrytning: Estradiol bryts ned långsamt i miljön.
Bioackumulering: Estradiol har låg potential att bioackumuleras.


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Detaljerad miljöinformation

Estradiol valerate, estradiol hemihydrate, polyestradiol phosphate

Estradiol valerate is an ester of estradiol. Estradiol hemihydrate is estradiol containing one molecule of water per molecule estradiol. Polyestradiol phosphate is a polymer prodrug of estradiol, which is metabolized to estradiol. The biological active moiety of these compounds is 17ß-estradiol. Therefore, the classification is based on estradiol.


Detailed background information

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) = 1.5*10-6*A(100-R)

In order to normalize the different estradiol esters on estradiol units, all sales volumes are adjusted to estradiol based on molecular weight. For polyestradiol phosphate the molecular weight of one unit estradiol phosphate is used.


Molecular weight, normalization factor estradiol

Estradiol

272.4 g/Mol

--

Estradiol valerate

356.5 g/Mol

0.76

Estradiol hemihydrate

562.8 g/Mol

0.48

Polyestradiol phosphate

370.4 g/Mol

0.74

PEC = 0.0036 μg/L

Where:

A = [18.5520847 kg * 0.76 =] 14.099584 kg (estradiol valerate) + [19.45314398 kg * 0.48 = ] 9.337509 kg (estradiol hemihydrate) + [0.46376 kg * 0.74 = ] 0.3431824 kg (polyestradiol phosphate) = 23.780275 kg normalized on estradiol (total sold amount API in Sweden year 2016, data from QuintilesIMS).

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 = 9 *106 

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (1) 

D = factor for dilution of wastewater by surface waterflow = 10 (ECHA default) (1)


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies
(All studies were performed with estradiol as active moiety in estradiol-esters such as valerate or hemihydrate).

Algae (Desmodesmus subspicatus):

EC50 /72 h (growth inhibition, growth rate) = >3100 μg/L (as estradiol) (guideline OECD 201) (2)

Crustacean (waterflea Daphnia magna):

Chronic toxicity

NOEC /21 days (reproduction) = ≥ 139 μg/L (NOEC, reproduction, mortality (guideline FDA TAD 4.09) (3)

Fish:

Acute toxicity (Rainbow trout Oncorhynchus mykiss)

LC50 /96 h (mortality) = >500 μg/L (guideline FDA TAD 4.11) (4)

Chronic toxicity (fathead minnow Pimephales promelas) (extended development test: hatching, survival, growth, secondary sexual characteristics, histology) (EPA FIFRA Subdev. E,72-5, with modifications)
NOEC growth, 52 days = 0.008 μg/L (5)

Chronic toxicity (medaka Oryzias latipes) (2 generation test: fertility/fecundity (F0), hatching, survival, growth, sexual development (F1))
NOEC fertility (F0), 59d = 0.0029 µg/L (6)

PNEC = 0.00029 μg/L (Lowest chronic NOEC fish = 0.0029 µg/L; AF 10)


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0.0036/0.00029 = 12.4, i.e. PEC/PNEC >10 which justifies the phrase "Use of estradiol (including esters) has been considered to result in high environmental risk".


Degradation

Biotic degradation

Ready degradability: not readily biodegradable, but significant mineralization.

Estradiol was studied for aerobic biodegradability in water in three different CO2 evolution tests. In one test, biodegradation was studied according to OECD method 301B (7). Estradiol was introduced into the test system at concentrations of 10 mg/L. In two other tests, the degradation was studied according to FDA TAD method 3.11(8)(9). In the latter, two concentrations (1 and 10 mg/L) were tested. In all assays, estradiol was degraded to more than 60 % after 28 days. However, degradation proceeded too slowly to formally classify the compound as being readily biodegradable.

Abiotic degradation

Hydrolysis:

Estradiol is hydrolytically stable (10).

Due to the high mineralization rate in the ready biodegradability test, the phrase estradiol (as valerate or hemihydrate) is slowly degrading in the environment.


Bioaccumulation

Partitioning coefficient:

Log POW 4.0 (HPLC method, FDA TAD 3.02) (11).

A bioaccumulation study was performed with 14C labeled estradiol (12). Twenty fish were exposed to 14C labeled estradiol and additionally 40 to the dilution water (tap water) for a period of 22 days. Additionally, the fish was depurated over a period of 8 days.

The test substance solution was delivered continuously to the tanks. The nominal concentration of estradiol in the water was 276 ng/L. The concentration of the test substance in the fish and in the water was determined through both phases of the test. The 14C concentration in the fish was analyzed by liquid scintillation after oxidative degradation of the fish in samples taken on day 4, 6, 10, 14, 21, 24, 26, and 30. The 14C concentration in the water was analyzed by liquid scintillation in samples taken at the same time points.
The bioconcentration factor in fish (BCFss) was calculated as the ratio of the mean values of the 14C concentration in fish and in water.

The BCFss was 108.8 (normalized to 6 % lipid: 85.9). The uptake rate constant (k1) was 1.1, the depuration rate constant (k2) was -2.2. The DT50 for depuration was determined with 3.2 days, indicating a rapid turnover of estradiol. This was expected, since estradiol is an endogenous hormone metabolized rapidly during normal physiological processes.

Justification of chosen bioaccumulation phrase:

Since log POW was 4.0  but the BCF was 109 (86 normalized on 6 % fat), the trigger of a BCF of 500 was not exceeded. Therefore, the substance was considered to have a low potential for bioaccumulation.


Excretion (metabolism)

Estradiol valerate is readily cleaved into estradiol and valeric acid. Estradiol undergoes the same metabolic pathways as endogenous estrogen, i.e. it is further metabolized into the major metabolites estrone, estriol, estrone sulfate and estrone glucuronide (13), (14), (15).


PBT/vPvB assessment

Estradiol is not PBT/vPvB, because the threshold of a BCF of 2000 was not exceeded.


References

  1. 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

  2. Growth inhibition test with estradiol (ZK 5018) on the green algae Desmodesmus subspicatus. Experimental Toxicology, Schering AG, study no. TXST20020260, report no. A30506 (2006)

  3. Reproduction and chronic immobilization study of estradiol in Daphnia magna. Experimental Toxicology, Schering AG, study no. TX96156, report no. AQ94 (2001)

  4. Acute toxicity of 1717β-estradiol with the rainbow trout. Experimental

    Toxicology, Schering AG, study no TX95070, report no A05662 (2001).

  5. 17β estradiol - Extended early life-stage toxicity test with fathead minnow (Pimephales promelas). Experimental Toxicology, Schering AG, report no. B945 (1999)

  6. Seki M, Yokota H, Maeda M, Kobayashi K. Fish full lifecycle testing for 17β-estradiol on medaka (Oryzias latipes). Environmental Toxicology and Chemistry 24, 1259-1266 (2005)

  7. Study of aerobic biodegradablity of estradiol. Experimental Toxicology, Schering AG, study no TX95270, report no A05658 (2001)

  8. Study on the biodegradability of estradiol in the CO2-evolution test (Modified Sturm-Test). Experimental Toxicology, Schering AG, study no TXST19970041, report no A05659 (2001)

  9. Study of aerobic biodegradability of estradiol. Experimental Toxicology, Schering AG, study no TX96181, report no A05814 (2001)

  10. Estradiol/ZK 5018/Report on physicochemical properties/Rate of hydrolysis. General Physical Chemistry, Schering AG, study no 0353, report no N408 (2001)

  11. Estradiol/ZK5018/Report on physicochemical properties/Water solubility/N-octanol/water partition coefficient. General Physical Chemistry, Schering AG, study no 2966, report no A02014 (2000)

  12. Bioconcentration flow-through fish test with estradiol [BAY 86-5435 (14-C)].

    Non-clinical Drug Safety, Bayer Schering Pharma AG, study no TOXT7082197, report no A52549 (2011)

  13. Hobkirk, R, Mellor JD, Nilsen M: In vitro metabolism of 17β-estradiol by human liver tissue. Can J Biochem. 53, 903-906 (1975). (1.6.1.3.1 Hobkirk et al. 1975)

  14. Lievertz, R.W.: Pharmacology and pharmacokinetics of estrogens. Am. J. Obstet. Gynecol. 156, 1289-1293 (1987). (1.6.1.3.1 Lievertz 1987)

  15. Slaunwhite, R.W, Kirdani, R.Y., Sandberg A.A.: Metabolic aspects of estrogens in man. In: Greep, R. O., Astwood, E. B. (Eds.): Handbook of Physiology, Section 7: Endocrinology, Vol. 2, Female Reproductive Sytem, part 1, Chapter 21, American Physiology Society, Washington DC, 1973, pp. 485-523. (1.6.1.3.1 Slaunwhite et al. 1973)