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Activelle®


MiljöinformationReceptstatusFörmånsstatus
Novo Nordisk

Filmdragerad tablett 1 mg/0,5 mg
(vit, rund, 6 mm, märkt NOVO 288)

Östrogen och gestagen, kombinationspreparat - systemisk effekt

Aktiva substanser:
ATC-kod: G03FA01
Företaget omfattas av Läkemedelsförsäkringen

Miljöpåverkan (Läs mer om miljöpåverkan)

Estradiol

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


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Detaljerad miljöinformation

Environmental risk assessment of estrogens in pharmaceutical products marketed by Novo Nordisk in Sweden in 2013


This document includes environmental risk assessment of 17β-estradiol and its primary metabolites estrone and estriol in pharmaceutical products marketed by Novo Nordisk in Sweden in 2013. The risk assessment is performed in accordance with the FASS.se guidelines on environmental classification of pharmaceuticals (ref. 1).


1. The active pharmaceutical ingredients (API)


17β-estradiol, estrone and estriol are natural estrogens which belong to the class of steroid hormones. 17β-estradiol is the primary female sex hormone and estrone is the primary metabolite of 17β-estradiol. 17β-estradiol is used for hormone replacement therapy of women with menopause complications.


Chemical name 17β-estradiol

CAS no. 50-28-2

Molecular formula C18H24O2

Molecular weight 272.38 g/mol


Chemical name Estrone

CAS no. 53-16-7

Molecular formula C18H22O2

Molecular weight 270.37 g/mol


Chemical name Estriol

CAS no. 50-27-1

Molecular formula C18H24O3

Molecular weight 288.38 g/mol


2. Eco-toxicological data


Available eco-toxicological data for 17β-estradiol, estrone and estriol is presented in the Appendix.


On basis of the eco-toxicological tests presented in the Appendix it is concluded that the critical effect due to exposure of 17β-estradiol and its primary metabolites estrone and estriol is the induction of vitellogenin in fish that may cause a change in sex from male to female.


The No Observed Effect Concentration (NOEC) for induction of vitellogenin, which is considered a chronic eco-toxicity test, is 0.002 µg/l for 17β-estradiol, 0.04 µg/l for estrone and 2.9 µg/l for estriol.


3. Calculation of the risk quotient (PEC/PNEC)


3.1. Sold amount in Sweden

The total amount of estradiol (hemihydrate and valerat) sold in Sweden in 2013 was 41.1 kg API based on IMS Health sales data.


3.2. Calculation of PEC in surface water

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


PEC = 1.5*10-6*A*(100-R) µg/L, where

  • A = Total amount of API (kg) sold in Sweden in a given year. Reduction of A may be justified based on metabolism data.

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


Calculation of PEC in surface water is based on the following assumptions regarding metabolism and removal rates in waste water treatment plants of 17β-estradiol (ref. 12 in the Appendix):


It can be assumed that 17β-estradiol is metabolised in the female body and excreted as:

  • 17β-estradiol: 33% of 41.1 kg = 13.56 kg

  • Estrone: 54% of 41.1 kg = 22.19 kg

  • Estriol: 13% of 41.1 kg = 5.34 kg


The following removal rates in waste water treatment plants are estimated to:

  • 17β-estradiol: 40%

  • Estrone: 8%

  • Estriol: 2%


The removal rates are based on estimation of distribution of estrogens in a municipal waste water treatment plant in accordance with the principles of the EU TGD and by use of the program SimpleTreat 3.0, which estimates the relative distribution of chemicals to each compartment: effluent, sludge and air.


On this basis the following PEC in surface water can be calculated:

  • PEC for 17β-estradiol: 1.5 * 10-6 * 13.56 * (100-40) = 0.0012 µg/L

  • PEC for estrone: 1.5 * 10-6 * 22.19 * (100-8) = 0.0031 µg/L

  • PEC for estriol: 1.5 * 10-6 * 5.34 * (100-2) = 0.00078 µg/L


3.3. Calculation of PNEC in surface water

PNEC (Predicted No Effect Concentration) in surface water for 17β-estradiol, estrone and estriol is calculated from NOEC based on results from eco-toxicological tests (ref. 11 and 12 in the Appendix).


The following NOEC for induction of vitellogenin in fish, which is the most critical effect, is achieved:

  • NOEC for 17β-estradiol: 0.0023 µg/L

  • NOEC for estrone: 0.01 µg/L

  • NOEC for estriol: 2.9 µg/L


Since a broad range of chronic eco-toxicity tests conducted on different species at three trophic levels have shown that the most critical effect of estrogens in the environment is induction of vitellogenin in fish it is evaluated that an assessment factor of 10 is reasonable. Based on this, PNEC for the three APIs in surface water is:

  • PNEC for 17β-estradiol: 0.00023 µg/L

  • PNEC for estrone: 0.001 µg/L

  • PNEC for estriol: 0.29 µg/L


3.4. Calculation of the risk quotient (PEC/PNEC)

The following risk quotient PEC/PNEC can be calculated:

  • PEC/PNEC for 17β-estradiol: 0.0012/0.00023 = 5.217

  • PEC/PNEC for estrone: 0.0031/0.001 = 3.100

  • PEC/PNEC for estriol: 0.00078/0.29 = 0.003


The total risk quotient for 17β-estradiol, estrone and estriol is thus 8.32.


4. Information about degradation, bioaccumulation and PBT/vPvB


4.1. Degradation of 17β-estradiol

Activated sludge test according to OECD guideline no. 302A has shown that 17β-estradiol is inherent biodegradable under aerobic conditions in activated sludge (ref. 10 in the Appendix). 17β-estradiol is thus slowly degraded in the environment.


4.2. Bioaccumulation of 17β-estradiol, estrone and estriol

The following data on bioaccumulation can be found in the literature (ref. 12 in the Appendix):

  • Log Pow for 17β-estradiol: 4.01

  • Log Pow for estrone: 3.13

  • Log Pow for estriol: 2.45


According to the FASS.se guidelines (ref. 1) substances with Log Kow ≥ 4 or BCF ≥ 500 are considered to have high potential for bioaccumulation.


In conclusion, 17β-estradiol has high potential for bioaccumulation. Estrone and estriol has low potential for bioaccumulation.


4.3. PBT/vPvB assessment

Persistence:

There is no available data on persistence of 17β-estradiol, estrone and estriol in marine or freshwater environment. However, since activated sludge tests show that 17β-estradiol is inherent biodegradable under aerobic conditions, 17β-estradiol and its metabolites are assessed to be “not persistent” in the aquatic environment.


Bioaccumulation:

Assuming that Log Pow = 4 equals BCF = 500 (according to ref. 1), the bioaccumulation potential for 17β-estradiol, estrone and estriol - stated in section 4.2 - is significantly below the PBT-criteria for bioaccumulation i.e “BCF > 2000” (ref. 1). The three substances do therefore not fulfil the criteria for classification as a PBT substance with regard to bioaccumulation.


Eco-toxicity:

The critical eco-toxicological effect from exposure to 17β-estradiol, estrone and estriol is the induction of vitellogenin in fish that may cause a change in sex from male to female. The No Observed Effect Concentration (NOEC) for induction of vitellogenin, which is considered a chronic eco-toxicity test, is 0.002 µg/l for 17β-estradiol, 0.04 µg/l for estrone and 2.9 µg/l for estriol (as stated in section 2 and the Appendix).


The chronic NOEC for 17β-estradiol is significantly lower than the PBT criteria for toxicity ”Chronic NOEC < 0.01 µg/L” according to ref. 1, while the NOEC for estrone and estriol is higher than the PBT criteria. 17β-estradiol is thus regarded as toxic to aquatic organisms.


In addition 17β-estradiol and estrone – and to minor degree estriol – has potential for endocrine disruption.


Consequently, 17β-estradiol and estrone meet the criteria for classification as a PBT substance with regard to toxicity.


Conclusion regarding PBT/vPvB properties:

Considering all three aspects, 17β-estradiol, estrone and estriol do not meet the criteria for classification as a PBT or vPvB substance.


5. Environmental risk classification of estrogens


In conclusion:

  • The total risk quotient for 17β-estradiol, estrone and estriol is 8.32.

  • 17β-estradiol, estrone and estriol do not meet the criteria for classification as a PBT or vPvB substance.


Based on the calculated risk quotients and information about degradation, bioaccumulation and eco-toxicity of 17β-estradiol, estrone and estriol the following environmental risk phrase should be applied to pharmaceutical products with estrogens according to the criteria in the FASS.se guidelines (ref. 1):


”Use of pharmaceutical products with estrogens has been considered to result in moderate environmental risk”


This risk phrase is according to the FASS.se guidelines applicable for risk quotients in the interval: 1 < PEC/PNEC ≤ 10.


6. References


1) Environmental classification of pharmaceuticals at www.fass.se – Guidance for pharmaceutical companies 2012.



Appendix


Eco-toxicological properties of 17β-estradiol, estrone and estriol


In 2001 Novo Nordisk engaged the Danish consultant “DHI, Institute for water and environment” to perform a literature review and supplementary studies of the eco-toxicological effects of 17β-estradiol and its primary metabolites estrone and estriol.


The objective was to provide eco-toxicological information necessary for an environmental risk assessment of 17β-estradiol, estrone and estriol according to the OECD guidelines.


Results of the literature review

The literature review covered the period 1996 – 2001 and was based on search in relevant databases. Eco-toxicity data on 17β-estradiol, estrone and estriol was only found for crustaceans and fish and the literature review showed that:

  • The effect concentrations for long term exposure of 17β-estradiol, estrone and estriol are far below the effect concentrations for acute toxicity

  • The critical eco-toxicological effect was the induction of vitellogenin in fish (a protein produced by female fish).


The following LOEC and NOEC for chronic toxicity were found for crustaceans and fish (ref. 1 and 12):

Substance

Species

Effect & Exposure time

LOEC (µg/L)

NOEC (µg/L)

17β-estradiol

Crustacean:

Tisbe battagliai

Sex ratio

21 days

> 100

≥ 100

 

Fish:

Oncorhynchus mykiss

Vitellogenin induction

14 days

0,0047

0,0023

Estrone

Crustacean:

Tisbe battagliai

Sex ratio

21 days

> 100

≥ 100

 

Fish:

Pimephales promelas

Vitellogenin induction

21 days

0,032

0,01

Estriol

Fish:

Danio rerio

Vitellogenin induction

18 days

-

2,9

LOEC = Lowest Observed Effect Concentration

NOEC = No Observed Effect Concentration


Results of supplementary eco-toxicological tests

In addition to the literature review, DHI has performed the following eco-toxicological tests on 17β-estradiol and/or estrone:

  • Growth inhibition test on micro algae (ref. 2+3)

  • Chronic toxicity test on crustaceans (ref. 4)

  • Early life stage test on zebra fish (ref. 5)

  • Nitrification inhibition test with activated sludge (ref. 6+7)

  • Reproduction test on earth worms (ref. 8)

  • Biodegradation test (ref. 9+10)


The results are reported in separate reports (ref. 2-10) and summarised in a summary report (ref. 11). The tests in ref. 2-8 are conducted and reported according to GLP (Good Laboratory Practise).


The following test results have been obtained:


Growth inhibition test on the alga Pseudokirchneriella subcapitata (ref. 2+3):

Substance

Method

Concentration & Exposure time

NOEC for growth inhibition

NOEC for produced biomass

17β-estradiol

OECD 201 & ISO 8692

62,5–1.000 µg/L

72 hrs

≥ 523 µg/L

≥ 523 µg/L

Estrone

OECD 201 & ISO 8692

62,5–1.000 µg/L

72 hrs

≥ 451 µg/L

≥ 451 µg/L


The studies did not show significant inhibition of the growth rate or produced biomass.


Chronic toxicity test on the crustacean Acartia tonsa (ref. 4):

Substance

Method

Concentration & Exposure time

Effect parameter

NOEC

17β-estradiol

OECD GLP

0,01–500 µg/L

21 days

See below *

≥ 368 µg/L


* Effect parameters:

  • Growth measured as length of the separate life stages

  • Time of development for the separate life stages

  • Estimate of initial hatching success

  • Malformed larvae

  • Mortality

  • Egg production

  • Egg/naupliae hatching


The study did not show significant effect on neither of the stated parameters at the tested concentrations.


Early life stage test on zebra fish, Danio rerio (ref. 5):

Substance

Method

Concentration & Exposure time

Effect parameter

Effect conc.

Estrone

OECD Draft Test Guideline, see below *

10-200 ng/L

40 days

Mortality

< 10%

 

Do

Do

Vitellogenin induction

LOEC = 49,8 ng/L

NOEC = 35,5 ng/L

 

Do

Do

Sex ratio

LOEC = 49,8 ng/L

NOEC = 35,5 ng/L

 

Do

Do

Growth

No significant effect on growth


* Method: OECD Draft Test Guideline: “A 40-day Juvenile Zebrafish Assay for Screening of Endocrine Disrupting Chemicals”.


Nitrification inhibition test with activated sludge (ref. 6+7):

Substance

Method

Concentration & Exposure time

Effect parameter

EC20

17β-estradiol

ISO 9509

62,5–1.000 µg/L

2 hrs

Inhibition of nitrification rate

> 918 µg/L

Estrone

ISO 9509

62,5–1.000 µg/L

2 hrs

Inhibition of nitrification rate

> 172 µg/L


The studies did not show significant inhibition of the nitrification rate in activated sludge at the tested concentrations.


Reproduction test on the earth worm, Enchytraeus albidus (ref. 8):

Substance

Method

Concentration & Exposure time

Effect parameter

NOEC

17β-estradiol

OECD Draft Test Guideline: “Enchytraeidae Reproduction Test”

50–1.000 mg/kg soil d.w.

21 days

See below *

> 1.000 mg/kg


* Effect parameters:

  • Adult mortality

  • Inhibition of reproduction

  • Changes in behaviour and/or morphology


The study did not show significant effect on neither of the stated parameters at the tested concentrations.


Biodegradation test (ref 9+10):

Substance

Method

Concentration & Exposure time

Biodegradability

17β-estradiol

OECD Test Method no. 301D: “Closed Bottle Test”

1,64 mg/L

28 days

3,5-9,8 % of ThoD

17β-estradiol (E2)

OECD Guideline no. 302A: “Inherent Biodegradability: Modified SCAS Test” and “Activated Sludge Biodegradability Simulation Test”

Ca. 20 µg/L

Aerobic: 48 hrs

Anoxic: 8 days

Aerobic:

See below *

Anoxic:

No significant degradation


* Results according to OECD Guideline no. 302A:

  • The total 14C-concentration decreased by 70% of the initial added 14C within the first 45 minutes of the test period

  • During the first 45 minutes of the test period, a 1. order rate constant was estimated at 2,2 ± 0,2 L*day-1*gSS-1 for the total test substance concentrations > 2,5 µg E2/L

  • During the test period from 3-48 hours, a 1. order rate constant was estimated at 0,031 ± 0,003 L*day-1*gSS-1 for the total test substance concentrations < 2,5 µg E2/L


On basis of the biodegradation test results it can be concluded that:

  • 17 β-estradiol is not readily degradable under closed bottle conditions since the minimum requirement BOD = 60% of ThOD within 10 days is not fulfilled.

  • 17 β-estradiol is inherent biodegradable under aerobic conditions but not under anoxic conditions in activated sludge simulation.


Conclusion on the eco-toxicity tests

The literature review and the conducted eco-toxicological tests document that the critical effect due to exposure of 17β-estradiol, estrone and estriol is the induction of vitellogenin in fish that may cause a change in sex from male to female. The No Observed Effect Concentration (NOEC) for induction of vitellogenin, which is considered a chronic eco-toxicity test, is 0.002 µg/l for 17 β-estradiol, 0.04 µg/l for estrone and 2.9 µg/l for estriol.


References

1) Litteratur-review over økotoksikologiske data for østradiol og østron. November 2001. Udført af DHI. (only in Danish)

2) Algal growth inhibition test of ß-Estradiol with the micro alga Pseudokirchneriella subcapitata. 2002.06.17. Prepared by DHI.

3) Algal growth inhibition test of Estrone with the micro alga Pseudokirchneriella subcapitata. 2002.06.27. Prepared by DHI.

4) Chronic toxicity test of ß-Estradiol [CAS no. 50-28-2] with the crustacean Acartia tonsa. 2002.06.28. Prepared by DHI.

5) Zebra fish chronic toxicity test with Estrone [CAS no. 53-16-7]. 2002.08.30. Prepared by DHI.

6) Nitrification inhibition test of ß-Estradiol with activated sludge. 2002.07.03. Prepared by DHI.

7) Nitrification inhibition test of Estrone with activated sludge. 2002.07.04. Prepared by DHI.

8) Enchytraeus albidus chronic toxicity test with ß-Estradiol. 2002.07.05. Prepared by DHI.

9) Ready Biodegradability – Closed Bottle Test with Estradiol. 2002.07.12. Prepared by DHI.

10) Activated Sludge Biodegradability Simulation Test with Estradiol. 2002.07.12. Prepared by DHI.

11) Summary of selected investigations performed for Novo Nordisk A/S - Steroid hormones. October 2003. Prepared by DHI.

12) Fate and effects of humanly excreted estrogens - 17 β-estradiol, estrone, estriol and ethinylestradiol. October 2003. Prepared by DHI.

Noretisteron

Miljörisk: Risk för miljöpåverkan av noretisteron kan inte uteslutas då det inte finns tillräckliga ekotoxikologiska data.
Nedbrytning: Noretisteron är potentiellt persistent.
Bioackumulering: Noretisteron har låg potential att bioackumuleras.


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Detaljerad miljöinformation

Environmental risk assessment of norethisterone acetate (NETA) in pharmaceutical products marketed in Sweden in 2013


This document includes environmental risk assessment of norethisterone acetate (NETA) in pharmaceutical products marketed in Sweden in 2013. The risk assessment is performed in accordance with the FASS.se guidelines on environmental classification of pharmaceuticals (ref. 1).


1. The active pharmaceutical ingredient


Norethisterone acetate (NETA), also known as norethindrone acetate, is a steroidal progestin that is used as a hormonal contraceptive. It is an acetate ester of norethisterone which belongs to the class of steroid hormones.


Chemical name Norethisterone Acetate (NETA)

CAS no. 51-98-9

Molecular formula C22H28O3

Molecular weight 340.46 g/mol

Water solubility 4.4 mg/L at 20ºC


2. Eco-toxicological data


The following tests have been performed with norethisterone or norethisterone acetate (NETA):

• Immobilisation test on dapnia

• Growth inhibition test on green alga

• Growth inhibition test on bacteria

• Biodegradation

• Octanol/water coefficient


The tests are performed by Schering in accordance with OECD principles for good laboratory practice.


Immobilisation test on dapnia (ref 2 and 3):

Acute immobilization test with norethisterone and NETA on Daphnia magna, 48h:

• No effect was observed at saturated concentration. EC50 > 4.4 - 4.6 mg/L.

Method: OECD guidelines for testing of chemicals, no. 202: “Daphnia sp., Acute immobilisation test and reproduction test”.


Growth inhibition test on green alga (ref 4):

Growth inhibition test with NETA on the green alga Desmodesmus subspicatus:

• EC50 (biomass): 0.4 mg/L

• EC50 (growth rate): 0.6 mg/L


Method: OECD guidelines for testing of chemicals, no. 201: “Alga, growth inhibition test”


Growth inhibition test on bacteria (ref. 5):

Growth inhibition test with norethisterone on the bacterium Pseudomonas putida:

• No inhibition at saturated concentration (ca. 7.8 mg/l)


Method: Schering method no. TX.ME.572.3 and DIN 38412 L8, March 1991.


Biodegradation test (ref. 6 and 7):

Biodegradation test on norethisterone and NETA:

• norethisterone and NETA are not readily biodegradable under “modified Sturm test” conditions since less than 10% of the substance was biodegraded within 28 days.


Method: OECD guideline for testing of chemicals, Ready biodegradability: CO2-evolution test, no 301B.


Octanol/water coefficient (ref. 8):

The octanol/water coefficient for NETA has been determined to LogPow = 3.7. Since LogPow < 4 it indicates that NETA has low potential for bioaccumulation according to ref. 1.


Summary of test results:

The obtained test results indicate that norethisterone/NETA:


• is very toxic to the green alga Desmodesmus subspicatus (since EC50 < 1 mg/L)

• has no effect on immobilisation of Daphnia magna

• has no effect on the growth of the bacteria Pseudomonas putida

• is not readily biodegradable

• has low potential for bioaccumulation


3. Calculation of the risk quotient (PEC/PNEC)


3.1. Sold amount in Sweden

The total amount of norethisterone and norethisterone acetate (NETA) sold in Sweden in 2013 was 17.16 kg API based on IMS Health sales data.


3.2. Calculation of PEC in surface water

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


PEC = 1.5*10-6*A*(100-R) µg/L, where


• A = Total amount of API (kg) sold in Sweden in a given year. Reduction of A may be justified based on metabolism data.

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


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


• no metabolism of in the body

• no removal in waste water treatment plants.


Without taking removal effects of metabolism and waste water treatment into consideration the following PEC of NETA in surface water can be calculated according to ref. 1:


• PEC = 1.5*10-6*17.16*(100-0) = 0.00257 µg/L.


Since PECSurface water is below the action limit 0.01 µg/L stated in ref. 1 it is unlikely that NETA constitutes a significant risk for the environment.


3.3. Calculation of PNEC in surface water

According to ref. 1, calculation of PNEC (Predicted No Effect Concentration) in surface water should be based on eco-toxicological data for three trophic levels. However, it has only been possible to present eco-toxicological data for two trophic levels i.e. green alga and daphnia. Furthermore, it is not known if these organisms are the most sensitive to NETA.


Consequently, it is not possible to calculate a valid PNEC according to the requirement in ref. 1 on basis of the available eco-toxicological data.


3.4. Calculation of the risk quotient (PEC/PNEC)

The risk quotient (PEC/PNEC) cannot be calculated for the reason stated in section 3.3.


4. PBT and vPvB assessment


Persistence:

NETA is not readily biodegradable under “modified Sturm test” conditions since less than 10% of the substance was biodegraded within 28 days (ref. 6 and 7).


According to ref. 1, it cannot be excluded that NETA is potentially persistent in the environment.


Bioaccumulation:

The Log Pow for NETA is estimated to 3.7 (ref. 8).


Since Log Pow < 4, it indicates that NETA has low potential for bioaccumulation (ref. 1).


Eco-toxicity:

The obtained results of the performed eco-toxicity tests indicate – as stated in section 2 - that norethisterone/NETA:


• is very toxic to the green alga Desmodesmus subspicatus (since EC50 < 1 mg/L)

• has no effect on the immobilisation of Daphnia magna

• has no effect on the growth of the bacteria Pseudomonas putida


Conclusion regarding PBT/vPvB properties:

Considering all three PBT-aspects, NETA does not meet the criteria for classification as a PBT or vPvB substance.


5. Environmental risk classification of NETA


In conclusion:

- A valid risk quotient (PEC/PNEC) for NETA cannot be calculated due to lack of eco-toxicity data.

- NETA:

  • is potentially persistent in the environment

  • has low potential for bioaccumulation

  • is very toxic to green algae

  • 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 NETA according to the criteria in ref. 1:


”Risk of environmental impact of norethisterone acetate (NETA) cannot be excluded due to lack of eco-toxicity data”.


6. References


1) Environmental classification of pharmaceuticals at www.fass.se – Guidance for pharmaceutical companies 2012.

2) Research report from Schering, no. X211: Acute immobilization test of norethisterone with Daphnia magna, 02 May 1997.

3) Research report from Schering, no. X224 - draft: Acute immobilization test of norethisterone acetate (ZK 5422) with Daphnia magna, 23 June 1997.

4) Research report from Schering, no. A08345: Growth inhibition test of norethisterone acetate (ZK 5422) on the green algae Desmodesmus subspicatus, 20 January 2004.

5) Research report from Schering, no. X126: Growth inhibition test of norethisterone on the bacterium Pseudomonas putida, 12. aug. 1996

6) Research report from Schering, no. X128: Study on the biodegradability of norethisterone in the CO2-evolution test (modified Sturm-test), 12 Aug. 1996

7) Research report from Schering, no. X308 – Draft: Study on the biodegradability of norethisterone acetate in the CO2-evolution test (modified Sturm test), 17 May 1999.

8) Report from Schering, LJ03.

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