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Primolut®-Nor

MiljöinformationReceptstatusFörmånsstatus
Bayer

Tablett 5 mg
(vita, runda, plana med krysskåra märkta AP inom sexhörning, 7 mm)

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  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Noretisteron

Miljörisk: Användning av noretisteron har bedömts medföra medelhög risk för miljöpåverkan.
Nedbrytning: Noretisteron är potentiellt persistent.
Bioackumulering: Noretisteron 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 = 0.0022 μg/L

Where:

A = 14.896 kg (total sold amount norethisterone (2.802 kg and norethisterone acetate 12.094 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 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) 0.51 mg/L, NOEC 0.013 mg/L, LOEC 0.059 mg/L (guideline OECD 201) (2)

Crustacean (waterflea Daphnia magna):

Acute toxicity

EC50 /48 h (immobilization) > 4.6 mg/L (saturated solution) (guideline OECD 202) (3)

Fish:

Acute toxicity Zebrafish (Danio rerio)

LC50/96h >5.03 mg/L saturated solution (guideline OECD 203) (4)

Chronic toxicity

NOEC 28 days = 0.005 μg/L , LOEC 0.025 µg/L (adult reproduction test, non-standard) (5)

Microorganisms (Pseudomonas putida growth inhibition):

EC10 /16 h > 7.8 mg/L (saturated solution) (guideline DIN 38412, part 8) (6)

PNEC = 0.0005 μg/L (Lowest chronic NOEC fish = 0.005 µg/L; AF 10)
An assessment factor of 10 has been used despite only two tests (algae and fish) were set up as chronic tests, while for invertebrates (Daphnia magna) only an acute test has been performed. Because fish are known to be generally the most sensitive species for effects of steroid hormones and invertebrates like daphnids lack a physiological function of sex steroids, it is highly unlikely that a chronic test with Daphnia magna would result in a lower NOEC than in fish. Therefore, it is justified to use the lower assessment factor of 10.


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0.0022/0.0005 = 4.4, i.e. 1 < PEC/PNEC ≤ 10 which justifies the phrase Use of *Norethisterone / Norethisterone acetate* has been considered to result in moderate environmental risk.


Degradation

Biotic degradation

Ready degradability: not readily biodegradable

The biodegradability was studied in a CO2 evolution test (OECD 301B) (7). The test substance was incubated in an aqueous solution including nutrients with microorganisms form a municipal sewage treatment plant for 30 days in a concentration of 10 mg carbon/L in triplicates. Additionally, sodium acetate as reference substance, a blank control and sodium acetate plus norethisterone as toxicity control were tested. CO2 production was measured/calculated on day 4, 7, 11, 14, 17, 23, 28 and 30. No degradation was observed within 28 days of incubation.


The results of the study on ready biodegradability justifies the phrase: Norethisterone/norethisterone acetate is potentially persistent.


Abiotic degradation

Hydrolysis:

Norethisterone can be classified as hydrolytically stable at pH 5, 7 and 9 (25 °C). (8)


Bioaccumulation

Partitioning coefficient:

Log POW 2.7 at pH 7 and 25 °C (Shake flask method, OECD 117) (9)


Justification of chosen bioaccumulation phrase:

Since Log POW (at pH 7) < 4, the phrase norethisterone / norethisterone acetate has a low potential for bioaccumulation is justified. 


Excretion (metabolism)

Norethisterone acetate is hydrolyzed in the gastrointestinal tract to nortehisterone. Norethisterone is excreted via the urine mainly as glucuronide and sulfate conjugates (10).


References

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

  2. Alga, growth inhibition test with norethisterone, Currenta GmbH & Co OHG, ownership: Bayer AG, report no. 2015/0057/04 (2016)

  3. Acute immobilization of norethisterone e with Daphnia magna. Experimental Toxicology, Schering AG, study no. TX96099, report no. X211 (1997)

  4. Fish, acute toxicity with norethisterone, Currenta GmbH & Co OHG, ownership: Bayer AG, report no. 2015/0057/03 (2016)

  5. Paulos P, Runnalls TJ, Nallani G, La Point T, Scott AP, Sumpter JP, Huggett DB. (2010). Reproductive responses in fathead minnow and Japanese medaka following exposure to a synthetic progestin, norethindrone. Aquat Toxicol 99:256–262.

  6. Growth inhibition test with norethisterone on the bacterium Pseudomonas putida. Experimental Toxicology, Schering AG, study no TX96079, report no. X126 (1996)

  7. Study on the biodegradability of norethisterone in the CO2-evolution test (modified Sturm-test). Experimental Toxicology, Schering AG, study no. TX96088, report no. X128 (1996)

  8. Norethisterone/ZK5378/Report on physicochemical propertes/estimation of the hydrolytic stability on the basis of hydrolytic behavior of structurally similar compounds. General Physical Chemistry, Schering AG, study no APC194/00 (2000)

  9. Norethisterone/ZK5378/Report on the partition coefficient. General Physical Chemistry, Schering AG, study no. APC132/95, report no. LJ0 (1995)

  10. Prescriber information for norethisterone acetate/norethisterone.