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) = 1.37*10^-6 * 2417.445 kg * 100 = 0.33190 μg/L

Where:

A = 2417.445kg (total sold amount API in Sweden year 2022, data from IQVIA).

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) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008).

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subspicata) (OECD201) (NOTOX Project 490915):

EC50 72 h (growth rate) > 100.0 mg/L

NOEC 72 h = 100.0 mg/L

Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilisation) > 100.0 mg/L (OECD202) (Ciba-Geigy Test No: 948032)

Chronic toxicity

NOEC 21 days (reproduction, survival and parental length) = 100 mg/L; no effect up to the highest concentration tested (OECD 211) (NOTOX Project 485928)

Fish:

Acute toxicity (Danio rerio, zebra fish)

LC50 96 h (mortality) > 100.0 mg/L (OECD203) (Ciba-Geigy Test No. 811678)

Chronic toxicity (Pimephales promelas, fathead minnow)

NOEC 30 days (hatchability, survival, length and weight) = 10.0 mg/L; no effect up to the highest concentration tested (OECD 210) (NOTOX Project 485928)

Other ecotoxicity data:

Bacterial respiration inhibition

EC₅₀ 3 h > 750 mg/L (activated sludge respiration inhibition) (OECD209) (Ciba-Geigy Test No. 948033)

Sediment-dwelling organisms (Chironomus riparius, non-biting midge)

NOEC 28 days (emergence rate and development rate) = 10.0 mg/L (OECD 218) (Report No BR0137/B)

PNEC derivation:

PNEC = 1000 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used if three chronic toxicity studies from three trophic levels are available. The NOEC for fish early life stage toxicity has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.33 μg/L / 1000 μg/L = 0.00033, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of hydrochlorothiazide has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

36.0 % degradation in 28 days, not readily biodegradable (OECD301E). (Report No. BR0030/B)

Simulation studies:

DT₅₀ (total system) = 34.7 – 37.3 days (OECD 308). (Report No. BR0040/B)

Sediments were extracted with 100 ml of methanol by agitating for at least 12 hours. This was followed by a further extraction with 100 ml of 90% ethanol.

A significant amount of mineralisation occurred throughout the study. At the end of the study ¹⁴CO₂ accounted for 58% to 70%. Non-extractable residues in sediment accounted for 9-23% of applied radioactivity by the end of the study. Parent substance was 10-11 % of applied radioactivity by the end of the study.

Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, hydrochlorothiazide can be classified as ‘Hydrochlorothiazide is slowly degraded in the environment' (DT₅₀ for total system <120days).

Bioaccumulation

Partitioning coefficient:

Log D_ow = 0.09 at pH 7 (OECD107). (NOTOX Project 490916)

Justification of chosen bioaccumulation phrase:

Since log Dow < 4 at pH 7, hydrochlorothiazide has low potential for bioaccumulation.

Excretion (metabolism)

Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. Within 72 hours, 60-80% of a single oral dose is excreted in the urine, 95% in unchanged form, and about 4% as the hydrolysate 2-amino-4-chloro-m-benzenedisulfonamide (ACBS). Up to 24% of an oral dose may be found in the feces, and a negligible amount is excreted via the bile. (ESIDREX^® (hydrochlorothiazide) Core Data Sheet).

PBT/vPvB assessment

Hydrocholorthiazide is slowly degraded and has low potential for bioaccumulation based on the screening criteria for B and can therefore not be considered a potential PBT substance.

References

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• NOTOX Project 490915. Fresh water algal growth inhibition test with HCTZ DS. Final report: 09 October 2009.                                           

• Ciba-Geigy Test No: 948032. Report on the acute toxicity test of PBS 000397.1 on Daphnia. Final report: 27 January 1995.                                  

• NOTOX Project 485927. Daphnia magna, reproduction test with HCTZ DS (semi-static). Final report: 09 November 2007.                                          

• Ciba-Geigy Test No: 811678.      Full report / full reference not available.

• NOTOX Project 485928. Fish early-life stage toxicity test with HCTZ DS (semi-static). Final report: 09 November 2008.                         

• Ciba-Geigy Test No. 948033. Report on the test for activated sludge respiration inhibition of PBS 000397.1. Final report: 21 October 1994.

• Report No BR0137/B. [¹⁴C] hydrochlorothiazide: Determination of the effects in a water-sediment system on the emergence of Chironomus riparius using spiked sediment. Final report: 03 March 2010.                               

• Report No BR0030/B.                  [¹⁴C]Hydrochlorothiazide: 28 day ready biodegradation. 06 October 2009.

• Report No BR0040/B. HYDROCHLOROTHIAZIDE: Aerobic Transformation in Aquatic Sediment Systems. Final report: 02 February 2010.             

• NOTOX Project 490916. Determination of the partition coefficient (n-octanol/water) of HCTZ DS. Final report: 01 July 2009.   

• ESIDREX^®(hydrochlorothiazide) Core Data Sheet Version 2.0. September 2014.

Detaljerad miljöinformation

Losartan potassium is an angiotensin II receptor (AT1) antagonist that mediates the vasoconstricting activity of angiotensin II in vascular smooth muscle and aldosterone secreting effects of the adrenal gland. It is used alone or with other blood pressure medicines to lower high blood pressure (hypertension), to lower the chance of stroke in patients with high blood pressure and a heart problem called left ventricular hypertrophy and to slow the worsening of diabetic kidney disease (nephropathy) in patients with type 2 diabetes who have or had high blood pressure.

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)

PEC =      1.487 μg/L

Where:

A = 10854.72 kg (total sold amount API in Sweden year 2021, data from IQVIA). Reduction of A may be justified based on metabolism data.

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available. (If R not =0 this should be justified under the degradation section) 

P = number of inhabitants in Sweden = 10 *10⁶

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

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Ref. I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Selenastrum capricornutum) (FDA 4.01) (Ref. II):

NOEC 10 day (cell growth) = 143 mg/L

Blue Green Algae (Microcystis aeruginosa) (FDA 4.01) (Ref. III):

NOEC 10 day (cell growth) = 556 mg/L

Crustacean, water flea (Daphnia magna):

Acute toxicity

LC50 48 h (mortality) = 331 mg/L (OECD 202) (Ref.IV )

NOEC = 80 mg/L

Chronic toxicity

NOEC 21 day (survival, reproduction, growth) = 100 mg/L (OECD 211) (Ref IV)

No effects noted up to the highest concentration tested

Flathead Minnow (Pimephales promelas) (Ref V)

Acute toxicity

LC50 48 h (mortality) = >1000 mg/L

No effects noted up to the highest concentration tested

Chronic toxicity

NOEC 32-day > 10 mg/L

No effects noted up to the highest concentration tested

Fish, rainbow trout (Oncorhynchus mykiss):

Acute toxicity

LC50 96 h (mortality) > 929 mg/L (FDA 4.11) (Ref.VI)

NOEC = 929 mg/L

PNEC = 1000 μg/L (10000 μg/L/ 10 based on the most sensitive chronic NOEC for the fish with an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 1.487/1000 = , i.e. PEC/PNEC ≤ 0.0014

Which justifies the phrase ‘Use of Losartan has been considered to result in insignificant environmental risk.’

Degradation

Biotic degradation

Bacteria > 90% of initial concentration remaining Algal = 71% of initial concentration remaining after 28 days (FDA 3.11). (Ref VII)

Abiotic degradation

Hydrolysis:

Hydrolytically stable between pH 5-9 (FDA 3.09). (Ref. VIII)

Photolysis:

Susceptible to aqueous photolysis and rapidly degrades under clear sky conditions Half-Lifemax < 18 hours (pH 9) over wavelength interval 290-800 nm

(FDA 3.10). (Ref. IX)

Justification of chosen degradation phrase:

Losartan has been found to degrade under natural light conditions however no data are available on metabolites. Therefore the phrase “Losartan is potentially persistent” was thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Kow = 1.2 (OECD 107). (Ref. XI)

Justification of chosen bioaccumulation phrase:

Since log Kow < 4 at pH 7, the substance has low potential for bioaccumulation

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. Toxikon Environmental Sciences, 1993. "Losartan (MK-0954): Toxicity to the Freshwater Green Alga, Selenastrum capricornutum, Under Static Test Conditions," Study No., J9209001f, TOX, Jupiter, FL, USA, 16 June 1993.

3. Toxikon Environmental Sciences, 1993. "Losartan (MK-0954): Toxicity to the Blue-Green Alga, Microcystis aeruginosa, Under Static Test Conditions," Study No., J9209001g, TOX, Jupiter, FL, USA, 16 June 1993.

4. Smithers Visicent, 2013. "Losartan – Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static Renewal Conditions Following OECD Guideline #211" Smithers Viscient Study Number 359.6707" Wareham, MA, USA, 18 June 2013.

5. Smithers Visicent, 2013. "Losartan – Early Life-Stage Toxicity Test with Fathead Minnow, Pimephales promelas, Following OECD Guideline #210" Smithers Viscient Study Number 359.6706" Wareham, MA, USA, 10 June 2013.

6. Toxikon Environmental Sciences, 1993. "Losartan (MK-0954): Acute Toxicity to Rainbow Trout, Oncorhynchus mykss, Under Static Test Conditions," Study No., J9209001i, TOX, Jupiter, FL, USA, 28 May 1993.

7. Toxikon Environmental Sciences, 1993. "Losartan (MK-0954): Biodegradation Inoculum Source Screening and Aerobic Biodegradation in Water," Study No., J9209001d, TOX, Jupiter, FL, USA, 06 August 1993.

8. Toxikon Environmental Sciences, 1993. "Losartan (MK-0954): Determination of the Rate of Hydrolysis as a Function of pH," Study No., J9209001b, TOX, Jupiter, FL, USA, 02 March 1993.

9. Toxikon Environmental Sciences, 1993. "Losartan (MK-0954): Determination of Aqueous Photolysis," Study No., J9209001c, TOX, Jupiter, FL, USA, 02 July 1993

10. Toxikon Environmental Sciences, 1993. "Losartan (MK-0954): Determination of Aqueous Photolysis," Study No., J9209001c, TOX, Jupiter, FL, USA, 02 July 1993.

11. Merck & Co., Inc., 1995 “New Drug Application for Tablets Losartan Potassium, Environmental Assessment, Feb 1 1995”