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

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 = 0.184 µg/L

Where:

A = 1342.937 kg (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)

P = number of inhabitants in Sweden = 10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA, 2008; Ref I).

D = factor of dilution of waste water by surface water flow = 10 (ECHA, 2008; Ref I).

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata):

EC₅₀ 72 h (biomass): 79 000 μg/L

NOEC: 7200 μg/L

(Protocol: OECD 201)

(Ref II)

EC₅₀ 72 h (growth inhibition): 460 000 μg/L

NOEC: 23 000 μg/L

(Protocol: OECD 201)

(Ref II)

Crustacean (Daphnia magna):

EC₅₀ 48 h (immobilization): 191 000 μg/L

NOEC 48 h: 86 400 μg/L

(Protocol: FDA 4.08/OECD 202)

(Ref III)

EC₅₀ 21 days (reduction in reproduction): 15 600 μg/L

NOEC 21 days (reduction in reproduction): 10 400 μg/L

LOEC 21 days (reduction in reproduction): 23 300 μg/L

(Protocol: OECD 211)

(Ref IV)

Fish (Oncorhynchus mykiss):

LC₅₀ 96 h (mortality) > 290 000 μg/lL

(Protocol: OECD 203)

(Ref IV)

Fish (Pimephales promelas):

NOEC 28 days (growth): 7040 μg/L

(Protocol: OECD 210)

(Ref VI)

Other ecotoxicity data:

PNEC = 704 µg/L, lowest EC₅₀/10 using results from the most sensitive chronic toxicity endpoint and an assessment factor of 10 (Long-term results from at least three species of the base set), to add a safety margin to the toxicity endpoint. The most sensitive species was Pimephales promelas for which the NOEC 28 days (growth) was 7040 μg/L.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC= 0.184/704 = 0.000261, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase:
“Use of Irbesartan has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

Test results showed 22.5 % degradation in 28 days (FDA 3.11/OECD 301)
(Ref VII)

Simulation studies

DT50 in water:

DT50_{total system} = 8.7 (sediment 1) -12.5 (sediment 2) days. At the end of the study, there were 17.9% (sediment 1) and 23.9% (sediment 2) of parent compound remaining (in 100 days). Ambient extractions were carried out by shaking the sediment/solvent mixture at room temperature for 20 min. Reflux extraction was allowed to proceed for 4 h. The extract solution and sediment solids were separated by centrifugation. The non-extractable radioactivity in selected samples, where this was greater than 10 % of the applied radioactivity, was characterized using an acid/base fractionation procedure.

(Protocol: OECD 308)
(Ref VIII)

Abiotic degradation

Hydrolysis:

The half-life of Irbesartan was 40.1 days at pH 7, 25°C .

(Protocol: FDA 3.09/OECD111)

(Ref IX)

Photolysis:

Test showed a half-life of 6.41 h at pH 7.

(Protocol: FDA 3.10)

(Ref X)

Justification of chosen degradation phrase:

Irbesartan fails to pass the criteria for ready biodegradability. As DT50_{total system} < 32 days with still more than 15 % of the parent compounds remaining at the end of the study, the correct phrase is:
“Irbesartan is slowly degraded in the environment”.

Bioaccumulation

Partition coefficient:

Log K_ow = 1.13 at pH 7 (OECD 107)
(Ref XI)

Justification of chosen bioaccumulation phrase:

Since log K_ow < 4 at pH 7, irbesartan has low potential for bioaccumulation.

Excretion (metabolism)

The substance is excreted almost exclusively as metabolites with only 2 % as unchanged.
(Ref XII)

Metabolites identified are (1) Tetrazole N2-beta-glucuronide conjugate of irbesartan, (2) monohydroxylated metabolite resulting from omega-1 oxidation of the butyl side chain, (3, 4) two different monohydroxylated metabolites resulting from oxidation of the spirocyclopentane ring, (5) a diol resulting from omega-1 oxidation of the butyl side chain and oxidation of the spirocyclopentane ring, (6) a keto metabolite resulting from further oxidation of the omega-1 monohydroxy metabolite, (7) a keto-alcohol resulting from further oxidation of the omega-1 hydroxyl of the diol, and (8) a carboxylic acid metabolite resulting from oxidation of the terminal methyl group of the butyl side chain.
(Ref XIII)
The pharmacological activity of the metabolites is not known.

References

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

2. Sanofi, internal report: Irbesartan - Acute toxicity to the freshwater green alga, Pseudokirchneriella subcapitata. OECD 201. Report # 12534.6285. February 2006.

3. Sanofi, internal report: Static acute toxicity of Irbesartan (SR47436) to Daphnia magna. FDA 4.08. Report # 43075. July 1996.

4. Sanofi, internal report: Prolonged toxicity to Daphnia magna. OECD 211. Report # BMY1106/064353. February 2007.

5. Sanofi, internal report: Irbesartan - Acute toxicity to rainbow trout (Oncorhynchus mykiss) understatic-renewal conditions. OECD 203. Report # 12534.6286. February 2006.

6. Sanofi, internal report: Irbesartan - Fish early life stage toxicity test for fathead minnow. OECD 210. Report # BMY 1107. February 2007.

7. Sanofi, internal report: Aerobic biodegradation in water using 14C-Irbesartan (SR47436). FDA 3.11. Report # 43090. July 1996.

8. Sanofi, internal report: Irbesartan – Aerobic transformation in aquatic sediment systems. OECD 308. Report # BMY 1266. July 2008.

9. Sanofi, internal report: Hydrolysis as a function of pH of 14C-Irbesartan (SR47436). FDA 3.09. Report # 43092. August 1996.

10. Sanofi, internal report: Determination of the aqueous photodegradation of 14C-Irbesartan (SR47436). FDA 3.10. Report # 43089. August 1996.

11. Sanofi, internal report: Determination of octanol/water partition coefficient (shake flask method) of Irbesartan (SR47436). FDA 3.02. Report # 43084. July 1996.

12. Base de données publique des medicaments, Ministère des affaires sociales et de la santé, online consultation, March 2014: http://ec.europa.eu/health/documents/community-register/2013/20130731126402/anx_126402_fr.pdf

13. Chando TJ, Everett DW, Kahle AD, Starrett AM, Vachharajani N, Shyu WC, Kripalani KJ, Barbhaiya RH. 1998. Biotransformation of Irbesartan in man. The American Society for Pharmacology and Experimental Therapeutics. 26 (5): 408-417.