Detaljerad miljöinformation

PEC/PNEC = 0.724 µg/L/100 µg/L = 0.0072

PEC/PNEC ≤ 0.1

Environmental Risk Classification

Total sales of esomeprazole and omeprazole are included in the calculation of the Predicted Environmental Concentration (PEC), as a worst case, as esomeprazole is the S-enantiomer of the racemate omeprazole and the toxicity is assumed to be very similar.

Only short-term (acute) toxicity data are available for omeprazole (A2E303_Pharmaceutical in the environment_A4_Final_V4.pdf (astrazeneca.com). Therefore, in the absence of comprehensive environmental data for omeprazole, the more scientifically robust long-term data set for esomeprazole has been used to generate the Predicted No Effect Concentration (PNEC). These data are in accordance with the EU European Medicines Agency (EMA) guideline (ref. 1).

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 = 0.724 μg/L

Where:

A = 5287.85 kg (total sold amount API in Sweden year 2020, data from IQVIA). This figure is based on sales figures (142.85 kg esomeprazole magnesium + 867.24 kg esomeprazole magnesiumdihydrate + 38.29 kg esomeprazole magnesiumtrihydrate + 73.89 kg esomeprazole sodium + 4134.06 kg omeprazole + 31.52 kg omeprazolmagnesium).

R = X % 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) (Ref. I)

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

(Note: The factor 109 converts the quantity used from kg to μg).

Metabolism

After administration, esomeprazole and omeprazole are almost completely metabolised, with <1% found in urine as the parent compound. Approximately 80% of the metabolites are excreted by urine and approximately 20% via faeces. The two main excreted human metabolites are both excreted via urine, and are considerably less pharmacologically active than the parent compounds (ref. 3). The total residue approach considered here is considered worst-case in terms of environmental risk.

Ecotoxicity data - Esomeprazole

Endpoint	Species	Common Name	Method	Time	Result	Ref.
NOEC - Based on Biomass	Pseudokirchneriella subcapitata (formerly known as Selenastrum capri-cornutum)	Green Alga	OECD 201	72 h	3.9 mg/L Note 1	4
LOEC - Based on Biomass					8.4 mg/L Note 1
NOEC - Based on Logarithmic Growth Rate					8.4 mg/L Note 1
LOEC - Based on Logarithmic Growth Rate					19 mg/L Note 1
ErC50 - Based on Logarithmic Growth Rate					85 mg/L Note 1
EbC50 - Based on Biomass					19 mg/L Note 1
NOEC - Overall Note 2	Daphnia magna	Giant Water Flea	OECD 211	21 d	10 mg/L Note 3	5
LOEC - Overall Note 5	Pimephales promelas	Fathead Minnow	OECD 210	32 d	3.2 mg/L Note 3	6
NOEC - Overall Note  5					1.0 mg/L Note 3
EC50 - Based on Activated Sludge Respiration Inhibition	-	-	OECD 209	3 h	>100 mg/L Note 6	7
NOEC - Based on Activated Sludge Respiration Inhibition					100 mg/L Note 6
NOEC – Based on overall endpoints Note 4	Chironomus riparius	Midge	OECD 218	28 d	400 mg/kg Note 3	8
LOEC – Based on emergence, development rate and sex ratio					1000 mg/kg dry sediment

Ecotoxicity data - Omeprazole

Endpoint	Species	Common Name	Method	Time	Result	Ref.
EbC50 – Based on Biomass Note 7	Pseudokirchneriella subcapitata (formerly known as Selenastrum capricornutum)	Green Alga	OECD 201	72 h	30.1 mg/L Note 1	9
ErC50 – Based on Growth Rate Note 7					>75.9 mg/L Note 1
NOEC - Based on Biomass Note 7					<1.81 mg/L Note 1
NOEC - Based on Growth Rate Note 7					1.81 mg/L Note 1
EC50 - Based on Immobilisation Note 7	Daphnia magna	Giant Water Flea	OECD 202	48 h	>100 mg/L Note 3	10
LC50 Note 7	Danio rerio (formerly known as Brachydanio rerio)	Zebra fish	OECD 203	96 h	41.9 mg/L Note 1	11
NOEC - Based on Activated Sludge Respiration Inhibition	-	-	OECD 209	3 h	100 mg/L	12
EC50 - Based on Activated Sludge Respiration Inhibition Note 8					>100 mg/L

Note 1:  Results are expressed as mean measured concentrations.

Note 2:  The population relevant endpoints measured were survival, fecundity and adult length.

Note 3:  Concentrations were confirmed by analysis, and results expressed as nominal.

Note 4:  The population relevant endpoints measured were total number of emerged adult insects, sex ratio and replicate mean plus individual emergence times (development rates).

Note 5:  The population relevant endpoints measured were hatch, survival, length and dry weight.

Note 6:  Results are expressed as nominal concentrations.

Note 7: Data from studies on omeprazole sodium.

Note 8:  Data from studies on omeprazole.

Predicted No Effect Concentration (PNEC)

Long-term tests of esomeprazole have been undertaken for species from three trophic levels, based on internationally accepted guidelines. The most sensitive species of these is the fathead minnow. Therefore, the PNEC is based on the results from the fathead minnow early life stage test, and an assessment factor of 10 is applied, in accordance with ECHA guidance (ref. 2).

PNEC = 1000/10 µg/L = 100 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.942 µg/L/100 µg/L = 0.0094,

i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of esomeprazole has been considered to result in insignificant environmental risk”.

In Swedish: ”Användning av esomeprazol har bedömts medföra försumbar risk för miljöpåverkan” under the heading ”Miljörisk”.

Environmental Fate Data - Esomeprazole

Endpoint	Method	Test Substance Concentration	Time	Result	Ref.
Partition Coefficient Octanol Water	OECD 117	10 and 20 mg/L	-	Log Dow = 1.65 @ pH 5	13
				Log Dow = 1.58 @ pH 7
				Log Dow = 1.53 @ pH 9
Percentage Anaerobic Mineralisation	OECD 308	0.42 mg/L in high organic matter	95 d	<2 % Mineralisation	14
Percentage Aerobic Mineralisation				<2 % Mineralisation
Degradation Half-life				T1/2 =20 h @ 25oC, pH 7	15
DT50	OECD 308	0.1 mg/L in sediment with high organic matter content	-	3.1 d in total system	16
		0.1 mg/L in sediment with low organic matter content		6.3 d in total system
		0.1 mg/L in sediment with high organic matter content		2.2 d in water compartment
		0.1 mg/L in sediment with low organic matter content		3.0 d in water compartment

Environmental Fate Data - Omeprazole

Endpoint	Method	Test Substance Concentration	Time	Result	Ref.
Half-life	Unknown	In aqueous solution	-	T1/2 @ 20 oC: pH 4 = 15 mins pH 7 = 30 h pH 9 = > week	17
				T1/2 =10 h @ 37oC, pH 7

Degradation

Biotic degradation

Neither esomeprazole nor omeprazole are readily biodegradable in biodegradability studies.

However, esomeprazole is rapidly degraded in aquatic sediment systems. The biological degradation of esomeprazol in aquatic sediments was assessed according to the OECD 308 Test Guideline (ref 12). In this test two different sediments were used, one with high and one with low organic matter content. Radiolabelled test substance was dosed into the overlying water and the subsequent dissipation from the water phase and partitioning and/or degradation in the sediment was observed over a 100 day test period, leaving less than 7 % of the parent substance in the sediment-water system.  In both the high organic matter (HOM) and low organic matter (LOM) test vessels, esomeprazol was observed to be rapidly dissipated from the water phase and total system, with half-lives <14 days. Greater than 90 % of the partitioned radioactivity was extractable from the sediment using 3 solvent extractions of acetonitrile plus 0.5% ammonium hydroxide. HPLC analysis of the extracts showed that >95% of the 14C was associated with the parent test substance peak.

Adsorption to sludge

The adsorption and desorption of esomeprazole to sludge was assessed according to the OPPTS guideline 835.1110 (ref 13). The Kd(ads) was 48, indicating that esomeprazole is likely to partition into the aqueous phase during wastewater treatment.

The substance has hence been assigned the phrase: “Esomeprazole is slowly degraded in the environment”.

In Swedish: ”Esomeprazol bryts ned långsamt i miljön.” under the heading ”Nedbrytning”.

Bioaccumulation

Since Log Dow < 4, esomeprazole has low potential to bioaccumulate and the phrase “Esomeprazole has low potential for bioaccumulation” is assigned.

In Swedish: ”Esomeprazol har låg potential att bioackumuleras” under the heading ”Bioackumulering”.

Physical Chemistry Data – Esomeprazole

Endpoint	Method	Test Substance Concentration	Result	Ref.
Adsorption Coefficient Note 1	OPPTS 835.1110	40 mg/L Note 5	Kd (Adsorption) = 48	18
Solubility Water	Note 8	-	340 mg/L	19
Dissociation Constant	Note 8	-	pKa(1) = 4 (Pyridinium ion)	19
Dissociation Constant			pKa(2) = 8.8 (Benzimidazole)

Physical Chemistry Data- Omeprazole

Endpoint	Method	Test Substance Conditions	Result	Ref.
Distribution Coefficient Octanol Water	Unknown	-	Log D (experimental) = 2.24	17
Solubility Water	Note 8	22oC	130 mg/L
Dissociation Constant Note 8	Unknown	-	pKa(1) = 4 (Pyridinium ion)
Dissociation Constant			pKa(2) = 8.8 (Benzimidazole ion)

Note 1:  Results are expressed as mean measured concentrations.

Note 5:  The population relevant endpoints measured were hatch, survival, length and dry weight.

Note 8:  This study predates current ERA regulatory requirements and may not have been undertaken to standardised test guidelines.

References

1. Committee for Medicinal Products for Human Use (CHMP); Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006, Ref EMEA/CPMP/SWP/4447/00.

2. [ECHA] European Chemicals Agency.  Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0). February 2016.

3. AstraZeneca, access June 2019.<https://www.astrazeneca.com/content/dam/az/our-company/Sustainability/2017/esomeprazole%20and%20omeprazole.pdf>

4. Esomeprazole Na: Toxicity to the green alga Selenastrum capricornutum. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8021 March 2005

5. Esomeprazole sodium: Chronic toxicity to Daphnia magna.Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8555 February 2008

6. Esomeprazole Sodium: Determination of Effects on the Early-Life Stage of Fathead Minnow (Pimephales promelas). Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8452 July 2007

7. Esomeprazole sodium: Effect on the Respiration Rate of Activated Sludge.Brixham Environmental Laboratory, AstraZeneca, UK, Report BR0162 March 2010

8. [14C]Esomeprazole sodium: Effects in sediment on emergence of the midge, Chironomus riparius Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8557 March 2008

9. H 168/68 Na salt: acute Toxicity to Pseudokirchneriella sucapitata. Document No. T3355, Corning Hazelton, Harrogate, England. June 1996.

10. H 168/68 Na salt: acute Toxicity to Daphnia Magna. Document No. T3353, Corning Hazelton, Harrogate, England. June 1996.

11. H 168/68 Na salt: acute Toxicity to Brachydanio rerio. Document No. T3354, Corning Hazelton, Harrogate, England. June 1996.

12. IVL Swedish Environmental Research Institute Commissioned Report; Investigation of the ‘ready biodegradability’ of A001 drug substance, Report BD3984. June 1991.

13. Esomeprazole sodium: Partition Coefficient (n-octanol-water), HPLC correlation.Brixham Environmental Laboratory, AstraZeneca, UK, Report BR0547 October 2011.

14. Esomeprazole sodium: OECD 308 Screening Test. Brixham Environmental Laboratory, AstraZeneca, UK, Report BLS3431 June 2008.

15. AstraZeneca Exisitng Product Review: Omeprazole and Esomeprazole Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7930 September 2007.

16. Esomeprazole sodium: Aerobic Transformation in Aquatic Sediment Systems. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8602 May 2008.

17. Marketing. S1-03 (pre-CTD) Physicochemical Data,  APCD 23075, Omeprazole pwd. August 1985.

18. Esomeprazole Sodium: Adsorption and desorption to sewage sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8468 February 2008.

19. Marketing. S1-03 General Properties: Esomeprazole Sodium. Brixham Environmental Laboratory, AstraZeneca, UK, Report BD4174. Doc ID-002134457, document status date: January 2015.