Detaljerad miljöinformation

Predicted Environmental Concentration (PEC)

PEC is calcluated according to the following formula:

PEC (μg/L) = (A*10⁹*(100))/(365*P*V*D*100) = 1.5*10^-6*A = 0.0022 μg/L

Where:

A = 16,17 kg ipratropium bromide (monohydrate), total sold amount API in Sweden year 2022, data from IQVIA).

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 = 10 (ECHA default) (Ref I)

Predicted No Effect Concentration (PNEC)

Environmental assessment was based on toxicity data; however as only one and not three different trophic levels were available, a valid PNEC cannot be calculated. Therefore, the following phrase is used:

“Risk of environmental impact of ipratropium cannot be excluded, since there is not sufficient ecotoxicity data available”.

Degradation

Ipratropium is not readily biodegradable (CO₂-production test, detailed method unknown, no standard guideline used) (Ref II).

The phrase ”Ipratropium is potentially persistent” is therefore used.

Bioaccumulation

log P = -2.2 at pH 7 (Detailed method unknown, no standard guideline used. log P was estimated via the determination of Ipratropium concentrations in the water and octanol phase, respectively. ) (Ref III)

Justification: As log P is below 4, the phrase “Ipratropium has low potential for bioaccumulation” is used.

Excretion (metabolism)

Following inhalation 10 to 30% of a dose, depending on the formulation and inhalation technique, is generally deposited in the lungs (Ref IV, V, VI, VII, VIII, IX). The portion of the dose deposited in the lungs reaches the circulation rapidly and has a nearly complete systemic availability (Ref X). The major part of the dose is swallowed and passes the gastro-intestinal tract. Due to the negligible gastro-intestinal absorption of Ipratropium bromide the bioavailability of the swallowed dose portion accounts for only ~2% of the dose (Ref X, XI, XII, XIII). The major portion of approximately 60% of the systemic available dose is eliminated by metabolic degradation, probably in the liver (Ref XIV, XV).

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. Boehringer Ingelheim GmbH internal report U91-0792, 1991

3. Boehringer Ingelheim GmbH internal report A082322, 2012

4. Taburet AM, Schmit B. Pharmacokinetic optimisation of asthma treatment. Clin Pharmacokinet 1994;26(5):396-418

5. Short MD, Singh CA, Few JD, Studdy PR, Heaf PJD, Spiro SG. The labelling and monitoring of lung deposition of an inhaled synthetic anticholinergic bronchodilating agent. Chest 1981;80:918-21

6. Timsina MP, Martin GP, Marriott C, Ganderton D, Yianneskis M. Drug delivery to the respiratory tract using dry powder inhalers.Int J Pharm 1994;101(1/2):1-13

7. Chrystyn H. Standards for bioequivalence of inhaled products. Clin Pharmacokinet 1994;26(1):1-6.

8. Dolovich M. Lung dose, distribution, and clinical response to therapeutic aerosols.Aerosol Sci Technol 1993;18(3):230-40.

9. Boehringer Ingelheim GmbH internal report U95-0166, 1995

10. Ensing K, Zeeuw Rd, Nossent GD, Koeter GH, Cornelissen PJG. Pharmacokinetics of ipratropium bromide after single dose inhalation and oral and intravenous administration. Eur J Clin Pharmacol 1989; 36(2):189-94.

11. Boehringer Ingelheim GmbH internal report U86-0434, 1986

12. Boehringer Ingelheim GmbH internal report U92-0550, 1992

13. Boehringer Ingelheim GmbH internal report U96-0020, 1995

14. Adlung J, Hoehle KD, Zeren S, Wahl D. Studies on pharmacokinetics and biotransformation of ipratropium bromide in man. Untersuchungen zur Pharmakokinetik und Biotransformation von Ipratropiumbromid am Menschen. Arzneimittelforschung 1976;26:1005-10.

15. Boehringer Ingelheim GmbH internal report U73-0141, 1973

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)

PEC = 0.027 μg/L

Where:

A = 199,81 kg (total sold amount API in Sweden year 2022, derived from data from IQVIA). Reduction of A may be justified based on metabolism data.

R = 0% removal rate (conservatively, it has been assumed there is no 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 default) (Reference 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Reference 1)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies:

Green algae: EC50 = 2.03 mg/L (Desmodesmus subspicatus, 72 h (growth rate), (OECD 201) (Reference 2)

Daphnia acute toxicity: EC50 = 5.63 mg/L (Daphnia magna, 48h, OECD 202) (Reference 2)

Fish acute toxicity: LC50 = 71 mg/L (Rainbow trout (Oncorhynchus mykiss), 96h, OECD203) (Reference 2)

Bacterial Respiration Inhibition: IC20 = 90 mg/L (activated sludge, 0.5h, OECD 209) (Reference 2)

The PNEC is based on the following data:

PNEC (µg/l) = lowest acute EC50 / 1,000, where 1,000 is the assessment factor used.

An EC50 of 2.03 mg/l for green algae has been used for this calculation

PNEC = 2,030 µg/L /1000 = 2.03 µg/l

PNEC (μg/L) = lowest NOEC/1,000, where 1000 is the assessment factor applied for three short-term EC50s. EC50 for green algae (= 2.03 mg/L) has been used for this calculation since it is the most sensitive of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.027/2.03 = 13,3 x 10^-3, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of Xylometazoline has been considered to result in insignificant environmental risk.”

Environmental fate studies:

Degradation:

Degradation: < 10% (aerobic, 28d, 20-24°C, OECD 301A) (Reference 2)

This substance is not readily biodegradable.

Bioaccumulation

Partition Coefficient: log Kow 2.84 (OECD107) (Reference 2)

Justification of chosen bioaccumulation phrase:

Since log Kow < 4, the substance has low potential for bioaccumulation.

PBT/vPvB assessment

Xylometazoline does not fulfil the criteria for PBT and/or vBvP.

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Xylometazoline does not fulfil the criteria for PBT and/or vBvP based on log Kow < 4.

References

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

2. Safety Data Sheet. Xylometazoline hydrochloride Version No.23. Fagron UK Ltd, July 2014.