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) = 1.37*10^-6*A(100-R)

PEC = 0.0072 μg/L

Where:

A = 52.87 kg (total sold amount API in Sweden year 2023, data from IQVIA).

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 wastewater by surface water flow = 10 (ECHA default) (Reference 1)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae

No data

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 240,000 μg/L (OECD 202) (Reference 6)

Water flea (Ceriodaphnia dubia):

Chronic toxicity

NOEC 8 days (reproduction) = 100,000 μg/L (USEPA 1002) (Reference 9)

Fish:

Acute toxicity

No data

Chronic toxicity

NOEC 21 day (biomass) = 8,300 ug/L (OECD 210) (Reference 10)

Microorganisms in activated sludge:

EC50 3 h (inhibition) = 830,000 µg/L (OECD 209) (Reference 5)

PNEC cannot be calculated because data is not available for all three (algae, crustacean and fish) of the toxicity endpoints.

Environmental risk classification (PEC/PNEC ratio)

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of Salbutamol is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit 0.01 μg/L.

Degradation

Biotic degradation

Ready degradability:

1% degradation in 28 days (TAD 3.11) (Reference 7)

Inherent degradability:

No Data

Soil Degradation

1.3 to 38.7% degradation in 64d (TAD 3.12) (Reference 8)

Abiotic degradation

Hydrolysis:

DT50 > 1 year (OECD 111) (Reference 4)

Photolysis:

No data

Justification of chosen degradation phrase:

Salbutamol is not readily degradable or inherently degradable. The phrase “Salbutamol is potentially persistent in the environment” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow = -2.80 at pH 7 (TAD 3.04). (Reference 3)

Log Dow at pH5 = -1.50

Log Dow at pH7 = -2.80

Log Dow at pH9 = -2.80

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism

The primary route of elimination of hydrofluoroalkane-propelled albuterol (HFA) parent or primary metabolite compound is through the kidney. After an IV dose of racemic albuterol, between 24% to 46% of the R enantiomer is excreted unchanged in the urine (Reference 2)

Please, also see Safety data sheets on http://www.msds-gsk.com/ExtMSDSlist.asp.

References

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

2. Product Information: VENTOLIN(R) HFA inhalation aerosol, albuterol sulfate HFA inhalation aerosol. GlaxoSmithKline, Research Triangle Park, NC, 2008. Prod Info PROAIR HFA(R) inhalation aerosol, 2008

3. Colwyn TC. AH3365F: Determination of Physico-Chemical Properties. Report No. 94/GLX139/0366. Pharmaco Life Science Research Laboratories, November 1994.

4. Colwyn TC. AH3365F: Determination of Hydrolysis as a Function of pH. Report No. 94/GLX140/0202. Pharmaco Life Science Research Laboratories, November 1994.

5. Jenkins WR. AH3365F: Activated Sludge – Respiration Inhibition Test. Report No. 93/GLX141/1050. Pharmaco Life Science Research Laboratories, January 1995.

6. Jenkins CA. AH3365F: Acute Toxicity to Daphnia magna. Report No. 93/GLX142/0028. Pharmaco Life Science Research Laboratories, December 1994.

7. Jenkins WR. AH3365F: Biotic Degradation with Acclimatised Composite Inoculum- Modified Sturm Test. Report No. 93/GLX143/1128. Pharmaco Life Science Research Laboratories, January 1995.

8. O’Connor J. AH3365F: Aerobic Biodegradation in Soil. Report No. 95/GLX145/0118. Pharmaco Life Science Research Laboratories, February 1995.

9. Wetton PM. Salbutamol: Daphnid, Ceriodaphnia dubia Survival and Reproduction Test. Report No. 1127/0952. Safepharm Laboratories Limited, March 2006.

10. Weil M et al. Uptake and Effects of the Beta‐Adrenergic Agonist Salbutamol in Fish: Supporting Evidence for the Fish Plasma Model. Environmental Toxicology and Chemistry 28: 2509-2519, 2019.