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) = 1.5*10^-6*A(100-R)

PEC = 19,508 µg/L

Where:

A = 130053,307 kg (total sold amount API in Sweden year 2016, data from QuintilesIMS).

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 = 9 *10⁶ 

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default (1))

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus):

NOEC/72 h (growth inhibition, growth rate) 14180 µg/L (guideline OECD 201) (2)

Crustacean (waterflea Daphnia magna):

Chronic toxicity

NOEC/21 days (reproduction, mortality) ≥1000 μg/L (guideline OECD 211) (3)

Fish:

Chronic toxicity

NOEC 30 days (growth) = 283 μg/L, LOEC 834 µg/L (ELS test, guideline OECD 210) (4)

Microorganisms (activated sludge, respiration inhibition):

NOEC/30 min > 100000 µg/L (nominal) (guideline OECD 209) (5)

PNEC = 28,3 μg/L (Lowest chronic NOEC fish = 283 µg/L; AF 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 19.508/28,3 = 0.69, i.e. 0,1 < PEC/PNEC ≤ 1 which justifies the phrase Use of acetylsalicylic acid has been considered to result in low environmental risk.

Degradation

Biotic degradation

Ready degradability: Readily biodegradable

Acetylsalicylic acid was studied for aerobic biodegradability in water in a manometric respiration test according to guideline OECD 301F (6). The substance was introduced into the test system at a concentration of 200 mg/L as theoretical oxygen demand (ThOD) and was found to be degraded to 69.6% after 10 and 83.3 % after 28 days. Hence, acetylsalicylic acid can be regarded as readily biodegradable.

The results of the study on ready biodegradability justifies the phrase Acetylsalicylic acid is degraded in the environment.

Abiotic degradation

Hydrolysis:

Acetylsalicylic acid is known to hydrolyze in contact with moisture yielding acetic acid and salicylic acid. In basic solutions acetylsalicylic acid hydrolyzes rapidly, and the half-life decreases with increasing pH (7).

Bioaccumulation

Partitioning coefficient:

A study on the n-octanol/water partition coefficient was conducted according to OECD 107 (8). The log K_OW/ 20 °C was - 0.32, - 1.62, and - 1.61 at pH 5, 7 and 9, respectively. The negative log K_OW indicated an insignificant lipophilicity and hence, a lack of a bioaccumulation potential.

Since the log P_OW (at pH 7) is -1.62, the phrase Acetylsalicylic acid has a low potential for bioaccumulation is justified. 

Excretion (metabolism)

In human body acetylsalicylic acid is deacetylated to salicylic acid and then further metabolized. It is predominantly excreted via urine as salicylic acid and subsequent salicylate metabolites salicyluric acid (glycine conjugate), salicyl phenolic glucuronide, salicyl acyl glucuronide, gentisic acid (oxidation product), gentisuric acid (glycine conjugate) and to a lesser extent in the unmetabolized form as parent compound (9). However, the acetylsalicylic acid metabolism in humans and therefore the proportions of the excreted urine metabolites significantly vary inter-individually depending on urine pH, sex, ethnicity, and variants in metabolizing enzymes (10).

References

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

(2) Growth inhibition test of BAY e4465 (Acetylsalicylic acid) with Desmodesmus subspicatus. Nonclinical Drug Safety, Bayer Schering AG, study no. T100981-9, report no. PH-38090 (2014)

(3) Reproduction study of BAY e4465 (Acetylsalicylic acid) in Daphnia magna. Nonclinical Drug Safety, Bayer Schering AG Study no. T100979-6, report no. PH-38263 (2014)

(4) ASS 180/840 KG Early-life-stage test with Zebrafish (Danio rerio) under Flow-Through Conditions). Nonclinical Drug Safety, Bayer Schering AG Study no. T100876-2, report no. R-9373 (2014)

(5) Respiration inhibition test with BAY e4465 (Acetylsalicylic acid) on activated sludge microorganisms. Nonclinical Drug Safety, Bayer Pharma AG, study no T101029-3, report no. PH-3898 (2014)

(6) Study on the biodegradability of BAY e4465 (Acetylsalicylic acid) in the manometric respiration test. Nonclinical Drug Safety, Bayer Schering Pharma AG, study no T101073-2, report no. PH-37791 (2014)

(7) Mitchell AG, Broadhead JF. Hydrolysis of solubilized aspirin. J Pharm Sci. 1967, 56(10):1261-6.

(8) BAY e 4465: Determination of the partition coefficient (n-octanol/water) by the shake-flask method at different pH values. Nonclinical Drug Safety, Bayer Pharma AG, study no T101857-2, report no. R-9744 (2016)

(9) Jjemba PK. Excretion and ecotoxicity of pharmaceutical and personal care products in the environment. Ecotoxicology and Environmental Safety, 2006; 63(1): 113-130.

(10) Navarro SL, Saracino MR, Makar KW, Sushma TS, Li L, Zheng Y, Levy L, Schwarz Y, Bigler J, Potter JD, Lampe JW. Determinants of aspirin metabolism in healthy men and women: effects of dietary inducers of UDP-glucuronosyltransferases. J Nutrigenet Nutrigenomics, 2011; 4(2): 110-118.

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) = 1.5*10^-6*A(100-R)

PEC = 1,10 μg/L

Where:

A = 7340,6845 kg (total amount API of caffeine and caffeine citrate in Sweden year 2017, data from IQVIA). (Ref. 1)

R = removal rate = 0% (no data available)

P = number of inhabitants in Sweden = 9*10⁶

V (L/day) = volume of waste water per capita and day = 200 (ECHA default) (Ref. 2)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. 2)

Ecotoxicological studies

Green algae (Scenedesmus subspicatus) (ref. 3)

EC₅₀ 72 hours (reproduction): > 100 mg/L (OECD 201)

Crustacean (Daphnia magna) (ref. 4)

EC₅₀ 24 hours (immobility): 684 mg/L (OECD, 1980, (slightly modified))

Crustacean (Daphnia magna) (ref. 5)

EC₅₀ 48 hours (immobility): 160 mg/L (OECD, 1984)

Crustacean (Ceriodaphnia dubia) (ref. 6)

LC₅₀ 48 hours: 57 mg/L (USEPA, 2002a, static)

LC₅₀ 7 days: 47 mg/L (USEPA, 2002a, static-renewal)

IC₅₀ 7 days (reproduction): 44 mg/L (USEPA, 2002a, static-renewal)

IC₂₅ 7 days (reproduction): 40 mg/L (USEPA, 2002a, static-renewal)

Freshwater fish (Pimephales promelas) (ref. 6)

LC₅₀ 48 hours: 97 mg/L (USEPA, 2002a, static)

LC₅₀ 7 days: 57 mg/L (USEPA, 2002a, static-renewal, slightly modified)

IC₅₀ 7 days (growth): 71 mg/L (USEPA, 2002a, static-renewal, slightly modified)

IC₂₅ 7 days (growth): 50 mg/L (USEPA, 2002a, static-renewal, slightly modified)

For the calculation of PNEC, ecotoxicological data for the most sensitive species, Ceriodaphnia dubia, is used. Since no NOEC is available, the long-term IC25 is used. An assessment factor (AF) of 1000 is applied, in accordance with the ECHA guideline (Ref. 2 chapter R.10).

PNEC is calculated as IC₂₅(Ceriodaphnia dubia)/1000 (AF)

PNEC = 40 μg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0,028

PEC/PNEC < 0,1 which justifies the phrase “Use of Caffeine has been considered to result in insignificant environmental risk”.

Degradation

Concerning biodegradation there is only a not valid study available for caffeine. However, for the structurally analogous compound theophylline there is a test on ready biodegradability available from which it can be concluded that this substance is readily biodegradable (OECD 301 A, 90-100% after 22 days, >90% at the end of the 10-day window). As the two substances differ only by one methyl group it can be concluded with high probability that also the substance caffeine is readily biodegradable. (Ref. 3)

Available degradation data are not sufficient to determine degradability for caffeine in accordance with the FASS guideline, and caffeine is assigned the phrase “The potential for persistence of caffeine cannot be excluded, due to lack of data”.

Bioaccumulation

An experimentally derived Log K_ow of -0,07 (unknown method) (Ref. 7) indicates that Caffeine has low potential for bioaccumulation.

Log K_ow<4 which justifies the phrase “Caffeine has low potential for bioaccumulation”.

Excretion (metabolism)

Caffeine is metabolized almost completely in the liver and caffeine and its metabolites are excreted through the kidneys of which 3 % or less will be unchanged upon urinary excretion. (Ref. 8, 9)

References:

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2018 (data 2017)”.

2. ECHA, European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Ver 2.1, 2011. http://echa.europa.eu/documents/10162/13643/information_requirements_r2_en.pdf

3. OECD SIDS (Screening Information Data Set) Initial Assessment Report: Caffeine, Paris 2002, UNEP Publication.

4. Lilius H et al. (1994), Aquatic Toxicology 30 p47-60

5. Calleja MC et al. (1994), Archives of Environmental Contamination and Toxicology 26 p69-78

6. Moore MT et al. (2008), Archives of Environmental Contamination and Toxicology 54 p31-35

7. Hansch C et al. (1994), ChemID+, US National Library of Medicin, National Institutes of Health, http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp

8. SPC (Summary of Product Characteristics) Treo Brustablett 500mg/50mg, 2018-12-13, FASS.se

9. Thorn CF et al. PharmGKB, Caffeine Pathway Pharmacokinetics, updated 2019-06-27, https://www.pharmgkb.org/pathway/PA165884757, Retrieved 2019-08-16.