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 = 0.02911661 μg/L

Where:

A = 212.53 kg (total sold amount API in Sweden year 2020, data from IQVIA). Reduction of A may be justified based on metabolism data.

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 default) (Ref. 1)

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Endpoint	Species	Common Name	Method	Time	Result	Ref
EC50 - based on growth rate	Pseudo-kirchneriella subcapitata	Green Algea	OECD 201	72 h	9.8 mg/L	2
EC50 - based on yield					4.5 mg/L
NOEC – based on growth rate & yield					2.4 mg/L
EC50	Daphnia magna	Water Flea	OECD 202	48 h	25 mg/L	3
NOEC					4.4 mg/L
NOEC – based on survival & reproduction			OECD 211	21 d	1.3 mg/L	4
EC50 - based on reproduction					>4.9 mg/L
LC50	Brachydanio rerio	Zebra Fish	OECD 203	96 h	77 mg/L	5
NOEC					12 mg/L
NOEC – based on early-life stage	Pimephales promelas	Fathead Minnow	OECD 210		0.53 mg/L	6
LOEC – based on early-life stage					1.0 mg/L
EC50 - based on Activated Sludge Respiration Inhibition			OECD 209	3 h	586 mg/L	7
1NOEC - based on Activated Sludge Respiration Inhibition					95.9 mg/L
EC50 - based on emergence	Chironomus riparius	Midge	OECD 218		571 mg/kg	8
NOEC - based on emergence					250 mg/kg

¹Calculated as the EC15, the Effective Concentration affecting 15% of population tested

Environmental risk classification (PEC/PNEC ratio)

Long-term tests 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 results from the assessment of the fathead minnow (Pimephales promelas) study, NOEC = 530 µg/L and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 9).

PNEC = 530 µg/L / 10 = 53 µg/L

PEC/PNEC = 0.02911661/53 = 0.00054937, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase 'Use of tapentadol has been considered to result in insignificant risk.'

Degradation

Readily Biodegradation

Tapentadol was investigated for its ready biodegradation in a 28 day CO₂ Evolution Modified Sturm Test, according to OECD Guideline 301B (Reference 10).

Based on the results of this study, tapentadol is not readily biodegradable according to the OECD Guideline 301B.

Aerobic Transformation in Aquatic Sediment Systems

Tapentadol was investigated for its aerobic degradation in a 100 day aquatic sediment test, according to OECD Guideline 308 (ref 11).

Primary degradation was observed for [¹⁴C]tapentadol in the aerobic water/sediment test samples. One major degradation product was observed at >10% of the radioactivity during the study and numerous minor degradation products (<10% of the radioactivity for individual degradants) were observed in the HPLC analyses. Ultimate biodegradation was minimally observed in the aerobic test systems. The accumulative amount of evolved 14CO2 was 0.9% of the radioactivity for the Taunton River aerobic test systems and 1.3% of the radioactivity for the Weweantic aerobic test systems at Day 101. The DT50 (half-life) for the aerobic primary degradation of [¹⁴C]tapentadol in the water layer ranged from 1.3 days to 3.3 days. The DT50 for the aerobic primary degradation of [¹⁴C]tapentadol in the water/sediment test systems ranged from 41 days to 126 days.

Anaerobic Transformation in Aquatic Sediment Systems

Tapentadol was investigated for its anaerobic degradation in a 100 day aquatic sediment test, according to OECD Guideline 308 (reference 11).

Primary degradation was observed for [¹⁴C]tapentadol in the anaerobic water/sediment test samples. Numerous minor degradation products (<10% of the radioactivity for individual degradants) were observed in the HPLC analyses. Ultimate biodegradation was minimally observed in the anaerobic test systems. The accumulative amount of evolved ¹⁴CO₂ was less than 1% for the Goose River and Golden Lake anaerobic test systems at Day 101. No radioactivity was detected in the volatile organic and ¹⁴CH₄ trapping systems for the anaerobic test systems at Day 101. The DT₅₀ for the anaerobic primary degradation of [¹⁴C]tapentadol in the water layer ranged from 10.7 days to 22.8 days. The DT₅₀ for the anaerobic primary degradation of [¹⁴C]tapentadol in the water/sediment test systems ranged from 51 days to 60 days.

Information on the Extraction Method of Sediment Residues

The above mentioned aerobic and anaerobic sediments varied in textural characteristics, organic matter content and microbial content (Taunton River aerobic, Weweantic River aerobic, Goose River anaerobic and Golden Lake anaerobic sediments). The untreated flooded sediment samples (50 g dry weight sediment plus 150 mL water) were incubated under aerobic and anaerobic conditions for at least one week. Following incubation, [¹⁴C]tapentadol was applied to the water layers of each of the systems to achieve a final nominal concentration of approximately 1 mg/L in the water layer. A flow-through test system was used in order to determine the aerobic rate and route of degradation of [¹⁴C]tapentadol at a temperature of 20 ± 2 °C continuously in the dark. For the aerobic test systems, the aerobic environment was maintained by continuously bubbling hydrated air through the water layer for 103 days. The anaerobic test systems were prepared in a nitrogen atmosphere and tightly sealed throughout the study to ensure anaerobic test conditions. All test systems used potassium hydroxide (KOH) and ethylene glycol organic volatile traps to collect ¹⁴CO₂ and any volatile components that evolved during the study. Water and sediment samples from all test systems were assayed at 0, 4, 10, 28, 60 and 101 days after application of the test substance. The test conditions outlined in the study protocol were maintained throughout the study.

Based on the data above the phrase ‘Tapentadol is slowly degraded in the environment’ is chosen.

Bioaccumulation

The n-octanol/water partition coefficient (log K_ow) indicates the transfer of the active substance from the aquatic environment into organisms and a potential to bioaccumulate.

The log Kow for tapentadol is 2.89 (reference 12), which is below 4. Consequently, tapentadol has a low tendency to bioaccumulate in aquatic organisms and no bioconcentration test is required and the statement 'Tapentadol has low potential for bioaccumulation' is assigned.

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. Tapentadol HCl - Acute Toxicity to the Freshwater green alga, Pseudokirchneriella subcapitata. OECD Guideline 201.

3. Tapentadol HCl – full life-cycle toxicity test with water fleas, Daphnia magna, under static-renewal conditions. OECD Guideline 211. Grünenthal R&D, 2007.

4. Tapentadol HCl – acute toxicity to water fleas, (Daphnia magna), under static conditions, following OECD draft guideline 202. Grünenthal R&D, 2007.

5. Tapentadol HCl – acute toxicity to zebra fish (Brachydanio rerio), under static-renewal conditions. OECD Guideline 203. Grünenthal R&D, 2007.

6. Tapentadol HCl – early life-stage toxicity test with fathead minnow, (Pimephales promelas), following OECD guideline 210. Grünenthal R&D, 2007.

7. Tapentadol HCl – activated sludge respiration inhibition. OECD Guideline 209.

8. Tapentadol: Sediment-Water Chironomus riparius Toxicity Test using Spiked Sediment. OECD Guideline 218. Grünenthal R&D, 2010.

9. ECHA, European Chemicals Agency. May 2008. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

10. Tapentadol HCl – determination of the biodegradability based on OECD method 301B (CO₂ evolution test). Grünenthal R&D, 2007

11. Tapentadol HCl – aerobic and anaerobic transformation in aquatic sediment systems following OECD guideline 308. Grünenthal R&D, 2007.

12. Tapentadol HCl (R331333) Ionization Constants and Lipophilicity Report