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 = 0.014 μg/L

Where:

A = 91.46 kg (total amount API of orphenadrine citrate in Sweden year 2020, data from IQVIA) (Ref. 1)

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

P = number of inhabitants in Sweden = 10*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

Crustacean (Daphnia magna) (Ref. 3)

EC₅₀ 24 hours (immobility): 8.87 mg/L (OECD 202, 1980)

Crustacean (Daphnia magna) (Ref. 4)

EC₅₀ 24 hours (immobility): 12.6 mg/L (OECD 202, 1984)

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

Degradation

No degradation data available.

Bioaccumulation

An experimentally derived Log K_ow of 3.77 (unknown method) (Ref. 5) indicates that orphenadrine has low potential for bioaccumulation.

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

References:

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2021 (data 2020)”.

2. ECHA, European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Ver 2.1, 2011.

3. Lilius, H et al. (1994), Aquatic Toxocology 30 p47-60

4. Calleja M C et al. (1994), Archives of Environmental Contamination and Toxicology, v26, issue 1, p69-78

5. Sangster (1993), ChemID+, US National Library of Medicin, National Institutes of Health

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*0.85*A(100-98)

PEC = 1.61 μg/L

Where:

A = 537906 kg (total sold amount API in Sweden year 2019, data from IQVIA). No metabolism has been assumed in the PEC calculation.

R = 98% removal rate from waste water treatment plant (Reference 9)

P = number of inhabitants in Sweden = 9*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 (Scenedesmus subspicatus):

IC50 72h (growth) = 134,000 μg/L (OECD 201) (Reference 5)

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 9,200 μg/L (OECD 202) (Reference 7)

Zebra Fish (Brachydanio rerio):

Acute toxicity

LC50 96 h (lethality) = 378,000 μg/L (OECD 203) (Reference 5)

Green Algae (Chlorella vulgaris)

Chronic toxicity

NOEC 72 hours (growth) 46,000 ug/L (OECD 201) (Reference 13)

Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) = 1,000 μg/L (OECD 211) (Reference 10)

Fathead minnow (Pimephales promelas):

Chronic toxicity

NOEC (survival) = 460 μg/L (OECD 210) (Reference 11)

Microorganisms in activated sludge

EC50 3 hours (Inhibition) > 1,000,000 µg/L (OECD 209) (Reference 12)

PNEC = 460/10 = 46 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three chronic NOECs.The NOEC for Fathead minnow (= 460 µg/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 = 1.61/46 = 0.035, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of paracetamol has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Inherent degradability:

99% degradation in 5 days (OECD 302B) (Reference 3)

Simulation studies:

WWTP study:

Biodegradation constant = 58-80 L g^-1_ss d^-1 (Reference 6)

Water-sediment study:

50% (DT50) degradation in 3.10 days days (OECD 308) (Reference 8)

Abiotic degradation

Hydrolysis:

Half-life, pH 7 > 1 year (TAD 3.09) (Reference 4)

Photolysis:

No Data

Justification of chosen degradation phrase:

Results of biological degradation: Inherent biodegradation = 99% in 5 days (OECD 302B, IUCLID data set). The substance is inherently biodegradable. The material is expected to be highly removed in wastewater treatment plants, 98% removal (Reference 9). This is supported by a measured biodegradation constant of 58-80 L g^-1_ss d^-1 in a WWTP simulation test (Reference 6). Biodegradation constants greater than 10 are expected to result in greater than 90% biodegradation. Additionally, a DT50 of 3.1d and a DT90 of 10d was measured (Reference 8) using a water-sediment study (OECD 308) indicating a low potential for persistence. The phrase ‘Paracetamol is slowly degraded in the environment’ is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Pow = 0.51 at pH 7 (OECD 107) (Reference 3)

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

85% of the dose is excreted in urine within 24 hrs as free and conjugated paracetamol (Reference 4). For purposes of the risk assessment assume conjugates are converted back into free paracetamol (Reference 2).

PBT/vPvB assessment

Paracetamol 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). Paracetamol does not fulfil the criteria for PBT and/or vBvP based on a log Dow < 4.

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. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Ziagen (Paracetamol) 300mg Film Coated Tablets. ViiV Healthcare UK Ltd., March 2013.

3. European Chemicals Bureau 2000. IUCLID Dataset Paracetamol.

4. AHFS Drug Information, 2002. American Society of Health-System Pharmacists.

5. Henschel, K., Wenzel, A., Diedrich,M., Fliedner, A. 1997. Regulatory Toxicology and Pharmacology 25, 220-225.

6. Joss, A., et al. 2006. Water Research 40, 1686-1696.

7. Kuhn, R., Pattard, M., Pernak, KD.,Winter, A. 1989. Water Research 23, No.4, 495-499.

8. Loffler, D., Rombke, J., Meller, M., Ternes, T. 2005. Environmental Science and Technology 39, 5209-5218.

9. Ternes, T. 1998. Water Research 32, No.11 3245-3260.

10. [Smithers Viscient AG Study No. 1162.000.230] 4’Hydroxyacetanilide: Chronic reproduction test with daphnids (Daphnia magna) under semi-static conditions OECD No. 211, Dated August 11, 2011.

11. [Smithers Viscient AG Study No. 1162.000.122] 4’-Hydroxyacetanilide: Early life-stage toxicity test with fathead minnow (Pimephales promelas) under flow-through conditions, OECD 210, Dated October 14, 2011.

12. [Smithers Viscient AG Study No. 1162.000.790] 4’-Hydroxyacetanilide: Activated sludge respiration inhibition test, OECD # 209, Dated August 8, 2011

13. ECHA REACH Registration Paracetamol. National Institute of Technology and Evaluation. 1998. Toxicity to aquatic algae and cyanobacteria.https://echa.europa.eu/registration-dossier/-/registered-dossier/12532/1/2